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• Published: 20 July 2023

Advances in vaccines: revolutionizing disease prevention

• Timir Tripathi   ORCID: orcid.org/0000-0001-5559-289X 1  

Scientific Reports volume  13 , Article number:  11748 ( 2023 ) Cite this article

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• Biochemistry
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Vaccines have revolutionized modern medicine by preventing infectious diseases and safeguarding public health. This Collection showcases cutting-edge research on advancements in vaccine development and their impact on disease prevention. The papers presented here report various facets of vaccine efficacy, immunological responses, and design, providing insight into future immunization strategies. I believe this Collection will serve as a catalyst for further advancements in the field of vaccine research.

Vaccines have long been credited as the most effective tool in preventing and managing infectious diseases. They have drastically reduced the global disease burden 1 . Over the years, significant progress has been made in understanding the immune system and developing novel vaccine design and delivery platforms 2 , 3 . From developing mRNA vaccines 4 that offer rapid response to identifying novel antigenic targets for broader protection, we have been at the forefront of innovation. Furthermore, the exploration of advanced adjuvants and delivery systems is enhancing vaccine efficacy and accessibility 5 . These cutting-edge technologies and advancements in vaccine research hold immense potential for tackling infectious diseases and improving global public health. In this Collection, I am delighted to present research articles highlighting the latest advances in vaccine development, shedding light on innovative vaccine design and delivery strategies, novel targets, and promising candidates. These breakthrough articles have the potential to revolutionize the field of vaccines and move us one step closer to a world free from the grip of devastating infectious diseases and outbreaks 6 .

Early strategies for investigating new vaccine targets or developing formulations increasingly rely on sophisticated computational approaches. These approaches help save resources and refine in vitro and in vivo studies. For example, in one of the papers in this Collection, Goodswen et al. 7 present a state-of-the-art methodology for high-throughput in silico vaccine discovery against protozoan parasites, exemplified by discovered candidates for Toxoplasma gondii . Vaccine discovery against protozoan parasites is challenging due to the limited number of current appropriate vaccines compared to the number of protozoal diseases that need one. The group generated a ranked list of T. gondii vaccine candidates and proposed a workflow integrating parasite biology, host immune system defences, and bioinformatics programs to predict vaccine candidates. Although testing in animal models is required to validate these predictions, most of the top-ranked candidates are supported by publications reinforcing the confidence in the approach.

In another paper showcasing the benefits of an in silico approach, Palatnik‐de‐Sousa et al. 8 report the design and development of a multiepitope multivariant vaccine based on highly conserved epitopes of multiple proteins of all SARS-CoV-2 variants. The authors propose that this could offer more long-lasting protection against different strains of SARS-CoV-2 compared with current vaccines. The vaccine was developed based on highly promiscuous and robust HLA binding CD4 + and CD8 + T cell epitopes of the S, M, N, E, ORF1ab, ORF 6 and ORF8 proteins of SARS-CoV-2 variants Alpha to Omicron. The study found that the selected epitopes were 100% conserved among all 10 studied variants, supporting the potential efficacy of the multivariant multiepitope vaccine in generating cross-protection against infections by viruses of different human SARS-CoV-2 clades. The use of immunoinformatics and in silico approaches to design the vaccines in these articles could be a cost-effective and time-efficient method for developing vaccines for other infectious diseases in the future.

The translation of scientific discoveries into practical applications ensures the successful development and evaluation of effective vaccines, such as those reported by Quach et al. 9 and Uddin et al. 10 . Quach et al. 9 report the development of a peptide-based smallpox vaccine by identifying and evaluating immunogenic peptides from vaccinia-derived peptides. They assessed the immunogenicity of these T-cell peptides in both transgenic mouse models and human peripheral blood mononuclear cells. The vaccine, based on four selected peptides, provided 100% protection against a lethal viral challenge and induced a long-term memory T-cell response, highlighting the potential of peptide-based vaccines for infectious diseases. Uddin et al. 10 developed and evaluated a mucosal vaccine against the bovine respiratory pathogen Mannheimia haemolytica using Bacillus subtilis spores as an adjuvant. They found that intranasal immunization of spore-bound antigens generated the best secretory IgA-specific response against both PlpE and LktA in all bronchoalveolar lavage, saliva, and faeces samples. The spore-based vaccine may offer protection in cattle by limiting colonization and subsequent infection, and Spore-MhCP warrants further evaluation in cattle as a mucosal vaccine against M. haemolytica . This technology has potential commercial benefits as production of B. subtilis is well established and has low-cost inputs, and B. subtilis is recognized as a probiotic that has generally regarded as safe status, used commercially in food/feed products for human beings, poultry, cattle, swine, and fish. The use of oral administration of the vaccine would allow for large-scale administration, which is especially important as livestock management strategies, including vaccination, are cost- and ease-of-use dependent. The work highlights innovative approaches to address pressing challenges in vaccine development.

Understanding cellular responses following the administration of vaccines is crucial in assessing their efficacy and safety and in the development of improved vaccine strategies. Gmyrek et al. 11 characterize the B cell response in mice vaccinated with a live-attenuated HSV-1 mutant, 0ΔNLS, and compare it to the parental virus, GFP105. The study found that 0ΔNLS vaccination resulted in a more robust B cell response, including an increase in CD4 + follicular helper T cells, germinal B cells, and class-switched B cells, as well as an elevated titer of HSV-1-specific antibody. The study reports that HSV-1 thymidine kinase and glycoprotein M are likely expendable components in the efficacy of a humoral response to ocular HSV-1 infection. Lunardelli et al. 12 provide a detailed assessment of the immune responses induced after immunization with different regions of the ZIKV envelope protein. The study found that immunization with E ZIKV, EDI/II ZIKV, and EDIII ZIKV proteins induced specific IFNγ-producing cells and polyfunctional CD4 + and CD8 + T cells. The study also identified four peptides present in the envelope protein capable of inducing a cellular immune response to the H-2Kd and H-2Kb haplotypes. The results suggest that the ZIKV envelope glycoprotein is highly immunogenic and could be a potential target for developing a vaccine against ZIKV. A paper by Suryadevara et al. 13 contributes to understanding the molecular signature of CD8 + Trm cells elicited by subunit vaccination and their potential to protect against respiratory infectious diseases. The molecular signature of subunit vaccine-elicited CD8 + Trm cells resembles those elicited by virus infection or vaccination, with distinct molecular signatures distinguishing lung interstitial CD8 + Trm cells from effector memory and splenic memory counterparts. The transcriptome signature of the elicited CD8 + Trm cells provided clues to the basis of their tissue residence and function. Insights into cellular responses, such as those provided by the studies mentioned above, can not only help us understand tissue-specific responses to diseases but also how to harness them to promote resistance or treatment.

The advancements in vaccine research are transforming the landscape of disease prevention. From mRNA vaccines to novel antigenic targets, adjuvants, and delivery systems, these breakthroughs offer new avenues for combating infectious diseases and improving global public health 2 , 3 , 5 , 6 , 14 , 15 . Addressing vaccine hesitancy 16 , 17 and ensuring equitable access to vaccines are also top priorities 18 . Continued investment in research, collaboration, and development is essential to drive innovation and overcome challenges. The Collection highlights the innovative strategies, novel technologies, and cutting-edge research in vaccine technology, formulation, and delivery systems that have revolutionized vaccine development. With these advancements, we are inching closer to a future where the burden of preventable diseases is significantly reduced, paving the way for healthier communities and a safer world.

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Acknowledgements

On behalf of all the editors of this Collection, I extend my deepest appreciation to the authors for their invaluable contributions. I appreciate the peer reviewers who generously dedicated their time to evaluate and help improve these articles. I am also grateful to Nature Research and the editorial team at Scientific Reports for extending me an invitation to organize and edit this Collection.

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Tripathi, T. Advances in vaccines: revolutionizing disease prevention. Sci Rep 13 , 11748 (2023). https://doi.org/10.1038/s41598-023-38798-z

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Development of mRNA Vaccines: Scientific and Regulatory Issues

Affiliations.

• 1 Department of Health Product Policy and Standards, World Health Organization, Avenue Appia 20, CH-1211 Geneva, Switzerland.
• 2 ProTherImmune 3656 Happy Valley Road, Lafayette, CA 94549, USA.
• 3 Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, US Food & Drug Administration, Silver Spring, MD 20993, USA.
• PMID: 33498787
• PMCID: PMC7910833
• DOI: 10.3390/vaccines9020081

The global research and development of mRNA vaccines have been prodigious over the past decade, and the work in this field has been stimulated by the urgent need for rapid development of vaccines in response to an emergent disease such as the current COVID-19 pandemic. Nevertheless, there remain gaps in our understanding of the mechanism of action of mRNA vaccines, as well as their long-term performance in areas such as safety and efficacy. This paper reviews the technologies and processes used for developing mRNA prophylactic vaccines, the current status of vaccine development, and discusses the immune responses induced by mRNA vaccines. It also discusses important issues with regard to the evaluation of mRNA vaccines from regulatory perspectives. Setting global norms and standards for biologicals including vaccines to assure their quality, safety and efficacy has been a WHO mandate and a core function for more than 70 years. New initiatives are ongoing at WHO to arrive at a broad consensus to formulate international guidance on the manufacture and quality control, as well as nonclinical and clinical evaluation of mRNA vaccines, which is deemed necessary to facilitate international convergence of manufacturing and regulatory practices and provide support to National Regulatory Authorities in WHO member states.

Keywords: WHO standards; mRNA vaccines; prophylactic vaccines; regulatory considerations; vaccine development.

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• Published: 14 November 2021

Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis

• Qiao Liu 1   na1 ,
• Chenyuan Qin 1 , 2   na1 ,
• Min Liu 1 &
• Jue Liu   ORCID: orcid.org/0000-0002-1938-9365 1 , 2  

Infectious Diseases of Poverty volume  10 , Article number:  132 ( 2021 ) Cite this article

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To date, coronavirus disease 2019 (COVID-19) becomes increasingly fierce due to the emergence of variants. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance. We aimed to systematically evaluate the effectiveness and safety of COVID-19 vaccines in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.

We searched PubMed, Embase and Web of Science from inception to July 22, 2021. Observational studies that examined the effectiveness and safety of SARS-CoV-2 vaccines among people vaccinated were included. Random-effects or fixed-effects models were used to estimate the pooled vaccine effectiveness (VE) and incidence rate of adverse events after vaccination, and their 95% confidence intervals ( CI ).

A total of 58 studies (32 studies for vaccine effectiveness and 26 studies for vaccine safety) were included. A single dose of vaccines was 41% (95% CI : 28–54%) effective at preventing SARS-CoV-2 infections, 52% (31–73%) for symptomatic COVID-19, 66% (50–81%) for hospitalization, 45% (42–49%) for Intensive Care Unit (ICU) admissions, and 53% (15–91%) for COVID-19-related death; and two doses were 85% (81–89%) effective at preventing SARS-CoV-2 infections, 97% (97–98%) for symptomatic COVID-19, 93% (89–96%) for hospitalization, 96% (93–98%) for ICU admissions, and 95% (92–98%) effective for COVID-19-related death, respectively. The pooled VE was 85% (80–91%) for the prevention of Alpha variant of SARS-CoV-2 infections, 75% (71–79%) for the Beta variant, 54% (35–74%) for the Gamma variant, and 74% (62–85%) for the Delta variant. The overall pooled incidence rate was 1.5% (1.4–1.6%) for adverse events, 0.4 (0.2–0.5) per 10 000 for severe adverse events, and 0.1 (0.1–0.2) per 10 000 for death after vaccination.

Conclusions

SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.

Graphical Abstract

Since its outbreak, coronavirus disease 2019 (COVID-19) has spread rapidly, with a sharp rise in the accumulative number of infections worldwide. As of August 8, 2021, COVID-19 has already killed more than 4.2 million people and more than 203 million people were infected [ 1 ]. Given its alarming-spreading speed and the high cost of completely relying on non-pharmaceutical measures, we urgently need safe and effective vaccines to cover susceptible populations and restore people’s lives into the original [ 2 ].

According to global statistics, as of August 2, 2021, there are 326 candidate vaccines, 103 of which are in clinical trials, and 19 vaccines have been put into normal use, including 8 inactivated vaccines and 5 protein subunit vaccines, 2 RNA vaccines, as well as 4 non-replicating viral vector vaccines [ 3 ]. Our World in Data simultaneously reported that 27.3% of the world population has received at least one dose of a COVID-19 vaccine, and 13.8% is fully vaccinated [ 4 ].

To date, COVID-19 become increasingly fierce due to the emergence of variants [ 5 , 6 , 7 ]. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance [ 6 , 8 ]. Several reviews systematically evaluated the effectiveness and/or safety of the three mainstream vaccines on the market (inactivated virus vaccines, RNA vaccines and viral vector vaccines) based on random clinical trials (RCT) yet [ 9 , 10 , 11 , 12 , 13 ].

In general, RNA vaccines are the most effective, followed by viral vector vaccines and inactivated virus vaccines [ 10 , 11 , 12 , 13 ]. The current safety of COVID-19 vaccines is acceptable for mass vaccination, but long-term monitoring of vaccine safety is needed, especially in older people with underlying conditions [ 9 , 10 , 11 , 12 , 13 ]. Inactivated vaccines had the lowest incidence of adverse events and the safety comparisons between mRNA vaccines and viral vectors were controversial [ 9 , 10 ].

RCTs usually conduct under a very demanding research circumstance, and tend to be highly consistent and limited in terms of population characteristics and experimental conditions. Actually, real-world studies differ significantly from RCTs in terms of study conditions and mass vaccination in real world requires taking into account factors, which are far more complex, such as widely heterogeneous populations, vaccine supply, willingness, medical accessibility, etc. Therefore, the real safety and effectiveness of vaccines turn out to be a major concern of international community. The results of a mass vaccination of CoronaVac in Chile demonstrated a protective effectiveness of 65.9% against the onset of COVID-19 after complete vaccination procedures [ 14 ], while the outcomes of phase 3 trials in Brazil and Turkey were 50.7% and 91.3%, reported on Sinovac’s website [ 14 ]. As for the Delta variant, the British claimed 88% protection after two doses of BNT162b2, compared with 67% for AZD1222 [ 15 ]. What is surprising is that the protection of BNT162b2 against infection in Israel is only 39% [ 16 ]. Several studies reported the effectiveness and safety of the COVID-19 vaccine in the real world recently, but the results remain controversial [ 17 , 18 , 19 , 20 ]. A comprehensive meta-analysis based upon the real-world studies is still in an urgent demand, especially for evaluating the effect of vaccines on variation strains. In the present study, we aimed to systematically evaluate the effectiveness and safety of the COVID-19 vaccine in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.

Search strategy and selection criteria

Our methods were described in detail in our published protocol [PROSPERO (Prospective register of systematic reviews) registration, CRD42021267110]. We searched eligible studies published by 22 July 2021, from three databases including PubMed, Embase and Web of Science by the following search terms: (effectiveness OR safety) AND (COVID-19 OR coronavirus OR SARS-CoV-2) AND (vaccine OR vaccination). We used EndNoteX9.0 (Thomson ResearchSoft, Stanford, USA) to manage records, screen and exclude duplicates. This study was strictly performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

We included observational studies that examined the effectiveness and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among people vaccinated with SARS-CoV-2 vaccines. The following studies were excluded: (1) irrelevant to the subject of the meta-analysis, such as studies that did not use SARS-CoV-2 vaccination as the exposure; (2) insufficient data to calculate the rate for the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, or adverse events after vaccination; (3) duplicate studies or overlapping participants; (4) RCT studies, reviews, editorials, conference papers, case reports or animal experiments; and (5) studies that did not clarify the identification of COVID-19.

Studies were identified by two investigators (LQ and QCY) independently following the criteria above, while discrepancies reconciled by a third investigator (LJ).

Data extraction and quality assessment

The primary outcome was the effectiveness of SARS-CoV-2 vaccines. The following data were extracted independently by two investigators (LQ and QCY) from the selected studies: (1) basic information of the studies, including first author, publication year and study design; (2) characteristics of the study population, including sample sizes, age groups, setting or locations; (3) kinds of the SARS-CoV-2 vaccines; (4) outcomes for the effectiveness of SARS-CoV-2 vaccines: the number of laboratory-confirmed COVID-19, hospitalization for COVID-19, admission to the ICU for COVID-19, and COVID-19-related death; and (5) outcomes for the safety of SARS-CoV-2 vaccines: the number of adverse events after vaccination.

