A Neutralizing Human Monoclonal Antibody Protects African Green Monkeys from Hendra Virus Challenge

Abstract Background Nipah virus (NiV) and Hendra virus (HeV) are zoonotic paramyxoviruses that cause severe disease in both animals and humans. There are no approved vaccines or treatments for use in humans; however, therapeutic treatment of both NiV and HeV infection in ferrets and non-human primates with a cross-reactive, neutralizing human monoclonal antibody (mAb), m102.4, targeting the G glycoprotein has been demonstrated. In a previous study, we isolated, characterized, and humanized a cross-reactive, neutralizing anti-F mAb (h5B3.1). The mAb h5B3.1 blocks the required F conformational change needed to facilitate membrane fusion and virus infection, and the epitope recognized by h5B3.1 has been structurally defined; however, the efficacy of h5B3.1 in vivo is unknown. Methods The post-infection antiviral activity of h5B3.1 was evaluated in vivo by administration in ferrets after NiV and HeV virus challenge. Results All subjects that received h5B3.1 from 1 to several days after infection with a high-dose, oral-nasal virus challenge were protected from disease, whereas all controls died. Conclusions This is the first successful post-exposure antibody therapy for NiV and HeV using a humanized cross-reactive mAb targeting the F glycoprotein, and the findings suggest that a combination therapy targeting both F and G should be evaluated as a therapy for NiV/HeV infection.

Download Full-text

Heterosubtypic Protection Conferred by the Human Monoclonal Antibody PN-SIA28 against Influenza A Virus Lethal Infections in Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00118-15 ◽

2015 ◽

Vol 59 (5) ◽

pp. 2647-2653 ◽

Cited By ~ 1

Author(s):

Miguel Retamal ◽

Yacine Abed ◽

Chantal Rhéaume ◽

Francesca Cappelletti ◽

Nicola Clementi ◽

...

Keyword(s):

Monoclonal Antibody ◽

Body Weight ◽

Influenza Virus ◽

Influenza A ◽

Human Monoclonal Antibody ◽

Influenza A Viruses ◽

Virus Challenge ◽

Influenza A H1n1

ABSTRACTPN-SIA28 is a human monoclonal antibody (Hu-MAb) targeting highly conserved epitopes within the stem portion of the influenza virus hemagglutinin (HA) (N. Clementi, et al, PLoS One 6:e28001, 2011,http://dx.doi.org/10.1371/journal.pone.0028001). Previousin vitrostudies demonstrated PN-SIA28 neutralizing activities against phylogenetically divergent influenza A subtypes. In this study, the protective activity of PN-SIA28 was evaluated in mice inoculated with lethal influenza A/WSN/33 (H1N1), A/Quebec/144147/09 (H1N1)pdm09, and A/Victoria/3/75 (H3N2) viruses. At 24 h postinoculation (p.i.), animals received PN-SIA28 intraperitoneally (1 or 10 mg/kg of body weight) or 10 mg/kg of unrelated Hu-MAb (mock). Body weight loss and mortality rate (MR) were recorded for 14 days postinfection (p.i.). Lung viral titers (LVT) were determined at day 5 p.i. In A/WSN/33 (H1N1)-infected groups, all untreated and mock-receiving mice died, whereas MRs of 87.5% and 25% were observed in mice that received PN-SIA28 1 and 10 mg/kg, respectively. In influenza A(H1N1) pdm09-infected groups, an MR of 75% was recorded for untreated and mock-treated groups, whereas the PN-SIA28 1-mg/kg and 10-mg/kg groups had rates of 62.5% and 0%, respectively. In A/Victoria/3/75 (H3N2)-infected animals, untreated and mock-treated animals had MRs of 37.5% and 25%, respectively, and no mortalities were recorded after PN-SIA28 treatments. Accordingly, PN-SIA28 treatments significantly reduced weight losses and resulted in a ≥1-log reduction in LVT compared to the control in all infection groups. This study confirms that antibodies targeting highly conserved epitopes in the influenza HA stem region, like PN-SIA28, not only neutralize influenza A viruses of clinically relevant subtypesin vitrobut also, more importantly, protect from a lethal influenza virus challengein vivo.

Download Full-text

A Hendra Virus G Glycoprotein Subunit Vaccine Protects African Green Monkeys from Nipah Virus Challenge

Science Translational Medicine ◽

10.1126/scitranslmed.3004241 ◽

2012 ◽

Vol 4 (146) ◽

pp. 146ra107-146ra107 ◽

Cited By ~ 72

Author(s):

K. N. Bossart ◽

B. Rockx ◽

F. Feldmann ◽

D. Brining ◽

D. Scott ◽

...

