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

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.

Vaccine-Induced Protection against Orthopoxvirus Infection Is Mediated through the Combined Functions of CD4 T Cell-Dependent Antibody and CD8 T Cell Responses

“…It is not known whether a reduction in neutralizing antibody titers is due to a drop in IgG1, IgG2b, IgG2c, or all 3 subclasses in our study. However, each of the subclasses can contribute to antiviral mechanisms, and induction of IgG2a and IgG1 is a far better correlate for vaccine efficacy and protection (54). In addition to providing help to cognate B cells for antibody production, CD4 T cells can also contribute both directly and indirectly to virus control through other mechanisms (17).…”

Rickettsia rickettsiiouter membrane protein YbgF induces protective immunity in C3H/HeN mice

“…22 A high level of specific IgG2a has been shown to be involved in T-helper cell type 1 (Th1)-immune responses and enhanced efficacy of protein vaccination. 23 Eliciting high levels of specific IgG2a could be considered an important property of rYbgF in inducing protection against R. rickettsii infections.…”

Correlates of vaccine protection from influenza and its complications

“…42 In addition to their neutralizing characteristics, certain IgG antibody isotypes (IgG2a in mice, IgG1 in humans) have the ability to interact with Fc receptors, 44 and this interaction makes a distinct contribution toward clearance of influenza virus infections, particularly lethal infections in animal models. 45 In fact, when directed against the same epitope and compared head-to-head, monoclonal antibodies of the IgG2a isotype demonstrate more efficient protection in mice than those of the IgG1 isotype. 46 We recently demonstrated a similar phenomenon using vaccine-induced antibodies of either the IgG1 or IgG2a isotype directed toward influenza hemagglutinin.…”

“…49 In pre-clinical models, a balanced immune response with induction of both neutralizing IgG1 and Fc-interacting IgG2a has proven to be ideal. 45,50,51 The contribution of the corresponding human Fc-interacting isotypes (i.e., IgG1) toward protective immunity is not as clear as it is in mice, and the majority of vaccine approaches target neutralizing antibodies preferentially without regard to isotype. Interestingly, however, the IgG1 isotype is preferentially induced in humans during natural infection, which may have implications for protective immunity.…”

“…46 We recently demonstrated a similar phenomenon using vaccine-induced antibodies of either the IgG1 or IgG2a isotype directed toward influenza hemagglutinin. 45 Antibodies that interact with activatory Fc receptors have been associated with enhanced uptake of several pathogens including influenza viruses, 47 by Fc receptor-bearing cells (i.e., macrophages). For some pathogens, this increased uptake, termed antibodydependent enhancement, contributes to disease severity.…”