We evaluated the risk of bias using the Newcastle–Ottawa quality assessment scale for cohort studies and case–control studies [ 21 ]. and assess the methodological quality using the checklist recommended by Agency for Healthcare Research and Quality (AHRQ) [ 22 ]. Cohort studies and case–control studies were classified as having low (≥ 7 stars), moderate (5–6 stars), and high risk of bias (≤ 4 stars) with an overall quality score of 9 stars. For cross-sectional studies, we assigned each item of the AHRQ checklist a score of 1 (answered “yes”) or 0 (answered “no” or “unclear”), and summarized scores across items to generate an overall quality score that ranged from 0 to 11. Low, moderate, and high risk of bias were identified as having a score of 8–11, 4–7 and 0–3, respectively.

Two investigators (LQ and QCY) independently assessed study quality, with disagreements resolved by a third investigator (LJ).

Data synthesis and statistical analysis

We performed a meta-analysis to pool data from included studies and assess the effectiveness and safety of SARS-CoV-2 vaccines by clinical outcomes (rates of the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, and adverse events after vaccination). Random-effects or fixed-effects models were used to pool the rates and adjusted estimates across studies separately, based on the heterogeneity between estimates ( I 2 ). Fixed-effects models were used if I 2  ≤ 50%, which represented low to moderate heterogeneity and random-effects models were used if I 2  > 50%, representing substantial heterogeneity.

We conducted subgroup analyses to investigate the possible sources of heterogeneity by using vaccine kinds, vaccination status, sample size, and study population as grouping variables. We used the Q test to conduct subgroup comparisons and variables were considered significant between subgroups if the subgroup difference P value was less than 0.05. Publication bias was assessed by funnel plot and Egger’s regression test. We analyzed data using Stata version 16.0 (StataCorp, Texas, USA).

A total of 4844 records were searched from the three databases. 2484 duplicates were excluded. After reading titles and abstracts, we excluded 2264 reviews, RCT studies, duplicates and other studies meeting our exclude criteria. Among the 96 studies under full-text review, 41 studies were excluded (Fig.  1 ). Ultimately, with three grey literatures included, this final meta-analysis comprised 58 eligible studies, including 32 studies [ 14 , 15 , 17 , 18 , 19 , 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ] for vaccine effectiveness and 26 studies [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ] for vaccine safety. Characteristics of included studies are showed in Additional file 1 : Table S1, Additional file 2 : Table S2. The risk of bias of all studies we included was moderate or low.

Flowchart of the study selection

Vaccine effectiveness for different clinical outcomes of COVID-19

We separately reported the vaccine effectiveness (VE) by the first and second dose of vaccines, and conducted subgroup analysis by the days after the first or second dose (< 7 days, ≥ 7 days, ≥ 14 days, and ≥ 21 days; studies with no specific days were classified as 1 dose, 2 dose or ≥ 1 dose).

For the first dose of SARS-CoV-2 vaccines, the pooled VE was 41% (95% CI : 28–54%) for the prevention of SARS-CoV-2 infection, 52% (95% CI : 31–73%) for the prevention of symptomatic COVID-19, 66% (95% CI : 50–81%) for the prevention of hospital admissions, 45% (95% CI : 42–49%) for the prevention of ICU admissions, and 53% (95% CI : 15–91%) for the prevention of COVID-19-related death (Table 1 ). The subgroup, ≥ 21 days after the first dose, was found to have the highest VE in each clinical outcome of COVID-19, regardless of ≥ 1 dose group (Table 1 ).

For the second dose of SARS-CoV-2 vaccines, the pooled VE was 85% (95% CI : 81–89%) for the prevention of SARS-CoV-2 infection, 97% (95% CI : 97–98%) for the prevention of symptomatic COVID-19, 93% (95% CI: 89–96%) for the prevention of hospital admissions, 96% (95% CI : 93–98%) for the prevention of ICU admissions, and 95% (95% CI : 92–98%) for the prevention of COVID-19-related death (Table 1 ). VE was 94% (95% CI : 78–98%) in ≥ 21 days after the second dose for the prevention of SARS-CoV-2 infection, higher than other subgroups, regardless of 2 dose group (Table 1 ). For the prevention of symptomatic COVID-19, VE was also relatively higher in 21 days after the second dose (99%, 95% CI : 94–100%). Subgroups showed no statistically significant differences in the prevention of hospital admissions, ICU admissions and COVID-19-related death (subgroup difference P values were 0.991, 0.414, and 0.851, respectively).

Vaccine effectiveness for different variants of SARS-CoV-2 in fully vaccinated people

In the fully vaccinated groups (over 14 days after the second dose), the pooled VE was 85% (95% CI: 80–91%) for the prevention of Alpha variant of SARS-CoV-2 infection, 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. There was only one study [ 23 ] focused on the Beta variant, which showed the VE was 75% (95% CI : 71–79%) for the prevention of the Beta variant of SARS-CoV-2 infection. BNT162b2 vaccine had the highest VE in each variant group; 92% (95% CI : 90–94%) for the Alpha variant, 62% (95% CI : 2–88%) for the Gamma variant, and 84% (95% CI : 75–92%) for the Delta variant (Fig.  2 ).

Forest plots for the vaccine effectiveness of SARS-CoV-2 vaccines in fully vaccinated populations. A Vaccine effectiveness against SARS-CoV-2 variants; B Vaccine effectiveness against SARS-CoV-2 with variants not mentioned. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, COVID-19 coronavirus disease 2019, CI confidence interval

For studies which had not mentioned the variant of SARS-CoV-2, the pooled VE was 86% (95% CI: 76–97%) for the prevention of SARS-CoV-2 infection in fully vaccinated people. mRNA-1273 vaccine had the highest pooled VE (97%, 95% CI: 93–100%, Fig.  2 ).

Safety of SARS-CoV-2 vaccines

As Table 2 showed, the incidence rate of adverse events varied widely among different studies. We conducted subgroup analysis by study population (general population, patients and healthcare workers), vaccine type (BNT162b2, mRNA-1273, CoronaVac, and et al.), and population size (< 1000, 1000–10 000, 10 000–100 000, and > 100 000). The overall pooled incidence rate was 1.5% (95% CI : 1.4–1.6%) for adverse events, 0.4 (95% CI : 0.2–0.5) per 10 000 for severe adverse events, and 0.1 (95% CI : 0.1–0.2) per 10 000 for death after vaccination. Incidence rate of adverse events was higher in healthcare workers (53.2%, 95% CI : 28.4–77.9%), AZD1222 vaccine group (79.6%, 95% CI : 60.8–98.3%), and < 1000 population size group (57.6%, 95% CI : 47.9–67.4%). Incidence rate of sever adverse events was higher in healthcare workers (127.2, 95% CI : 62.7–191.8, per 10 000), Gam-COVID-Vac vaccine group (175.7, 95% CI : 77.2–274.2, per 10 000), and 1000–10 000 population size group (336.6, 95% CI : 41.4–631.8, per 10 000). Incidence rate of death after vaccination was higher in patients (7.6, 95% CI : 0.0–32.2, per 10 000), BNT162b2 vaccine group (29.8, 95% CI : 0.0–71.2, per 10 000), and < 1000 population size group (29.8, 95% CI : 0.0–71.2, per 10 000). Subgroups of general population, vaccine type not mentioned, and > 100 000 population size had the lowest incidence rate of adverse events, severe adverse events, and death after vaccination.

Sensitivity analysis and publication bias

In the sensitivity analyses, VE for SARS-CoV-2 infections, symptomatic COVID-19 and COVID-19-related death got relatively lower when omitting over a single dose group of Maria et al.’s work [ 33 ]; when omitting ≥ 14 days after the first dose group and ≥ 14 days after the second dose group of Alejandro et al.’s work [ 14 ], VE for SARS-CoV-2 infections, hospitalization, ICU admission and COVID-19-related death got relatively higher; and VE for all clinical status of COVID-19 became lower when omitting ≥ 14 days after the second dose group of Eric et al.’s work [ 34 ]. Incidence rate of adverse events and severe adverse events got relatively higher when omitting China CDC’s data [ 74 ]. P values of Egger’s regression test for all the meta-analysis were more than 0.05, indicating that there might not be publication bias.

To our knowledge, this is a comprehensive systematic review and meta-analysis assessing the effectiveness and safety of SARS-CoV-2 vaccines based on real-world studies, reporting pooled VE for different variants of SARS-CoV-2 and incidence rate of adverse events. This meta-analysis comprised a total of 58 studies, including 32 studies for vaccine effectiveness and 26 studies for vaccine safety. We found that a single dose of SARS-CoV-2 vaccines was about 40–60% effective at preventing any clinical status of COVID-19 and that two doses were 85% or more effective. Although vaccines were not as effective against variants of SARS-CoV-2 as original virus, the vaccine effectiveness was still over 50% for fully vaccinated people. Normal adverse events were common, while the incidence of severe adverse events or even death was very low, providing reassurance to health care providers and to vaccine recipients and promote confidence in the safety of COVID-19 vaccines. Our findings strengthen and augment evidence from previous review [ 75 ], which confirmed the effectiveness of the BNT162b2 mRNA vaccine, and additionally reported the safety of SARS-CoV-2 vaccines, giving insight on the future of SARS-CoV-2 vaccine schedules.

Although most vaccines for the prevention of COVID-19 are two-dose vaccines, we found that the pooled VE of a single dose of SARS-CoV-2 vaccines was about 50%. Recent study showed that the T cell and antibody responses induced by a single dose of the BNT162b2 vaccine were comparable to those naturally infected with SARE-CoV-2 within weeks or months after infection [ 76 ]. Our findings could help to develop vaccination strategies under certain circumstances such as countries having a shortage of vaccines. In some countries, in order to administer the first dose to a larger population, the second dose was delayed for up to 12 weeks [ 77 ]. Some countries such as Canada had even decided to delay the second dose for 16 weeks [ 78 ]. However, due to a suboptimum immune response in those receiving only a single dose of a vaccine, such an approach had a chance to give rise to the emergence of variants of SARS-CoV-2 [ 79 ]. There remains a need for large clinical trials to assess the efficacy of a single-dose administration of two-dose vaccines and the risk of increasing the emergence of variants.

Two doses of SARS-CoV-2 vaccines were highly effective at preventing hospitalization, severe cases and deaths resulting from COVID-19, while the VE of different groups of days from the second vaccine dose showed no statistically significant differences. Our findings emphasized the importance of getting fully vaccinated, for the fact that most breakthrough infections were mild or asymptomatic. A recent study showed that the occurrence of breakthrough infections with SARS-CoV-2 in fully vaccinated populations was predictable with neutralizing antibody titers during the peri-infection period [ 80 ]. We also found getting fully vaccinated was at least 50% effective at preventing SARS-CoV-2 variants infections, despite reduced effectiveness compared with original virus; and BNT162b2 vaccine was found to have the highest VE in each variant group. Studies showed that the highly mutated variants were indicative of a form of rapid, multistage evolutionary jumps, which could preferentially occur in the milieu of partial immune control [ 81 , 82 ]. Therefore, immunocompromised patients should be prioritized for anti-COVID-19 immunization to mitigate persistent SARS-CoV-2 infections, during which multimutational SARS-CoV-2 variants could arise [ 83 ].

Recently, many countries, including Israel, the United States, China and the United Kingdom, have introduced a booster of COVID-19 vaccine, namely the third dose [ 84 , 85 , 86 , 87 ]. A study of Israel showed that among people vaccinated with BNT162b2 vaccine over 60 years, the risk of COVID-19 infection and severe illness in the non-booster group was 11.3 times (95% CI: 10.4–12.3) and 19.5 times (95% CI: 12.9–29.5) than the booster group, respectively [ 84 ]. Some studies have found that the third dose of Moderna, Pfizer-BioNTech, Oxford-AstraZeneca and Sinovac produced a spike in infection-blocking neutralizing antibodies when given a few months after the second dose [ 85 , 87 , 88 ]. In addition, the common adverse events associated with the third dose did not differ significantly from the symptoms of the first two doses, ranging from mild to moderate [ 85 ]. The overall incidence rate of local and systemic adverse events was 69% (57/97) and 20% (19/97) after receiving the third dose of BNT162b2 vaccine, respectively [ 88 ]. Results of a phase 3 clinical trial involving 306 people aged 18–55 years showed that adverse events after receiving a third dose of BNT162b2 vaccine (5–8 months after completion of two doses) were similar to those reported after receiving a second dose [ 85 ]. Based on V-safe, local reactions were more frequently after dose 3 (5323/6283; 84.7%) than dose 2 (5249/6283; 83.5%) among people who received 3 doses of Moderna. Systemic reactions were reported less frequently after dose 3 (4963/6283; 79.0%) than dose 2 (5105/6283; 81.3%) [ 86 ]. On August 4, WHO called for a halt to booster shots until at least the end of September to achieve an even distribution of the vaccine [ 89 ]. At this stage, the most important thing we should be thinking about is how to reach a global cover of people at risk with the first or second dose, rather than focusing on the third dose.

Based on real world studies, our results preliminarily showed that complete inoculation of COVID-19 vaccines was still effective against infection of variants, although the VE was generally diminished compared with the original virus. Particularly, the pooled VE was 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. Since the wide spread of COVID-19, a number of variants have drawn extensive attention of international community, including Alpha variant (B.1.1.7), first identified in the United Kingdom; Beta variant (B.1.351) in South Africa; Gamma variant (P.1), initially appeared in Brazil; and the most infectious one to date, Delta variant (B.1.617.2) [ 90 ]. Israel recently reported a breakthrough infection of SARS-CoV-2, dominated by variant B.1.1.7 in a small number of fully vaccinated health care workers, raising concerns about the effectiveness of the original vaccine against those variants [ 80 ]. According to an observational cohort study in Qatar, VE of the BNT162b2 vaccine against the Alpha (B.1.1.7) and Beta (B.1.351) variants was 87% (95% CI : 81.8–90.7%) and 75.0% (95% CI : 70.5–7.9%), respectively [ 23 ]. Based on the National Immunization Management System of England, results from a recent real-world study of all the general population showed that the AZD1222 and BNT162b2 vaccines protected against symptomatic SARS-CoV-2 infection of Alpha variant with 74.5% (95% CI : 68.4–79.4%) and 93.7% (95% CI : 91.6–95.3%) [ 15 ]. In contrast, the VE against the Delta variant was 67.0% (95% CI : 61.3–71.8%) for two doses of AZD1222 vaccine and 88% (95% CI : 85.3–90.1%) for BNT162b2 vaccine [ 15 ].

In terms of adverse events after vaccination, the pooled incidence rate was very low, only 1.5% (95% CI : 1.4–1.6%). However, the prevalence of adverse events reported in large population (population size > 100 000) was much lower than that in small to medium population size. On the one hand, the vaccination population in the small to medium scale studies we included were mostly composed by health care workers, patients with specific diseases or the elderly. And these people are more concerned about their health and more sensitive to changes of themselves. But it remains to be proved whether patients or the elderly are more likely to have adverse events than the general. Mainstream vaccines currently on the market have maintained robust safety in specific populations such as cancer patients, organ transplant recipients, patients with rheumatic and musculoskeletal diseases, pregnant women and the elderly [ 54 , 91 , 92 , 93 , 94 ]. A prospective study by Tal Goshen-lag suggests that the safety of BNT162b2 vaccine in cancer patients is consistent with those previous reports [ 91 ]. In addition, the incidence rate of adverse events reported in the heart–lung transplant population is even lower than that in general population [ 95 ]. On the other hand, large scale studies at the national level are mostly based on national electronic health records or adverse event reporting systems, and it is likely that most mild or moderate symptoms are actually not reported.

Compared with the usual local adverse events (such as pain at the injection site, redness at the injection site, etc.) and normal systemic reactions (such as fatigue, myalgia, etc.), serious and life-threatening adverse events were rare due to our results. A meta-analysis based on RCTs only showed three cases of anaphylactic shock among 58 889 COVID-19 vaccine recipients and one in the placebo group [ 11 ]. The exact mechanisms underlying most of the adverse events are still unclear, accordingly we cannot establish a causal relation between severe adverse events and vaccination directly based on observational studies. In general, varying degrees of adverse events occur after different types of COVID-19 vaccination. Nevertheless, the benefits far outweigh the risks.