Keyword(s):

Subunit Vaccine ◽

Nipah Virus ◽

Hendra Virus ◽

Virus Challenge ◽

Green Monkeys

Download Full-text

Crystal Structure of the Hendra Virus Attachment G Glycoprotein Bound to a Potent Cross-Reactive Neutralizing Human Monoclonal Antibody

PLoS Pathogens ◽

10.1371/journal.ppat.1003684 ◽

2013 ◽

Vol 9 (10) ◽

pp. e1003684 ◽

Cited By ~ 26

Author(s):

Kai Xu ◽

Barry Rockx ◽

Yihu Xie ◽

Blair L. DeBuysscher ◽

Deborah L. Fusco ◽

...

Keyword(s):

Crystal Structure ◽

Monoclonal Antibody ◽

Human Monoclonal Antibody ◽

Hendra Virus ◽

Virus Attachment

Download Full-text

Faculty Opinions recommendation of Crystal structure of the Hendra virus attachment G glycoprotein bound to a potent cross-reactive neutralizing human monoclonal antibody.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718145476.793490802 ◽

2014 ◽

Author(s):

Anne Moscona ◽

Laura M Palermo ◽

Matteo Porotto

Keyword(s):

Crystal Structure ◽

Monoclonal Antibody ◽

Human Monoclonal Antibody ◽

Hendra Virus ◽

Virus Attachment

Download Full-text

Clinical and virological responses to a broad-spectrum human monoclonal antibody in an influenza virus challenge study

Antiviral Research ◽

10.1016/j.antiviral.2020.104763 ◽

2020 ◽

Vol 184 ◽

pp. 104763

Author(s):

Susan E. Sloan ◽

Kristy J. Szretter ◽

Bharathi Sundaresh ◽

Kristin M. Narayan ◽

Patrick F. Smith ◽

...

Keyword(s):

Monoclonal Antibody ◽

Influenza Virus ◽

Broad Spectrum ◽

Human Monoclonal Antibody ◽

Virus Challenge ◽

Challenge Study

Download Full-text

Phase 2 Randomized Trial of the Safety and Efficacy of MHAA4549A, a Broadly Neutralizing Monoclonal Antibody, in a Human Influenza A Virus Challenge Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01154-17 ◽

2017 ◽

Vol 61 (11) ◽

Cited By ~ 32

Author(s):

Jacqueline M. McBride ◽

Jeremy J. Lim ◽

Tracy Burgess ◽

Rong Deng ◽

Michael A. Derby ◽

...

Keyword(s):

Monoclonal Antibody ◽

Viral Load ◽

Influenza A Virus ◽

Influenza A ◽

Human Monoclonal Antibody ◽

Area Under The Curve ◽

Inflammatory Biomarkers ◽

Double Blind ◽

Safety And Efficacy ◽

Virus Challenge

ABSTRACT MHAA4549A, a human monoclonal antibody targeting the hemagglutinin stalk region of influenza A virus (IAV), is being developed as a therapeutic for patients hospitalized with severe IAV infection. The safety and efficacy of MHAA4549A were assessed in a randomized, double-blind, placebo-controlled, dose-ranging study in a human IAV challenge model. One hundred healthy volunteers were inoculated with A/Wisconsin/67/2005 (H3N2) IAV and, 24 to 36 h later, administered a single intravenous dose of either placebo, MHAA4549A (400, 1,200, or 3,600 mg), or a standard oral dose of oseltamivir. Subjects were assessed for safety, pharmacokinetics (PK), and immunogenicity. The intent-to-treat-infected (ITTI) population was assessed for changes in viral load, influenza symptoms, and inflammatory biomarkers. MHAA4549A was well tolerated in all IAV challenge subjects. The 3,600-mg dose of MHAA4549A significantly reduced the viral burden relative to that of the placebo as determined by the area under the curve (AUC) of nasopharyngeal virus infection, quantified using quantitative PCR (98%) and 50% tissue culture infective dose (TCID50) (100%) assays. Peak viral load, duration of viral shedding, influenza symptom scores, mucus weight, and inflammatory biomarkers were also reduced. Serum PK was linear with a half-life of ∼23 days. No MHAA4549A-treated subjects developed anti-drug antibodies. In conclusion, MHAA4549A was well tolerated and demonstrated statistically significant and substantial antiviral activity in an IAV challenge model. (This study has been registered at ClinicalTrials.gov under identifier NCT01980966.)

Download Full-text