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Title: Live attenuated influenza A virus vaccine protects against heterologous challenge with A(H1N1)pdm09 without inducing vaccine associated enhanced respiratory disease

Author
item GAUGER, PHILLIP - IOWA STATE UNIVERSITY
item Loving, Crystal
item KHURANA, SURENDER - U.S. FOOD & DRUG ADMINISTRATION (FDA)
item LORUSSO, ALESSIO
item PEREZ, DANIEL - UNIVERSITY OF MARYLAND
item KEHRLI JR, MARCUS
item ROTH, JAMES - IOWA STATE UNIVERSITY
item GOLDING, HANA - U.S. FOOD & DRUG ADMINISTRATION (FDA)
item Vincent, Amy

Submitted to: Virology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/2/2014
Publication Date: 12/1/2014
Citation: Gauger, P.C., Loving, C.L., Khurana, S., Lorusso, A., Perez, D.R., Kehrli, Jr., M.E., Roth, J.A., Golding, H., Vincent, A.L. 2014. Live attenuated influenza A virus vaccine protects against A(H1N1)pdm09 heterologous challenge without vaccine associated enhanced respiratory disease. Virology. 471-473:93-104.

Interpretive Summary: Control of swine influenza A virus (flu) 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. Whole inactivated virus (WIV) vaccines provide only partial protection against flu that are substantially mismatched from the vaccine strains and have the potential risk of vaccine-associated enhanced respiratory disease (VAERD). We previously demonstrated a recombinant flu virus with specific gene modifications was weakened and could be used as an intranasal live attenuated influenza virus (LAIV) vaccine. In the present study, this intranasal LAIV was compared to wild type live virus exposure (WT) and an intramuscular WIV vaccine in a model shown to cause VAERD. Collectively, the results of this experiment demonstrate very distinct outcomes of flu vaccination when pigs are infected with mismatched virus. The LAIV and WT provided protection from challenge with the mismatched strain whereas WIV led to VAERD. These results emphasize 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 flu vaccine evaluation that focus simply on protection against a matched challenged (or closely matched) strain in seronegative pigs or would be unlikely to identify these problems. Determining better indicators of protection versus disease exacerbation than currently used blood tests would significantly aid the evaluation of vaccine safety and efficacy under field conditions.

Technical Abstract: Influenza A virus (IAV) vaccines that provide broad cross-protection against antigenic variants are necessary to prevent infection and shedding of the wide array of IAV cocirculating in swine. Whole inactivated virus (WIV) vaccines provide only partial protection against IAV with substantial antigenic drift and have the potential risk of vaccine-associated enhanced respiratory disease (VAERD). Mucosally delivered, live-attenuated influenza virus (LAIV) vaccines are an alternative that may provide robust cross-protection against contemporary IAV in swine. A temperature sensitive, triple reaasortant intranasal LAIV was compared to wild type exposure (WT) and an intramuscular WIV vaccine in a model shown to induce VAERD. Swine vaccinated with WIV and subsequently challenged with pandemic A/H1N1 (H1N1pdm09) were not protected from infection and demonstrated severe respiratory disease with extensive macroscopic and micrscopic lung lesions and elevated pro-inflammatory and adaptive cytokine concentrations consistent with VAERD. In contrast, lung lesions were mild and challenge virus was not detected in the upper or lower respiratory tract of LAIV vaccinates. Cross-reactive anti-H1N1pdm09 hemagglutination inhibition (HI) and serum neutralization (SN) antibody titers were not detected in any immune groups. Post-challenge, whole virus cross-reactive IgG antibodies were detected in the lungs from WIV, LAIV, and WT immune groups, whereas mucosal IgA was only detected at significant levels in pigs that received intranasal LAIV or WT. This is the first study to demonstrate the effectiveness of the temperature sensitive LAIV vaccine in the H1 VAERD model.