Our results showed the effectiveness and safety of different types of vaccines varied greatly. Regardless of SARS-CoV-2 variants, vaccine effectiveness varied from 66% (CoronaVac [ 14 ]) to 97% (mRNA-1273 [ 18 , 20 , 45 , 46 ]). The incidence rate of adverse events varied widely among different types of vaccines, which, however, could be explained by the sample size and population group of participants. BNT162b2, AZD1222, mRNA-1273 and CoronaVac were all found to have high vaccine efficacy and acceptable adverse-event profile in recent published studies [ 96 , 97 , 98 , 99 ]. A meta-analysis, focusing on the potential vaccine candidate which have reached to the phase 3 of clinical development, also found that although many of the vaccines caused more adverse events than the controls, most were mild, transient and manageable [ 100 ]. However, severe adverse events did occur, and there remains the need to implement a unified global surveillance system to monitor the adverse events of COVID-19 vaccines around the world [ 101 ]. A recent study employed a knowledge-based or rational strategy to perform a prioritization matrix of approved COVID-19 vaccines, and led to a scale with JANSSEN (Ad26.COV2.S) in the first place, and AZD1222, BNT162b2, and Sputnik V in second place, followed by BBIBP-CorV, CoronaVac and mRNA-1273 in third place [ 101 ]. Moreover, when deciding the priority of vaccines, the socioeconomic characteristics of each country should also be considered.

Our meta-analysis still has several limitations. First, we may include limited basic data on specific populations, as vaccination is slowly being promoted in populations under the age of 18 or over 60. Second, due to the limitation of the original real-world study, we did not conduct subgroup analysis based on more population characteristics, such as age. When analyzing the efficacy and safety of COVID-19 vaccine, we may have neglected the discussion on the heterogeneity from these sources. Third, most of the original studies only collected adverse events within 7 days after vaccination, which may limit the duration of follow-up for safety analysis.

Based on the real-world studies, SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its additional information files.

Abbreviations

Coronavirus disease 2019

Severe Acute Respiratory Syndrome Coronavirus 2

Vaccine effectiveness

Confidence intervals

Intensive care unit

Random clinical trials

Preferred reporting items for systematic reviews and meta-analyses

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (72122001; 71934002) and the National Science and Technology Key Projects on Prevention and Treatment of Major infectious disease of China (2020ZX10001002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. No payment was received by any of the co-authors for the preparation of this article.

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Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China

Qiao Liu, Chenyuan Qin, Min Liu & Jue Liu

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LQ and QCY contributed equally as first authors. LJ and LM contributed equally as correspondence authors. LJ and LM conceived and designed the study; LQ, QCY and LJ carried out the literature searches, extracted the data, and assessed the study quality; LQ and QCY performed the statistical analysis and wrote the manuscript; LJ, LM, LQ and QCY revised the manuscript. All authors read and approved the final manuscript.

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Supplementary Information

Additional file 1: table s1..

Characteristic of studies included for vaccine effectiveness.

Additional file 2: Table S2.

Characteristic of studies included for vaccine safety.

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Liu, Q., Qin, C., Liu, M. et al. Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis. Infect Dis Poverty 10 , 132 (2021). https://doi.org/10.1186/s40249-021-00915-3

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DOI : https://doi.org/10.1186/s40249-021-00915-3

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Development of next-generation covid-19 vaccines: barda supported phase 2b study designs.

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Daniel N Wolfe, Elizabeth Arangies, Gloria L David, Brian Armstrong, Theresa Z Scocca, Janel Fedler, Ramya Natarajan, James Zhou, Lakshmi Jayashankar, Ruben Donis, Mirjana Nesin, H Cody Meissner, Laurence Lemiale, Gerald R Kovacs, Shyam Rele, Robin Mason, Huyen Cao, Development of Next-Generation COVID-19 Vaccines: BARDA Supported Phase 2b Study Designs, Clinical Infectious Diseases , 2024;, ciae286, https://doi.org/10.1093/cid/ciae286

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In response to the COVID-19 pandemic, vaccines were quickly and successfully developed and deployed, saving millions of lives globally. While first generation vaccines are safe and effective in preventing disease caused by SARSCoV-2, next-generation vaccines have the potential to improve efficacy and safety. Vaccines delivered by a mucosal route may elicit greater protective immunity at respiratory surfaces thereby reducing transmission. Inclusion of viral antigens in addition to the spike protein may enhance protection against emerging variants of concern. Next-generation vaccine platforms with a new mechanism of action may necessitate efficacy trials to fulfill regulatory requirements. The Biomedical Advanced Research and Development Authority (BARDA) will be supporting Phase 2b clinical trials of candidate next-generation vaccines. The primary endpoint will be improved efficacy in terms of symptomatic disease relative to a currently approved COVID-19 vaccine. In this paper, we discuss the planned endpoints and potential challenges to this complex program.

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Reexamining Misinformation: How Unflagged, Factual Content Drives Vaccine Hesitancy

Research from the Computational Social Science Lab finds that factual, vaccine-skeptical content on Facebook has a greater overall effect than “fake news,” discouraging millions from the COVID-19 shot.

By Ian Scheffler, Penn Engineering 

What threatens public health more, a deliberately false Facebook post about tracking microchips in the COVID-19 vaccine that is flagged as misinformation, or an unflagged, factual article about the rare case of a young, healthy person who died after receiving the vaccine?

According to Duncan J. Watts, Stevens University Professor in Computer and Information Science at Penn Engineering and Director of the Computational Social Science (CSS) Lab , along with David G. Rand, Erwin H. Schell Professor at MIT Sloan School of Management, and Jennifer Allen, 2024 MIT Sloan School of Management Ph.D. graduate and incoming CSS postdoctoral fellow, the latter is much more damaging. “The misinformation flagged by fact-checkers was 46 times less impactful than the unflagged content that nonetheless encouraged vaccine skepticism,” they conclude in a new paper in Science. 

Historically, research on “fake news” has focused almost exclusively on deliberately false or misleading content, on the theory that such content is much more likely to shape human behavior. But, as Allen points out, “When you actually look at the stories people encounter in their day-to-day information diets, fake news is a miniscule percentage. What people are seeing is either no news at all or mainstream media.” 

“Since the 2016 U.S. presidential election, many thousands of papers have been published about the dangers of false information propagating on social media,” says Watts. “But what this literature has almost universally overlooked is the related danger of information that is merely biased. That’s what we look at here in the context of COVID vaccines.” 

In the study, Watts, one of the paper’s senior authors, and Allen, the paper’s first author, used thousands of survey results and AI to estimate the impact of more than 13,000 individual Facebook posts. “Our methodology allows us to estimate the effect of each piece of content on Facebook,” says Allen. “What makes our paper really unique is that it allows us to break open Facebook and actually understand what types of content are driving misinformed-ness.” 

One of the paper’s key findings is that “fake news,” or articles flagged as misinformation by professional fact-checkers, has a much smaller overall effect on vaccine hesitancy than unflagged stories that the researchers describe as “vaccine-skeptical,” many of which focus on statistical anomalies that suggest that COVID-19 vaccines are dangerous. 

“Obviously, people are misinformed,” says Allen, pointing to the low vaccination rates among U.S. adults, in particular for the COVID-19 booster vaccine, “but it doesn’t seem like fake news is doing it.” One of the most viewed URLs on Facebook during the time period covered by the study, at the height of the pandemic, for instance, was a true story in a reputable newspaper about a doctor who happened to die shortly after receiving the COVID-19 vaccine. 

That story racked up tens of millions of views on the platform, multiples of the combined number of views of all COVID-19-related URLs that Facebook flagged as misinformation during the time period covered by the study. “Vaccine-skeptical content that’s not being flagged by Facebook is potentially lowering users’ intentions to get vaccinated by 2.3 percentage points,” Allen says. “A back-of-the-envelope estimate suggests that translates to approximately 3 million people who might have gotten vaccinated had they not seen this content.”

Despite the fact that, in the survey results, fake news identified by fact-checkers proved more persuasive on an individual basis, so many more users were exposed to the factual, vaccine-skeptical articles with clickbait-style headlines that the overall impact of the latter outstripped that of the former. 

“Even though misinformation, when people see it, can be more persuasive than factual content in the context of vaccine hesitancy,” says Allen, “it is seen so little that these accurate, ‘vaccine-skeptical’ stories dwarf the impact of outright false claims.” 

As the researchers point out, being able to quantify the impact of misleading but factual stories points to a fundamental tension between free expression and combating misinformation, as Facebook would be unlikely to shut down mainstream publications. “Deciding how to weigh these competing values is an extremely challenging normative question with no straightforward solution,” the authors write in the paper. 

Allen points to content moderation that involves the user community as one possible means to address this challenge. “Crowdsourcing fact-checking and moderation works surprisingly well,” she says. “That’s a potential, more democratic solution.” 

With the 2024 U.S. Presidential election on the horizon, Allen emphasizes the need for Americans to seriously consider these tradeoffs. “The most popular story on Facebook in the lead-up to the 2020 election was about military ballots found in the trash that were mostly votes for Donald Trump,” she notes. “That was a real story, but the headline did not mention that there were nine votes total, seven of them for Trump.” 

This study was conducted at the University of Pennsylvania’s School of Engineering and Applied Science, the Annenberg School for Communication and the Wharton School, along with the Massachusetts Institute of Technology Sloan School of Management, and was supported by funding from Alain Rossmann.

This article originally appeared on the Penn Engineering Blog.

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Countries Fail to Agree on Treaty to Prepare the World for the Next Pandemic

Negotiators plan to ask for more time. Among the sticking points are equitable access to vaccines and financing to set up surveillance systems.

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By Apoorva Mandavilli

Countries around the globe have failed to reach consensus on the terms of a treaty that would unify the world in a strategy against the inevitable next pandemic, trumping the nationalist ethos that emerged during Covid-19.

The deliberations, which were scheduled to be a central item at the weeklong meeting of the World Health Assembly beginning Monday in Geneva, aimed to correct the inequities in access to vaccines and treatments between wealthier nations and poorer ones that became glaringly apparent during the Covid pandemic.

Although much of the urgency around Covid has faded since the treaty negotiations began two years ago, public health experts are still acutely aware of the pandemic potential of emerging pathogens, familiar threats like bird flu and mpox, and once-vanquished diseases like smallpox.

“Those of us in public health recognize that another pandemic really could be around the corner,” said Loyce Pace, an assistant secretary at the Department of Health and Human Services, who oversees the negotiations in her role as the United States liaison to the World Health Organization.

Negotiators had hoped to adopt the treaty next week. But canceled meetings and fractious debates — sometimes over a single word — stalled agreement on key sections, including equitable access to vaccines.

The negotiating body plans to ask for more time to continue the discussions.

“I’m still optimistic,” said Dr. Jean Kaseya, director general of Africa Centers for Disease Control and Prevention. “I think the continent wants this agreement. I think the world wants this agreement.”

Once adopted, the treaty would set legally binding policies for member countries of the W.H.O., including the United States, on surveillance of pathogens, rapid sharing of outbreak data, and local manufacturing and supply chains for vaccines and treatments, among others.

Contrary to rhetoric from some politicians in the United States and Britain , it would not enable the W.H.O. to dictate national policies on masking, or use armed troops to enforce lockdowns and vaccine mandates.

Next week’s deadline was self-imposed, and some public health experts have said it was far too ambitious — most treaties take many years — for such a complex endeavor. But negotiators were scrambling to ratify the treaty before elections in the United States and multiple European countries.

“Donald Trump is in the room,” said Lawrence Gostin, director of the W.H.O. Center on Global Health Law, who has helped to draft and negotiate the treaty.

“If Trump is elected, he will likely torpedo the negotiations and even withdraw from W.H.O.,” Mr. Gostin said.

During his tenure as president, Mr. Trump severed ties with the W.H.O. , and he has recently signaled that, if re-elected, he might shutter the White House pandemic preparedness office.

Among the biggest bones of contention in the draft treaty is a section called Pathogen Access and Benefits Sharing, under which countries would be required to swiftly share genetic sequences and samples of emerging pathogens. This information is crucial for rapid development of diagnostic tests, vaccines and treatments.

Low-income nations, including those in Africa, want to be compensated for the information with quick and equitable access to the developed tests, vaccines and treatments. They have also asked that pharmaceutical manufacturers share information that would allow local companies to manufacture the products at low cost.

“We don’t want to see Western countries coming to collect pathogens, going with pathogens, making medicines, making vaccines, without sending back to us these benefits,” Dr. Kaseya said.

Member countries have only ever agreed to one other health treaty, the 2003 Framework Convention on Tobacco Control , which strengthened control of the tobacco industry and decreased smoking rates in participating countries. But they were jolted by the devastation of the Covid pandemic and the inequities it reinforced to embark on a second.

The countries are also working on bolstering the W.H.O.’s International Health Regulations, which were last revised in 2005 and set detailed rules for countries to follow in the event of an outbreak that may breach borders.

In May 2021, an independent review of the global reaction to Covid-19 “found weak links at every point in the chain of preparedness and response.”

The pandemic also deepened mistrust between wealthier nations and poorer ones. By the end of 2021, more than 90 percent of people in some high-income countries had received two doses of Covid vaccines, compared with less than 2 percent in low-income nations. The lack of access to vaccines is thought to have caused more than a million deaths in low-income nations.

The treaty would be an acknowledgment of sorts that an outbreak anywhere threatens the entire globe, and that providing vaccines and other resources is beneficial to everyone. Variants of the coronavirus that emerged in countries with large unvaccinated populations swiftly swept across the world.

“Nearly half of U.S. deaths came from variants, so it’s in everybody’s interest to have a strong accord,” said Peter Maybarduk, who directs Public Citizen’s Access to Medicines program.

In December 2021, the W.H.O. established a group of negotiators to develop a legally binding treaty that would enable every country to prevent, detect and control epidemics, and allow for equitable allocation of vaccines and drugs.

More than two years into the negotiations, negotiators have agreed, at least in principle, on some sections of the draft.

But much of the good will generated during Covid has evaporated, and national interests have returned to the fore. Countries like Switzerland and the United States have been reluctant to accept terms that may affect the pharmaceutical industry; others like Argentina have fought against strict regulations on meat exports.

“It’s evident that people have very short memories,” said Dr. Sharon Lewin, director of the Cumming Global Center for Pandemic Therapeutics in Melbourne.

“But it can happen again, and it can happen with a pathogen that is far trickier to deal with than Covid was,” she warned.

One proposal for the Pathogen Access and Benefits Sharing section would require manufacturers to set aside 10 percent of vaccines to be donated, and another 10 percent to be provided at cost to the W.H.O. for distribution to low-income nations.

But that idea proved to be too complicated, said Roland Driece, who is one of the leaders of the negotiations. “We found along the way that that was too ambitious in the time frame.”

Instead, a working group established by the World Health Assembly will be tasked with hammering out the details of that section by May 2026, Mr. Driece said.

The terms of the proposed agreement have generated some confusion. In Britain, Nigel Farage, the conservative broadcaster and populist politician, and some other conservative politicians have claimed that the W.H.O. would force richer countries to give away 20 percent of their vaccines.

But that is an incorrect reading of the proposed agreement, Mr. Driece said. “It’s not the countries that have to come up with those vaccines, it’s the companies,” he said. Pharmaceutical companies would commit to the system in exchange for guaranteed access to data and samples needed to make their products.

Britain will not sign the treaty unless “it is firmly in the U.K. national interest and respects national sovereignty,” a spokesperson for the country’s health department told Reuters earlier this month.

In the United States, Republican senators have demanded that the Biden administration reject the treaty because it would “potentially weaken U.S. sovereignty.”

Dr. Tedros Adhanom Ghebreyesus, W.H.O.’s director general, has roundly criticized what he called the “the litany of lies and conspiracy theories,” noting that the organization does not have the authority to dictate national public health policies, nor does it seek such power.

The secrecy surrounding the negotiations has made it difficult to counter misinformation, said James Love, director of Knowledge Ecology International, one of the few nonprofits with a window into the negotiations.

