Vaccine-Induced Anti-HA2 Antibodies Promote Virus Fusion and Enhance Influenza Virus Respiratory Disease
Science Translational Medicine
28 Aug 2013
Vol 5, Issue 200
p. 200ra114
The (Mis)match Game
Even the most beneficial things—like vaccines—sometimes have a downside. Learning what causes the downside is critical for avoiding it. In the case of viral vaccines, there have been some reports of rare vaccine-induced disease enhancement—for example, vaccine-associated enhanced respiratory disease (VAERD) for influenza. Khurana et al. now report that mismatched strains of the same subtype of influenza may lead to VAERD in pigs.
The authors vaccinated pigs with whole inactivated H1N2 influenza virus. These pigs had enhanced pneumonia and disease after infection with another strain—pH1N1. Looking more closely, the authors found that the immune sera from the H1N2-vaccinated pigs contained high titers of cross-reactive hemagglutinin antibodies. These antibodies actually enhanced pH1N1 infection in cell culture by promoting virus membrane fusion activity, and this enhanced fusion correlated with lung pathology. This mechanism of VAERD should be considered when devising strategies to devise a universal flu vaccine.
Abstract
Vaccine-induced disease enhancement has been described in connection with several viral vaccines in animal models and in humans. We investigated a swine model to evaluate mismatched influenza vaccine-associated enhanced respiratory disease (VAERD) after pH1N1 infection. Vaccinating pigs with whole inactivated H1N2 (human-like) virus vaccine (WIV-H1N2) resulted in enhanced pneumonia and disease after pH1N1 infection. WIV-H1N2 immune sera contained high titers of cross-reactive anti-pH1N1 hemagglutinin (HA) antibodies that bound exclusively to the HA2 domain but not to the HA1 globular head. No hemagglutination inhibition titers against pH1N1 (challenge virus) were measured. Epitope mapping using phage display library identified the immunodominant epitope recognized by WIV-H1N2 immune sera as amino acids 32 to 77 of pH1N1-HA2 domain, close to the fusion peptide. These cross-reactive anti-HA2 antibodies enhanced pH1N1 infection of Madin-Darby canine kidney cells by promoting virus membrane fusion activity. The enhanced fusion activity correlated with lung pathology in pigs. This study suggests a role for fusion-enhancing anti-HA2 antibodies in VAERD, in the absence of receptor-blocking virus-neutralizing antibodies. These findings should be considered during the evaluation of universal influenza vaccines designed to elicit HA2 stem-targeting antibodies.
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Supplementary Material
Summary
Fig. S1. Pairwise alignment of the HA amino acid sequence of pH1N1 (A/California/04/2009) and H1N2 (A/Swine/Minnesota/02011/2008).
Fig. S2. Phylogenetic tree of HA proteins from human and swine H1 viruses.
Fig. S3. Anti-HA2 antibodies can compete with pH1N1-neutralizing antibodies.
Fig. S4. WIV-H1N2 postvaccination serum antibody binding to N-terminal HA1 domain is mediated by IgM isotype antibody.
Fig. S5. Binding of pH1N1 virus to sialic acid receptor in the absence and presence of WIV-H1N2 sera in SPR assay.
Fig. S6. No enhancement of pH1N1 virus–mediated hemagglutination in the presence of WIV-H1N2 serum antibodies.
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Published In
Science Translational Medicine
Volume 5 | Issue 200
August 2013
August 2013
Copyright
Copyright © 2013, American Association for the Advancement of Science.
Submission history
Received: 6 April 2013
Accepted: 26 June 2013
Acknowledgments
We thank J. Yewdell, M. Eichelberger, and C. Weiss for their thorough review and insightful comments. We also thank M. Harland and G. Nordholm for technical assistance and J. Huegel, J. Crabtree, and T. Standley for assistance with animal studies. Funding: Funding was provided by Agricultural Research Service, U.S. Department of Agriculture (USDA). Mention of trade names or commercial products in this article is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the USDA. USDA is an equal opportunity provider and employer. Author contributions: S.K., C.L.L., A.L.V., and H.G. designed and performed the experiments, analyzed the data, and wrote and edited the paper. J.M., L.R.K., J.H., and P.C.G. performed the experiments, analyzed the data, and read the paper. Competing interests: The authors declare that they have no competing interests.
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