1. VIS410, a human antibody which targets the hemagglutinin (HA) glycoprotein on the surface of flu viruses, showed strong binding to a variety of influenza A virus strains based on computational and in vitro experiments.
2. Administration of VIS410 either alone or in combination with oseltamivir, a neuraminidase inhibitor, led to increased survival and mitigated cytokine response in various mouse models of H7N9 challenge.
Evidence Rating Level: 2 (Good)
Study Rundown: Influenza virus remains a significant cause of human mortality and morbidity, and particularly virulent strains such as H7N9 are associated with greater adverse patient outcomes despite available treatments. Current flu vaccines use inactivated virus antigens to provoke antibody production, and infections are also therapeutically treated with neuraminidase inhibitors such as oseltamivir. This work instead tested an antibody to broadly target HA in H7N9 and other virus strains, for use as a pre- or post-infection treatment.
The authors first used computational methods to design the VIS410 antibody candidate based on its ability to bind HAs from multiple virus strains. In vitro experiments confirmed predicted binding affinities. In an initial set of animal experiments, one-time therapeutic administration of VIS410 increased survival in mice given a lethal dose of the H3N2 strain. In a mouse model of lethal H7N9 challenge, treatment with VIS410 alone or with daily administration of oseltamivir increased survival when compared to oseltamivir treatment alone. In a separate murine model of sublethal H7N9 challenge, mice prophylactically given VIS410 in combination with twice daily oseltamivir showed lower lung cytokine levels than those given mock treatment.
Overall, this work represents a promising new and potent antibody-based approach to treating influenza infection. Future work should address optimization of VIS410 administration, including whether it should be given prophylactically or therapeutically. Additionally, safety of VIS410 must be rigorously evaluated before the drug can be considered for clinical use.
Click to read the study in PNAS
Relevant Reading: Clinical Findings in 111 Cases of Influenza A (H7N9) Virus Infection
In-Depth [animal study]: Initial computational experiments focused on developing an antibody to bind to the HA stem region, whose highly interconnected trimeric interface may be more resistant to mutation than other HA regions. In vitro enzyme-linked immunosorbent assays confirmed the high binding affinity of VIS410 for a variety of flu viruses, with dissociation constants measuring 50-730 pM.
An initial baseline animal experiment involved challenging BALB/c mice with a lethal intranasal dose of H3N2. Intraperitoneal administration of 2.5-20 mg/kg VIS410 48 hours after exposure increased survival compared to placebo-treated mice (p<0.001, n=10-15 per group). Next, DBA mice were used to model lethal H7N9 infection, since they are more sensitive to influenza infection than other mice. Mice given 50 mg/kg VIS410 24 hours before H7N9 exposure and again 48 hours after exposure showed increased survival over mice given 50 mg/kg oseltamivir twice daily for 8 days (p=0.015, n=10 per group). Combining one dose of VIS410 with daily oseltamivir treatment improved survival as compared to administering oseltamivir alone (p<0.001, n=10 per group).
A third animal model involved subjecting C57BL/6 mice to a sublethal dose of H7N9. Animals given 50 mg/kg VIS410 at 12 hours before infection combined with 40 mg/kg oseltamivir twice daily showed lower lung viral loads than mock-treated animals at 5 days following inoculation (p=0.002, n=6 per group). In comparison to mock-treated mice, the combination-treated animals also showed lower levels of several cytokines, including monocyte chemotactic protein-3 (MCP-3), interferon gamma-induced protein 10 (IP-10), and macrophage inflammatory protein 1α (MIP-1α) (p<0.05 for each, n=3 per group).
Image: PD
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