The Hemagglutinin Stem-Binding Monoclonal Antibody VIS410 Controls Influenza Virus-Induced Acute Respiratory Distress Syndrome

Baranovich, Tatiana; Jones, Jeremy C.; Russier, Marion; Vogel, Peter; Szretter, Kristy J.; Sloan, Susan; Seiler, Patrick; Trevejo, José; Webby, Richard J.; Govorkova, Elena A.

doi:10.1128/aac.02457-15

Cited by 48 publications

(34 citation statements)

References 50 publications

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“…Similarly, the MAbs VIS410 (27) and 1H5 (47), as well as 41-5D06, 07-5E01, and 24-4C01 (30), were also shown to protect mice from lethal infections with H7N9 virus, although it failed to neutralize the virus in vitro . Another prime example is CR9114, which binds to influenza B HA and is protective against influenza B challenge; however, this MAb only neutralizes influenza A and not influenza B viruses (23).…”

Section: Discussionmentioning

confidence: 99%

“…These MAbs are 39.29 and 81.39 (21); FI6v3 (22); CR9114 (23); PN-SIA-28 (24); CT149 (25); VIS410 (26, 27); 045-051310-2B06 and S6-B01 (28); 05-2G02 (29); 07-5E01, 41-5D06, and 41-5E04 (30); HV6-1+HD3-3, HV1-18+HD3-9, and HV1-18 (Q-x-x-V) (31); and MEDI8852 (32). Nonetheless, their antiviral activities against all known subtypes of influenza A viruses has not been completely characterized.…”

Section: Introductionmentioning

confidence: 99%

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Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins

Marjuki

Mishin

Chai³

et al. 2016

J Virol

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The pandemic threat posed by emerging zoonotic influenza A viruses necessitates development of antiviral agents effective against various antigenic subtypes. Human monoclonal antibody (hMAb) targeting the hemagglutinin (HA) stalk offers a promising approach to control influenza virus infections. Here, we investigated the ability of the hMAb 81.39a to inhibit in vitro replication of human and zoonotic viruses, representing 16 HA subtypes. The majority of viruses were effectively neutralized by 81.39a at a 50% effective concentration (EC50) of <0.01 to 4.9 μg/ml. Among group 2 HA viruses tested, a single A(H7N9) virus was not neutralized at 50 μg/ml; it contained HA2-Asp19Gly, an amino acid position previously associated with resistance to neutralization by the group 2 HA-neutralizing MAb CR8020. Notably, among group 1 HA viruses, H11-H13 and H16 subtypes were not neutralized at 50 μg/ml; they shared the substitution HA2-Asp19Asn/Ala. Conversely, H9 viruses harboring HA2-Asp19Ala were fully susceptible to neutralization. Therefore, amino acid variance at HA2-Asp19 has subtype-specific adverse effects on in vitro neutralization. Mice given a single injection (15 or 45 mg/kg of body weight) at 24 or 48 h after infection with recently emerged A(H5N2), A(H5N8), A(H6N1), or A(H7N9) viruses were protected from mortality and showed drastically reduced lung viral titers. Furthermore, 81.39a protected mice infected with A(H7N9) harboring HA2-Asp19Gly, although the antiviral effect was lessened. A(H1N1)pdm09-infected ferrets receiving a single dose (25 mg/kg) had reduced viral titers and showed less lung tissue injury, despite 24- to 72-h-delayed treatment. Taken together, this study provides experimental evidence for the therapeutic potential of 81.39a against diverse influenza A viruses. IMPORTANCE Zoonotic influenza viruses, such as A(H5N1) and A(H7N9) subtypes, have caused severe disease and deaths in humans, raising public health concerns. Development of novel anti-influenza therapeutics with a broad spectrum of activity against various subtypes is necessary to mitigate disease severity. Here, we demonstrate that the hemagglutinin (HA) stalk-targeting human monoclonal antibody 81.39a effectively neutralized the majority of influenza A viruses tested, representing 16 HA subtypes. Furthermore, delayed treatment with 81.39a significantly suppressed virus replication in the lungs, prevented dramatic body weight loss, and increased survival rates of mice infected with A(H5Nx), A(H6N1), or A(H7N9) viruses. When tested in ferrets, delayed 81.39a treatment reduced viral titers, particularly in the lower respiratory tract, and substantially alleviated disease symptoms associated with severe A(H1N1)pdm09 influenza. Collectively, our data demonstrated the effectiveness of 81.39a against both seasonal and emerging influenza A viruses.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins

