Pravin Sivagnanakumar

Background: Coronaviruses such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Middle East respiratory syndrome coronavirus (MERS-CoV), and HCoV-OC43 have been responsible for many epidemics in the past two decades.¹ Betacoronaviruses include SARS-CoV, MERS-CoV, and SARS-CoV-2 which cause severe respiratory syndrome as well as OC43 and HKU1 which cause mild upper-respiratory-tract infections.^2,3 SARS-CoV-2 has caused about 6.9 million deaths worldwide.⁴ The development of a betacoronavirus vaccine depends upon our understanding of pre-existing cross-reactive immunity between SARS-CoV-2 and other betacoronaviruses.⁵

Objective: In this narrative review, we explored the viability of a betacoronavirus vaccine through the investigation of the cross-reactivity of betacorona viruses and the viability of targets for the vaccine.

Search Methods: An online search in the PubMed database was conducted from 2021 to 2024 using the following keywords: “coronavirus”, “SARS-CoV-2″, “OC43 Coronavirus”, and “spike proteins”.

Results: In developing a Betacoronavirus Vaccine, it is first important to establish the ability of memory T cells to maintain long-term viral immunity. In a study of UK patients recovered from COVID-19, blood samples were used to determine the T-cell response.⁶ CD4+ and CD8+ T-cell responses showed broad and robust memory for SARS-CoV-2.⁶  Now we need to establish that there is potential for cross-reactivity between different betacoronaviruses. SARS-CoV-2, MERS-CoV, HCoV-HKU1, HCoV-OC43, and SARS-CoV spike plasmids were used to determine the cross-reactivity of the serological samples from 22 patients infected with SARS-CoV-2. The results suggest that there is cross-reactivity between SARS-CoV-2 antibodies and the other four coronaviruses.¹ Next, we investigated if OC43 T-cells react with SARS-CoV-2 peptides. Prior exposure of OC43 was protective in mice against SARS-CoV-2 and at least partly dependent on CD4+ T cell and CD8+ T cell response.⁷ We then switch to determining the cross-reactivity of OC43 peptides with SARS-CoV-2 T cells.⁸ Spike protein S903-917 and S1085-1099 presented with cross-reactivity with CD4+ T cells from SARS-CoV-2.⁸ Know that we have established the cross-reactivity between betacoronaviruses, we can start to look at potential targets for betacoronavirus vaccines.⁵ Experiments elucidated that S2P6 had neutralizing abilities for betacoronavirus when targeting stem helix-specific human mAbs.⁵ The SARS-CoV-2 S protein has three major immunogenic domains: the N-terminal domain, the receptor-binding domain (RBD), and the subunit 2 domain (S2).⁹ These conserved epitopes across beta coronaviruses are protected by glycans.⁹ Therefore, deletion of glycosite leads to stronger antibody, CD4+, and CD8+ T cell responses against variants Alpha, Beta, Gamma, Delta, and Omicron.⁹ Lastly, in a similar study, deleting sugar coats in spike mRNA that shield these conserved epitopes elicit broadly protective immune response to Wuhan strain or Delta Strain.¹⁰

Conclusion: Overall, these findings provide important insights into the development of a vaccine against Betacoronaviruses like SARS-CoV-2. By understanding the cross-reactivity between different coronaviruses and identifying conserved epitopes, researchers can target these areas to generate vaccines that offer broad protection against multiple strains and variants.

Work Cited:

1. Hicks J, Klumpp-Thomas C, Kalish H, et al. Serologic Cross-Reactivity of SARS-CoV-2 with Endemic and Seasonal Betacoronaviruses. J Clin Immunol. 2021;41(5):906-913. doi:10.1007/s10875-021-00997-6
2. V’kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol. 2021;19(3):155-170. doi:10.1038/s41579-020-00468-6
3. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020;324(8):782-793. doi:10.1001/jama.2020.12839
4. Moneshwaran S, Macrin D, Kanagathara N. An unprecedented global challenge, emerging trends and innovations in the fight against COVID-19: A comprehensive review. Int J Biol Macromol. Published online April 3, 2024:131324. doi:10.1016/j.ijbiomac.2024.131324
5. Pinto D, Sauer MM, Czudnochowski N, et al. Broad betacoronavirus neutralization by a stem helix–specific human antibody. Science. 2021;373(6559):1109-1116. doi:10.1126/science.abj3321
6. Peng Y, Mentzer AJ, Liu G, et al. Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19. Nat Immunol. 2020;21(11):1336-1345. doi:10.1038/s41590-020-0782-6
7. dos Santos Alves RP, Timis J, Miller R, et al. Human coronavirus OC43-elicited CD4+ T cells protect against SARS-CoV-2 in HLA transgenic mice. Nat Commun. 2024;15(1):787. doi:10.1038/s41467-024-45043-2
8. Becerra-Artiles A, Nanaware PP, Muneeruddin K, et al. Immunopeptidome profiling of human coronavirus OC43-infected cells identifies CD4 T-cell epitopes specific to seasonal coronaviruses or cross-reactive with SARS-CoV-2. PLOS Pathog. 2023;19(7):e1011032. doi:10.1371/journal.ppat.1011032
9. Wu CY, Cheng CW, Kung CC, et al. Glycosite-deleted mRNA of SARS-CoV-2 spike protein as a broad-spectrum vaccine. Proc Natl Acad Sci. 2022;119(9):e2119995119. doi:10.1073/pnas.2119995119
10. Cheng CW, Wu CY, Wang SW, et al. Low-sugar universal mRNA vaccine against coronavirus variants with deletion of glycosites in the S2 or stem of SARS-CoV-2 spike messenger RNA (mRNA). Proc Natl Acad Sci. 2023;120(49):e2314392120. doi:10.1073/pnas.2314392120