­Refined Semi-Lethal H5N1 Influenza Model Through Aerosolized Virus Infection in Macaques

Abstract

Highly pathogenic avian influenza A (HPAI) H5N1 viruses can cause high mortality in humans and have pandemic potential. Effective vaccines and treatments against this threat are urgently needed. Here, we refined a previously established model of lethal H5N1 infection in cynomolgus macaques and show that repeated vaccination of adjuvanted commercial quadrivalent influenza vaccine confers protection against lethality using the model. We determined that an inhaled aerosol virus dose of 5.1 log₁₀ pfu induced a strong febrile response, acute respiratory distress, with 4 out of 6 naïve cynomolgus macaques succumbing between 4-6 days after challenge, establishing a semi-lethal severe influenza disease model for studying protective countermeasures. Macaques vaccinated with three doses of adjuvanted licensed seasonal quadrivalent influenza vaccine elicited neutralizing antibody response to H1N1 and to a lesser extent, H5N1. All 6 vaccinated macaques survived an inhaled dose of 5.7 log₁₀ pfu (~4 LD₅₀) H5N1 while 4 of 6 unvaccinated control macaques succumbed to lethal disease. Although vaccination did not protect against severe disease, vaccinees developed a significantly milder fever, reduced respiratory disease, and had lower viral load in bronchoalveolar lavage compared to controls. We anticipate that our macaque model will play a vital role in evaluating vaccines and antivirals against influenza pandemics.

Note:
Funding Information: This work was supported in part by the National Institutes of Health and the Leidos Foundation, contract number HHSN261201500003I; and Intramural Research Program of the Vaccine Research Center, NIAID, NIH.

Declaration of Interests: The authors declare no conflict of interest.

Ethical Approval Statement: All experiments were conducted in compliance with the Animal Welfare Act and other Federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, National Research Council, 1996, and approved by the Institutional Animal Care and Use Committee. The facility where the study was conducted is fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International.

Keywords: Influenza, nonhuman primate, NHP, H5N1, cynomolgus macaque, animal model, aerosol, vaccine, HPAI, pandemic