Marjuki

Mishin

Chai³

et al. 2016

J Virol

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“…These include anti-HA stalk monoclonal antibodies (mAbs) like CR6162 [13], F10 [15], 6F12 [29] or KB2 [30] that bind to group 1 HAs and mAbs like CR8020 [31], CR8043 [32], 9H10 [33] or 12D1 [34], 042-100809-2F04 [35] and 41-5E04 [36] that bind to group 2 HAs. Anti-stalk mAbs that bind to group 1 and to group 2 HAs are rarer but these antibodies, including mAb anti-stalk mAbs FI6 [37], 05-2G02 [38], 81.39a [39, 40], 39.29/MHAA4549A [40–43], MEDI8852 [44], CT-P27, VIS410 [45–47] and CT149 [48], have been isolated as well. Finally, one mAb, CR9114, has been shown to bind to all influenza A and B HAs [49].…”

Section: Novel Antibody-based Universal Influenza Virus Therapeuticsmentioning

confidence: 99%

Universal influenza virus vaccines and therapeutic antibodies

Nachbagauer

Krammer

2017

Clinical Microbiology and Infection

170

152

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Background Current influenza virus vaccines are effective when well matched to the circulating strains. Unfortunately, antigenic drift and the high diversity of potential emerging zoonotic and pandemic viruses make it difficult to select the right strains for vaccine production. This problem causes vaccine mismatches which lead to sharp drops in vaccine effectiveness and long response times in case of novel pandemic viruses. Aims To provide an overview of universal influenza virus vaccines and therapeutic antibodies in pre-clinical and clinical development. Sources PubMed and clinicaltrials.gov were used as sources for this review. Content Universal influenza virus vaccines that target conserved regions of the influenza virus including the hemagglutinin stalk domain, the ectodomain of the M2 ion channel or the internal matrix and nucleoproteins are in late pre-clinical and clinical development. These vaccines could confer broad protection against all influenza A and B viruses including drift variants and thereby abolish the need for annual re-formulation and re-administration of influenza virus vaccines. In addition, these novel vaccines would enhance our preparedness against emerging influenza virus pandemics. Finally, novel therapeutic antibodies against the same conserved targets are in clinical development and could become valuable tools in the fight against influenza virus infection. Implications Both universal influenza virus vaccines and therapeutic antibodies are potential future options for the control of human influenza infections.

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“…Another HA mAb, VIS‐410, was effective at protecting mice from A(H7N9) virus challenge and improved viral clearance and spread in the lungs when delivered prophylactically. A single dose of 10 or 50 mg/kg protected all mice from death following infection with an oseltamivir‐resistant strain of influenza . In a phase I trial, 2‐50 mg/kg doses of VIS‐410 were found to be safe and well tolerated by the cohort …”

Section: Monoclonal Antibodiesmentioning

confidence: 99%

Influenza antivirals currently in late‐phase clinical trial

Koszalka

Tilmanis

Hurt

2017

Influenza Resp Viruses

119

102

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Influenza antiviral drugs are important for the control of influenza, most specifically for the treatment of influenza patients with severe disease following infection with a seasonal influenza virus, a newly emerging influenza strain, or in the event of a pandemic. Many influenza antivirals that are currently under investigation in late‐stage clinical trials differ in their mechanism of action compared to drugs currently licensed for the treatment of influenza. Nitazoxanide and DAS181 target components of the host cell and alter the ability of the virus to replicate efficiently, while small molecule drugs such as T705, JNJ63623872 and S‐033188 bind to the viral polymerase complex and restrict viral replication. Monoclonal antibodies that are currently in clinical trial for the treatment of influenza most commonly are targeted to the stem region of the haemagglutinin molecule. Early findings from animal models and in vitro studies suggest that many of the new antiviral drugs when tested in combination with oseltamivir have improved effectiveness over monotherapy. Clinical trials assessing both monotherapy and combination therapy are currently under investigation. It is hoped that as new antivirals are licensed, they will improve the standard of care and outcomes for influenza patients with severe disease.

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The Hemagglutinin Stem-Binding Monoclonal Antibody VIS410 Controls Influenza Virus-Induced Acute Respiratory Distress Syndrome

Cited by 48 publications

References 50 publications

Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins

Human Monoclonal Antibody 81.39a Effectively Neutralizes Emerging Influenza A Viruses of Group 1 and 2 Hemagglutinins

Universal influenza virus vaccines and therapeutic antibodies

Influenza antivirals currently in late‐phase clinical trial

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