Prophylactic and Therapeutic Efficacy of Human Monoclonal Antibodies against H5N1 Influenza

Abstract

BackgroundNew prophylactic and therapeutic strategies to combat human infections with highly pathogenic avian influenza (HPAI) H5N1 viruses are needed. We generated neutralizing anti-H5N1 human monoclonal antibodies (mAbs) and tested their efficacy for prophylaxis and therapy in a murine model of infection.Methods and FindingsUsing Epstein-Barr virus we immortalized memory B cells from Vietnamese adults who had recovered from infections with HPAI H5N1 viruses. Supernatants from B cell lines were screened in a virus neutralization assay. B cell lines secreting neutralizing antibodies were cloned and the mAbs purified. The cross-reactivity of these antibodies for different strains of H5N1 was tested in vitro by neutralization assays, and their prophylactic and therapeutic efficacy in vivo was tested in mice. In vitro, mAbs FLA3.14 and FLD20.19 neutralized both Clade I and Clade II H5N1 viruses, whilst FLA5.10 and FLD21.140 neutralized Clade I viruses only. In vivo, FLA3.14 and FLA5.10 conferred protection from lethality in mice challenged with A/Vietnam/1203/04 (H5N1) in a dose-dependent manner. mAb prophylaxis provided a statistically significant reduction in pulmonary virus titer, reduced associated inflammation in the lungs, and restricted extrapulmonary dissemination of the virus. Therapeutic doses of FLA3.14, FLA5.10, FLD20.19, and FLD21.140 provided robust protection from lethality at least up to 72 h postinfection with A/Vietnam/1203/04 (H5N1). mAbs FLA3.14, FLD21.140 and FLD20.19, but not FLA5.10, were also therapeutically active in vivo against the Clade II virus A/Indonesia/5/2005 (H5N1).ConclusionsThese studies provide proof of concept that fully human mAbs with neutralizing activity can be rapidly generated from the peripheral blood of convalescent patients and that these mAbs are effective for the prevention and treatment of H5N1 infection in a mouse model. A panel of neutralizing, cross-reactive mAbs might be useful for prophylaxis or adjunctive treatment of human cases of H5N1 influenza.

Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin

“…Oseltamivir-resistant H1N1, which emerged rapidly beginning in 2007-2008, has become the predominant strain of seasonal influenza, and management of severe infection could benefit from a broadly reacting, immunebased therapeutic (18). Previous studies with a human mAb targeting the globular head of H5N1 predict that the effective neutralizing concentrations we find for CH65 would be protective in vivo (19). Blood was drawn on day 7 postvaccination, and peripheral blood mononuclear cells (PBMCs) were isolated and cryopreserved on the same day.…”

Cross-Protection of Chicken Immunoglobulin Y Antibodies against H5N1 and H1N1 Viruses Passively Administered in Mice

“…High levels of protection against lethal challenge with the virus was found using the F(abЈ) 2 fragments of the antisera. In addition, another study showed that sheep antisera raised against a single strain of H5N1 can cross-protect against a variety of H5N1 strains from other clades of viruses (13). However, only in chicken IgY samples did we observe this cross-protection between H5N1 and H1N1 viruses.…”

“…Humanized monoclonal antibodies raised against these conserved epitopes from a single influenza virus strain were shown to provide strong cross-protection against heterologous strains (13). These results provide hope toward producing either antigens or antibodies that can be used for active or passive immunization against a large variety of influenza viruses.…”

Anticorps thérapeutiques et maladies infectieuses

“…Il y a actuellement une vingtaine d'essais cliniques testant des Acm dans le domaine infectieux. Leur développement peut être également basé sur le fait qu'il n'existe pas de stratégie vaccinale envisageable comme dans le cas des toxines du bacille du charbon où la réponse thérapeutique doit être très rapide ou par exemple pour une prophylaxie en cas de pandémie grippale [8,9] …”