Having more people allowed into the discussion rooms or to see the drafts as they evolve would help clarify complicated aspects of the treaty, Mr. Love said.

“Also, the public could relax a bit if they’re actually reading the actual agreement on a regular basis,” he said.

Some proposals in the draft treaty would require massive investments, another sticking point in the negotiations.

To monitor emerging pathogens, wealthier nations endorse a so-called One Health strategy, which recognizes the interconnections between people, animals, plants and their shared environment. They want low-income countries to regulate live animal markets and limit trade in animal products — a big economic blow for some nations.

Last month, the Biden administration released its own strategy for global health security , with a focus on bilateral partnerships aimed at helping 50 countries bolster their pandemic response systems. The administration hopes to expand the list to 100 countries by the end of the year.

American support would help the countries, most of which are in Asia and Africa, strengthen their One Health systems and better manage outbreaks.

The U.S. strategy is meant to be complementary to the global treaty, and cannot serve as an alternative, public health experts said.

“In my view, this is the most important moment in global health since W.H.O. was founded in 1948,” Mr. Gostin said. “It would just be an unforgivable tragedy if we let this slip away after all the suffering of Covid.”

Apoorva Mandavilli is a reporter focused on science and global health. She was a part of the team that won the 2021 Pulitzer Prize for Public Service for coverage of the pandemic. More about Apoorva Mandavilli

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Shingles Vaccination in Medicare Part D After Inflation Reduction Act Elimination of Cost Sharing

• 1 Program on Medicines and Public Health, University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, Los Angeles
• 2 Leonard D. Schaeffer Center for Health Policy and Economics, University of Southern California, Los Angeles
• 3 Sol Price School of Public Policy, University of Southern California, Los Angeles
• 4 Department of Population Health Sciences, University of Wisconsin-Madison
• 5 Center for Value-Based Insurance Design, University of Michigan, Ann Arbor

Although vaccinations prevent morbidity and mortality among Medicare beneficiaries, uptake of vaccines recommended by the Advisory Committee on Immunization Practices covered by Medicare Part D (ie, shingles, tetanus, diphtheria, pertussis, and hepatitis A and B) is suboptimal. 1 Unlike commercially insured individuals who have no cost sharing for recommended vaccinations, in 2021, Medicare beneficiaries receiving vaccines covered under Medicare Part D paid $234 million out of pocket (OOP), with a mean OOP cost of $76.94 for shingles vaccines.

Read More About

Qato DM , Romley JA , Myerson R , Goldman D , Fendrick AM. Shingles Vaccination in Medicare Part D After Inflation Reduction Act Elimination of Cost Sharing. JAMA. Published online May 23, 2024. doi:10.1001/jama.2024.7348

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Thousands of NHS patients to access trials of personalised cancer ‘vaccines’

31 May 2024

Today, the NHS announced it has treated its first patient in England with a personalised vaccine against their bowel cancer, in a clinical trial part of NHS England’s new Cancer Vaccine Launch Pad .  

As part of the platform, thousands of cancer patients in England are set to gain fast-tracked access to trials of personalised cancer vaccines following the launch of a world-leading NHS trial ‘matchmaking’ service to help find new life-saving treatments.  

The vaccines being tested as part of the trials aim to help patients with different types of cancer and, if successfully developed, researched and approved, cancer vaccines could become part of standard care.  

“It’s incredibly exciting that patients in England are beginning to access personalised cancer vaccines for bowel cancer,” said Iain Foulkes, executive director of research and innovation at Cancer Research UK.  

“This technology pioneers the use of mRNA-based vaccines to sensitise people’s immune system and in turn detect and target cancer at its earliest stages.   

“Clinical trials like this are vital in helping more people live longer, better lives, free from the fear of cancer. If successful, the vaccine will be a game changer in preventing the onset or return of bowel cancer.”  

A UK first trial

Elliot Pfebve, 55, received the developmental jab at University Hospitals Birmingham NHS Foundation Trust, one of several sites taking part in the colorectal cancer vaccine trial sponsored by BioNTech SE.  

A higher-education lecturer, Elliot had no cancer symptoms and was diagnosed through a routine health check with his GP.   

Following blood tests, he was immediately invited to Manor Hospital in Walsall and triaged to a hospital ward to receive blood transfusions.  

A CT scan and a colonoscopy confirmed he had colon cancer and Eliott had surgery to remove the tumour and 30 cm of his large intestine.  

He was then referred to the Queen Elizabeth Hospital Birmingham for initial rounds of chemotherapy and to take part in a clinical trial.  

“Taking part in this trial tallies with my profession as a lecturer, and as a community-centred person,” he said.  

“I want to impact other people’s lives positively and help them realise their potential.   

“Through the potential of this trial, if it is successful, it may help thousands, if not millions of people, so they can have hope, and may not experience all I have gone through. I hope this will help other people.”  

How do cancer vaccines work?

The vaccine trial Elliot’s taking part in is one of several that will be taking place across the country to treat different types of cancer.  

Patients who agree to take part have a sample of their cancer tissue and a blood test taken.  

If they meet a clinical trial’s eligibility criteria, they can be referred to their nearest participating NHS site, meaning patients from hospitals across the country will find it easier than ever to take part in groundbreaking research.   

The investigational cancer vaccines evaluated in the colorectal cancer trial are based on a molecule called mRNA, the same technology used for the COVID-19 vaccine .  

They’re created by analysing a patient’s tumour to identify mutations specific to their own cancer. Using this information, medics can create an individualised cancer vaccine.  

The developmental vaccines are designed to induce an immune response that may prevent cancer from returning after surgery by stimulating the patient’s immune system to specifically recognise and potentially destroy any remaining cancer cells.  

The investigational cancer vaccines, which are being jointly developed by biopharmaceutical companies BioNTech and Genentech, are still undergoing trials and have not yet been approved by regulators.  

If successful, the vaccine will be a game changer in preventing the onset or return of bowel cancer.

The launch pad

19 hospitals in England are already signed up to the Cancer Vaccine Launch Pad, one of the biggest projects of its kind in the world, with more sites joining the platform over the coming months.    

Some trials have already enlisted patients, although the majority of participants are expected to be enrolled from 2026 onwards.  

The scheme aims to expand and work with a range of partners in the pharmaceutical industry to include patients across many cancer types who could potentially join a vaccine trial, such as those with pancreatic and lung cancer.   

“Seeing Elliot receive his first treatment as part of the Cancer Vaccine Launch Pad is a landmark moment for patients and the health service as we seek to develop better and more effective ways to stop this disease,” said Amanda Pritchard, NHS chief executive.  

“Thanks to advances in care and treatment, cancer survival is at an all-time high in this country, but these vaccine trials could one day offer us a way of vaccinating people against their own cancer to help save more lives.   

“The NHS is in a unique position to deliver this kind of world-leading research at size and scale, and as more of these trials get up and running at hospitals across the country, our national match-making service will ensure as many eligible patients as possible get the opportunity to access them.”  

The NHS is working in partnership with Genomics England on the launch pad, with work already helping patients access the latest testing technologies and ensures they are given more targeted precision treatments for their cancer.  

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Effect of the HPV vaccination programme on incidence of cervical cancer and grade 3 cervical intraepithelial neoplasia by socioeconomic deprivation in England: population based observational study

Linked editorial.

HPV vaccine: the key to eliminating cervical cancer inequities

• Related content
• Peer review
• Milena Falcaro , senior statistician 1 ,
• Kate Soldan , scientist and epidemiologist 2 ,
• Busani Ndlela , cancer information analyst 3 ,
• Peter Sasieni , professor of cancer epidemiology 1
• 1 Centre for Cancer Screening, Prevention and Early Diagnosis, Wolfson Institute of Population Health, Queen Mary University of London, London EC1M 6BQ, UK
• 2 Blood Safety, Hepatitis, Sexually Transmitted Infections and HIV Division, UK Health Security Agency (UKHSA), London, UK
• 3 National Disease Registration Service (NDRS), NHS England, London, UK
• Correspondence to: P Sasieni p.sasieni{at}qmul.ac.uk (or @petersasieni on X)
• Accepted 27 March 2024

Objectives To replicate previous analyses on the effectiveness of the English human papillomavirus (HPV) vaccination programme on incidence of cervical cancer and grade 3 cervical intraepithelial neoplasia (CIN3) using 12 additional months of follow-up, and to investigate effectiveness across levels of socioeconomic deprivation.

Design Observational study.

Setting England, UK.

Participants Women aged 20-64 years resident in England between January 2006 and June 2020 including 29 968 with a diagnosis of cervical cancer and 335 228 with a diagnosis of CIN3. In England, HPV vaccination was introduced nationally in 2008 and was offered routinely to girls aged 12-13 years, with catch-up campaigns during 2008-10 targeting older teenagers aged <19 years.

Main outcome measures Incidence of invasive cervical cancer and CIN3.

Results In England, 29 968 women aged 20-64 years received a diagnosis of cervical cancer and 335 228 a diagnosis of CIN3 between 1 January 2006 and 30 June 2020. In the birth cohort of women offered vaccination routinely at age 12-13 years, adjusted age standardised incidence rates of cervical cancer and CIN3 in the additional 12 months of follow-up (1 July 2019 to 30 June 2020) were, respectively, 83.9% (95% confidence interval (CI) 63.8% to 92.8%) and 94.3% (92.6% to 95.7%) lower than in the reference cohort of women who were never offered HPV vaccination. By mid-2020, HPV vaccination had prevented an estimated 687 (95% CI 556 to 819) cervical cancers and 23 192 (22 163 to 24 220) CIN3s. The highest rates remained among women living in the most deprived areas, but the HPV vaccination programme had a large effect in all five levels of deprivation. In women offered catch-up vaccination, CIN3 rates decreased more in those from the least deprived areas than from the most deprived areas (reductions of 40.6% v 29.6% and 72.8% v 67.7% for women offered vaccination at age 16-18 and 14-16, respectively). The strong downward gradient in cervical cancer incidence from high to low deprivation in the reference unvaccinated group was no longer present among those offered the vaccine.

Conclusions The high effectiveness of the national HPV vaccination programme previously seen in England continued during the additional 12 months of follow-up. HPV vaccination was associated with a substantially reduced incidence of cervical cancer and CIN3 across all five deprivation groups, especially in women offered routine vaccination.

Introduction

Human papillomavirus (HPV) comprises a family of viruses, a subset of which are responsible for virtually all cervical and some anogenital and oropharyngeal cancers. 1 More than 100 countries worldwide have introduced prophylactic HPV vaccination as part of routine immunisation schedules. 2 One important outcome yet to be reported is whether vaccination has reduced or increased the inequalities seen for cervical disease in the UK and elsewhere.

In England, the national HPV vaccination programme started in 2008 using the bivalent Cervarix vaccine to prevent infections due to HPV types 16 and 18, which are estimated to cause around 80% of all cervical cancers in the UK. 3 Vaccination was offered routinely to 12-13 year old (school year 8) girls and as part of a catch-up campaign to those aged <19 years. 4 In September 2012 the programme switched to the quadrivalent vaccine (Gardasil), which additionally protects against HPV types 6 and 11 (responsible for genital warts), and in 2019 the programme was extended to 12-13 year old boys. Those who are eligible but not vaccinated can receive the vaccine free of charge from their general practitioner until their 25th birthday. 5

The introduction and implementation of HPV immunisation in this way means that noticeable discontinuities exist in the proportion of women vaccinated by date of birth, enabling a rigorous evaluation of the effectiveness of the programme. 6 For example, women born in August 1990 are unlikely to have received HPV vaccination, whereas among those born in the year from 1 September 1990 nearly 70% have received at least one dose of the vaccine.

Findings on the early effect of national HPV vaccination programmes have been encouraging. A wealth of real world evidence for the effect of vaccination on HPV prevalence exists 7 8 9 10 11 and evidence is growing for its effectiveness in reducing high grade cervical intraepithelial neoplasia (CIN) 12 13 14 15 and cervical cancer in vaccinated women. 14 16 17 18 19 For instance, we found that in England rates of grade 3 CIN (CIN3) and of cervical cancer were greatly reduced among those who were offered HPV vaccination, and that the magnitude of the reduction was greatest in the cohorts with the highest uptake and younger age at vaccination. 14 We estimated that by mid-2019 the immunisation programme had prevented cervical cancer in nearly 450 women and CIN3 in around 17 000 women.

Along with preventing ill health, a key aim of the NHS is to reduce health inequalities. 20 To this end, we investigated whether the effect of immunisation against HPV has resulted in a reduction in inequalities in cervical disease or a widening. Concern has been expressed that if the uptake of HPV vaccination is lower in those at greatest risk of cervical cancer, as has been seen in the US, 21 this could accentuate health inequalities. One study found that the introduction of HPV immunisation in England might initially have increased inequities in HPV related cancer incidence among ethnic minority groups because of the differential effect of herd protection in subpopulations with dissimilar vaccination coverage. 22 Previous studies have suggested that white people have a higher awareness of HPV and acceptance of the immunisation 23 and that vaccination uptake is lower in women from ethnic minority groups and more deprived areas. 24 Using data on HPV vaccination coverage by local area, however, a study found little variation by deprivation score in women offered routine vaccination (83% v 86% for most and least deprived areas, respectively) and only a small negative correlation between deprivation and vaccine uptake in those offered catch-up vaccination (47% v 53% for most and least deprived areas, respectively). 25 A full understanding of the effect of HPV vaccination across different socioeconomic groups is complicated by the poor uptake of cervical screening observed among younger women in the most deprived areas, leading to lower rates of screen detected cervical cancer and CIN3 at age 25 years compared with women in less deprived areas. 26 27

We replicated results from an analysis of population based cancer registry data to evaluate if the high vaccination effectiveness seen previously continued during an additional year of follow-up. The combined data were also used to investigate the effect of the vaccination programme by socioeconomic deprivation.

To represent socioeconomic deprivation, we used the index of multiple deprivation, a small area measure based on several domains of deprivation, such as income, employment, and health. The index is determined by using a standard statistical geographical unit, called lower super output area, which divides England into small areas of similar sized populations (on average about 1500 residents, or 650 households). 28 The lower super output areas are then ranked from the most to the least deprived and divided into five equal groups. The first and fifth groups correspond to the 20% most deprived and 20% least deprived lower super output areas in England, respectively.

We retrieved the records of all women aged 20-64 years resident in England with a diagnosis of invasive cervical cancer (ICD-10 (international classification of diseases, 10th revision) code C53) or CIN3 (ICD-10 code D06) between 1 January 2006 and 30 June 2020. These records are stored in the database managed by NHS England’s National Disease Registration Service, 29 and for each patient included information on index of multiple deprivation derived from the patient’s home postcode at the time of diagnosis. To convert these counts into rates, we used mid-year estimates of the female population for England by single year of age, calendar year (January 2006 to June 2020), and index of multiple deprivation (five groups). These estimates were retrieved from multiple tables publicly available on the website of the UK’s Office for National Statistics (ONS). 30 The supplementary material provides more details about the index of multiple deprivation versions used by the National Disease Registration Service and ONS, along with information on how we derived the population estimates required in our statistical analysis.

Statistical analysis

We separately analysed incidence rates of cervical cancer and CIN3 by using extensions of our previously described age-period-cohort Poisson model. 14 31 32 Data on women with cancer or CIN3 were aggregated by single month of age, calendar time (period), and date of birth (cohort). We derived the corresponding population risk time by subdividing the mid-year ONS population estimates into one month intervals for age, period, and cohort. For the analysis of the effectiveness by deprivation, we further split both the data on women with cancer or CIN3 and the population estimates by deprivation group (fifths). We then used the population risk time as the denominator for calculating rates (formally, the subdivided population estimates were log transformed and included in the Poisson regression model as an offset). Confidence intervals were computed using robust standard errors. 33 34

The code for the analysis was written and tested on synthetic data (extending the Simulacrum dataset) 35 by a statistician (MF) at King’s College London and then run on the real dataset by an analyst (BN) at the National Disease Registration Service.

