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From Left: Dr Bae Ki Hyun, Professor Yang Yi Yan, Dr Zhang Li

Science

Despite recent progress in vaccine development, the ongoing challenge of SARS-CoV-2 variants poses a significant global health threat due to their increased severity and ease of transmission. In response, we have engineered mRNA vaccines encapsulated in tiny lipid nanoparticles to target various variants of the virus. Our study shows that administering these vaccines through three doses under the skin enhances protection against various SARS-CoV-2 variants, including Omicron B1.1.529 and BA.2, for up to 28 weeks in mice. Importantly, these vaccines demonstrate good safety profiles, offering promising prospects for combating the evolving landscape of COVID-19¹.

Societal Impact

According to the World Health Organization, coronavirus disease 2019 (COVID-19) has caused more than 770 million confirmed cases with over 7 million deaths globally. Although COVID-19 may have reached an endemic stage in most countries, SARS-CoV-2 virus continues to mutate and evolve into new variants that pose challenges to the existing immunity and vaccine efficacy. To tackle this challenge, a tremendous effort has been devoted to developing pan-SARS-CoV-2 or “variant-proof” vaccines, capable or providing broad protection against diverse SARS-CoV-2 variants.

Our research contributes to this global effort by offering insights into the development of mRNA vaccines encapsulated in lipid nanoparticles (mRNA-LNP vaccines) that confer robust and lasting cross-protection against both current and emerging SARS-CoV-2 variants. By advancing our understanding of vaccine design and efficacy, our study has the potential to inform the development of next-generation vaccines that can adapt to the evolving landscape of the pandemic. This has significant implications for public health by potentially reducing the burden of COVID-19 cases, hospitalizations, and deaths, and by contributing to the broader goal of controlling the spread of the virus globally.

Technical Summary

The emergence of SARS-CoV-2 variants with distinct mutations is posing challenges to vaccine efficacy. This has prompted global endeavors to enhance vaccine formulations. Lipid nanoparticles (LNPs) offer remarkable advantages such as flexibility in design, scalability and reproducibility, making them promising candidates for developing advanced mRNA vaccines against evolving SARS-CoV-2 variants. In this study, we evaluated the efficacy of LNP-encapsulated mRNA booster vaccines encoding the spike protein of SARS-CoV-2, targeting Delta and Omicron variants, as well as a precursor strain (YN2016C from bats), to induce enduring cross-protective neutralizing antibody responses.

These mRNA-LNP vaccines exhibit favorable physicochemical properties, including small size (< 100 nm), low polydispersity index (< 0.20), and high encapsulation efficiency (> 90%). Utilizing in vivo bioluminescence imaging, we demonstrated robust mRNA expression in lymph nodes and areas beneath the skin at the injection site following LNP administration. In a BALB/c mouse model, three doses of subcutaneous immunization with mRNA-LNP vaccines elicited significant cross-neutralization against Omicron B1.1.529 and BA.2 variants for up to 28 weeks, with favorable safety profiles observed across all constructs, including those targeting the YN2016C bat virus sequences. These findings underscore the potential of mRNA-LNP vaccines to induce durable cross-protective immunity against current and emerging SARS-CoV-2 variants, informing the design of future vaccine strategies.

Figure 1. Design of a cross-protective mRNA-LNP vaccine providing long-lasting protection against multiple SARS-CoV-2 variants.

References

1. K. H. Bae ^§, B. Shunmuganathan ^§, L. Zhang ^§, A. Lim, R. Gupta, Y. Wang, B. L. Chua, Y. Wang, Y. Gu, X. Qian, I. S. L. Tan, K. Purushotorman, P. A. MacAry*, K. P. White*, Y. Y. Yang*, Durable cross-protective neutralizing antibody responses elicited by lipid nanoparticle-formulated SARS-CoV-2 mRNA vaccines. npj Vaccines 9, 43 (2024).
(§ denotes equal contribution).