Gabriela Benitez

Background: As the COVID-19 pandemic arose, quickly infected, and caused more than 7 million deaths, so did the race to create a vaccine.¹ As of November 2021, many vaccines such as BNT162b2 and mRNA-1273 had been distributed to millions and deemed effective against the circulating variants at that time.¹ As the pandemic progresses, so do the emerging variants of concern that are no longer protected against using the original spike protein-based mRNA vaccines.¹

Objective: In this review, we explore the surfacing methods of mRNA immunization to better defend against emerging COVID-19 VoC.¹

Search Methods: An online search in the PubMed database was conducted from 2019 to 2024 using the following keywords: COVID-19, mRNA vaccines, COVID-19 mRNA vaccines, Pfizer vaccine, Moderna vaccine, COVID-19 variants of concern.

Results: In October 2020-March 2021 researchers sought to test the Pfizer vaccine efficacy against the Alpha variant. The results confirmed about 90% neutralization efficacy, but they then determined less efficacy against the emerging Beta variant.² Later, researchers thought to investigate if increasing or delaying the time between vaccinations would further increase efficacy. Again, they found great neutralization abilities against the Alpha variant, with decreased efficacy against the Beta variant. Both these studies revealed the issue of emerging variants of concern and how they are able to avoid neutralization induced by existing vaccinations.³ This proved a significant problem prohibiting the cessation of the COVID-19 pandemic is the rapid mutation and replication rate of the COVID virus. The high mutation rate leads to multiple variants of concern with different mechanisms of actions that must be targeted by vaccines.⁵ It is also believed the spike protein is constantly evolving thus maintaining the infection within the patient. ⁵  Researchers aimed to defeat this by packaging the native mRNA with the alpha strand mRNA or the beta strand mRNA and then tested their neutralization ability against various strands in mice.⁴ Those mice injected with mRNA strands of the native and alpha variant spike proteins had greater immunity against the alpha variant than the beta variant.⁴ Those injected with native and beta variant mRNA strands provided greater immunity against the beta variant, but less against the delta variant.⁴ Thus, proving the need to explore mRNA vaccines that promote cell-mediated immunity as well as humoral immunity.⁵ Researchers then developed an mRNA-based T-cell inducing antigen targeting 3 different COVID proteome regions enriched in human HLA epitopes.⁵ The group of mice who were dually immunized had a significantly greater number of lymphocyte production. This study suggests that dual immunization activating humoral and cell-mediated immunity protects against emerging variants of concern better than humoral immunity alone.⁵

Conclusion: COVID-19 is a persistent and a constantly mutating virus that we have yet to conquer. According to the studies discussed today, it is clear vaccinations that promote mainly humoral immunity, although effective against native variants, are ineffective against quickly and continuously arising variants of concern.^3,4 Thus, stimulating T-cell-mediated immunity in combination with humoral immunity has proven to increase this efficacy the most against new VoC, although there remains the need to increase vaccine efficacy even further.⁵

Works Cited:

1. Thomas SJ, Moreira ED Jr, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months. N Engl J Med. 2021;385(19):1761-1773. doi:10.1056/NEJMoa2110345
2. Nasreen S, Chung H, He S, et al. Effectiveness of COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes with variants of concern in Ontario. Nat Microbiol. 2022;7(3):379-385. doi:10.1038/s41564-021-01053-0
3. Wang Z, Schmidt F, Weisblum Y, et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature. 2021;592(7855):616-622. doi:10.1038/s41586-021-03324-6
4. Hawman DW, Meade-White K, Archer J, et al. SARS-CoV2 variant-specific replicating RNA vaccines protect from disease following challenge with heterologous variants of concern. Elife. 2022;11:e75537. Published 2022 Feb 22. doi:10.7554/eLife.75537
5. Tai W, Feng S, Chai B, et al. An mRNA-based T-cell-inducing antigen strengthens COVID-19 vaccine against SARS-CoV-2 variants. Nat Commun. 2023;14(1):2962. Published 2023 May 23. doi:10.1038/s41467-023-38751-8