An oseltamivir-resistant avian H1N1 influenza A virus can transmit from mallards to chickens similarly to a wild-type strain: implications for the risk of resistance transmission to humans

Abstract

The neuraminidase inhibitor (NAI) oseltamivir is stockpiled globally as part of influenza pandemic preparedness. However, oseltamivir carboxylate (OC) resistance develops in avian influenza virus (AIV) infecting mallards exposed to environmental-like OC concentrations, suggesting that environmental resistance is a real concern. Herein we used an in vivo model to investigate if avian influenza H1N1 with the OC-resistant mutation NA-H274Y (51833/H274Y) as compared to the wild-type (wt) strain (51833 /wt) could transmit from mallards, which would potentially be exposed to environmentally contaminated environments, to and between chickens, thus posing a potential zoonotic risk of antiviral-resistant AIV. Regardless of whether the virus had the OC-resistant mutation or not, chickens became infected both through experimental infection, and following exposure to infected mallards. We found similar infection patterns between 51833/wt and 51833/H274Y such that, one chicken inoculated with 51833/wt and three chickens inoculated with 51833/H274Y were AIV positive in oropharyngeal samples more than 2 days consecutively, indicating true infection, and one contact chicken exposed to infected mallards was AIV positive in faecal samples for 3 consecutive days (51833/wt) and another contact chicken for 4 consecutive days (51833/H274Y). Importantly, all positive samples from chickens infected with 51833/H274Y retained the NA-H274Y mutation. However, none of the virus strains established sustained transmission in chickens, likely due to insufficient adaptation to the chicken host. Our results demonstrate that an OC-resistant avian influenza virus can transmit from mallards and replicate in chickens. NA-H274Y does not constitute a barrier to interspecies transmission per se, as the resistant virus did not show reduced replicative capacity compared to the wild-type counterpart. Thus, responsible use of oseltamivir and surveillance for resistance development is warranted to limit the risk of an OC-resistant pandemic strain.

The effect of antibiotic usage on resistance in humans and food-producing animals: a longitudinal, One Health analysis using European data

“…However, other evidence has suggested that resistance in the environment may be affected by human medicines. For example, recent evidence suggests that use of oseltamivir in humans may result in environmental exposure for birds that in turn develop oseltamivir-resistant avian influenza virus (44).…”

Vaccination and Antiviral Treatment against Avian Influenza H5Nx Viruses: A Harbinger of Virus Control or Evolution

“…Fortunately, the administration of oseltamivir as prophylaxis in poultry flocks is costly, which renders its wide application difficult; nevertheless, oseltamivir-resistant H5N1 AIVs have been also reported [87][88][89][90]. Experimentally, several studies revealed the development of oseltamivir-resistant mutants in aquatic birds (mallards) after exposure to oseltamivir treatment and the ability of these mutants to transmit to domestic chickens [91,92]. Although oseltamivir-resistant IAVs are documented in humans [93,94], the drug is still effective and is considered the drug of choice in treating human influenza infections.…”

Rational Design of Novel Peptidomimetics against Influenza A Virus: Biological and Computational Studies

“…Finally, it has been demonstrated that mallards can transmit an avian influenza virus that is oseltamivir-resistant to chickens. As this mutant is able to cross the species barrier and also maintain fitness, it could be able to infect humans [ 21 ]. Finding alternative antiviral drugs with distinct modes of action is therefore urgently needed to fight infection by emerging viruses with pandemic potential, especially those carrying drug resistance markers.…”