Human IgG Subclasses against Enterovirus Type 71: Neutralization versus Antibody Dependent Enhancement of Infection

Abstract

The emerging human enterovirus 71 (EV71) represents a growing threat to public health, and no vaccine or specific antiviral is currently available. Human intravenous immunoglobulin (IVIG) is clinical used in treating severe EV71 infections. However, the discovery of antibody dependent enhancement (ADE) of EV71 infection illustrates the complex roles of antibody in controlling EV71 infection. In this study, to identify the distinct role of each IgG subclass on neutralization and enhancement of EV71 infection, different lots of pharmaceutical IVIG preparations manufactured from Chinese donors were used for IgG subclass fractionation by pH gradient elution with the protein A-conjugated affinity column. The neutralization and ADE capacities on EV71 infection of each purified IgG subclass were then assayed, respectively. The neutralizing activity of human IVIG is mainly mediated by IgG1 subclass and to less extent by IgG2 subclass. Interestingly, IgG3 fraction did not have neutralizing activity but enhanced EV71 infection in vitro. These results revealed the different roles of human IgG subclasses on EV71 infection, which is of critical importance for the rational design of immunotherapy and vaccines against severe EV71 diseases.

Immunodominant IgM and IgG Epitopes Recognized by Antibodies Induced in Enterovirus A71-Associated Hand, Foot and Mouth Disease Patients

“…In EV-A71, IgG1 subclass demonstrated the strongest neutralizing ability and is found in human intravenous immunoglobulin [43]. In the present study, IgG1 subclass was identified as the predominant isotype in EV-A71-infected patient sera.…”

Severe Enterovirus Type 71 Nervous System Infections in Children in the Shanghai Region of China

“…16 Design of such a trial will need to take into account the more recent observation that antibodies may enhance and, hence, worsen EV71 infection severity. 24 Furthermore, Cao et al 25 confirmed that that IVIG manufactured in China had EV71 neutralizing activity, mainly mediated by IgG1 subclass but not by IgG3 subclass. The latter IgG3 subclass fraction enhanced EV71 infection in vitro, 25 again raising concerns regarding IVIG treatment safety.…”

Protective antibodies against Clostridium difficile are present in intravenous immunoglobulin and are retained in humans following its administration

“…For example, an early study compared purified subclass antibodies in Herpesvirus neutralization assays, determining that IgG3 and IgG4 had the greatest viral neutralizing ability despite not being the predominant subclass [25]. A further study of responses against human enterovirus 71 found that IgG1 and IgG2 fractions were the most effective at neutralization, and that IgG3 led to enhanced infection [26]. The knowledge obtained from IgG subclass studies, combined with a greater molecular understanding of IgG subclass properties, will facilitate the engineering and development of highly effective CD-specific monoclonal therapeutic antibodies.…”