Human IgG Subclasses: In Vitro Neutralization of and In Vivo Protection against West Nile Virus

Abstract

West Nile virus (WNV)-neutralizing intravenous immune globulins (IVIG)were fractionated into IgG subclasses, and the contribution of each subclass to in vitro neutralization of and in vivo protection against WNV was evaluated. The results indicate that IgG1 (i) is the main subclass induced following WNV infection of humans, (ii) contained nearly all the in vitro WNV neutralization capacity, and (iii) mediates effector functions in vivo that render it superior to other subclasses in protection against WNV. The importance of human IgG1 indicates that a candidate WNV vaccine should induce an immune response that includes WNV-specific IgG1.West Nile virus (WNV), a flavivirus which has become endemic in North America (1) and has now also been recognized as a major public health concern in Europe (6), causes mostly asymptomatic infections (in ϳ80% of cases), and less than 1% of WNV-infected persons develop neuroinvasive disease (7). There are currently no WNV-specific antiviral drugs available, and treatment of patients is limited to supportive care. To optimize efficacy of a potential vaccine, an understanding of the factors involved in successful WNV clearance after infection of humans is important. Some aspects of the immune response to WNV infection have been studied in detail, especially the affinities and specificities of WNV-neutralizing antibodies (Abs), properties which are crucial for effective virus neutralization (5,8,16,26). During these investigations, it became evident that the murine immune response to WNV differs to some degree from that of humans; e.g., the strongly neutralizing Abs that recognize an epitope on the lateral ridge of domain III of the WNV envelope protein in mice are generated far less frequently in the human immune response (16,27). Reports of protective immune responses following the induction of WNV-specific Abs without virus-neutralizing properties highlighted the involvement of Ab-mediated effector responses such as Ab-dependent cellular cytotoxicity, complement activation, and Ab interaction with Fc-␥ receptors (Fc␥Rs) in protection and immunity (3,14,15). The apparent importance of effector functions beyond virus neutralization in host defense renders an understanding of the profile of human IgG subclasses induced following WNV infection and the respective contributions of the subclasses to in vivo protection particularly interesting. The four human IgG subclasses, IgG1 to IgG4, differ in their affinities for Fc␥Rs and therefore in their abilities to induce effector responses (2). In addition, IgG subclass-dependent effects on in vitro virus neutralization were shown recently for another flavivirus, dengue virus (20). Although accumulating evidence highlights the differential involvement of IgG subclasses in the humoral response against flavivirus infection, no information on the contributions of the different human IgG subclasses to WNV neutralization in vitro and, more importantly, their contributions to in vivo protection is currently available.In this work, we used intraveno...

Cytomegalovirus Neutralization by Hyperimmune and Standard Intravenous Immunoglobulin Preparations

“…In addition to CMV, IgG3 was reported as the most important virus neutralizing IgG subclass against Rubella and Polio viruses (19). In contrast, the IgG1 subclass was most effective in in vitro neutralization of measles (16) and West Nile virus (20).…”

Single-dose vaccine against tick-borne encephalitis

“…One piece of evidence that this is the case was that both RepliVax-TBE and YF/TBE chimera elicited a Th1 biased immune response in mice (as opposed to Th2 for INV) as evidenced by a high IgG2a/IgG1 Ab ratio. The latter is also significant because the Th1-associated IgG1 isotype in humans (analog of mouse IgG2a) has been shown to be superior to other isotypes in terms of virus N activity (32). Further studies of innate immune responses in NHP using transcriptomic profiling and T-cell responses in mice are in progress and will be reported elsewhere.…”

TLR3- and MyD88-Dependent Signaling Differentially Influences the Development of West Nile Virus-Specific B Cell Responses in Mice following Immunization with RepliVAX WN, a Single-Cycle Flavivirus Vaccine Candidate

“…WNV-specific antibody is an important component in immune protection against WNV disease, as shown by WNV infection of B cell-deficient mice and by passive transfer of WNV-specific IgM and IgG antibodies (33)(34)(35)(36). Therefore, in addition to generating polyfunctional T cell responses, effective WNV vaccines will need to elicit vigorous and durable antibody responses to protect against WNV disease.…”