The chimpanzee study to assess the presence of neutralizing antibodies for hepatitis C virus (HCV)in an experimental intravenous immune globulin (HCIGIV) preparation, derived from anti-HCV positive plasma units and had high-levels of antibodies to HCV envelope glycoproteins, E1 and E2, has been completed. HCIGIV incubated with a low-dose HCV inoculum, 64 CID50, did not infect a chimpanzee (experimental) for one year while a commercial IGIV lot, made from anti-HCV screened plasma and devoid of both anti-E1 and anti-E2, incubated with a comparable inoculum infected a chimpanzee (control). When the experimental was subsequently challenged with the same low-dose inoculum alone for checking its susceptibility, anti-HCV was detected within one week implicating an anamnestic response. Subsequent analysis with a supplemental anti-HCV testing revealed that anti-HCV was not confirmed positive till 12 weeks post challenge. The challenged chimpanzee produced antibodies to HCV core, NS-3, and NS-4 proteins, whereas the infected control chimpanzee did not elicit any immune response to the HCV core region. The immune responses to E1 and E2 regions have yet to be investigated. Nevertheless, we can conclude that neutralizing antibodies albeit at low levels, do exist in anti-HCV positive plasma units. This study strongly supports the evidence that anti-HCV screening of plasma compromises the safety of immune globulins unless they are virally inactivated. As a result of the WHO International collaborative study on hepatitis A antibody standards in which we were one of participating laboratories, a second International Standard for Hepatitis A Immune Globulin and a serum standard have been established. We also assessed the levels of anti-HAV, protective antibody to HAV, in products, i.e., Immune Globulin (Human)(IG) made by 4 manufacturers (mfrs) and Immune Globulin Intravenous (IGIV) made by 6 mfrs. The assay was by an EIA (Abbott Laboratories) using the first WHO/CBER anti-HAV Standard, 100 IU/mL (when reconstituted), as a potency reference. The results indicate that the main variable for anti-HAV levels is the type of starting plasma, products from Source Plasma having significantly higher levels than those from recovered plasma. Recently, many lots of solvent-detergent treated pooled plasma made by one mfr were recalled because some lots contained high levels of parvovirus B19 DNA and were associated with B19 transmissions in phase IV safety studies in normal individuals. We investigated whether the lack of complexing/neutralizing antibodies to parvovirus B19 in products was the cause. B19 IgG EIA (kit from Biotrin) was set up using an International Standard, 100 IU/mL of anti-B19 IgG, as a potency standard. Of lots assayed, we found, however, no measurable difference in anti-B19 titers. The investigation of such protective antibodies in other plasma derived products is in progress.
