J Infect Dis: Intranasal M2SR (M2-deficient single replicate) H3N2 influenza vaccine enhances mucosal and serum antibodies in adults

Background: In recent years, influenza A(H3N2) viruses have evolved into multiple co-circulating clades, resulting in low vaccine efficacy and highlighting the need for
widespread protection and effective influenza vaccines.
For the fifth consecutive year (25 February 2022), the World Health Organization announced changes in the strain of the northern hemisphere H3N1 component influenza vaccine for 2022-2023
.
Despite record low influenza levels during the COVID pandemic, multiple H3N2 subtypes were detected and were not sero-recognized by people who had received the licensed and recommended 2021-2022 influenza vaccine, so the vaccine strain
needs to be replaced again.
The common circulation of multiple H3N2 lineages poses a serious challenge to current strain-specific influenza vaccines, which need to be updated almost annually to try to maintain a match
for viral antigen drift.

Despite updates to vaccine strains to account for antigen drift, vaccine-induced protection against H3N2 remains low, especially in years
of mismatch between vaccines and circulating strains.
Over the past 10 years, the effectiveness (VE) of vaccines against H3N2 in the United States has been less than 40%, and in 2021-2022, the VE against H3N2 in the United States was 35%.

Therefore, new influenza vaccines are needed to induce a broader cross-reactive immune response that provides greater protection
against infection and disease.
Currently available inactivated and recombinant influenza vaccines depend primarily on a close match between vaccine immunogens and circulating viruses to be effective
.
As a result, these vaccines are relatively ineffective
against emerging influenza viruses or viruses that have been detached from vaccine strains.
In addition, administration with conventional inactivated vaccines generally does not elicit mucosal and T-cell immune responses, even though these types of immune responses are associated with
a reduction in influenza disease severity in subjects who are seronegative for influenza virus-specific antibodies.
Although live influenza virus vaccines provide different immune responses, data accumulated using the licensed live attenuated influenza vaccine FluMist suggest that pre-existing cross-reactive immunity present in most adults limits vaccine virus replication, thereby mitigating an effective immune response; Thus limiting its main use to children
.

Objective: The M2SR vaccine in this dose-response study updated the hemagglutinin (HA) and neuraminidase (NA) sequences of similar strains of H3N2 components from the 2018-2019 commercial seasonal influenza vaccine
.

Methods: Serosusceptible subjects aged 18-49 years were randomized to receive two doses (108109 TCID50) of M2SR or placebo 28 days
apart.
Clinical specimens
are collected before and after each dose.
The primary objective is to demonstrate the safety of the
M2SR vaccine (clinical trial government number NCT03999554).

Results: The vaccine was well tolerated at all dose levels
.
Compared with Belgium in 2015, a single injection of 108TCID50M2SR increased 2-fold in 40% (95% confidence interval 24.
9-56.
7) of participants MN antibody levels, and 80.
6% (95% confidence interval 61.
4-92.
3) of participants with 109TCID50M2SR increased ≥ antibody levels 2-fold (P<0.
001).

A single dose of 109TCID50M2SR resulted in 4-≥fold HAI seroconversion
to vaccine strains in 71% (95% CI 52.
0-85.
8%) of recipients.
It also induces mucosal and cellular immune responses
.

Figure 1 Treatment-related adverse events
.
A.
Proportion
of subjects with TEAE present 8 days after first dose.
B.
Proportion of subjects taking TEAE 8 days after the second dose

Fig.
2 Serum hemagglutination inhibition and neutralizing antibody response
after intranasal vaccination.
A.
Proportion
of subjects with a ≥4-fold increase in hemagglutinin titers 28 days after the first injection against a matched and drifting H3N2 influenza strain.
B.
Proportion
of subjects with a ≥4-fold increase in hemagglustatin titer 28 days after second dose injection of matched and drifting H3N2 virus strains.
Error bars are 95% CI.

The H3N2 strain was: Singapore 2016= A/Singapore/INFIMH-16-0019/2016; Hong Kong 2019=A/Hong Kong/2671/2019; Switzerland 2017 = / Switzerland / 8060/2017; Kansas, Kansas 2017 = / / 14/2017; Brisbane 2007 = / Brisbane / 10/2007
.
C.
Proportion of subjects showing a ≥2-fold increase in microneutralization titer (MNT) 2-fold after the first dose to the matched and drifting H3N2 influenza strain
.
Error bars are 95% CI.

The H3N2 strain was: Singapore 2016= A/Singapore/INFIMH-16-0019/2016; Hong Kong 2019=A/Hong Kong/2671/2019; Switzerland 2017 = / Switzerland / 8060/2017; Belgium 2015 = / Belgium / 4217/2015; Kansas 2017 cell=A/Kansas/14/2017 cell based; Kansas 2017 eggs = A/Kansas/14/2017 eggs; Brisbane 2007 = / Brisbane / 10/2007
.
p<0.
001， **p<0.
01， *p<0.
05

Fig.
3 Serum neuraminidase inhibitory antibody titer after intranasal inoculation
.
The figure shows the proportion
of subjects with a ≥2-fold increase in NAIs 2-fold and ≥-fold after 28 days after the first dose of anti-neuraminidase H6N2 recombinant influenza virus.
Error bars are 95% CI.

p<0.
001， **p<0.
01， *p<0.
05

Fig.
4 Nasal swab mucosal secretions IgA and serum IgA antibody ELISA titer A.
Secretion of IgA (sIgA) 28 days after the first dose and 28 days after the second dose The geometric mean fold (GMFR) of IgA (sIgA)
is higher than the baseline.
Anti-sing2016 HA ELISA titers in nasal specimens were normalized to total secreted IgA
.
B.
Proportion
of subjects with ≥2-fold increase in sIgA titer 28 days after the first and second doses.
p<0.
001 and **p<0.
01, M2SR dose level vs placebo#p<0.
05, 109 M2SR vs 108 M2SR C.
Geometric mean doubling rate (GMFR)
of anti-sing2016 HA serum IgA ELISA 28 days after the first and second doses.
D.
Proportion
of subjects with a ≥-fold increase in serum IgA titer 28 days after the first dose and 28 days after the second dose.
p<0.
001， **p<0.
01， *p<0.
05

Fig.
5 Cell-mediated immune response
after intranasal administration of M2SR vaccine.
Geometric mean ELISpot response (spot-forming cells/106 PBMC) on days 1 (baseline)
and 28 post-immunization.
Stimulate PBMCs
with NP peptide pools.
The error bar is a 95% confidence interval
.

Conclusions: These results suggest that M2SR may provide substantial protection
against infection with high-drift H3N2 influenza strains.

Eiden J, Fierro C, Schwartz H, et al.
Intranasal M2SR (M2-deficient Single Replication) H3N2 Influenza Vaccine Provides Enhanced Mucosal and Serum Antibodies In Adults.
J Infect Dis 2022 Nov 09