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33. Intranasal M2SR (M2-deficient Single Replication) Live H3N2 Influenza Investigational Vaccine Induces Serum HAI & Broad Immune Responses in High Proportion of Adults

ABSTRACT: Abstract

Background

A single intranasal (IN) dose of 108 TCID50 M2SR protected a responder subset of adults against infection and disease in a prior human influenza challenge study (EudraCT number: 2017-004971-30). Higher dose levels of M2SR were assessed in this phase 1b study to enhance immune responses and further increase protection levels in adults.

Methods

A double-blind, randomized, placebo-controlled dose escalation study (NCT03999554) was conducted at 4 US study sites with two different H3N2 M2SR vaccines that contained HA & NA from either A/Brisbane/10/2007 or A/Singapore/INFIMH-16–0019/2016. Serosusceptible 18–49 year old subjects (n = 206) received 2 IN doses of either saline or 1 of 3 different dose levels of vaccine (108 – 109 TCID50), administered 28 days apart.

Results

Study vaccination was well-tolerated at all dose levels. A single 109 dose of A/Singapore/2016 M2SR generated significantly increased serum HAI responses compared to the 108 dose of A/Brisbane/10/2007 M2SR that had provided protection against infection & illness in an earlier human influenza challenge study (Fig. 1). HAI titers ?40 were achieved in 0%, 23% & 58% of subjects after the first dose of placebo, 108 or 109 M2SR, respectively (p< 0.003). Increases also were stimulated in serum microneutralization titers (MNT) to drifted strains of H3N2 (Fig 2) & in serum NAI (Fig 3) and mucosal sIgA (Fig 4) titers. Further increases in serum and mucosal immune response were noted after a 2nd IN vaccination. Proportion of subjects with seroprotective HAI titers after vaccination Proportion of subjects with increased microneutralization titers against drifted H3N2 viruses after vaccination Geometric mean fold rise in serum neuraminidase inhibition antibody titers after vaccination

Conclusion

An earlier clinical trial with a 108 dose of M2SR provided protection against infection and illness upon challenge with a highly drifted strain of H3N2. Protection correlated with vaccine induced serum MNT responses. In the current study, a single, 109 dose of M2SR significantly increased serum MNT, HAI & NAI titers as well as mucosal immune responses among greater proportions of study subjects. Since HAI, alone, is a well-accepted surrogate marker for vaccine protection against influenza, these broader enhancements indicate the potential for M2SR to protect against both matched and drifted strains of influenza in a high proportion of adults and strongly support clinical assessment in younger and older age groups as well as development of multivalent M2SR. Geometric mean fold rise in nasal mucosal secretory IgA antibody titers after vaccination

Disclosures

Joseph Eiden, MD, PhD, FluGen (Consultant) Ruth Ellis, MD, FluGen (Consultant) Roger Aitchison, ScM, FluGen (Consultant) Renee Herber, BS, FluGen (Employee) Pamuk Bilsel, PhD, FluGen (Employee)

SUBMITTER: Eiden J

PROVIDER: S-EPMC7776045 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Demonstration of protection by a M2SR (M2 deficient Single Replication) monovalent H3N2 vaccine was assessed in a phase 2a clinical trial in which the challenge virus was substantially drifted from the vaccine. M2SR is an investigational, live virus vaccine containing hemagglutinin (HA) and neuraminidase (NA) selected from targeted Type A influenza strains. M2SR undergoes only a single round of infection in the respiratory epithelium but evokes an immune response profile similar to wild-type influenza virus and protects ferrets against both homologous and heterologous influenza variants. Methods A blinded, randomized, placebo-controlled human challenge study (EudraCT #: 2017-004971-30) was conducted with M2SR containing HA and NA from A/Brisbane/10/2007 (H3N2). 18–55-year-old subjects received 1 IN dose of saline or 108 TCID50 of vaccine. 4 weeks later, 99 subjects were challenged IN with 106 TCID50 H3N2 A/Belgium/4217/2015 (Figures 1 and 2). Results Adverse events (AE) were similar between placebo (N = 51) and M2SR recipients (N = 48) during the 28 days after immunization. After challenge with A/Belgium/4217/2015, 35% of M2SR recipients experienced influenza infection and illness, compared with 49% of placebo subjects (Figure 3). An 18% reduction in viral load was noted after challenge for M2SR subjects. Serum microneutralization response to vaccine was detected in 54% of M2SR subjects (vs. 0/51 placebo subjects), and among these subjects a 34% reduction in viral load and 51% reduction in symptom scores was noted after challenge vs placebo. Among the 29% of subjects with post-vaccine response to both vaccine and challenge strains, a 62% reduction in viral load and 56% reduction in symptom scores was noted after challenge with highly drifted H3N2 (Figure 4). Conclusion One dose of M2SR protected healthy adults against influenza infection and illness with a highly drifted challenge strain. This is believed to be the first study to demonstrate protection against challenge with an influenza strain substantially different from the vaccine and indicates potential for improved breadth of protection by M2SR compared with current vaccines. The mild vaccine AE profile supports clinical trials of additional dose levels and regimens to enhance drifted strain protection by M2SR. Disclosures All authors: No reported disclosures.

