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

• Published in: Vaccines (Basel) 2022-12, Vol.10 (12), p.2131
• Main Authors: Sarawar, Sally, Gabaglia, Claudia R, Sanchez, Adriana, Hatta, Yasuko, Dias, Peter, Neumann, Gabriele, Kawaoka, Yoshihiro, Bilsel, Pamuk
• Format: Article
• Language: English
• Subjects: Animal models; Antibodies; antibody; Antibody response; Antigens; Cross-protection; Cytotoxicity; Deactivation; Depletion; Dosage and administration; duration; Enzymes; Exo-a-sialidase; Experiments; Fc receptors; Health aspects; Hemagglutinins; heterosubtypic; Infections; Influenza; Influenza A; Influenza vaccines; Intranasal medication; Laboratory animals; Lymphocytes; Lymphocytes B; Lymphocytes T; Pandemics; Proteins; Public health; Replication; Statistical analysis; Strains (organisms); Survival; Survival analysis; Testing; Toxicity; vaccine; Vaccines; Viruses
• ISSN: 2076-393X; 2076-393X
• DOI: 10.3390/vaccines10122131

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