We started by considering a core model where we included the main effects for age, period, and birth cohort, along with selected age by cohort and age by period interactions (see supplementary table S1). The interaction terms were included to account for variations in screening policy and historical events that affected cervical cancer rates. Specifically, we defined seven birth cohorts to capture differences in the age at first invitation to screening and the school years in which HPV vaccination was offered (see table 1 ). We added terms for seasonality and for events that may have affected registrations for cervical cancer and CIN3, such as the covid-19 lockdown, the “Jade Goody effect,” 36 37 and the 2019 cervical screening awareness campaign. In our previous paper, 14 we used several similar regression models to study the sensitivity of results to the precise way in which we adjusted for potential confounding factors. Because we found that the estimates of the cohort specific incidence rate ratios changed little across the various models, here we report on only a single model adjustment for confounders.

Characteristics of the birth cohorts

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Using the core model described, we investigated if the high effectiveness of the HPV immunisation programme reported previously 14 continued during an additional 12 months of follow-up. To do this we split the main effect of each cohort offered vaccination into two subgroup effects depending on whether the data related to the periods 1 January 2006 to 30 June 2019 or 1 July 2019 to 30 June 2020; this approach corresponded to adding three cohort by period interaction terms.

To evaluate the impact of socioeconomic deprivation on incidences of cervical cancer and CIN3, we extended the core model by adding main effects for deprivation and deprivation by cohort interactions. Specifically, we allowed the effect of each deprivation level to vary between unvaccinated women (cohorts 1-4) and those offered vaccination (cohorts 5-7), but we assumed it was otherwise constant within these two groups. We did not include further interactions between deprivation and other covariates as they were not of primary interest in this analysis. Using the fitted Poisson regression models, we made “what if” predictions by changing the value of one or more predictors and by leaving the others as observed. In this way it was possible to compare what happened (factual scenario) with what would have happened under an alternative (counterfactual) scenario.

We also carried out a sensitivity analysis where the effects of these deprivation by cohort interactions were allowed to vary across the three different groups offered vaccination (ie, we used 15 terms instead of five). For cervical cancer, owing to small numbers in cohort 7, we fitted a reduced model where the effects of these interactions were constrained to be the same for cohorts 6 and 7.

All analyses were performed in Stata, version 17. 38

Patient and public involvement

Patient and public involvement contributors were not formally involved in this research. We did, however, engage with Cancer Research UK (CRUK), Jo’s Cervical Cancer Trust, and the HPV Coalition on the importance of these analyses and the dissemination of the results. This included taking part in a video produced by ITN Business for World Cancer Day 2023, writing a piece for the 20th anniversary of the creation of CRUK, and engaging with international media about our research findings on the effect of the English HPV vaccination programme. We have also discussed the research and a draft of this paper with individual patients, journalists, and patient and public involvement representatives linked to broader research programmes.

Table 1 lists the characteristics of the birth cohorts included in the study. We defined the different cohorts so that each cohort is homogeneous in terms of the age women would have been offered HPV vaccination (if at all) and the age at which they would have first been invited for cervical screening.

Overall, there were 231.1 million women years of observation between 1 January 2006 and 30 June 2020 on women aged 20-64 years in England. During this time, 29 968 women received a diagnosis of invasive cervical cancer and 335 228 a diagnosis of CIN3 ( table 2 ). Observations between 1 July 2019 and 30 June 2020 have not been reported previously. With these additional 12 months of follow-up, there are, in the routine vaccination group (cohort 7), about twice the number of diagnoses compared with the same group in our previous study (we now have 13 v 7 previously for cervical cancer, 109 v 49 for CIN3; see supplementary table S2).

Summary statistics of study population

Our previously published findings on the effect of the national HPV vaccination were largely confirmed with the new data ( table 3 , also see supplementary table S3). The analysis showed that the previously observed low rates of disease and the estimated high effectiveness of the immunisation programme continued during the additional 12 months of follow-up (diagnoses in July 2019 to June 2020) among women born since 1 September 1990. In particular, the estimated effects of vaccination for that later period in cohort 7 (those born since 1 September 1995) imply a reduction in incidence of 83.9% (95% confidence interval (CI) 63.8% to 92.8%) for cervical cancer and 94.3% (92.6% to 95.7%) for CIN3 ( table 3 ). The relative risk reduction estimates for the earlier period are not identical to those reported previously because we also had new data for the unvaccinated cohorts that affected the baseline rates.

Estimated relative risk reductions (percentages) in incidence of invasive cervical cancer and CIN3 in the three cohorts offered HPV vaccination compared with the most recent unvaccinated cohort

Supplementary table S4 shows the full estimates from modelling the effects of vaccination in different levels of socioeconomic deprivation, with summary results reported in table 4 , table 5 , and table 6 . The highest incidence rates for invasive cervical cancer were observed among women living in the most deprived areas (first fifth) but, while in the reference unvaccinated group there was a strong downward gradient moving from women in the most deprived areas to those in the least deprived, little difference was found between the second and fifth fifths of deprivation in the groups offered vaccination. In both the reference and the vaccination cohorts the highest rates of CIN3 occurred in those from the most deprived areas, but no clear trend was observed among the other four fifths of deprivation (see supplementary tables S5 and S6).

Estimated number of invasive cervical cancers and CIN3s predicted and prevented by mid-2020 in the three cohorts of women offered HPV vaccination

Estimated cohort specific numbers of invasive cervical cancers predicted and prevented by mid-2020 among women in the least and most deprived areas

Estimated cohort specific numbers of CIN3 predicted and prevented by mid-2020 among women in the least and most deprived areas

Overall, our model estimated that 687 (95% CI 556 to 819) cervical cancers and 23 192 (22 163 to 24 220) CIN3s had been prevented by the vaccination programme up to mid-2020 among young women in England ( table 4 ). The greatest numbers for cervical cancer were prevented in women in the most deprived areas (192 and 199 for first and second fifths, respectively) and the fewest in women in the least deprived fifth (61 cancers prevented). The number of women with CIN3 prevented was high across all deprivation groups but greatest among women living in the more deprived areas: 5121 and 5773 for first and second fifths, respectively, compared with 4173 and 3309 in the fourth and fifth fifths, respectively. When we looked at the corresponding cohort specific figures ( table 5 and table 6 ), we noticed differences between the cohorts, particularly for CIN3. In all three cohorts offered vaccination the numbers and rates of prevented cervical cancers were much higher in women from the most deprived areas than least deprived areas ( table 5 ). The proportion of women with prevented cervical cancer in each cohort was, however, similar between the first and fifth fifths of deprivation. For CIN3 ( table 6 ), the results were more complicated. In women offered vaccination at age 16-18 years (cohort 5), the proportion of cervical cancers prevented was substantially less in those from the most deprived areas (29.6%) compared with those from the least deprived areas (40.6%). An inequality still existed in cohorts 6 and 7, but it was greatly reduced (67.7% v 72.8% in cohort 6 and 95.3% v 96.1% in cohort 7).

In England, the social-class gradient for cervical cancer is one of the steepest of any cancers: women in the most deprived fifth have had double the risk of those in the least deprived fifth. 39 40 Some of this results from differences in exposure to HPV and risk of an infection becoming persistent, 41 but differential uptake of cervical screening has also been an important factor. Previous research has highlighted the need for new engagement strategies to improve attendance for cervical screening among young women living in more socially deprived areas. 42 Encouragingly, the coverage of HPV vaccination has been (at least for the routine campaign and before the covid-19 pandemic) uniformly high. 43 It is, however, important to investigate whether immunisation—including the indirect effects achieved by high uptake—is helping to reduce health inequalities.

Using population based cancer registrations updated to mid-2020, which provided information on about twice the expected number of cancers in women offered HPV vaccination aged 12-13 years than in our previous analysis, we were able to show that the high vaccination effectiveness seen previously was confirmed with more recent data. The largest differences between the old and the new data were found for cohort 6 (the catch-up group offered the vaccine at age 14-16 years): for cervical cancer the estimated effectiveness increased, whereas for CIN3 it decreased. The reasons behind these differences are unclear. The results for cohorts 6 and 7 in the new data are more in keeping with what we would have expected given that the proportion of disease caused by HPV types 16 and 18 is greater for invasive cancer than for CIN3.

We also investigated the effect of the HPV immunisation programme by socioeconomic deprivation. Overall, we found that the programme was associated with a substantial reduction in the expected number of women with cervical cancers and CIN3 in all fifths of deprivation. For cervical cancer before vaccination, the downward gradient with decreasing deprivation was strong. In all cohorts offered vaccination, the highest rate was still seen among women living in the most deprived areas, but little difference was observed between women living in the second to fifth deprived areas. For CIN3, similar patterns were observed for the reference unvaccinated group and the three cohorts offered vaccination, but rates were greatly reduced in all fifths of deprivation in the latter. When we compared women in the most deprived areas with those in the least deprived areas in terms of percentage of disease averted, we observed differences across the cohorts for CIN3, with women in the least deprived areas in the older catch-up cohort (vaccine offered at age 16-18 years) having a greater proportion of averted CIN3s after HPV immunisation than women in the most deprived area (40.6% v 29.6%). The same, although to a much less extent, was observed for the younger catch-up cohort (72.8% v 67.7%). For invasive cervical cancer, we found no evidence of a less beneficial impact (in terms of percentage of cases averted) of the vaccination in women living in the most deprived areas; in fact, especially for the older catch-up cohort, the percentage was slightly higher in women in the most deprived areas compared with those in the least deprived areas.

The observed incidences of cervical cancer and CIN3 depend on three key factors: the intensity of exposure to HPV infections (including age at first exposure), the uptake of cervical screening, and HPV vaccination coverage. It is therefore difficult to disentangle the effects of these three drivers on the index of multiple deprivation specific rates with the data at hand. The health inequality in CIN3 in cohort 5 might result from the lower vaccination coverage among women in the most deprived areas since at age 16-18 years when they became eligible for vaccination more of those from the most deprived fifth may not have been in school or, for other reasons, may have missed the offer of HPV immunisation. These observations are consistent with previous understanding that higher uptake of catch-up vaccination was associated, although not as strongly as in some countries, with lower deprivation. 25 It is, however, reassuring that cohorts 6 and 7 showed little inequality in relative reductions in cancer (as in vaccination coverage).

However, since the UK has recently announced a change to a one dose schedule for routine HPV vaccination, ensuring this change achieves high coverage (including in the birth cohorts currently with lower coverage owing to covid-19 related interruption to schooling, and to immunisation services) is important to maintain the effects we have seen on cervical disease and on inequalities. Further investigations could be carried out in the future to check for any effect on cancer incidence caused by covid-19, gender neutral vaccination (since 2019), a change in the type of vaccine used, or reduced dose schedules.

Strengths and limitations of this study

Our analysis has several strengths. Our study provides direct evidence for the effect of a public health intervention (such as HPV vaccination) on cancer rates by deprivation. We used high quality data from population based cancer registries and were able to investigate the extent of socioeconomic inequalities in cohorts offered vaccination and whether the effectiveness of the HPV immunisation continued in an additional year of follow-up. The code for the analysis was written and tested using simulated data and an independent analyst later ran the code on the real dataset, guaranteeing reliable and robust results and preserving patient confidentiality.

The main limitations of our study are that it was observational and individual level data on vaccination status were not available. However, previous published research 14 provided detailed information on potential confounding factors and the best way to adjust for these in the analysis. Additionally, the discontinuities in vaccine uptake with date of birth makes this study powerful and less prone to biases from unobserved confounders than an analysis based on individual level data on HPV vaccination status.

Women born after 1 September 1999 were offered the Gardasil vaccine from 1 September 2012. As these women were at most aged 20 years and 10 months at the end of the study follow-up (30 June 2020), it is not yet possible with the data available to compare the effectiveness of the programme among those offered Cervarix and those offered Gardasil. This additional comparative analysis will become feasible with a longer follow-up on the recipients of Gardasil.

Policy implications

We found that the high effectiveness of the national HPV immunisation continued in the additional year of follow-up (July 2019 to June 2020). This is encouraging as it validates the previously published results and further supports consideration of more limited cervical screening for cohorts with high vaccination coverage aged 12-13 years. Moreover, although women living in the most deprived areas are still at higher risk of cervical cancer than those in less deprived areas, the HPV vaccination programme is associated with substantially lowered rates of disease across all fifths of socioeconomic deprivation. For cervical cancer, this has led to the levelling-up of the rates across the second to fifth fifths of deprivation so that the strong downward gradient observed in the reference unvaccinated cohort is no longer present in the cohorts offered vaccination. For CIN3, in the older catch-up cohorts women living in the least deprived areas seem to have benefited more from vaccination than those living in the most deprived areas, but the rates were still greatly reduced in all socioeconomic groups. Cervical screening strategies for women offered vaccination should carefully consider the differential effect both on rates of disease and on inequalities that are evident among women offered catch-up vaccination.

Conclusions

The HPV vaccination programme in England has not only been associated with a substantial reduction in incidence of cervical neoplasia in targeted cohorts, but also in all socioeconomic groups. This shows that well planned and executed public health interventions can both improve health and reduce health inequalities.

What is already known on this topic

In England, immunisation against human papillomavirus (HPV) has been associated with greatly reduced incidence rates of cervical cancer and grade 3 cervical intraepithelial neoplasia (CIN3) up to June 2019, especially among women offered routine vaccination at age 12-13 years

The social-class gradient for cervical cancer incidence has been one of the steepest of any cancers

Concern has been raised that HPV vaccination could least benefit those at highest risk of cervical cancer

What this study adds

The high effectiveness of vaccination against HPV seen previously continued during an additional year of follow-up, from July 2019 to June 2020

The English HPV vaccination programme was associated with substantially lower rates of cervical cancer and CIN3 in all fifths of socioeconomic deprivation, although the highest rates remained among women in the most deprived areas

For cervical cancer, the strong downward gradient from high to low deprivation observed in the reference unvaccinated cohort was no longer present among those offered vaccination

Ethics statements

Ethical approval.

Not required as the study used aggregated data from the National Disease Registration Service as well as publicly available information from the Office for National Statistics website.

Data availability statement

The cancer registry data analysed for this paper are securely held by the National Disease Registration Service (NDRS). Requests to access the data can be made through NHS England’s DARS service ( https://digital.nhs.uk/services/data-access-request-service-dars ). The Simulacrum ( https://simulacrum.healthdatainsight.org.uk/ ) is a synthetic dataset developed by Health Data Insight and derived from anonymous cancer data provided by NHS England’s NDRS. Mid-year population estimates are freely downloadable from the Office for National Statistics website ( https://www.ons.gov.uk/ ).

Acknowledgments

We thank Alejandra Castañon (LCP Health Analytics), Marta Checchi (UK Health Security Agency), and Lucy Elliss-Brookes (NHS England) for helpful comments on the study protocol, and Kwok Wong (NHS England) for contributing to the quality assurance of the data extraction code.

Contributors: PS had the original idea. He is the guarantor. MF and PS conceptualised the study and prepared the study protocol, which was subsequently reviewed by the other co-authors. MF wrote and tested the Stata code (checked by PS) for the data analysis and drafted the manuscript. BN extracted the dataset and ran the Stata code on it. All authors critically reviewed and approved the final submitted version. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: This work was supported by Cancer Research UK (grant No C8162/A27047). The funder had no role in the study design or in the collection, analysis, interpretation of data, writing of the report or decision to submit the article for publication.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare support from Cancer Research UK for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Transparency: The lead author (the manuscript’s guarantor) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Dissemination to participants and related patient and public communities: The results of this research will be disseminated through the media, blogs and scientific meetings and will inform the design and implementation of interventions to reduce health inequalities. We will also work with others to produce information for the public to support human papillomavirus immunisation and cervical screening programmes and, if the opportunity arises, to contribute summary data for an international meta-analysis of similar studies.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ .

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Scientists are testing mRNA vaccines to protect cows and people against bird flu

FILE - Cows stand in the milking parlor of a dairy farm in New Vienna, Iowa, on Monday, July 24, 2023. The bird flu outbreak in U.S. dairy cows is prompting development of new, next-generation mRNA vaccines — akin to COVID-19 shots — that are being tested in both animals and people. In June 2024, the U.S. Agriculture Department is to begin testing a vaccine developed by University of Pennsylvania researchers by giving it to calves. (AP Photo/Charlie Neibergall, File)

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The bird flu outbreak in U.S. dairy cows is prompting development of new, next-generation mRNA vaccines — akin to COVID-19 shots — that are being tested in both animals and people.