Project description:Abstract Background Influenza vaccines are needed with greater effectiveness and breadth of coverage. FluGen is developing M2SR (M2 deficient Single Replication), an investigational, live virus vaccine. M2SR contains the internal proteins of donor A/Puerto Rico/8/34 and hemagglutinin (HA) and neuraminidase (NA) selected from targeted Type A influenza strains. M2SR undergoes only a single round of infection in the respiratory epithelium but evokes an immune response profile similar to wild-type influenza viruses. In influenza naïve and pre-immune ferrets, M2SR protects against multiple influenza A subtypes. Methods A Phase 1, first-in-human, randomized, placebo-control study (FluGen-H3N2-V001; ClinicalTrials.gov identifier NCT02822105) was conducted at a single USA site, with 96 adults, ages 18–49 years. Study vaccine contained HA and NA from A/Brisbane/10/2007 (H3N2). Study volunteers received a single intranasal (IN) inoculation with either M2SR at dose levels of 106, 107 or 108 TCID50 or saline placebo (N = 24/cohort). Study subjects were evaluated for virus replication and solicited local and systemic reactions for 7 days, all adverse events (AE) for 28 days and serious AE (SAE) for 180 days. Results No infectious virus was detected in nasal swabs from any vaccinated subject. The most commonly reported AE was mild nasal rhinorrhea/congestion during the first 7 days after vaccination (Figure 1). No subject had fever or a severe reaction to the vaccine. No SAEs were reported. At least one AE was reported among 29%, 58%, and 83% of M2SR subjects administered 106, 107, or 108 TCID50, respectively, and 46% among placebo subjects. There were no notable imbalances among study groups for other events. T- and B-cell responses, including influenza-specific serum and mucosal antibody responses were detected at a significantly higher frequency among vaccine than placebo subjects (Figure 2).Figure 1. Common adverse events first 7 days post-vaccinationFigure 2. Influenza-specific immune responses Conclusion M2SR vaccine was safe and well tolerated at all dose levels, generated a dose-response effect for humoral (HA antibody) and mucosal antibodies against both homologous and heterologous influenza variants, and elicited robust T-cell responses. No infectious virus was detected in nasal swabs from any vaccinated subject. Disclosures J. Eiden, FluGen, Inc.: Consultant, Consulting fee and Stock Options. G. Gordon, FluGen: Consultant, Consulting fee. C. Fierro, FluGen: Investigator, Fee for service. R. Belshe, FluGen: Consultant, Consulting fee and Stock Options. H. Greenberg, FluGen: Consultant, Consulting fee and Stock OpTions. D. Hoft, FluGen: Research Contractor, Fee for service. Y. Hatta, FluGen: Employee, Salary and Stock Options. M. Imboden, FluGen: Employee, Salary and Stock Options. M. Moser, FluGen: Employee, Salary and Stock Options. R. Herber, FluGen: Employee, Salary and Stock Options. D. Boltz, FluGen: Research Contractor, fee for service. M. Tary-Lehmann, FluGen: Research Contractor, Fee for service. CTL: Founder and Owner, Salary. Y. Kawaoka, FluGen: Founder, Stock Options. G. Neumann, FluGen: Founder, Stock Options. P. Radspinner, FluGen: Board Member and Founder, Salary and Stock Options. R. Aitchison, FluGen: Consultant, Consulting fee. P. Bilsel, FluGen: Employee, Salary and Stock Options.

