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

TLDR

Vaccination is the most effective protection against influenza, yet nonneutralizing antibodies may also contribute to immunity. The study aims to dissect the individual contributions of IgG1 and IgG2a antibody isotypes to vaccine‑induced immunity against influenza. The authors used a vaccine regimen that selectively enhanced IgG1 or IgG2a by employing DNA or viral replicon particle vectors expressing hemagglutinin (HA‑DNA or HA‑VRP). HA‑DNA vaccination induced neutralizing antibodies and IgG1, whereas HA‑VRP vaccination induced IgG2a and was associated with viral clearance and protection; overall, simultaneous induction of both IgG1 and IgG2a correlated better with vaccine efficacy than neutralization alone, underscoring distinct roles for each isotype.

Abstract

ABSTRACT 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.