Next month, the U.S. Agriculture Department is to begin testing a vaccine developed by University of Pennsylvania researchers by giving it to calves. The idea: If vaccinating cows protects dairy workers, that could mean fewer chances for the virus to jump into people and mutate in ways that could spur human-to-human spread.

Meanwhile. the U.S. Department of Health and Human Services has been talking to manufacturers about possible mRNA flu vaccines for people that, if needed, could supplement millions of bird flu vaccine doses already in government hands.

“If there’s a pandemic, there’s going to be a huge demand for vaccine,” said Richard Webby, a flu researcher at St. Jude Children’s Research Hospital in Memphis. “The more different (vaccine manufacturing) platforms that can respond to that, the better.”

The bird flu virus has been spreading among more animal species in scores of countries since 2020. It was detected in U.S. dairy herds in March, although investigators think it may have been in cows since December. This week, the USDA announced it had been found in alpacas for the first time.

At least three people — all workers at farms with infected cows — have been diagnosed with bird flu, although the illnesses were considered mild.

But earlier versions of the same H5N1 flu virus have been highly lethal to humans in other parts of the world. Officials are taking steps to be prepared if the virus mutates in a way to make it more deadly or enables it to spread more easily from person to person.

Traditionally, most flu vaccines are made via an egg-based manufacturing process that’s been used for more than 70 years. It involves injecting a candidate virus into fertilized chicken eggs, which are incubated for several days to allow the viruses to grow. Fluid is harvested from the eggs and is used as the basis for vaccines, with killed or weakened virus priming the body’s immune system.

Rather than eggs — also vulnerable to bird flu-caused supply constraints — some flu vaccine is made in giant vats of cells.

Officials say they already have two candidate vaccines for people that appear to be well-matched to the bird flu virus in U.S. dairy herds. The Centers for Disease Control and Prevention used the circulating bird flu virus as the seed strain for them.

The government has hundreds of thousands of vaccine doses in pre-filled syringes and vials that likely could go out in a matter of weeks, if needed, federal health officials say.

They also say they have bulk antigen that could generate nearly 10 million more doses that could be filled, finished and distributed in a matter of a few months. CSL Seqirus, which manufactures cell-based flu vaccine, this week announced that the government hired it to fill and finish about 4.8 million of those doses. The work could be done by late summer, U.S. health officials said this week.

But the production lines for flu vaccines are already working on this fall’s seasonal shots — work that would have to be interrupted to produce millions more doses of bird flu vaccine. So the government has been pursuing another, quicker approach: the mRNA technology used to produce the primary vaccines deployed against COVID-19.

These messenger RNA vaccines are made using a small section of genetic material from the virus. The genetic blueprint is designed to teach the body how to make a protein used to build immunity.

The pharmaceutical company Moderna already has a bird flu mRNA vaccine in very early-stage human testing. In a statement, Moderna confirmed that “we are in discussions with the U.S. government on advancing our pandemic flu candidate.”

Similar work has been going on at Pfizer. Company researchers in December gave human volunteers an mRNA vaccine against a bird flu strain that’s similar to — but not exactly the same as — the one in cows. Since then, researchers have performed a lab experiment exposing blood samples from those volunteers to the strain seen in dairy farms, and saw a “notable increases in antibody responses,” Pfizer said in a statement.

As for the vaccine for cows, Penn immunologist Scott Hensley worked with mRNA pioneer and Nobel laureate Drew Weissman to produce the experimental doses. Hensley said that vaccine is similar to the Moderna one for people.

In first-step testing, mice and ferrets produced high levels of bird flu virus-fighting antibodies after vaccination.

In another experiment, researchers vaccinated one group of ferrets and deliberately infected them, and then compared what happened to ferrets that hadn’t been vaccinated. All the vaccinated animals survived and the unvaccinated did not, Hensley said.

“The vaccine was really successful,” said Webby, whose lab did that work last year in collaboration with Hensley.

The cow study will be akin to the first-step testing initially done in smaller animals. The plan is for initially about 10 calves to be vaccinated, half with one dose and half with another. Then their blood will be drawn and examined to look for how much bird flu-fighting antibodies were produced.

The USDA study first will have to determine the right dose for such a large animal, Hensley said, before testing if it protects them like it did smaller animals.

What “scares me the most is the amount of interaction between cattle and humans,” Hensley said.

“We’re not talking about an animal that lives on a mountain top,” he said. “If this was a bobcat outbreak I’d feel bad for the bobcats, but that’s not a big human risk.”

If a vaccine reduces the amount of virus in the cow, “then ultimately we reduce the chance that a mutant virus that spreads in humans is going to emerge,” he said.

The Associated Press Health and Science Department receives support from the Howard Hughes Medical Institute’s Science and Educational Media Group. The AP is solely responsible for all content.

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Comprehensive literature review on COVID-19 vaccines and role of SARS-CoV-2 variants in the pandemic

Charles yap.

School of Medicine, National University of Ireland, Galway, Ireland

Abulhassan Ali

Amogh prabhakar, akul prabhakar, ying yi lim, pramath kakodkar.

School of Medicine, National University of Ireland, Galway, University Road, Galway H91 TK33, Ireland

Since the outbreak of the COVID-19 pandemic, there has been a rapid expansion in vaccine research focusing on exploiting the novel discoveries on the pathophysiology, genomics, and molecular biology of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although the current preventive measures are primarily socially distancing by maintaining a 1 m distance, it is supplemented using facial masks and other personal hygiene measures. However, the induction of vaccines as primary prevention is crucial to eradicating the disease to attempt restoration to normalcy. This literature review aims to describe the physiology of the vaccines and how the spike protein is used as a target to elicit an antibody-dependent immune response in humans. Furthermore, the overview, dosing strategies, efficacy, and side effects will be discussed for the notable vaccines: BioNTech/Pfizer, Moderna, AstraZeneca, Janssen, Gamaleya, and SinoVac. In addition, the development of other prominent COVID-19 vaccines will be highlighted alongside the sustainability of the vaccine-mediated immune response and current contraindications. As the research is rapidly expanding, we have looked at the association between pregnancy and COVID-19 vaccinations, in addition to the current reviews on the mixing of vaccines. Finally, the prominent emerging variants of concern are described, and the efficacy of the notable vaccines toward these variants has been summarized.

Introduction

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 192 million cases and 4.1 million deaths as of July 22, 2021. 1 This pandemic has brought along a massive burden in morbidity and mortality in the healthcare systems. Despite the implementation of stringent public health measures, there have been devasting effects in other sectors contributing to our economy. This has plunged the global economies toward deep recession and has racked up a debt of approximately 19.5 trillion USD. 2

Immune protection in COVID-19 infection can be conceptualized as a spectrum wherein sterile immunity is at the end of positive spectrum. This is followed by transient infection (<3 days) and asymptomatic infection (~1 week). The negative spectrum of immune protection includes patients who are symptomatic, or hospitalized, or admitted to the intensive care unit for multiorgan support. The extreme end of the negative spectrum of immune protection is encompassed by case fatality. The vaccine will intervene prior to the viral insult and stabilize the population at the positive end of the spectrum of the immune protection. It will also prevent the perpetuating cycle of infection and reinfection via variants of SARS-CoV-2 virus in those who have achieved prior convalescence. One study by Dan et al. showed that in patients infected with COVID-19, immunological memory to SARS-CoV-2 remained intact for up to 6 months. 3 Unfortunately, there is no long-term data on the duration of protected immunity against SARS-CoV-2 in patients after convalescence. Therefore, these patients may also require vaccination but the current priority for vaccination can be stretched relative to the unaffected population.

While the ideal goal of the COVID-19 vaccine roll-out is to instill a global herd immunity; it is important to remember that this goal may never be reached. Furthermore, additional goals of vaccination may be to reduce mortality and stress on healthcare systems by reducing the cases of admitted patients. Various countries have already approved COVID-19 vaccines for human use, and more are expected to be licensed in the upcoming year. It is important that these vaccines are safe, efficacious, and can be deployed on a large scale. It is also prudent to eliminate the concerns of both the scientific and general community regarding its effectiveness, side-effects, and dosing strategies.

Historically, the process of vaccine manufacturing and clinical trials required approximately 10 years, but due to the burden of this disease, various observational studies were expedited so that all crucial information regarding the vaccine pharmacokinetics, pharmacodynamics, dosing, efficacy, and adverse events can be collected within a short period of time. Furthermore, there is a need to provide a compilation of accredited and appraised scientific literature on each of these approved vaccines with an aim to instill public health knowledge and vaccine literacy to members of the scientific and general community. A section dedicated to COVID-19 vaccines and pregnancy is also included in the penultimate section of this review.

Finally, the emergence of the SARS-CoV-2 viral variants of concern (VOC) has attained increased replication, transmission, and infectivity warranting exploration of these genomic mutations as their phenotypes. Hence, the final section of this review will aim to clarify the jargon, highlight the vaccine efficacy (VE) against VOCs, and eliminate any misinformation regarding these variants.

Vaccine physiology

The global burden of the pandemic requires an efficacious vaccine that elicits a lasting protective immune response against SARS-CoV-2. This will be an essential armament for the prevention and mitigation of the downstream morbidity and mortality caused by SARS-CoV-2 infection. As of July 20, 2021, there are approximately 108 vaccines in clinical development and 184 vaccines in pre-clinical development with several vaccines being distributed globally. 4

The technologies employed in the vaccine synthesis and development aim to trigger the adaptive immune system and elicit memory cells that will protect the body from subsequent infections. These technologies may be mRNA-based vaccines such as the Moderna and Pfizer/BioNTech, inactivated virus vector vaccines, DNA vaccines, and numerous other technologies. 5

Due to the urgent implementation of vaccine development, the most obvious target will be the robust proteins expressed on the surface of the virus. Therefore, these technologies target molecular expression of the trimeric SARS-CoV-2 spike (S) glycoprotein. These targets could include its mRNA, DNA, full S1 subunit, or fusion subunits. The S protein is a major component of the virus envelope, it is vital for viral fusion, receptor binding, and virus-entry through recognition of host-cellular receptor. The S protein comprises of two main functional units, the S1 subunit, which contains the receptor-binding domain (RBD) and the S2 subunit which is responsible for virus fusion with the host-cell membrane. 6 The choice to proceed with S protein as the target was reinforced when a study by Dan et al. confirmed that in 169 patients infected with SARS-CoV-2, spike-specific immunoglobulin G (IgG) remained stable for over 6 months. 3 In addition, both spike-specific CD4+ T-cells (CD137+ and OX40+) and spike-specific CD8+ T-cells (CD69+ and CD137+) were present at the 6-month post-convalescence period, but their subpopulations exhibited a steady decline with a half-life of 139 days and 225 days, respectively. 3

There are subtle differences in the mechanism by which the different vaccine products interact within host cells to induce immunity. Many successful vaccines of the 20 century utilized the target proteins directly such as the tetanus and pertussis vaccine. A summary of the major types of vaccines and their mechanism of action are shown in Figure 1 .

Summary of major vaccine types and their mechanism of action.

DNA, deoxyribonucleic acid; HPV, Human papillomavirus; mRNA, messenger ribonucleic acid; MMR, Measles, Mumps, and Rubella; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Historically, vaccines usually contained adjuvants which are protein sensitizers that heighten the migratory and sampling response of antigen presenting cells (APCs). Interestingly, the current mRNA vaccines are engineered to code for their own sensitizing protein alongside the S-protein epitopes. Therefore, these new mRNA vaccines usually do not contain any adjuvants. In addition, the mRNA vaccines utilize lipid nanoparticles to deliver the genetic material of a viral S-protein. Contrastingly, vaccines such as the AstraZeneca vaccine may employ a chimpanzee adenovirus vector to carry the DNA genome of the S-protein to the host-cell. 7 Once undergoing the processes of transcription and translation into proteins, these are trafficked and expressed on the host cell surface wherein the adaptive immune system mounts a response via the major histocompatibility complex (MHC) molecules ( Figure 2 ).

Mechanism of induction of immunity through vaccination.

APC, antigen presenting cells; DNA, deoxyribonucleic acid; MHC, major histocompatibility complex; mRNA, messenger ribonucleic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

There are two types of MHC molecules, the first one that will be discussed is the MHC-II, which is found exclusively on APC: these comprise of B-cells, macrophages, and dendritic cells in the lymph nodes. Once the S-protein antigen is presented at the cell surface of the MHC-II molecules, the naïve helper T-cell’s (Th Cells) T-cell receptor (TCR) complex will interact with this antigen leading to activation of CD4+ Th cells. This activation is perpetuated by a secondary activation signal with B7 on the APC recognizing the CD28 on the Th cell which triggers the proliferation of Th cells that can recognize the S-protein antigen. Activated CD4+ Th cells then secrete numerous cytokines, namely interleukin (IL)-2 which activates CD8+ cytotoxic T-cells (Tc cell) and trigger clonal expansion of B-cells in memory B-cells and plasma cells. The cytokines IL-4 and IL-5 facilitate B-cell isotype switching and maturation to plasma cells; promoting secretion of IgG antibodies against S-protein. 8 Formation of antibodies allows the immune system to direct an immune response against cells expressing the S-protein of the virus. The second process involves MHC-I, which activates CD8+ Naïve Tc cells through TCR complex interaction with processed endogenously synthesized S-protein expressed on MHC-I. MHC-I is expressed in all nucleated cells, APCs, and platelets and require a second activation signal provided by IL-2 from activated CD4+ Th cells. This activates CD8+ Tc cells which can mount a cytotoxic response against SARS-CoV-2-infected cells through two mechanisms of apoptosis. The first mechanism is the secretion of perforin which create pores to allow granzyme to enter the targeted cell, thus activating apoptosis. The second mechanism is via the expression of FasL, which binds Fas on target cells and induces apoptosis. 8 A crucial part of this process is the stimulation of memory T-cells and memory B-cells. Importantly, while the SARS-CoV-2 vaccine’s lasting effect is still being researched in the context of the pandemic, theoretically these should provide lasting immunity and allow the immune system to mount a faster and more effective response should a vaccinated individual encounter the virus in the future.

Current prominent COVID-19 vaccines

Biontech/pfizer.

The BNT162b2 COVID-19 vaccine developed by BioNTech and Pfizer is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion membrane-anchored SARS-CoV-2 full-length spike protein. 9 It was the first vaccine approved by the US Food and Drug Association (FDA) and now it has been approved in many other countries. 10 The BNT162b2 COVID-19 vaccine may be stored at standard refrigerator temperatures prior to use, but it requires very cold temperatures for long-term storage and shipping (−70°C) to maintain the stability of the lipid nanoparticle. In a phase-1 trial, it was compared to another vaccine candidate BNT162b1, and it was found to have a milder systemic side-effect profile with a similar antibody response. 11 Therefore, it was pushed forward to a blinded phase-2/3 clinical study. 9 In total, 43,548 participants were randomized to receive either two doses of the BNT162b2 vaccine (n = 21,720) or a placebo (n = 21,728) 21 days apart. The participant ages ranged from 16 to 91 years, 35.1% of participants were classified as having obesity and comorbidities within participants included HIV, malignancy, diabetes, and vascular diseases. 9 Based on the results of the study, 7 days after the second BNT162b2 dose, the VE was 95% (95% confidence interval (CI), 90.3–97.6) with only eight observed cases of COVID-19 in the vaccine recipients and 162 cases in the placebo recipients. 9 The efficacy remained consistent across subgroups characterized by age, sex, race, ethnicity, body mass index (BMI), and comorbidities (generally 90–100%). 9 Although there were 10 cases of severe COVID-19 with onset after the first dose, only one occurred in a vaccine recipient and nine in placebo recipients. Like the phase-1 trial results, the safety profile remained favorable with the most common local reaction being mild-to-moderate pain at the injection site while the most common systemic symptoms were fatigue and headache (reported in ⩾50%). 9 In both the vaccine and placebo group, the incidence of severe adverse events did not differ significantly (0.6% and 0.5%, respectively) and no deaths occurred related to the vaccine. As indicated by the manufacturer’s information, contraindications for use include hypersensitivity to the active substance or any of the excipients. 12 These studies show that the mRNA-vaccine BNT162b2 is safe and effective in protecting against COVID-19. However, further investigations are needed to confirm long-term safety and to establish safety and efficacy for populations not included in this study.

