Exploiting the respiratory syncytial virus (RSV) fusion protein to potentiate the immune response to influenza virus

Abstract

Influenza A virus and respiratory syncytial virus (RSV) are two of the leading causes of respiratory tract infections worldwide. Annually, influenza kills more than 250,000 people worldwide despite the availability of a safe and effective vaccine. RSV is primarily a pathogen of the very young and elderly populations. More than 90% of children are infected with RSV in their first year of life. We developed a dual influenza and RSV vaccine composed of the hemagglutinin (HA) protein of influenza and the fusion (F) protein of RSV to combat both viruses. Our vaccine is designed to be given in an annual vaccine regimen, like the current influenza vaccine, but unlike the current influenza vaccine, the addition of the RSV F protein will help to additionally protect vaccine recipients against RSV. A major aim of this research was to determine if the F protein could enhance the immune response to the poorly immunogenic HA protein, thus serving as an immunological adjuvant as well as a vaccine antigen. We found that the F protein was effective at enhancing the antibody response to the HA protein and dual vaccination reduced the influenza viral burden. During these vaccination experiments we discovered that, surprisingly, anti-F antibodies not only bound to influenza H3N2 viruses but also neutralized them. We were able to demonstrate that a peptide (120-140) generated from the stalk region of the F protein was able to interfere with binding of anti-F antibodies to influenza X31 virus, an H3N2 influenza virus strain. Another aim of this research was to determine if prior exposure to the RSV F protein modulated the immune response to a subsequent influenza infection. We determined that immunization with the F protein modified the recruitment of innate and adaptive immune cells to the site of infection, as well as modified the chemokine and cytokine response to a subsequent influenza virus infection. Together, these findings demonstrate the dynamic properties of the RSV F protein as it pertains to influenza virus infection.