Intranasal M2SR (M2-Deficient Single Replication) H3N2 Influenza Vaccine Provides Enhanced Mucosal and Serum Antibodies in Adults
Joseph Eiden, Carlos Fierro, Howard Schwartz, Mark Adams, Kimberly J Ellis, Roger Aitchison, Renee Herber, Yasuko Hatta, David Marshall, Michael J Moser, Robert Belshe, Harry Greenberg, Kathleen Coelingh, Yoshihiro Kawaoka, Gabriele Neumann, Pamuk Bilsel, Joseph Eiden, Carlos Fierro, Howard Schwartz, Mark Adams, Kimberly J Ellis, Roger Aitchison, Renee Herber, Yasuko Hatta, David Marshall, Michael J Moser, Robert Belshe, Harry Greenberg, Kathleen Coelingh, Yoshihiro Kawaoka, Gabriele Neumann, Pamuk Bilsel
Abstract
Background: We previously demonstrated that an intranasal dose of 108 50% tissue culture infectious dose (TCID50) M2-deficient single replication (M2SR) influenza vaccine protected against highly drifted H3N2 influenza challenge in a subset of subjects who demonstrated ≥2-fold increase in microneutralization (MN) antibodies to Belgium2015 (the challenge strain) after vaccination. Here, we describe a phase 1b, observer-blinded, dose-escalation study demonstrating an increased proportion of responders with this signal of immune protection.
Methods: Serosusceptible subjects aged 18-49 years were randomized to receive 2 doses (108-109 TCID50) of M2SR or placebo administered 28 days apart. Clinical specimens were collected before and after each dose. The primary objective was to demonstrate safety of M2SR vaccines.
Results: The vaccine was well tolerated at all dose levels. Against Belgium2015, ≥ 2-fold increases in MN antibodies were noted among 40% (95% confidence interval [CI], 24.9%-56.7%) of subjects following a single 108 TCID50 M2SR dose and among 80.6% (95% CI, 61.4%-92.3%) after 109 dose (P < .001). A single 109 TCID50 dose of M2SR generated ≥4-fold hemagglutination inhibition antibody seroconversion against the vaccine strain in 71% (95% CI, 52.0%-85.8%) of recipients. Mucosal and cellular immune responses were also induced.
Conclusions: These results indicate that M2SR may provide substantial protection against infection with highly drifted strains of H3N2 influenza.
Clinical trials registration: NCT03999554.
Keywords: H3N2; drift; influenza; intranasal; live; mucosal; vaccine.
Conflict of interest statement
Potential conflicts of interest. J. E. is a consultant to FluGen. R. B., H. G., and K. C. serve on FluGen's Clinical Advisory Board. Y. K. and G. N. are founders of FluGen. R. H., Y. H., D. M., M. M., and P. B. are employees of FluGen. All other authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.
Figures
References
- Belongia EA, McLean HQ. Influenza vaccine effectiveness: defining the H3N2 problem. Clin Infect Dis 2019; 69:1817–23.
- World Health Organization . Recommended composition of influenza virus vaccines for use in the 2021–2022 northern hemisphere influenza season, 2021. . Accessed 30 July 2022.
- Centers for Disease Control and Prevention . CDC seasonal flu vaccine effectiveness studies, 2022. Accessed 3 August 2022.
- Wilkinson TM, Li CK, Chui CS, et al. . Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med 2012; 18:274–80.
- Clements ML, Betts RF, Tierney EL, Murphy BR. Serum and nasal wash antibodies associated with resistance to experimental challenge with influenza A wild-type virus. J Clin Microbiol 1986; 24:157–60.
- Treanor JJ, Kotloff K, Betts RF, et al. . Evaluation of trivalent, live, cold-adapted (CAIV-T) and inactivated (TIV) influenza vaccines in prevention of virus infection and illness following challenge of adults with wild-type influenza A (H1N1), A (H3N2), and B viruses. Vaccine 1999; 18:899–906.
- Belshe RB, Gruber WC, Mendelman PM, et al. . Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine. J Infect Dis 2000; 181:1133–7.
- Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12:36–44.
- Karron RA, Talaat K, Luke C, et al. . Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults. Vaccine 2009; 27:4953–60.
- He XS, Holmes TH, Sasaki S, et al. . Baseline levels of influenza-specific CD4 memory T-cells affect T-cell responses to influenza vaccines. PLoS One 2008; 3:e2574.
- Block SL, Reisinger KS, Hultquist M, Walker RE; CAIV-T Study Group . Comparative immunogenicities of frozen and refrigerated formulations of live attenuated influenza vaccine in healthy subjects. Antimicrob Agents Chemother 2007; 51:4001–8.
- Mohn KG, Smith I, Sjursen H, Cox RJ. Immune responses after live attenuated influenza vaccination. Hum Vaccin Immunother 2018; 14:571–8.
- Eiden J, Gordon G, Fierro C, et al. . Safety and immunogenicity of M2-deficient, single replication, live influenza vaccine (M2SR) in adults. Vaccines (Basel) 2021; 9:1388.
- Hatta Y, Boltz D, Sarawar S, Kawaoka Y, Neumann G, Bilsel P. M2SR, a novel live influenza vaccine, protects mice and ferrets against highly pathogenic avian influenza. Vaccine 2017; 35:4177–83.
- Sarawar S, Hatta Y, Watanabe S, et al.M2SR, a novel live single replication influenza virus vaccine, provides effective heterosubtypic protection in mice. Vaccine 2016; 34:5090–8.
- Hatta Y, Boltz D, Sarawar S, Kawaoka Y, Neumann G, Bilsel P. Novel influenza vaccine M2SR protects against drifted H1N1 and H3N2 influenza virus challenge in ferrets with pre-existing immunity. Vaccine 2018; 36:5097–103.
- Eiden J, Volckaert B, Rudenko O, et al. . M2-deficient single-replication influenza vaccine-induced immune responses associated with protection against human challenge with highly drifted H3N2 influenza strain. J Infect Dis 2022; 226:83–90.
- Gianchecchi E, Manenti A, Kistner O, Trombetta C, Manini I, Montomoli E. How to assess the effectiveness of nasal influenza vaccines? Role and measurement of sIgA in mucosal secretions. Influenza Other Respir Viruses 2019; 13:429–37.
- Hobson D, Curry RL, Beare AS, Ward-Gardner A. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg (Lond) 1972; 70:767–77.
- Coelingh K, Wu XW, Mallory RM, Ambrose C. An integrated multi-study analysis of serum HAI antibody responses to Ann Arbor strain live attenuated influenza vaccine in children and adults. Trials Vaccinol 2014; 3:150–3.
- Ambrose CS, Levin MJ, Belshe RB. The relative efficacy of trivalent live attenuated and inactivated influenza vaccines in children and adults. Influenza Other Respir Viruses 2011; 5:67–75.
- Murphy BR, Coelingh K. Principles underlying the development and use of live attenuated cold-adapted influenza A and B virus vaccines. Viral Immunol 2002; 15:295–323.
Source: PubMed