The mRNA-1273 vaccine, developed by Moderna, relies on mRNA technology to encode prefusion stabilized SARS-CoV-2 spike protein. It is the second COVID-19 vaccine to receive emergency use approval by the US FDA, and it is given as two 100-µg doses intramuscularly into the deltoid muscle, 28 days apart. 13 Storage of the vaccine is done at temperatures between −25°C to −15°C for long-term storage, 2°C to 8°C for 30 days, or 8°C to 25°C for up to 12 hours. Results from the COVE phase-3 trial showed that the mRNA-1273 vaccine was effective at preventing COVID-19 illness in persons 18 years of age or older. A total of 30,420 participants aged 18 years or older were randomized 1:1 to receive either two doses of the vaccine or a placebo, 28 days apart. 14 The mean age of the participants was 51.4 years, and enrollment was adjusted for equal representation of racial and ethnic minorities. In the trial, symptomatic COVID-19 illness occurred in 11 participants within the vaccine group versus 185 participants within the placebo group, showing a 94.1% (95% CI, 89.3–96.8%) efficacy of the vaccine. Efficacy was similar across age, sex, race, and ethnicity as well as in patients with and without risk factors for severe disease (e.g. chronic lung disease, cardiac disease, and severe obesity). Importantly, a secondary endpoint for determining the efficacy of the vaccine in preventing severe COVID-19 was also used. All 30 participants with severe COVID-19 were in the placebo group, indicating a 100% efficacy of no hospital admissions. 14 Regarding the side effects of the vaccine, adverse events at the injection site and systemic adverse events occurred more commonly with the mRNA-1273 group compared to the placebo. The most common local reaction was mild to moderate pain at the injection site (75%). The most common systemic symptoms were fatigue, myalgia, arthralgia, and headache (50%). 14 The overall incidence of serious adverse events did not differ significantly between groups and no deaths occurred in relation to the vaccine. While this vaccine is already being administered, further investigations are still necessary to establish safety and efficacy profiles for populations not included in this study as well as to assess its long-term effects. Current contraindications of the mRNA-1273 vaccine include any persons with known allergy to polyethylene glycol (PEG), another mRNA vaccine component or polysorbate. 15

AstraZeneca

The Oxford and AstraZeneca ChAdOx1 COVID-19 vaccine uses a chimpanzee adenovirus vector to deliver the genetic sequence of a full-length spike protein of SARS-CoV-2 into host cells. 16 The storage for the ChAdOx1 vaccine is favorable, as it may be refrigerated at 2°C–8°C for 6 months. Pooled analysis of four ongoing clinical studies was used to assess efficacy, safety, and immunogenicity of the ChAdOx1 vaccine: COV001 (phase 1/2), COV002 (phase 2/3), COV003 (phase 3), and COV005 (phase 1/2). 17 Across the four studies participants over 18 were randomized to receive either the vaccine or a control (meningococcal group A, C, W, or saline). ChAdOx1 vaccine recipients received two standard doses (SDs) of the vaccine (SD/SD cohort) except for a subset in the COV002 trial who received a half lower dose (LD) followed by an SD (LD/SD cohort). 17 In the four studies, there was a total 23,848 participants, all of whom were used for gathering safety data; only 11,636 participants from the COV002 and COV003 trials were included in the primary efficacy analysis. 17 Of the 11,636 participants in the efficacy analysis, 2741 were in the LD/SD cohort, 88% were between 18 and 55 years old, and comorbidities present included cardiovascular disease, respiratory disease, and diabetes. 17 The results show that in the intended dosing regimen (SD/SD cohort), the VE was 62.1% (95% CI, 41.0–75.7) ⩾14 days after the second injection for symptomatic COVID-19 (27 cases vs 71 cases respectively). 17 In the group that received an LD (LD/SD cohort), the VE was 90.0% (95% CI, 67.4–97.0; 3 cases vs 30 cases, respectively) while across the two dosing regimens the overall efficacy was 70.4% (95.8% CI, 54.8–80.6;30 cases vs 101 cases, respectively). 17 The higher efficacy observed in the LD/SD cohort can be attributed to this group having a longer dosing interval between the two doses in comparison to the SD/SD cohort. Regarding safety, most of the adverse events were mild-moderate with the most frequently reported being injection site pain/tenderness, fatigue, headache, malaise, and myalgia. 18 About 175 serious adverse events were noted, only three of which were possibly linked to intervention: transverse myelitis 14 days after second dose, haemolytic anemia in a control recipient and fever >40°C in a participant still masked to group allocation. One contraindication for use of the vaccine is hypersensitivity to any of its components. In very rare cases, AstraZeneca has been associated internationally with venous thromboembolic events with thrombocytopenia with current estimates being 10–15 cases per million vaccinated patients. 19 This adverse event has been termed thrombosis with thrombocytopenia syndrome (TTS). In summary, these studies demonstrate that the AstraZeneca ChAdOx1 vaccine has a good efficacy and side-effect profile. Limitations include that less than 4% of participants were >70, no one over 55 got the mixed-dose regimen (LD/SD cohort), and those with comorbidities were a minority. Additional investigations are required to analyze long-term effects and assess efficacy and safety in populations not included or underrepresented.

Janssen COVID-19 vaccine

The Janssen (Johnson & Johnson) COVID-19 vaccine, developed by Janssen Pharmaceutical in Netherlands. It is a single-dose intramuscular (IM) vaccine that contains a recombinant, replication incompetent human adenovirus (Ad26) vector encoding the spike protein of SARS-CoV-2 in the stabilized conformation. 20 It can be stored between 2°C and 8°C for up to 6 hours or at room temperature for a duration of 2 hours. The ENSEMBLE Phase-3 trial (n = 43,783) is a randomized, double-blind, placebo-controlled study which included participants ⩾18 years. Efficacy assessment was performed at day 14 and 28. The primary outcome only included moderate and severe (hospitalization and death) infection. Overall, the VE in the moderate to severe cohort was 66.9% (95% CI: 59.0–73.4) at 14 days and 66.1% (95% CI: 55.0–74.8) at 28 days. 20 In the severe cohort, the VE was 76.7% (95% CI: 54.6–89.1) and 85.4% (95% CI: 54.2–96.9) at day 14 and 28 days, respectively. 20 At the time of the study, 96.4% of the strains in the United States, 96.4% were identified as the Wuhan-H1 variant D614G. The VE in the United States for the moderate to severe cohort was 74.4% (95% CI: 65.0–81.6) and 72.0% (95% CI: 58.2–81.7) at 14 days and 28 days, respectively. 20 In the US severe cohort, the VE was 78.0% (95% CI: 33.1–94.6) and 85.9% (95% CI: −9.4 to 99.7) at day 14 and 28 days, respectively. 20 Alternatively, 94.5% of the strains in South Africa were identified as beta variant. The VE in South Africa for the moderate to severe cohort was 52.0% (95% CI: 30.3–67.4) and 64.0% (95% CI: 41.2–78.7) at 14 days and 28 days, respectively. 20 In the South African severe cohort, the VE was 73.1% (95% CI: 40.0–89.4) and 81.7% (95% CI: 46.2–95.4) at day 14 and 28 days, respectively. 20 In Brazil, 69.4% of the strains were identified as P.2 lineage variant and 30.6% were identified as Wuhan-H1 variant D614G. The VE in Brazil for the moderate to severe cohort was 66.2% (95% CI: 51.0–77.1) and 68.1% (95% CI: 48.8–80.7) at 14 days and 28 days, respectively. 20 In the Brazilian severe cohort, the VE was 81.9% (95% CI: 17.0–98.1) and 87.6% (95% CI: 7.8–99.7) at day 14 and 28 days, respectively. 20 The most common localized solitary adverse reaction was the injection site pain (48.6%). Conversely, the most common systemic adverse reactions included headache, fatigue, myalgia, and nausea. 20 In the post authorization phase, adverse reaction included anaphylaxis, thrombosis with thrombocytopenia, Guillain Barré syndrome, and capillary leak syndrome. 20 Overall, the data demonstrate that the Janssen vaccine has a good efficacy and side-effect profile.

Sputnik V or Gam-COVID-Vac, developed by the Gamaleya Institute, is a recombinant human adenovirus-based vaccine that uses two different vectors (rAd26 and rAd5) to carry the gene encoding for the spike protein of SARS-CoV-2. Only one vector (rAd26) is given at dose 1 and the other (rAd5) at dose 2. This strategy prevents immunity against the vector. It can be stored as either a liquid at −18°C, or it can be freeze-dried and stored at 2°C to 8°C. 21 Regarding the safety and efficacy of the vaccine, both were evaluated in a randomized, double-blind phase-3 trial performed in Moscow, Russia. In the trial, a total of 21,977 participants aged 18 years or older were randomized in a 3:1 ratio to the vaccine or placebo groups. Two doses of the vaccine or placebo were given 21 days apart to the respective groups. 21 The mean age of the participants was 45.3 years, and the majority of participants were Caucasian (98.5%). 21 From 21 days after the first dose of the vaccine, efficacy against symptomatic COVID-19 illness was 91.6% (95% CI, 85.6–95.2%) with 16 confirmed cases of COVID-19 in the vaccine group and 62 confirmed in the placebo group. 21 There were also 20 cases of moderate to severe COVID-19 infection confirmed in the placebo group at least 21 days after the first dose and 0 in the vaccine group, indicating a VE of 100% against moderate to severe infection. 21 The most common adverse effects in both groups were flu-like illness, injection site reactions, headaches, and asthenia, with the majority being grade 1 (94.0%). 21 Serious adverse events were also reported in both the vaccine group and placebo group, but they were deemed not to be associated with the vaccination. Further investigations are still needed to determine the duration of protection of the vaccine and to determine the safety and efficacy of the vaccine in populations not included in the study (e.g. children, adolescents, and pregnant and lactating women).

CoronaVac is an inactivated vaccine developed by SinoVac Biotech containing inactivated SARS-CoV-2. 22 The vaccine can be stored at 2°C to 8°C for up to 3 years making it an attractive option for development. Two phase-1/2 clinical trials assessed the safety, tolerability, and immunogenicity of the CoronaVac vaccine. 22 , 23 The first study (18–59 years old included only) placed 744 participants in either a vaccine or placebo group where they were further divided based on vaccination schedule and dosage (3 and 6 μg). In the second study (⩾60 years old included only), 422 participants were randomized to receive two doses of CoronaVac or placebo 28 days apart and then further divided based on dosage amount only (3 and 6 μg for phase 1; 1.5, 3, and 6 μg for phase 2). Safety results from both trials show a favorable side-effect profile with most symptoms being transient and of mild severity. The most common adverse effect was injection site pain; others included fatigue and fever. In the 18–59 years old study, one serious adverse event of acute hypersensitivity was possibly related to vaccination. 22 No serious adverse events were associated with the vaccine or placebo in the ⩾60-year-old study. Between the dosage amounts in both studies, the tolerability was consistent and the immunogenicity was also similar for the 3 and 6 μg doses (less in 1.5 μg). 23 Multiple phase-3 trials have also taken place to determine the effectiveness of CoronaVac in countries, such as Brazil, Indonesia, and Turkey. In the Brazil trial, 252 cases of COVID-19 were recorded from roughly 9200 health care workers, with 167 in the placebo group and 85 in the vaccine group. 24 The reported efficacy of the vaccine in preventing mild and severe COVID-19 infection was 50.4%. In comparison, the Turkey trial reported that the vaccine was 83.5% effective at preventing symptomatic infection based on 29 COVID-19 cases among 1,322 volunteers while results from the Indonesia trial found that the vaccine was 65.3% effective at preventing symptomatic infection based on 25 COVID-19 cases among 1,600 people. 24 Some reasons for the lower efficacy of CoronaVac in the Brazil trial may include increased likelihood of exposure to the virus since participants were healthcare workers, and insufficient time for participants to reach peak immunity since the doses were administered only 2 weeks apart. 24 The phase-3 SinoVac study in Chile showed the VE 14 days post second dose to prevent symptomatic COVID-19 (67%, 95% CI: 65–69%), hospital admission (85%, 95% CI: 83–87%), intensive care unit (ICU) admission (89%, 95%CI: 84–92%) and death (80%, 95%CI: 73–86%). 25 The Phase-3 SinoVac trial in Brazil showed an overall VE against symptomatic COVID-19 (50.7%, 95% CI: 35.9–62%), moderate cases requiring hospitalization (83.7%, 95% CI: 58–93.7%), and severe cases requiring hospitalization (100%, 95%CI: 56.4–100%). 26 As with any vaccine, a contraindication for CoronaVac is anaphylaxis to it or to one of its constituents.

Other prominent COVID-19 vaccines

Due to the disease burden of SARS-CoV-2, the development and manufacturing of COVID-19 vaccines has been occurring at a remarkable pace which has not been seen before. There are many emerging vaccines with different mechanisms of actions that will be briefly explored. Bharat Biotech, an Indian company, has designed the inactivated COVID-19 vaccine Covaxin (BBV152). Once inside the body, the inactivated viruses can initiate an immune response through the interaction of surface proteins with APCs. Phase-1/2 trials showed no serious side effects and phase-3 trials are currently underway. 27 The state-owned Chinese company Sinopharm has also made an inactivated COVID-19 vaccine called BBIBP-CorV. The Sinopharm phase-3 trial showed that the VE in symptomatic cases for the WIV04 strain-based vaccine (72.8, 95% CI: 58.1–82.4%) and HB02 strain-based vaccine (78.1 95% CI: 64.8–86.3%). 28 , 29 It is approved in Bahrain, U.A.E, and China. NVX-CoV2373 is another promising vaccine produced by Novavax. It is a protein subunit vaccine made by assembling SARS-CoV-2 spike proteins into nanoparticles. A phase-3 trial in the United Kingdom displayed an efficacy rate of 89.3%; however, a phase-2 trial in South Africa had an efficacy just under 50%. 28 This discrepancy is thought to arise because of a new variant in South Africa. Other emerging vaccines include CoVLP produced by Medicago which uses the plant N. benthamiana to create virus-like particles that mimic SARS-CoV-2, CVnCoV produced by CureVac which is an mRNA vaccine, Convidecia produced by CanSino Biologics which is adenovirus based (Ad5), Ad26.COV2.S produced by Johnson & Johnson which is also adenovirus based (Ad26), and ZF2001 created by Anhui Zhifei Longcom which is a protein subunit vaccine. Even though highly effective, COVID-19 vaccines are already in use, it is still important to have a range of vaccines such as those listed above to bring the pandemic under control. Having a diverse profile ensures that vaccines will work for individuals from all ethnic backgrounds and with various underlying health conditions. 30 Getting the virus under control will also require doses for a large proportion of the world. To meet this requirement as soon as possible, having multiple vaccines will help in maximizing the volume of doses that can be produced. In addition, there are many technical issues such as cold storage and transportation, cost, and dosing of certain vaccines that arise when trying to vaccinate remote populations. For example, both the Pfizer-BioNTech and Moderna vaccines are expensive and transported at temperatures of −70°C and −20°C making it difficult to access many locations all at once. Since most vaccines require two doses spaced a few weeks apart, it can be challenging for individuals without regular access to healthcare as well. 30 Such considerations highlight the importance of having a range of single-dose vaccines and vaccines without the need for cold storage. A summary of efficacy, prominent side effects and storage recommendations for all the notable COVID-19 vaccines are shown in Table 1 .

Summary of vaccine efficacy, dosing strategy, and side-effects of different COVID-19 vaccines.

CI, confidence interval; COVID-19, coronavirus disease 2019; IM, intramuscular.

