Longevity and Mechanism of Heterosubtypic Protection Induced by M2SR (M2-Deficient Single-Replication) Live Influenza Virus Vaccine in Mice

被引:3
|
作者
Sarawar, Sally [1 ]
Gabaglia, Claudia R. [1 ]
Sanchez, Adriana [1 ]
Hatta, Yasuko [2 ]
Dias, Peter [1 ]
Neumann, Gabriele [3 ]
Kawaoka, Yoshihiro [3 ,4 ,5 ]
Bilsel, Pamuk [2 ]
机构
[1] Biomed Res Inst Southern Calif, Oceanside, CA 92056 USA
[2] FluGen Inc, Madison, WI 53711 USA
[3] Univ Wisconsin, Influenza Res Inst, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53711 USA
[4] Univ Tokyo, Inst Med Sci, Int Res Ctr Infect Dis, Dept Microbiol & Immunol,Div Virol, Tokyo 1088639, Japan
[5] Univ Tokyo, Inst Med Sci, Int Res Ctr Infect Dis, Dept Special Pathogens, Tokyo 1088639, Japan
基金
美国国家卫生研究院;
关键词
influenza; vaccine; duration; antibody; heterosubtypic; depletion; A VIRUS; IMMUNITY; INFECTION; ANTIBODIES; PROTEIN; CELLS;
D O I
10.3390/vaccines10122131
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Seasonal influenza and the threat of global pandemics present a continuing threat to public health. However, conventional inactivated influenza vaccines (IAVs) provide little cross-protective immunity and suboptimal efficacy, even against well-matched strains. Furthermore, the protection against matched strains has been shown to be of a short duration in both mouse models and humans. M2SR (M2-deficient single-replication influenza virus) is a single-replication vaccine that has been shown to provide effective cross-protection against heterosubtypic influenza viruses in both mouse and ferret models. In the present study, we investigated the duration and mechanism of heterosubtypic protection induced by M2SR in a mouse model. We previously showed that M2SR generated from influenza A/Puerto Rico/8/34 (H1N1) significantly protected C57BL/6 mice against lethal challenge with both influenza A/Puerto Rico/8/34 (H1N1, homosubtypic) and influenza A/Aichi/2/1968 (H3N2, heterosubtypic), whereas the inactivated influenza vaccine provided no heterosubtypic protection. The homosubtypic protection induced by M2SR was robust and lasted for greater than 1 year, whereas that provided by the inactivated vaccine lasted for less than 6 months. The heterosubtypic protection induced by M2SR was of a somewhat shorter duration than the homosubtypic protection, with protection being evident 9 months after vaccination. However, heterosubtypic protection was not observed at 14 months post vaccination. M2SR has been shown to induce strong systemic and mucosal antibody and T cell responses. We investigated the relative importance of these immune mechanisms in heterosubtypic protection, using mice that were deficient in B cells or mice that were depleted of T cells immediately before challenge. Somewhat surprisingly, the heterosubtypic protection was completely dependent on B cells in this model, whereas the depletion of T cells had no significant effect on survival after a lethal heterosubtypic challenge. While antibody-dependent cellular cytotoxicity (ADCC) has been demonstrated to be important in the response to some influenza vaccines, a lack of Fc receptors did not affect the survival of M2SR-vaccinated mice following a lethal challenge. We examined the influenza proteins targeted by the heterosubtypic antibody response. Shortly after the H1N1 M2SR vaccination, high titers of cross-reactive antibodies to heterosubtypic H3N2 nucleoprotein (NP) and lower titers to the stalk region of the hemagglutinin (HA2) and neuraminidase (NA) proteins were observed. The high antibody titers to heterosubtypic NP persisted one year after vaccination, whereas the antibody titers to the heterosubtypic HA2 and NA proteins were very low, or below the limit of detection, at this time. These results show that the intranasal M2SR vaccine elicits durable protective immune responses against homotypic and heterosubtypic influenza infection not seen with intramuscular inactivated vaccines. Both the homo- and heterosubtypic protection induced by the single-replication vaccine are dependent on B cells in this model. While the homosubtypic protection is mediated by antibodies to the head region of HA, our data suggest that the heterosubtypic protection for M2SR is due to cross-reactive antibodies elicited against the NP, HA2, and NA antigens that are not targeted by current seasonal influenza vaccines.
引用
收藏
页数:13
相关论文
共 50 条
  • [1] Safety and Immunogenicity of M2-Deficient, Single Replication, Live Influenza Vaccine (M2SR) in Adults
    Eiden, Joseph
    Gordon, Gilad
    Fierro, Carlos
    Herber, Renee
    Aitchison, Roger
    Belshe, Robert
    Greenberg, Harry
    Hoft, Daniel
    Hatta, Yasuko
    Moser, Michael J.
