A Study on the Induction of Multi-Type Immune Responses in Mice Via an MRNA Vaccine Based on Hemagglutinin and Neuraminidase Antigen

Overview

Journal Vaccines (Basel)

Date 2025 Jan 24

PMID 39852870

Authors

Mengyuan Liu

Yixuan Liu

Shaohui Song

Qiurong Qiao

Jing Liu

Yun Xie

Jian Zhou

Guoyang Liao

Affiliations

Soon will be listed here.

Abstract

Background: The Influenza A virus (IAV), a pathogen affecting the respiratory system, represents a major risk to public health worldwide. Immunization remains the foremost strategy to control the transmission of IAV. The virus has two primary antigens: hemagglutinin (HA) and neuraminidase (NA). Our previous studies have demonstrated that an IAV NA mRNA vaccine can induce Th1-type immune responses in mice. This research examined the immune responses elicited by an mRNA vaccine targeting both HA and NA antigens in murine models.

Methods: In this study, we used two dual-antigen immunization strategies: single-site immunization with an IAV HA+NA mRNA vaccine and multi-site immunization with an IAV HA mRNA vaccine and IAV NA mRNA vaccine. Hemagglutination-inhibiting antibody titer and neutralizing antibody titer in the sera of immunized mice were evaluated, and a viral challenge experiment was conducted. Additionally, the immune responses elicited by the two immunization strategies were characterized using flow cytometry and ELISA. Comparative analyses were performed with mice immunized individually with the IAV HA mRNA vaccine, IAV NA mRNA vaccine, and inactivated vaccine.

Results: The results showed that by using a multi-site immunization strategy, mice were able to generate higher levels of hemagglutination-inhibiting and neutralizing antibodies, and were protected in a viral challenge experiment. Moreover, the multi-site regimen also promoted the generation of cytotoxic T cells and maintained a balanced Th1/Th2 immune response.

Conclusions: Using mRNA vaccine based on a HA and NA antigen with multi-site immunization strategy can induce higher levels of hemagglutination-inhibiting and neutralizing antibodies, and multi-type immune responses in mice, providing new theoretical and experimental support for advancing upcoming influenza vaccines.

References

Corbett K, Flynn B, Foulds K, Francica J, Boyoglu-Barnum S, Werner A . Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N Engl J Med. 2020; 383(16):1544-1555. PMC: 7449230. DOI: 10.1056/NEJMoa2024671. View

Arevalo C, Bolton M, Le Sage V, Ye N, Furey C, Muramatsu H . A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes. Science. 2022; 378(6622):899-904. PMC: 10790309. DOI: 10.1126/science.abm0271. View

Izikson R, Brune D, Bolduc J, Bourron P, Fournier M, Mallett Moore T . Safety and immunogenicity of a high-dose quadrivalent influenza vaccine administered concomitantly with a third dose of the mRNA-1273 SARS-CoV-2 vaccine in adults aged ≥65 years: a phase 2, randomised, open-label study. Lancet Respir Med. 2022; 10(4):392-402. PMC: 8803382. DOI: 10.1016/S2213-2600(21)00557-9. View

Harding A, Heaton N . Efforts to Improve the Seasonal Influenza Vaccine. Vaccines (Basel). 2018; 6(2). PMC: 6027170. DOI: 10.3390/vaccines6020019. View

Rockman S, Brown L, Barr I, Gilbertson B, Lowther S, Kachurin A . Neuraminidase-inhibiting antibody is a correlate of cross-protection against lethal H5N1 influenza virus in ferrets immunized with seasonal influenza vaccine. J Virol. 2013; 87(6):3053-61. PMC: 3592172. DOI: 10.1128/JVI.02434-12. View

Perez-Rubio A, Ancochea J, Eiros Bouza J . Quadrivalent cell culture influenza virus vaccine. Comparison to egg-derived vaccine. Hum Vaccin Immunother. 2020; 16(8):1746-1752. PMC: 7482778. DOI: 10.1080/21645515.2019.1701912. View

