|Ma, Wenjun -|
|Janke, Bruce -|
|Sandbulte, Matthew -|
|Gauger, Phillip -|
|Webby, Richard -|
|Garcia-Sastre, Adolfo -|
Submitted to: Journal of Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 13, 2012
Publication Date: October 1, 2012
Citation: Vincent, A.L., Ma, W., Lager, K.M., Richt, J.A., Janke, B.H., Sandbulte, M.R., Gauger, P.C., Loving, C.L., Webby, R.J., Garcia-Sastre, A. 2012. Live attenuated influenza vaccine provides superior protection from heterologous infection in pigs with maternal antibodies without inducing vaccine associated enhanced respiratory disease. Journal of Virology. 86(19):10597-10605. Interpretive Summary: Control of swine influenza A virus (IAV) in the US is hindered since the commonly used inactivated vaccines do not provide sufficient cross-protection against the multiple antigenic variants co-circulating in the field. Vaccine efficacy can be further limited when administered to young pigs that possess maternally derived immunity from suckling colostrum from their dams. We previously demonstrated a recombinant IAV with a specific gene modification was weakened and could be used as an intranasal live attenuated influenza virus (LAIV) vaccine. In the present study, we compared 1 dose of intranasal LAIV with 2 intramuscular doses of whole inactivated virus (WIV) vaccine with adjuvant, the traditional vaccine used in the swine industry, in weanling pigs with and without specific maternally-derived antibodies (MDA). Collectively, the results of this experiment demonstrate very distinct outcomes of IAV vaccination and infection with heterologous virus, with pivotal factors including the format and route of administration of vaccines, the presence or absence of MDA, and the antigenic similarity of challenge virus to the vaccine strain. The differences go beyond protection versus non-protection, and point to realistic scenarios in the field where vaccinating sows and their piglets could potentiate more severe respiratory disease. This underscores the need to re-evaluate the way in which efficacy studies are designed for swine influenza vaccine licensure for use in pigs in the United States. Methods of IAV vaccine evaluation that focus simply on protection against homologous challenge in seronegative pigs would be unlikely to identify this problem. Determining the immune correlates of protection versus disease exacerbation would significantly aid the improvement of vaccine safety and efficacy under field conditions.
Technical Abstract: Control of swine influenza A virus (IAV) in the US is hindered since inactivated vaccines do not provide robust cross-protection against the multiple antigenic variants co-circulating in the field. Vaccine efficacy can be further limited when administered to young pigs that possess maternally derived immunity. We previously demonstrated a recombinant A/sw/Texas/4199-2/1998 (TX98) (H3N2) expressing a truncated NS1 protein is attenuated in swine and shows potential for use as an intranasal live attenuated influenza virus (LAIV) vaccine. In the present study, we compared 1 dose of intranasal LAIV with 2 intramuscular doses of TX98 whole inactivated virus (WIV) with adjuvant in weanling pigs with and without TX98-specific maternally-derived antibodies (MDA). Pigs were subsequently challenged with wild type homologous TX98 H3N2 virus or with an antigenic variant A/sw/Colorado/23619/1999 (CO99) (H3N2). In the absence of MDA, both vaccines protected against homologous TX98 and heterologous CO99 shedding, although the LAIV elicited lower hemagglutination inhibiting (HI) antibody titers in serum. However, WIV vaccination of MDA-positive pigs led to dramatically enhanced pneumonia following heterologous challenge, a phenomenon known as vaccine-associated enhanced respiratory disease (VAERD). Although the efficacy of the single-dose LAIV was reduced by MDA, the data suggest it may be a safer vaccine for young pigs in field conditions where dams are routinely vaccinated and diverse IAV strains are in circulation. These results may have implications not only to pigs but to other influenza virus host species.