The 1999 introduction of West Nile virus (WNV) into the United States has resulted in the largest epidemic of arboviral illness in the Western Hemisphere, with an estimated 2.5 million cases of mostly asymptomatic human infections since then. As a consequence, an increasing occurrence of WNV antibodies in plasma collected in the United States, and thus in intravenous immunoglobulin (IVIG) products, can be expected. Using an in vitro assay to investigate antibody function, rather then presence, almost 1000-fold differences in neutralization capacity were demonstrated between individual IVIG lots. In a mouse model of lethal WNV infection, treatment with IVIG of a higher WNV antibody titer protected recipients, whereas mice treated with control IVIG died. IVIG lots with higher WNV antibody titers would seem to be desirable for substitution therapy for people with immunodeficiencies.

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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...

This study investigated the association of ongoing West Nile virus (WNV) infections with neutralizing antibody titers in US plasma-derived intravenous immune globulin released during [2003][2004][2005][2006][2007][2008]. Titers correlated closely with the prevalence of past WNV infection in blood donors, with 2008 lots indicating a prevalence of 1%. W est Nile virus (WNV) is a flavivirus endemic to the United States; typically, hundreds of clinical cases of infection occur each year. The observed number of clinical WNV infections as collated by ArboNET (www.cdc. gov) and the incidence of asymptomatic WNV infections as shown by nucleic acid testing (NAT) of the US blood supply (1) indicate that ≈3 million WNV infections occurred in humans during 1999-2008. Because the immune system elicits WNV neutralizing antibodies in response to WNV infection, detectable levels of WNV neutralizing antibodies in the blood of persons with previous WNV infection is expected. Consequently, lots of immune globulin-intravenous (human) (IGIV) manufactured from plasma collected in the United States contain WNV neutralizing antibodies (2). Those IGIV lots, each prepared from several thousand plasma donations to ensure a broad spectrum of antibodies, can be used as an epidemiologic tool that enables the surveillance of thousands of persons in a community through analysis of comparatively few samples. In this study, we demonstrated the increasing trend of WNV-neutralizing antibody titers in lots of IGIV.Comparing these titers with those of persons with confirmed past WNV infection provides an independent measure of the percentage of the US population previously infected with WNV. Several WNV vaccine trials are ongoing or imminent, so information about the prevalence of past WNV infection in the United States is valuable for planning the demonstration of vaccine efficacy. Low incidence and lack of highly WNV-endemic areas in the United States preclude classic vaccine field trials because of study size requirements and cost-logistics difficulties. The StudyThe WNV neutralization titers of several US plasmaderived IGIV products (Gammagard Liquid/KIOVIG; Gammagard S/D/ Polygam S/D; Iveegam EN [Baxter Healthcare Corporation, Westlake Village, CA, USA]) and plasma samples obtained from US blood donors after a NAT-confirmed WNV infection were determined by an infectivity assay as earlier described (2), adapted to a classical microneutralization format (3). WNV neutralization titers (i.e., the reciprocal dilution of a 1:2 series resulting in 50% neutralization [NT 50 ; detection limits <0.8 for undiluted IGIVs and <7.7 for 1:10 prediluted serum]) are reported as the mean ± SEM. An unpaired t test was used to evaluate whether titer differences between 2 groups were statistically significant.Using an extrapolation derived from screening the US blood supply for WNV (1), we calculated the average annual number of WNV infections in the United States for 1999-2008. The total number of neuroinvasive cases reported for those years to the US Centers f...

The higher functional CMV neutralization titers of standard IVIG preparations and the better availability of these preparations, suggest that these products could be a valuable alternative to the CMV hyperimmune preparation.