The COVID-19 pandemic, initially driven by the ancestral SARS-CoV-2 strain, has evolved significantly due to the emergence of Variants of Concern (VOCs). These VOCs, such as Alpha, Beta, Gamma, Delta, and Omicron, exhibit mutations within the viral spike protein, which is the primary target of neutralizing antibodies (nAbs) induced by vaccines and natural infection. These mutations can lead to reduced vaccine efficacy (VE) and increased transmissibility. Early COVID-19 vaccines were developed using the spike protein sequence from the ancestral strain, making them less effective against newer variants. This research focuses on addressing the limitations of first-generation COVID-19 vaccines by developing an updated vaccine that effectively neutralizes a broader range of SARS-CoV-2 variants, including the highly mutated Omicron variant. The study uses a hamster model to assess the efficacy of both a first-generation vaccine and an updated version against various VOCs, including evaluating the updated vaccine's ability to prevent transmission. This is crucial for controlling the pandemic, given the continuous emergence of new variants and their impact on vaccine effectiveness and disease severity. The study aims to understand how modifications to the vaccine antigen can improve protection against a wider range of VOCs and ultimately contribute to the development of more effective and durable vaccines.

Existing literature extensively documents the emergence of SARS-CoV-2 VOCs and their impact on vaccine efficacy. Studies have shown that the mutations in the spike protein of these VOCs, such as E484K, K417N, and others, contribute to immune escape. Early reports indicated that some vaccines, including those using mRNA technology or viral vector platforms, had reduced neutralizing capacity against variants like Beta. The Omicron variant, in particular, caused significant concern due to its numerous mutations and its ability to escape neutralization by many existing antibodies and vaccines. This extensive body of work highlights the urgent need for updated vaccine strategies that can overcome immune evasion and provide broad protection against emerging variants. The high transmissibility of some VOCs further underscores the importance of a vaccine that not only protects individuals but also prevents transmission, thus contributing to herd immunity. This review of literature provided a critical foundation for the study, guiding the development and evaluation of the updated vaccine candidate.

The study used Syrian hamsters as a model organism due to their susceptibility to SARS-CoV-2 infection and their ability to replicate the key features of human infection. Two YF17D-vectored vaccine candidates were compared: a first-generation vaccine (YF-SO) with a prototypic spike antigen and an updated vaccine (YF-SO*) with an evolved spike antigen incorporating mutations found in various VOCs and modifications for enhanced stability. Hamsters were vaccinated with either YF-SO or YF-SO*, followed by intranasal challenge with different SARS-CoV-2 variants, including Alpha, Beta, Gamma, Delta, and Omicron. Viral loads in lung tissues and nasal washes were quantified using qPCR and virus titration to assess viral replication. Neutralizing antibody (nAb) titers against various spike variants were measured using VSV-pseudotyped viruses. The study employed a rigorous statistical analysis to determine correlations between nAb levels and protection, evaluating vaccine efficacy (VE) based on viral load reduction. A transmission study using the Delta variant was also conducted to determine if vaccination prevented transmission from infected to unvaccinated hamsters. The methods included detailed descriptions of the viruses used, including their isolation and characterization, the animal handling and experimental infections, the design and construction of the vaccine candidates, the methods used to quantify nAbs, antigenic cartography to visualize the relationship between different spike variants, the vaccination protocols including varying dose schedules, the challenge methods and timing, and statistical analysis. This thorough methodological approach ensures the robustness and reliability of the study's findings.

The first-generation vaccine (YF-SO) showed good protection against ancestral and Alpha variants but significantly reduced efficacy against Beta. The updated vaccine (YF-SO*) showed significantly improved neutralizing antibody responses and protective immunity against all tested VOCs, including Beta, Gamma, Delta, and Omicron. Hamsters vaccinated with YF-SO* exhibited substantially lower viral loads compared to controls after challenge with high doses of Beta, Delta, and Omicron. Importantly, viral replication was reduced to undetectable levels in most YF-SO*-vaccinated hamsters across all variants. The analysis of correlates of protection showed that the required nAb titers for protection were substantially higher for Beta compared to the ancestral virus and Alpha variant, illustrating the immune evasion potential of this variant. This highlights that the updated YF-SO* provided superior protection even under stringent challenge conditions using a high viral dose of VOC Beta. The study also demonstrated that YF-SO* vaccination prevented the transmission of the Delta variant from vaccinated to unvaccinated hamsters. The antigenic cartography revealed clear differences in the antigenic profiles between the different spike variants tested, with the YF-SO* vaccine generating a broader immune response. The improved neutralization of Omicron by YF-SO* serum compared to YF-SO serum further emphasized the importance of the updated vaccine design.

This study provides compelling evidence demonstrating the enhanced efficacy of an updated COVID-19 vaccine against a broad range of SARS-CoV-2 variants, including the challenging Omicron variant. The improved protection is largely attributed to the modifications in the spike protein antigen, targeting key mutations associated with immune escape. The results validate the crucial need for ongoing vaccine updates to maintain effective protection against emerging variants and prevent transmission. The hamster model successfully replicated key aspects of human infection and provided a rigorous assessment of vaccine efficacy. The findings have significant implications for pandemic control strategies, highlighting the importance of developing variant-proof vaccines to combat the evolving nature of the virus. The success of YF-SO* in preventing transmission suggests that it could contribute to reducing community spread and the evolution of new variants. Further research is needed to translate these findings into human clinical trials and to assess the long-term durability and efficacy of the updated vaccine.

This research demonstrates the critical need for updated COVID-19 vaccines to effectively combat emerging SARS-CoV-2 variants. The updated YF17D-vectored vaccine candidate (YF-SO*) showed superior efficacy and transmission-blocking capabilities compared to its first-generation counterpart. Future studies should focus on larger-scale animal trials and human clinical trials to validate these findings and assess the long-term immunogenicity and effectiveness of the updated vaccine. Further research is warranted to investigate the mechanisms underlying the improved neutralizing antibody response and the broader protection offered by YF-SO*. These findings underscore the importance of continuous vaccine development and adaptation to maintain effective protection against evolving SARS-CoV-2 variants and control the pandemic effectively.

The study was conducted using a hamster model, which may not perfectly reflect the complexity of human immune responses. While hamsters are a valuable model for SARS-CoV-2 infection, there might be species-specific differences in immune responses that could influence the generalizability of the results to humans. The study focused on a specific set of VOCs; emerging future variants may require further vaccine updates. The relatively small number of animals used in some experimental groups may limit the statistical power of some of the analyses. Future work should address these aspects to further strengthen the conclusions of this study.