IVIG Highly Protective in Ferrets After Challenge with Severe Pandemic pH1N1 and Avian H5N1 Influenza Strains

Australian investigators tested the ability of intravenous immune globulin (IVIG) to protect against potential pandemic influenza virus in outbred ferrets, which are naturally susceptible to human influenza viruses and considered a relevant small animal model of human influenza infection. Two hours prior to intranasal challenge with the 2009 wildtype pH1N1 pandemic influenza virus, animals were administered IVIG prepared from donor plasma. A negative control group was given diluent only, and a positive control group was given homologous (pH1N1) hyperimmune serum by the intraperitoneal route. All animals were euthanized, and virus content was titrated from homogenates taken from 10 different lung sites.

Compared to diluent control animals, there was a marked reduction in the number of sampled lung sites containing pH1N1 virus in ferrets that were administered either IVIG or pH1N1 hyperimmune serum, indicating that IVIG acted to prevent deep lung viral replication.

In a separate ferret study, IVIG was intraperitoneally administered in varying doses, or a similar volume of diluent as a control, to ferrets at the time of challenge with the wildtype avian H5N1 influenza virus strain. Reactivity of IVIG (Privigen) against this lethal influenza strain in a standard hemagglutinin inhibition assay was found to be below detection limits. Nevertheless, while all eight diluent control animals not receiving IVIG succumbed to H5N1 infection, only one of seven animals given the highest IVIG dose (0.5 g/kg) succumbed to infection. Three of four ferrets that received 0.25 g/kg of IVIG survived lethal H5N1 challenge with little or no impact on activity. In the 0.125 g/kg treated group, two of the four animals survived.

To investigate the mechanism by which IVIG conferred protection against lethal H5N1 challenge, F(ab′)2 or Fc fragments derived from IVIG (equimolar to 0.5 g/kg) were administered at the time of challenge with H5N1. Overall, eight out of 10 (80%) of the F(ab′)2-treated animals survived, significantly greater than the Fc-treated and diluent control groups with only three out of 18 (17%) and one out of 10 (10%) survivors respectively. “Our data suggest that following exposure through either vaccination or infection, a level of endogenous antibody cross reactivity to highly pathogen influenza strains occurs in the community … these studies in the ferret model suggest that human IVIG may be effective in preventing serious influenza infection and provides a possible alternative treatment option requiring confirmation in human clinical trials,” the authors concluded.