Project description:Current influenza vaccines do not provide effective protection against heterologous influenza viruses. The ability of the novel M2SR influenza vaccine to protect against drifted influenza viruses was evaluated in naïve ferrets and in ferrets with pre-existing immunity to influenza. In naïve ferrets, M2SR provided similar protection against drifted challenge viruses as the comparator vaccine, FluMist®. However, in ferrets with pre-existing immunity, M2SR provided superior protection than FluMist in two model systems. In the first model, ferrets were infected with influenza A H1N1pdm and influenza B viruses to mimic the diverse influenza exposure in humans. The pre-infected ferrets, seropositive to H1N1pdm and influenza B but seronegative to H3N2, were then vaccinated with H3N2 M2SR or monovalent H3N2 FluMist virus (A/Brisbane/10/2007, clade 1) and challenged 6?weeks later with a drifted H3N2 virus (clade 3C.2a). Antibody titers to Brisbane/10/2007 were higher in M2SR vaccinated ferrets than in FluMist vaccinated ferrets in the pre-infected ferrets whereas the opposite was observed in naïve ferrets. After challenge with drifted H3N2 virus, M2SR provided superior protection than FluMist monovalent vaccine. In the second model, the impact of homologous pre-existing immunity upon vaccine-induced protection was evaluated. Ferrets, pre-infected with H1N1pdm virus, were vaccinated 90?days later with H1N1pdm M2SR or FluMist monovalent vaccine and challenged 6?weeks later with a pre-pandemic seasonal H1N1 virus, A/Brisbane/59/2007 (Bris59). While cross-reactive serum IgG antibodies against the Bris59 HA were detected after vaccination, anti-Bris59 hemagglutination inhibition antibodies were only detected post-challenge. M2SR provided better protection against Bris59 challenge than FluMist suggesting that homologous pre-existing immunity affected FluMist virus to a greater degree than M2SR. These results suggest that the single replication intranasal M2SR vaccine provides effective protection against drifted influenza A viruses not only in naïve ferrets but also in those with pre-existing immunity in contrast to FluMist viruses.

Project description:The emergence of highly pathogenic avian influenza H5N1 viruses has heightened global concern about the threat posed by pandemic influenza. To address the need for a highly effective universal influenza vaccine, we developed a novel M2-deficient single replication (M2SR) influenza vaccine virus and previously reported that it provided strong heterosubtypic protection against seasonal influenza viruses in mice. In the current study, we assessed M2SR induced protection against H5N1 influenza in mice and ferrets. Mice were intranasally inoculated with M2SR viruses containing the HA and NA from A/Vietnam/1203/2004 (M2SR H5N1) or A/California/07/2009 (M2SR H1N1). All M2SR vaccinated mice survived lethal challenge with influenza A/Vietnam/1203/2004 (H5N1), whereas 40% of mice vaccinated with recombinant H5 HA and none of the naïve controls survived. M2SR H5N1 provided sterile immunity, whereas low levels of virus were detected in the lungs of some M2SR H1N1 vaccinated mice. In contrast, recombinant H5 HA vaccinated mice and naïve controls showed systemic infection. M2SR H5N1 induced strong serum and mucosal antibody responses (IgG and IgA classes) against H5 HA, with high hemagglutination inhibition (HAI) titers. In contrast, while M2SR H1N1 elicited cross-reactive antibodies recognizing the H5 HA2 stalk region or the neuraminidase, no HAI activity against H5N1 virus was detected after M2SR H1N1 immunization. Both M2SR H5N1 and H1N1 also protected ferrets against lethal challenge with A/Vietnam/1203/2004. A prime-boost regimen provided optimal protection with no virus detected in the respiratory tract or brain after challenge. As in the mouse model, only the M2SR H5N1 vaccine induced HAI antibodies against the challenge virus in ferrets, while the M2SR H1N1 was able to provide protection without the induction of HAI antibodies. In summary, effective protection against highly pathogenic H5N1 influenza virus was provided by both homologous H5N1 M2SR and heterologous H1N1 M2SR demonstrating the cross-protective attributes of the M2SR platform.