Bivalent hemagglutinin and neuraminidase influenza replicon particle vaccines protect pigs against influenza a virus without causing vaccine associated enhanced respiratory disease

Authors: WYMORE BRAND, MEGHAN - Orise Fellow; Anderson, Tavis; KITIKOON, PRAVINA - Merck Animal Health; KIMBLE, BRIAN - Oak Ridge Institute For Science And Education (ORISE); Otis, Nicholas; GAUGER, PHILLIP - Iowa State University; SOUZA, CARINE - Oak Ridge Institute For Science And Education (ORISE); KAPLAN, BRYAN - Oak Ridge Institute For Science And Education (ORISE); MOGLER, MARK - Merck Animal Health; STRAIT, ERIN - Merck Animal Health; Baker, Amy

Submitted to: Vaccine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/26/2022
Publication Date: 9/6/2022
Citation: Wymore Brand, M., Anderson, T.K., Kitikoon, P., Kimble, B.J., Otis, N.J., Gauger, P.C., Souza, C.K., Kaplan, B.S., Mogler, M., Strait, E., Baker, A.L. 2022. Bivalent hemagglutinin and neuraminidase influenza replicon particle vaccines protect pigs against influenza a virus without causing vaccine associated enhanced respiratory disease. Vaccine. 40(38): 5569-5578. https://doi.org/10.1016/j.vaccine.2022.07.042.
DOI: https://doi.org/10.1016/j.vaccine.2022.07.042

Interpretive Summary: Influenza A virus is a major respiratory pathogen in swine that leads to significant economic loss in the swine industry, and there is a critical need to improve on commercial vaccines. Traditional vaccines target the hemagglutinin (HA) portion of the IAV virus, lose protection as viruses change, and may even lead to vaccine-associated enhanced respiratory disease (VAERD) after infection with a dissimilar influenza virus. A newer replicon particle (RP) vaccine platform targeting the influenza HA protein offers multiple advantages over traditional vaccines for swine, but have not yet been evaluated for the ability to avoid VAERD or the use of HA along with an additional viral vaccine target, such as neuraminidase (NA). In this work we demonstrated RP HA and NA influenza vaccines stimulate immune responses, protect from disease, and avoid VAERD following infection with a distantly related virus. This demonstrates the potential utility of RP vaccines against influenza and the importance in utilizing the NA in influenza vaccine design. Such improvement of IAV vaccines will reduce influenza disease and economic loss in commercial swine and reduce the risk of influenza transmission to people.

Technical Abstract: Alphavirus-derived RNA replicon particle (RP) vaccines represent the next generation of swine influenza A virus (IAV) vaccines, as they were shown to be safe, effective, and offer advantages over traditional vaccine platforms. IAV is a significant respiratory pathogen of swine and there is a critical need to improve current commercial swine IAV vaccine platforms. Adjuvanted whole inactivated virus (WIV) IAV swine vaccines provide limited heterologous protection and may lead to vaccine-associated enhanced respiratory disease (VAERD). This study investigated the ability of RP IAV hemagglutinin (HA) vaccines to avoid VAERD, and evaluated experimental multivalent HA and neuraminidase (NA) RP vaccines. RP vaccines were formulated with HA or NA heterologous or homologous to the challenge virus in monovalent HA or bivalent HA and NA combinations. Pigs were vaccinated with an HA RP, multivalent RP, or heterologous HA WIV, followed by IAV challenge and necropsy 5 days post infection. RP vaccines provided homologous protection from challenge and induced robust peripheral and local antibody responses. The RP vaccine did not induce VAERD after challenge with a virus containing the heterologous HA, in contrast to the traditional WIV vaccine. The HA monovalent and HA and NA bivalent RP- vaccines showed superior protection compared to traditional WIV. Additionally, the RP platform allows greater flexibility to adjust HA and NA content to reflect circulating IAV in swine antigenic diversity.