A Chimeric MRNA Vaccine of S-RBD with HA Conferring Broad Protection Against Influenza and COVID-19 Variants

Overview

Journal PLoS Pathog

Specialty Microbiology

Date 2024 Sep 20

PMID 39303003

Authors

Tianjiao Hao

Yulei Li

Peipei Liu

Xi Wang

Ke Xu

Wenwen Lei

Ying Li

Rong Zhang

Xiaoyan Li

Xin Zhao

Kun Xu

Xuancheng Lu

Yuhai Bi

Hao Song

Guizhen Wu

Baoli Zhu

George F Gao

Affiliations

Soon will be listed here.

Abstract

Influenza and coronavirus disease 2019 (COVID-19) represent two respiratory diseases that have significantly impacted global health, resulting in substantial disease burden and mortality. An optimal solution would be a combined vaccine capable of addressing both diseases, thereby obviating the need for multiple vaccinations. Previously, we conceived a chimeric protein subunit vaccine targeting both influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), utilizing the receptor binding domain of spike protein (S-RBD) and the stalk region of hemagglutinin protein (HA-stalk) components. By integrating the S-RBD from the SARS-CoV-2 Delta variant with the headless hemagglutinin (HA) from H1N1 influenza virus, we constructed stable trimeric structures that remain accessible to neutralizing antibodies. This vaccine has demonstrated its potential by conferring protection against a spectrum of strains in mouse models. In this study, we designed an mRNA vaccine candidate encoding the chimeric antigen. The resultant humoral and cellular immune responses were meticulously evaluated in mouse models. Furthermore, the protective efficacy of the vaccine was rigorously examined through challenges with either homologous or heterologous influenza viruses or SARS-CoV-2 strains. Our findings reveal that the mRNA vaccine exhibited robust immunogenicity, engendering high and sustained levels of neutralizing antibodies accompanied by robust and persistent cellular immunity. Notably, this vaccine effectively afforded complete protection to mice against H1N1 or heterosubtypic H5N8 subtypes, as well as the SARS-CoV-2 Delta and Omicron BA.2 variants. Additionally, our mRNA vaccine design can be easily adapted from Delta RBD to Omicron RBD antigens, providing protection against emerging variants. The development of two-in-one vaccine targeting both influenza and COVID-19, incorporating the mRNA platform, may provide a versatile approach to combating future pandemics.

References

Hu S, Wu C, Wu X, Ma X, Shu C, Chen Q . Classification of five SARS-CoV-2 serotypes based on RBD antigenicities. Sci Bull (Beijing). 2023; 68(23):3003-3012. DOI: 10.1016/j.scib.2023.09.048. View

Xu K, Dai L, Gao G . Humoral and cellular immunity and the safety of COVID-19 vaccines: a summary of data published by 21 May 2021. Int Immunol. 2021; 33(10):529-540. PMC: 8499872. DOI: 10.1093/intimm/dxab061. View

Shi R, Shan C, Duan X, Chen Z, Liu P, Song J . A human neutralizing antibody targets the receptor-binding site of SARS-CoV-2. Nature. 2020; 584(7819):120-124. DOI: 10.1038/s41586-020-2381-y. View

Dreyfus C, Laursen N, Kwaks T, Zuijdgeest D, Khayat R, Ekiert D . Highly conserved protective epitopes on influenza B viruses. Science. 2012; 337(6100):1343-8. PMC: 3538841. DOI: 10.1126/science.1222908. View

Chaturvedi S, Beutler N, Vasen G, Pablo M, Chen X, Calia G . A single-administration therapeutic interfering particle reduces SARS-CoV-2 viral shedding and pathogenesis in hamsters. Proc Natl Acad Sci U S A. 2022; 119(39):e2204624119. PMC: 9522362. DOI: 10.1073/pnas.2204624119. View

Tan A, Linster M, Tan C, Bert N, Chia W, Kunasegaran K . Early induction of functional SARS-CoV-2-specific T cells associates with rapid viral clearance and mild disease in COVID-19 patients. Cell Rep. 2021; 34(6):108728. PMC: 7826084. DOI: 10.1016/j.celrep.2021.108728. View

