Antigenic Landscape Analysis of Individuals Vaccinated with a Universal Influenza Virus Vaccine Candidate Reveals Induction of Cross-Subtype Immunity.

Current influenza virus vaccines have to be closely matched to circulating strains to provide good protection, and antigenic drift and emerging pandemic influenza virus strains present a difficult challenge for them. Universal influenza virus vaccines, including chimeric hemagglutinin (cHA)-based constructs that target the conserved stalk domain of hemagglutinin, are in clinical development. Due to the conservation of the stalk domain, antibodies directed to it show broad binding profiles, usually within group 1 and group 2 influenza A or influenza B virus phylogenies. However, determining the binding breadth of these antibodies with commonly used immunological methods can be challenging. Here, we analyzed serum samples from a phase I clinical trial (CVIA057, NCT03300050) using an influenza virus protein microarray (IVPM). The IVPM technology allowed us to assess immune responses not only to a large number of group 1 hemagglutinins but also group 2 and influenza B virus hemagglutinins. In CVIA057, different vaccine modalities, including a live attenuated influenza virus vaccine and inactivated influenza virus vaccines with or without adjuvant, all in the context of cHA constructs, were tested. We found that vaccination with adjuvanted, inactivated vaccines induced a very broad antibody response covering group 1 hemagglutinins, with limited induction of antibodies to group 2 hemagglutinins. Our data show that cHA constructs do indeed induce very broad immune responses and that the IVPM technology is a useful tool to measure this breadth that broadly protective or universal influenza virus vaccines aim to induce. IMPORTANCE The development of a universal influenza virus vaccine that protects against seasonal drifted, zoonotic, or emerging pandemic influenza viruses would be an extremely useful public health tool. Here, we test a technology designed to measure the breadth of antibody responses induced by this new class of vaccines.

An Influenza Virus Hemagglutinin-Based Vaccine Platform Enables the Generation of Epitope Specific Human Cytomegalovirus Antibodies.

Human cytomegalovirus (CMV) is a highly prevalent pathogen with ~60%-90% seropositivity in adults. CMV can contribute to organ rejection in transplant recipients and is a major cause of birth defects in newborns. Currently, there are no approved vaccines against CMV. The epitope of a CMV neutralizing monoclonal antibody against a conserved region of the envelope protein gH provided the basis for a new CMV vaccine design. We exploited the influenza A virus as a vaccine platform due to the highly immunogenic head domain of its hemagglutinin envelope protein. Influenza A variants were engineered by reverse genetics to express the epitope of an anti-CMV gH neutralizing antibody that recognizes native gH into the hemagglutinin antigenic Sa site. We determined that the recombinant influenza variants expressing 7, 10, or 13 residues of the anti-gH neutralizing antibody epitope were recognized and neutralized by the anti-gH antibody 10C10. Mice vaccinated with the influenza/CMV chimeric viruses induced CMV-specific antibodies that recognized the native gH protein and inhibited virus infection. In fact, the influenza variants expressing 7-13 gH residues neutralized a CMV infection at ~60% following two immunizations with variants expressing the 13 residue gH peptide produced the highest levels of neutralization. Collectively, our study demonstrates that a variant influenza virus inserted with a gH peptide can generate a humoral response that limits a CMV infection.