Antibody Breadth and Protective Efficacy Are Increased by Vaccination with Computationally Optimized Hemagglutinin but Not

One of the challenges for developing an H5N1 influenza vaccine is the diversity of antigenically distinct isolates within this sub-type. Previously, our group described a novel hemagglutinin (HA) derived from amethodology termed computationally opti-mized broadly reactive antigen (COBRA). This COBRAHA, when used as an immunogen, elicits a broad antibody response against H5N1 isolates from different clades. In this report, the immune responses elicited by the COBRAHA virus-like particle (VLP) vaccine were compared to responses elicited by a mixture of VLPs expressing representative HAmolecules from clade 2.1, 2.2, and 2.3 primary H5N1 isolates (polyvalent). The COBRAHAVLP vaccine elicited higher-titer antibodies to a panel of H5N1 HA proteins than did the other VLPs. Both COBRA and polyvalent vaccines protected vaccinated mice and ferrets from experi-mental infection with highly lethal H5N1 influenza viruses, but COBRA-vaccinated animals had decreased viral replication, less inflammation in the lungs of mice, and reduced virus recovery in ferret nasal washes. Both vaccines had similar cellular re-sponses postchallenge, indicating that higher-titer serum antibodies likely restrict the duration of viral replication. Further-more, passively transferred immune serum from the COBRAHAVLP-vaccinated mice protected recipient animals more effi-ciently than immune serum from polyvalent-vaccinated mice. This is the first report comparing these two vaccine strategies. The single COBRAHA antigen elicited a broader antibody response and reducedmorbidity and viral titers more effectively than a polyvalent mixture of primary H5N1HA antigens. In addition to yearly epidemics, pandemic outbreaks of influenzahave occurred sporadically throughout human history (20, 43)