Post-vaccination contagion

With the endurance of the COVID-19 vaccine still being heavily researched, a chief concern is the sustainability of the vaccine-mediated immune response. This is important in the consideration of whether vaccinated individuals could still contract, transmit, or be carriers of SARS-CoV-2 virus. Vaccinated individuals currently may not understand the rationale behind why social restriction rules still apply to them. Most COVID-19 mRNA vaccines require at least 3 weeks to mount an immunological response and create the required antibodies and proliferate accessory cells of the adaptive immune system of the appropriate recognition repertoire. 50 This may be particularly relevant in the context of travel, as the World Health Organization (WHO) states that a proof of vaccination should not exempt international travelers from complying with social restrictions and risk-reduction measures. 51

Contraindications for COVID-19 vaccines

All vaccines are contraindicated in cases of documented hypersensitivity to the active substance or any of the excipients. There are a set of general guidelines relative to patients which must be adhered to until further information is provided; predominantly regarding groups such as pregnant or lactating women and immunodeficient patients. The Centers for Disease Control and Prevention (CDC) considers absolute contraindications to patients who have had severe anaphylactic reactions to a previous dose of an mRNA COVID-19 vaccine or PEG, a component of the vaccine. Moreover, immediate allergic reactions of any severity to polysorbate are also a significant contraindication. Importantly, there are many precautions which are not classified as contraindications but must be considered, such as patients who have had allergic reactions to any vaccine or injectable therapy. In the cases of patients with a precaution to the vaccine, they should be counseled on the benefits and risks, but are not contraindicated from vaccination. 15 In the instance of patients with autoimmune diseases, there is currently insubstantial data regarding the efficacy of the vaccine; however, current guidelines suggest that individuals with autoimmune conditions may take the vaccine if they do not have any absolute contraindications. In the case of patients with HIV, limited data from COVID-19 mRNA vaccination trials suggest that they can receive the vaccine barring any contraindications.

COVID-19 vaccines and pregnancy

Prior to discussing the relationship between the current vaccines for COVID-19 and pregnancy, it is crucial to gain an insight of the relationship between pregnancy and COVID-19 itself. Adhikari et al. showed that there was no difference in the frequency of Caesarean section, pre-eclampsia, preterm births, and abnormal fetal cardiotocography in pregnant women with and without SARS-CoV-2 infection. In addition, examination of the placenta revealed were no abnormalities, which were initially suspected due to the cross-matching between the SARS-CoV-2 spike protein and the placental synctyin-1 protein. 52 Similarly, there was no association found between COVID-19 and first-trimester spontaneous abortions. 53 A systematic review and meta-analysis revealed that COVID-19 leads to higher preterm deliveries (odds ratio (OR): 3.01, 95% CI: 1.16–7.85) and an increase in the ICU admission rates (OR: 71.63, 95% CI: 9.81–523.06) in pregnant women. 54

Pregnancy remained an exclusion criterion for all the COVID-19 vaccine trial; therefore, the efficacy of the COVID-19 vaccines in pregnant women is unavailable. However, given the effectiveness of the influenza vaccines elucidated in a meta-analysis conducted by Quach et al ., it can be hypothesized that the effects of pregnancy on the vaccine would be minimal, but more data would be needed for confirmation. 55 Pfizer’s animal studies revealed antibodies in the maternal rats, fetus, and offspring, in addition to no effects on fertility pregnancy or fetal development. 56 A similar study was conducted with the Moderna vaccine which led the US FDA to conclude that the vaccine did not have any adverse effects on female reproduction, fetal development, or postnatal development. 34 Furthermore, the Oxford-AstraZeneca vaccine animal studies are still pending. However, as a precaution, the National Immunization Advisory Committee (NIAC) has recommended for the two-dose schedule to not commence before 14 weeks of gestation and to be completed by week 33 of gestation. This precaution reduces any potential associations with miscarriage or pre-term birth. 57

Despite the exclusion of pregnancy in the preliminary stages of the trials, 23 Pfizer, 13 Moderna, and 21 AstraZeneca subjects became pregnant after enrolment into the trial. Among this cohort, there was one miscarriage part of the Pfizer control group, no miscarriages part of the Pfizer vaccine group, one miscarriage part of the Moderna control group, no miscarriages part of the Moderna vaccine group, three miscarriages part of the AstraZeneca control group, and two miscarriages part of the AstraZeneca vaccine group. While these preliminary numbers support the current guidelines regarding the vaccines being safe in pregnancy, it is crucial to be aware of the ongoing studies as new data emerges.

The CDC v-safe COVID-19 Pregnancy Study explored the effect of mRNA vaccine (Pfizer-BioNTech or Moderna) on the pregnancy. The pregnancy loss within those with a completed pregnancy included a spontaneous abortion (<20 weeks) rate of 12.6% (104 out of 827) and stillbirth (⩾20 weeks) incidence of 0.1% (1 out of 725). 58 The neonatal outcomes within the live birth infant cohort showed preterm birth (<37 weeks) incidence at 9.4% (60 out of 636), small for gestational age incidence of 3.2% (23 out of 724), and congenital anomalies were seen in 2.2% (16 out of 724). 58 No neonatal deaths were observed in this study.

Vaccine dosing strategies

Limited vaccine resources have caused some governments to extend the date of the second dose beyond the recommended manufacturer date. On December 30, NHS England had made the decision to prioritize the administration of the first doses, and to extend the second doses of the vaccine to the end of 12 weeks, rather than the recommended 3–4 weeks as shown in the clinical phase-3 trial. Pfizer-BioNTech at the time had no data to support this decision, and thus stated that the safety and efficacy of the vaccine had not been evaluated on different dosing schedules, and importantly, the second dose should not be administered later than 42 days. 59

Newly accrued evidence might warrant changes in the landscape of this vaccination program. Estimation of the effectiveness of the Pfizer-BioNTech after a single dose from the primary data from Israeli population (n = 500,000) showed that from day 0 to day 8 post–vaccination, the likelihood of contracting COVID-19 infection doubled. 60 This result may appear counterintuitive, but it takes 3 weeks for the vaccine to instill efficacy during which this real-world population could have not maintained the stringent public health measures which lead to the increased incidence in COVID-19 in this time-period. Then from day 8 to day 21 the incidence of COVID-19 declined and at day 21 the vaccine effectiveness was documented at 91%. 60 This efficacy was seen to stabilize at 90% for the duration of the study (9 weeks), and the authors of this study extrapolate this stability up to 6 months. 60 This concludes that the single dose of Pfizer-BioNTech is highly protective from day 21 onwards and supports the NHS England’s vaccination policy for extending gaps between the doses. The data from the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) trial in the Scottish population revealed that a single dose of Pfizer (n = 650,000) and Oxford-AstraZeneca (n = 490,000) vaccines resulted in a decline in hospitalization at 4 weeks by 84% and 94%, respectively. 61

However, the trials for the Oxford-AstraZeneca vaccine included varied spacing schedules between doses. The findings from these trials displayed that a greater space between the first and second dose provided a superior immune response. This is supported by a combined trial between a UK and Brazil study, which demonstrated a higher VE 14 days after a second dose in patients who had greater than 6 weeks between their first and second dose than patients who had less than 6 weeks by 53.4%. 17 , 62

It was also proposed that to meet the supply shortage that vaccine dose can be halved. Half-dose of Moderna vaccine (50ug) was in a phase-IIa trial. Immune response in the half-dose group compared to those that received a full dose were the same. Therefore, this dosing strategy is supported from an immunogenicity perspective. It is reasonable to infer that the immunogenicity would translate to immune protection, but unfortunately no clinical trial has validated the immune protection for this dosing strategy.

SARS-CoV-2 genome mutations

Mutations are changes in the SARS-CoV-2 viral genome that occur naturally over time. These mutations from the parent SARS-CoV-2 virus create variants. A certain amount of genetic variation is expected as SARS-CoV-2 replicates as such it is important to monitor circulating viral variants to collate key mutations. Fortunately, coronaviruses have a slower rate of mutation of 1 to 2 nucleotides per month. 63 These definitions become complicated when environmental factors apply selective pressures on these variants that enable them to express distinct phenotypes that may facilitate viral fitness. This ability of a variant to express distinct phenotypes is termed as a strain. A compilation of beneficial lineage defining mutations can create a strain that has a higher transmission rate or induce severe disease. This raises the question: will the current vaccines or convalescent immunity from a non-variant SARS-CoV-2 infection provide adequate immunological protection against these new variants?

Coronaviruses mutate spontaneously via antigenic drift. This process typically utilizes the virus-specific transcription regulatory network (TRN) sequence to initiate the change, resulting in a new mRNA sequence virus being formed. Homologous and genetic recombination allows for the virus to gain more ecological features and has been speculated to be the reason why SARS-CoV-2 was zoonotic in origin. 64 A variant of the original SARS-CoV-2 virus with a D614G substitution in the spike protein encoding gene emerged in early February 2020, and by June 2020, D614G became the dominant form of the virus circulating globally. 65 Studies have shown that the D614G mutation resulted in increased infectivity and transmissibility. 66 Since then, there have been many viral lineages to note, most notable VOC include the B.1.1.7/20I/501.Y.V1 variant that was first detected in the United Kingdom in October 2020, the B.1.351/20 H/501Y.V2 variant that was detected in South Africa in December 2020, and the Lineage P.1. (B.1.1.28.1) variant that was detected in Tokyo in January 2021 but is believed to have originated from Brazil.

Currently, there exists two open-source real-time software tools to analyze and assign nomenclature of genetic variations in the SARS-CoV-2 virus: Nextstrain and PANGOLIN. 64 , 67 Both refer to the GISAID (Global Initiative on Sharing All Influenza Data) genomic database but have slight differences with regards to their nomenclature to describe various lineages of the virus. The COVID-19 Genomics UK Consortium has also developed CoV-GLUE, an open-source browser application that allows for easy referral of all sequenced SARS-CoV-2 genetic replacements, insertions, and deletions. 68 Therefore, sequencing every local infection will yield a repository to track the development of new mutations and variants.

Notable mutation drivers in the SARS-CoV-2 genome

Before diving deeper into these variants, it is important to understand the physical alteration in the S-protein at a molecular level and the perceived functional advantages that the SARS-CoV-2 gains. Table 2 highlights some of the notable S-protein mutations as they evolve amid the pandemic.

Summary of the physical and functional alterations of S-protein due to notable amino acid substitutions.

RBD, receptor-binding domain; VOC, variants of concern.

Notable emerging VOC

Newly emerged variants of SARS-CoV-2 have now become VOC which can be attributed to their new ability of increased transmission and infectivity. Therefore, it is important to collate the data on the mutations they acquired, the extend of spread, and the efficacy of different vaccines to create a repository for further analysis ( Table 3 ).

Summary of data on features, acquired cluster of S-protein mutations, and vaccine efficacy studies for the major COVID-19 variants of concern.

CI, confidence interval; COVID-19, coronavirus disease 2019; VOC, variants of concern.

There are more variants emerging as the pandemic progresses, but it is important to note that there is still a myriad of available vaccines in our armamentarium that are adequately efficacious in the performed neutralization assays as well as the real-world data. Furthermore, while vaccines induce the antibody-dependent immunity, they can also stimulate other components of the adaptative immune system such as the Memory B-cells, CD8+ Tc cells, and CD4+ Th cells to mount their own response against the viral variants. This can compensate for the reduction in neutralization rate by the vaccine induced antibodies. Interestingly, the adaptative immune system can proliferate libraries of memory B-cells with mutated antibody repertoires that can predict viral variants. Therefore, it is prudent to commence vaccinations in accordance with the local public health bodies. This combined with the continued implementation of public health measures until target level of herd immunity is acquired can lead toward mitigating the prevalence and incidence of COVID-19 variants.

This review highlighted the current available vaccines and candidates being rolled out amid the ongoing prevention measures and summarized the documented findings with regards to their efficacies, side-effects, and storage requirements. An overview of the physiology of immunogenic responses against the disease provided by the more prominent vaccines were discussed, alongside questions regarding the implementation of vaccines; heterologous prime-boosting, vaccine contraindications, dosing strategies, side effects, and the presence of SARS-CoV-2 mutations and variants.

There are still many unanswered questions that need to be addressed with regards to antibodies produced in individuals including their impact on the clinical course and severity of the disease, how long will they remain in the body to protect from the disease, and if what we have is enough to deal with newly emerging variants. Studies on these topics are rapidly being conducted and published on a global scale, and scientific communities are working on the clock to produce as much information to bring us a better understanding on how to deal with this disease.

For this global pandemic to end, it is imperative that people are vaccinated as quickly as possible until herd immunity can be achieved. One aspect of achieving this, in the face of vaccine hesitancy, is to address the lack of community understanding on how vaccines work, the risks, and the factors that keep this area of research volatile and distribution policies ever-changing. In addition, it is important to remain cautious about the information being released and to trust the accredited sources and experts, rather than the aberrant rumors being spread through social media. Nonetheless, the COVID-19 vaccines have shown to be highly promising and we recommend for everyone that is eligible to take the vaccine at the correct dosing interval when they are given the chance as this would potentiate a positive trend toward pandemic resolution.

Authors’ contributions: CY, AA, Amogh P, Akul P, AP performed acquisition and curation of the data; CY, AA, Amogh P, Akul P, AP, YYL and PK analyzed the data, performed interpretation of the data, and wrote of the original draft; YYL and PK performed the critical revision; All authors have read and approved the final manuscript.

Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Contributor Information

Charles Yap, School of Medicine, National University of Ireland, Galway, Ireland.

Abulhassan Ali, School of Medicine, National University of Ireland, Galway, Ireland.

Amogh Prabhakar, School of Medicine, National University of Ireland, Galway, Ireland.

Akul Prabhakar, School of Medicine, National University of Ireland, Galway, Ireland.

Aman Pal, School of Medicine, National University of Ireland, Galway, Ireland.

Ying Yi Lim, School of Medicine, National University of Ireland, Galway, Ireland.

Pramath Kakodkar, School of Medicine, National University of Ireland, Galway, University Road, Galway H91 TK33, Ireland.

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Thursday, May 30, 2024

Novel vaccine concept generates immune responses that could produce multiple types of HIV broadly neutralizing antibodies

NIH-funded animal model results will inform vaccine development in humans.

Using a combination of cutting-edge immunologic technologies, researchers have successfully stimulated animals’ immune systems to induce rare precursor B cells of a class of HIV broadly neutralizing antibodies (bNAbs). The findings, published today in Nature Immunology , are an encouraging, incremental step in developing a preventive HIV vaccine.   

HIV is genetically diverse making the virus difficult to target with a vaccine, but bNAbs may overcome that hurdle because they bind to parts of the virus that remain constant even when it mutates. Germline targeting is an immune system-stimulating approach that guides naïve (precursor) B cells to develop into mature B cells that can produce bNAbs. A class of bNAbs called 10E8 is a priority for HIV vaccine development because it neutralizes a particularly broad range of HIV variants. The 10E8 bNAb binds to a conserved region of the glycoprotein gp41 on HIV’s surface involved in its entry into human immune cells. Designing an immunogen—a molecule used in a vaccine that elicits a specific immune system response—to stimulate production of 10E8 bNAbs has been challenging because that key region of gp41 is hidden in a recessed crevice on HIV’s surface. Prior vaccine immunogens have not generated bNAbs with the physical structure to reach and bind to gp41.

To address this challenge, the researchers engineered immunogens on nanoparticles that mimic the appearance of a specific part of gp41. They vaccinated rhesus macaque monkeys and mice with those immunogens and elicited specific responses from the 10E8 B cell precursors and induced antibodies that showed signs of maturing into bNAbs that could reach the hidden gp41 region. They observed similar responses when they used mRNA-encoded nanoparticles in mice. The researchers also found that the same immunogens produced B cells that could mature to produce an additional type of gp41-directed bNAb called LN01. Finally, their laboratory analysis of human blood samples found that 10E8-class bNAb precursors occurred naturally in people without HIV, and that their immunogens bound to and isolated naïve human B cells with 10E8-like features. Together these observations suggest that the promising immunization data from mice and macaques has the potential for translation to humans.

The research was conducted by the Scripps Consortium for HIV/AIDS Vaccine Development, one of two consortia supported by the National Institutes of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID). The research also was supported by collaborating partners including the Bill & Melinda Gates Foundation and other NIH Institutes and Offices. According to the authors, these findings support the development of the immunogens as the first part of a multi-step vaccine regimen for humans. Their work further supports research in developing a germline-targeting strategy for priming the immune system to elicit a bNAb called VRC01. This bNAb was discovered by NIAID researchers almost 15 years ago. The goal of this line of research is to develop an HIV vaccine that generates multiple classes of bNAbs to prevent HIV.

Schiffner et al . Vaccination induces broadly neutralizing antibody precursors to HIV gp41. Nature Immunology DOI: 10.1038/s41590-024-01833-w (2024).

Angela Malaspina, program officer in NIAID’s Division of AIDS, is available to discuss this study.

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website .

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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