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Passive Immunization with Human Monoclonal Antibodies in H5N1

By Luciana Borio, M.D., May 30, 2007

In their study1 published this week by PLoS Medicine, Simmons and colleagues show that passive immunotherapy with neutralizing H5N1 human monoclonal antibodies (mAbs) is effective in preventing and treating H5N1 infection in a murine model.

In an ingenious experiment, scientists immortalized (with Epstein-Barr virus) memory B cells from four Vietnamese adults who had recovered from infections with HPAI H5N1 viruses. B cell lines that secreted neutralizing antibodies against H5N1 were cloned, and the mAbs were purified. In vitro neutralization assays were conducted to assess the antibodies’ cross-reactivity with different strains of H5N1. In vivo prophylactic and therapeutic efficacy was tested in mice challenged intranasally with HPAI H5N1 strains.

All of the mAbs neutralized Clade I H5N1 viruses. Some of the mAbs neutralized both Clade I and Clade II H5N1 viruses. When employed prophylactically, the mAbs reduced pulmonary virus titer and attenuated inflammation (by histological analysis), and restricted extrapulmonary dissemination of the virus. When administered up to 72 hours after infectious challenge with A/Vietnam/1203/04 H5N1 virus, the mAbs protected mice from death. Additionally, some of the mAbs protected mice from death when administered at 24 hours after infection with Clade II virus A/Indonesia/5/2005 H5N1 virus.

The overall mortality of HPAI H5N1 infection in humans is around 60%.2 Treatment options are limited, and the clinical benefit of antiviral drugs appears to be partial and requires early administration. In the event of an influenza pandemic, new prophylactic and therapeutic strategies will be needed to mitigate illness and associated mortality. This is especially true in the event the virus becomes resistant to available antiviral drugs. A recent meta-analysis3 suggests that when administered early, passive immunotherapy with plasma from convalescent patients was associated with a 50% reduction in the death rate during the Spanish flu pandemic. If found to be useful in ameliorating H5N1 infections in humans, passive immunotherapy with mAbs, could be a promising therapeutic modality. Large amounts of virus-specific neutralizing mAbs can be manufactured efficiently with technologies available today.4 With a concerted effort, and excluding FDA regulatory issues,  these could possibly be scaled up for production within approximately 18-24 months. 

References

  1. Simmons CP, Bernasconi NL, Suguitan Jr. AL, et al. Prophylactic and Therapeutic Efficacy of Human Monoclonal Antibodies against H5N1 Influenza. PLoS Medicine Vol. 4, No. 5, e178 doi:10.1371/journal.pmed.0040178.

  2. World Health Organization. Epidemiology of WHO-confirmed human cases of avian influenza A(H5N1) infection. Wkly Epidemiol 2006; Rec. 81:249–257.

  3. Luke TC, Kilbane EM, Jackson JL, Hoffman SL. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann Intern Med 2006;145:599-609.

  4. Traggiai E, Becker S, Subbarao K, et al. An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nat Med 2004;8:871-5.