Shi R, Zeng J, Xu L, Wang F, Duan X, Wang Y . A combination vaccine against SARS-CoV-2 and H1N1 influenza based on receptor binding domain trimerized by six-helix bundle fusion core. EBioMedicine. 2022; 85:104297. PMC: 9530591. DOI: 10.1016/j.ebiom.2022.104297. View

Hillary V, Ceasar S . An update on COVID-19: SARS-CoV-2 variants, antiviral drugs, and vaccines. Heliyon. 2023; 9(3):e13952. PMC: 9946785. DOI: 10.1016/j.heliyon.2023.e13952. View

Tan H, Jegaskanda S, Juno J, Esterbauer R, Wong J, Kelly H . Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem. J Clin Invest. 2018; 129(2):850-862. PMC: 6355240. DOI: 10.1172/JCI123366. View

10.

Tan C, Zhu F, Chia W, Young B, Yeoh A, Althaus T . Distinctive serotypes of SARS-related coronaviruses defined by convalescent sera from unvaccinated individuals. Hlife. 2024; 1(1):26-34. PMC: 11238253. DOI: 10.1016/j.hlife.2023.07.002. View

11.

Flynn J, Weber T, Cejas P, Cox K, Touch S, Austin L . Characterization of humoral and cell-mediated immunity induced by mRNA vaccines expressing influenza hemagglutinin stem and nucleoprotein in mice and nonhuman primates. Vaccine. 2022; 40(32):4412-4423. DOI: 10.1016/j.vaccine.2022.03.063. View

12.

Yang R, Sun H, Gao F, Luo K, Huang Z, Tong Q . Human infection of avian influenza A H3N8 virus and the viral origins: a descriptive study. Lancet Microbe. 2022; 3(11):e824-e834. DOI: 10.1016/S2666-5247(22)00192-6. View

13.

McMahon M, ODell G, Tan J, Sarkozy A, Vadovics M, Carreno J . Assessment of a quadrivalent nucleoside-modified mRNA vaccine that protects against group 2 influenza viruses. Proc Natl Acad Sci U S A. 2022; 119(45):e2206333119. PMC: 9659346. DOI: 10.1073/pnas.2206333119. View

14.

Shiryaev V, Skomorohov M, Leonova M, Bormotov N, Serova O, Shishkina L . Adamantane derivatives as potential inhibitors of p37 major envelope protein and poxvirus reproduction. Design, synthesis and antiviral activity. Eur J Med Chem. 2021; 221:113485. PMC: 9533879. DOI: 10.1016/j.ejmech.2021.113485. View

15.

Bliss C, Freyn A, Caniels T, Leyva-Grado V, Nachbagauer R, Sun W . A single-shot adenoviral vaccine provides hemagglutinin stalk-mediated protection against heterosubtypic influenza challenge in mice. Mol Ther. 2022; 30(5):2024-2047. PMC: 9092311. DOI: 10.1016/j.ymthe.2022.01.011. View

16.

Valkenburg S, Mallajosyula V, Li O, Chin A, Carnell G, Temperton N . Stalking influenza by vaccination with pre-fusion headless HA mini-stem. Sci Rep. 2016; 6:22666. PMC: 4780079. DOI: 10.1038/srep22666. View

17.

Gstottner C, Zhang T, Resemann A, Ruben S, Pengelley S, Suckau D . Structural and Functional Characterization of SARS-CoV-2 RBD Domains Produced in Mammalian Cells. Anal Chem. 2021; 93(17):6839-6847. PMC: 8078197. DOI: 10.1021/acs.analchem.1c00893. View

18.

Ekiert D, Bhabha G, Elsliger M, Friesen R, Jongeneelen M, Throsby M . Antibody recognition of a highly conserved influenza virus epitope. Science. 2009; 324(5924):246-51. PMC: 2758658. DOI: 10.1126/science.1171491. View

19.

McLean H, Belongia E . Influenza Vaccine Effectiveness: New Insights and Challenges. Cold Spring Harb Perspect Med. 2020; 11(6). PMC: 8168527. DOI: 10.1101/cshperspect.a038315. View

20.

Rydyznski Moderbacher C, Ramirez S, Dan J, Grifoni A, Hastie K, Weiskopf D . Antigen-Specific Adaptive Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and Disease Severity. Cell. 2020; 183(4):996-1012.e19. PMC: 7494270. DOI: 10.1016/j.cell.2020.09.038. View