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Clinical and Vaccine Immunology, September 2006, p. 981-990, Vol. 13, No. 9
1071-412X/06/$08.00+0     doi:10.1128/CVI.00156-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Distinct Contributions of Vaccine-Induced Immunoglobulin G1 (IgG1) and IgG2a Antibodies to Protective Immunity against Influenza

Victor C. Huber,1 Raelene M. McKeon,1 Martha N. Brackin,1 Laura A. Miller,1 Rachael Keating,2 Scott A. Brown,2 Natalia Makarova,3 Daniel R. Perez,4 Gene H. MacDonald,1 and Jonathan A. McCullers1*

Department of Infectious Disease, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,1 Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,2 Department of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee 38163,3 Department of Veterinary Medicine, University of Maryland, College Park, Maryland 207424

Received 26 April 2006/ Returned for modification 20 June 2006/ Accepted 5 July 2006

Vaccination represents the most effective form of protection against influenza infection. While neutralizing antibodies are typically measured as a correlate of vaccine-induced protective immunity against influenza, nonneutralizing antibodies may contribute to protection or amelioration of disease. The goal of this study was to dissect the individual contributions of the immunoglobulin G1 (IgG1) and IgG2a antibody isotypes to vaccine-induced immunity against influenza virus. To accomplish this, we utilized an influenza vaccine regimen that selectively enhanced IgG1 or IgG2a antibodies by using either DNA or viral replicon particle (VRP) vectors expressing influenza virus hemagglutinin (HA) (HA-DNA or HA-VRP, respectively). After HA-DNA vaccination, neutralizing antibodies were detected by both in vitro (microneutralization) and in vivo (lung viral titer) methods and were associated with increased IgG1 expression by enzyme-linked immunosorbent assay (ELISA). Vaccination with HA-VRP did not strongly stimulate either neutralizing or IgG1 antibodies but did induce IgG2a antibodies. Expression of IgG2a antibodies in this context correlated with clearance of virus and increased protection against lethal influenza challenge. Increased induction of both antibody isotypes as measured by ELISA was a better correlate for vaccine efficacy than neutralization alone. This study details separate but important roles for both IgG1 and IgG2a expression in vaccination against influenza and argues for the development of vaccine regimens that stimulate and measure expression of both antibody isotypes.

* Corresponding author. Mailing address: St. Jude Children's Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105-2794. Phone: (901) 495-3486. Fax: (901) 495-3099. E-mail: jon.mccullers{at}stjude.org.

Clinical and Vaccine Immunology, September 2006, p. 981-990, Vol. 13, No. 9
1071-412X/06/$08.00+0     doi:10.1128/CVI.00156-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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