Project Grant R01AI177376

BROAD SPECTRUM PROTECTION AND IMMUNE RESPONSES INDUCED BY AN NP-BASED UNIVERSAL INFLUENZA VACCINE IN HETEROLOGOUS NHP CHALLENGE MODEL - ABSTRACT INFLUENZA IS A MAJOR CAUSE OF RESPIRATORY DISEASE. MOREOVER, AN INFLUENZA PANDEMIC IS A PERENNIAL THREAT, WHICH MAY LEAD TO >30 MILLION DEATHS WORLDWIDE WITHIN 6 MONTHS. CURRENT VACCINES GENERATE AN ANTIBODY IMMUNE RE- SPONSE AGAINST SURFACE PROTEINS, WHICH CHANGE CONSTANTLY, REQUIRING ANNUAL UPDATES. MOREOVER, THEIR EFFECTIVE- NESS MAY BE AS LOW AS 10-20% WHEN CIRCULATING VIRUSES DO NOT MATCH THE VACCINE VIRUSES. AS SEASONAL INFLUENZA VACCINES ARE HIGHLY STRAIN-SPECIFIC, THEY WOULD PROVIDE VERY LIMITED PROTECTION AGAINST NOVEL PANDEMIC STRAINS. THE BEST WAY TO PREVENT AN UNKNOWN FUTURE SEASONAL OR PANDEMIC INFLUENZA STRAIN IS WITH A VACCINE WITH EFFICACY AGAINST AS BROAD A RANGE OF STRAINS AS POSSIBLE - PREFERABLY UNIVERSAL EFFICACY. TO DO SO, IT MUST TARGET AN ANTIGEN THAT IS HIGHLY CONSERVED AMONG ALL INFLUENZA STRAINS AND SUBTYPES. NUCLEOPROTEIN (NP) IS VERY WELL CONSERVED WITHIN A-STRAINS (UP TO 95%). NP-SPECIFIC T-CELLS PRESENT IN PATIENTS BEFORE EXPOSURE CORRELATE WITH >70% REDUC- TION IN INFLUENZA A - BOTH PANDEMIC AND SEASONAL. THEREFORE, WE HYPOTHESIZE THAT T-CELL IMMUNIZATION AGAINST NP WOULD HAVE BROAD-SPECTRUM (POSSIBLY UNIVERSAL) EFFICACY AGAINST INFLUENZA, INCLUDING PANDEMIC STRAINS. OSIVAX IS PROPOSING A NOVEL APPROACH BASED ON ITS PROPRIETARY PLATFORM TECHNOLOGY, OLIGODOM, TO GENERATE HEPTAMERIC ANTIGENS WITH IMPROVED HUMORAL AND CELLULAR IMMUNOGENICITY. USING THIS TECHNOLOGY, OSIVAX DEVEL- OPED OVX836: A RECOMBINANT PROTEIN IN WHICH THE FULL-LENGTH NP SEQUENCE OF AN H1N1 INFLUENZA STRAIN WAS FUSED TO OLIGODOM. OVX836 GENERATES HIGH, LONG-LASTING, AND DOSE-DEPENDENT HUMORAL AND T-CELL RESPONSES IN MICE, LEADING TO CROSS-PROTECTIVE EFFICACY AGAINST LETHAL CHALLENGE BY BOTH HOMOLOGOUS AND HETEROLOGOUS IN- FLUENZA A- AND B-STRAINS. THIS EFFICACY WAS CONFIRMED CLINICALLY IN TWO PHASE 2A CLINICAL TRIALS CONDUCTED DURING INFLUENZA SEASONS IN WHICH HETEROLOGOUS H1N1 AND H3N2 STRAINS WERE DOMINANT, WITH EFFICACY IN THE RANGE OF 75-80%, IN LINE WITH THE WHO/NIAID ASPIRATIONAL EFFICACY TARGET FOR INFLUENZA VACCINES. THE MAIN ADVANTAGE OF OVX836 OVER OTHER VACCINES IS THAT IT IS UNIVERSAL, MULTI-SEASON AND STRAIN-INDEPENDENT. MOREOVER, IT STIMULATES ALL THREE ARMS OF IMMUNITY - CD8+ T-CELLS, CD4+ T-CELLS AND ANTIBODIES - IN CONTRAST TO EXISTING VACCINES, WHICH RELY MOSTLY ON AN ANTIBODY RESPONSE AGAINST SURFACE ANTIGENS THAT ARE HIGHLY PRONE TO MUTATIONS. THIS PROJECT AIMS TO DEMONSTRATE THE BREADTH OF PROTECTION CONFERRED BY OVX836 AGAINST TWO HETEROLOGOUS INFLU- ENZA A-STRAINS - NAMELY THE ONCE PANDEMIC BUT NOW SEASONAL PH1N1 (SPECIFIC AIM #1) AND H5N1, A HIGHLY PATHOGENIC STRAIN WITH PANDEMIC POTENTIAL (SPECIFIC AIM #2) - IN A NON-HUMAN PRIMATE (NHP) CHALLENGE MODEL. WHILE A NAIVE INFECTION MODEL IS SIMPLER AND MORE CONVENIENT, A PRE-INFECTED MODEL IS LIKELY TO BETTER MIMIC THE HUMAN CONDITION. THEREFORE, IN ORDER TO VALIDATE A PRE-INFECTION MODEL, WE PROPOSE TO EVALUATE THE PROTECTION AND IMMUNE RESPONSE CONFERRED BY OVX836 IN NAIVE AND PRE-INFECTED NHPS. BY EVALUATING THE IMMUNE RE- SPONSES IN NHPS WE WILL ALSO FURTHER INVESTIGATE THE MECHANISM OF ACTION OF OUR VACCINE AND IDENTIFY POTENTIAL CORRELATES OF PROTECTION TO BE FURTHER EVALUATED IN HUMAN.