Hobson D, CURRY R, Beare A . The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg (Lond). 1972; 70(4):767-77. PMC: 2130285. DOI: 10.1017/s0022172400022610. View

Sridhar S, Brokstad K, Cox R . Influenza Vaccination Strategies: Comparing Inactivated and Live Attenuated Influenza Vaccines. Vaccines (Basel). 2015; 3(2):373-89. PMC: 4494344. DOI: 10.3390/vaccines3020373. View

ROBERTSON J, Bootman J, Newman R, Oxford J, Daniels R, Webster R . Structural changes in the haemagglutinin which accompany egg adaptation of an influenza A(H1N1) virus. Virology. 1987; 160(1):31-7. DOI: 10.1016/0042-6822(87)90040-7. View

10.

Turner P, Southern J, Andrews N, Miller E, Erlewyn-Lajeunesse M . Safety of live attenuated influenza vaccine in young people with egg allergy: multicentre prospective cohort study. BMJ. 2015; 351:h6291. PMC: 4673102. DOI: 10.1136/bmj.h6291. View

11.

Li M, Liu M, Song S, Zhao R, Xie Y, Liu J . Influenza a Neuraminidase-Based Bivalent mRNA Vaccine Induces Th1-Type Immune Response and Provides Protective Effects in Mice. Vaccines (Basel). 2024; 12(3). PMC: 10974139. DOI: 10.3390/vaccines12030300. View

12.

Johansson B, Moran T, KILBOURNE E . Antigen-presenting B cells and helper T cells cooperatively mediate intravirionic antigenic competition between influenza A virus surface glycoproteins. Proc Natl Acad Sci U S A. 1987; 84(19):6869-73. PMC: 299186. DOI: 10.1073/pnas.84.19.6869. View

13.

Des Roches A, Paradis L, Gagnon R, Lemire C, Begin P, Carr S . Egg-allergic patients can be safely vaccinated against influenza. J Allergy Clin Immunol. 2012; 130(5):1213-1216.e1. DOI: 10.1016/j.jaci.2012.07.046. View

14.

Lin Y, Wharton S, Whittaker L, Dai M, Ermetal B, Lo J . The characteristics and antigenic properties of recently emerged subclade 3C.3a and 3C.2a human influenza A(H3N2) viruses passaged in MDCK cells. Influenza Other Respir Viruses. 2017; 11(3):263-274. PMC: 5410720. DOI: 10.1111/irv.12447. View

15.

Wilson E, Goswami J, Baqui A, Doreski P, Perez-Marc G, Zaman K . Efficacy and Safety of an mRNA-Based RSV PreF Vaccine in Older Adults. N Engl J Med. 2023; 389(24):2233-2244. DOI: 10.1056/NEJMoa2307079. View

16.

KILBOURNE E, Johansson B, Grajower B . Independent and disparate evolution in nature of influenza A virus hemagglutinin and neuraminidase glycoproteins. Proc Natl Acad Sci U S A. 1990; 87(2):786-90. PMC: 53351. DOI: 10.1073/pnas.87.2.786. View

17.

Chen Z, Kim L, Subbarao K, Jin H . The 2009 pandemic H1N1 virus induces anti-neuraminidase (NA) antibodies that cross-react with the NA of H5N1 viruses in ferrets. Vaccine. 2012; 30(15):2516-22. PMC: 4792253. DOI: 10.1016/j.vaccine.2012.01.090. View

18.

Brandtzaeg P . Role of mucosal immunity in influenza. Dev Biol (Basel). 2004; 115:39-48. View

19.

Zhang X, Ross T . Anti-neuraminidase immunity in the combat against influenza. Expert Rev Vaccines. 2024; 23(1):474-484. PMC: 11157429. DOI: 10.1080/14760584.2024.2343689. View

20.

Momont C, Dang H, Zatta F, Hauser K, Wang C, di Iulio J . A pan-influenza antibody inhibiting neuraminidase via receptor mimicry. Nature. 2023; 618(7965):590-597. PMC: 10266979. DOI: 10.1038/s41586-023-06136-y. View