    Tary-Lehmann, Magdalena
    Kawaoka, Yoshihiro
    Neumann, Gabriele
    Radspinner, Paul
    Bilsel, Pamuk
    VACCINES, 2021, 9 (12)
  • [2] M2SR, a novel live single replication influenza virus vaccine, provides effective heterosubtypic protection in mice
    Sarawar, Sally
    Hatta, Yasuko
    Watanabe, Shinji
    Dias, Peter
    Neumann, Gabriele
    Kawaoka, Yoshihiro
    Bilsel, Pamuk
    VACCINE, 2016, 34 (42) : 5090 - 5098
  • [3] Quadrivalent Formulation of Intranasal Influenza Vaccine M2SR (M2-Deficient Single Replication) Protects against Drifted Influenza A and B Virus Challenge
    Hill-Batorski, Lindsay
    Hatta, Yasuko
    Moser, Michael J.
    Sarawar, Sally
    Neumann, Gabriele
    Kawaoka, Yoshihiro
    Bilsel, Pamuk
    VACCINES, 2023, 11 (04)
  • [4] Intranasal M2SR (M2-Deficient Single Replication) Influenza Vaccine Induces Broadly Reactive Mucosal Antibody Production in Adults
    Hill-Batorski, Lindsay
    Weiner, Joshua A.
    Ackerman, Margaret E.
    Hatta, Yasuko
    Hoft, Daniel F.
    Herber, Renee
    Moser, Michael J.
    Bilsel, Pamuk
    JOURNAL OF INFECTIOUS DISEASES, 2024,
  • [5] Intranasal M2SR (M2-Deficient Single Replication) H3N2 Influenza Vaccine Provides Enhanced Mucosal and Serum Antibodies in Adults
    Eiden, Joseph
    Fierro, Carlos
    Schwartz, Howard
    Adams, Mark
    Ellis, Kimberly J.
    Aitchison, Roger
    Herber, Renee
    Hatta, Yasuko
    Marshall, David
    Moser, Michael J.
    Belshe, Robert
    Greenberg, Harry
    Coelingh, Kathleen
    Kawaoka, Yoshihiro
    Neumann, Gabriele
    Bilsel, Pamuk
    JOURNAL OF INFECTIOUS DISEASES, 2022, 227 (01): : 103 - 112
  • [6] M2-Deficient Single-Replication Influenza Vaccine-Induced Immune Responses Associated With Protection Against Human Challenge With Highly Drifted H3N2 Influenza Strain
    Eiden, Joseph
    Volckaert, Bram
    Rudenko, Oleg
    Aitchison, Roger
    Herber, Renee
    Belshe, Robert
    Greenberg, Harry
    Coelingh, Kathleen
    Marshall, David
    Kawaoka, Yoshihiro
    Neumann, Gabriele
    Bilsel, Pamuk
    JOURNAL OF INFECTIOUS DISEASES, 2022, 226 (01): : 83 - 90
  • [7] M2SR, a novel live influenza vaccine, protects mice and ferrets against highly pathogenic avian influenza
    Hatta, Yasuko
    Boltz, David
    Sarawar, Sally
    Kawaoka, Yoshihiro
    Neumann, Gabriele
    Bilsel, Pamuk
    VACCINE, 2017, 35 (33) : 4177 - 4183
  • [8] Single-replication BM2SR vaccine provides sterilizing immunity and cross-lineage influenza B virus protection in mice
    Moser, Michael J.
    Hatta, Yasuko
    Gabaglia, Claudia
    Sanchez, Adriana
    Dias, Peter
    Sarawar, Sally
    Kawaoka, Yoshihiro
    Hatta, Masato
    Neumann, Gabriele
    Bilsel, Pamuk
    VACCINE, 2019, 37 (32) : 4533 - 4542
  • [9] An M2e-based synthetic peptide vaccine for influenza A virus confers heterosubtypic protection from lethal virus challenge
    Ji-Hong Ma
    Fu-Ru Yang
    Hai Yu
    Yan-Jun Zhou
    Guo-Xin Li
    Meng Huang
    Feng Wen
    Guangzhi Tong
    Virology Journal, 10
  • [10] An M2e-based synthetic peptide vaccine for influenza A virus confers heterosubtypic protection from lethal virus challenge
    Ma, Ji-Hong
    Yang, Fu-Ru
    Yu, Hai
    Zhou, Yan-Jun
    Li, Guo-Xin
    Huang, Meng
    Wen, Feng
    Tong, Guangzhi
    VIROLOGY JOURNAL, 2013, 10