The M2SR Intranasal H3N2 Single-Replication Live Influenza Virus Vaccine Induces More Potent
and Broad Mucosal Secretory IgA Response in Older Adults than the High-Dose Inactivated
FluzoneHD Vaccine

The M2-deficient single replication (M2SR) H3N2 intranasal influenza vaccine was shown to protect
from a drifted H3N2 virus in a phase 2a challenge human trial, inducing cross-reactive neutralizing
antibodies, as well as IgA and secretory IgA (sIgA) antibodies. Here we compared the vaccine
induced responses of M2SR to the licensed quadrivalent inactivated Fluzone High Dose (FluzoneHD)
vaccine in a phase 1b trial of 305 older adults (65-85 years). Participants were randomized to receive
placebo, FluzoneHD, M2SR or MS2R+FluzoneHD co-administration. Antigen microarrays spotted
with 90 recombinant hemagglutinin (HA) and neuraminidase (NA) proteins of 58 influenza strains
were used to profile the magnitude and breadth of serum IgG and IgA, and mucosal IgG and sIgA
antibody responses at enrollment and 28 days post-vaccination.
While both FluzoneHD and M2SR induced significant serum IgG and IgA responses to influenza
HA proteins (p<0.001), only M2SR induced nasal sIgA responses. Significant antibody responses to
NA proteins were not detectable with any vaccine, except for FluzoneHD induced serum IgG
response to B NA. Interestingly, although M2SR included only an H3N2 strain, it induced broad serum
sIgA responses to H1 and B HA proteins as well, while in the nasal swabs the sIgA response was
specific to H3 proteins only. The combination of M2SR and FluzoneHD was synergistic in inducing
serum IgG to the conserved HA2 subunit and swab sIgA to H3N2 HA proteins. We compared the
effects of both vaccines on individuals in the lowest quartile when ranked based on baseline H3 sIgA
magnitude. M2SR induced significantly higher mucosal IgG and sIgA H3N2 responses in this group
compared with FluzoneHD.
Overall, the H3N2 M2SR vaccine induced a significant mucosal sIgA response to H3 proteins in
older adults, while FluzoneHD did not affect their sIgA levels. This effect was particularly significant
for individuals with pre-vaccination low H3N2 mucosal antibody responses. M2SR also induced a
heterologous serum IgG responses to influenza subtypes that were not included in the vaccine. These
results suggest that M2SR vaccines may be used in populations with a limited response to the
traditional influenza vaccines and may induce more broader protection from multiple influenza
subtypes.