Abstract
BackgroundVaccination and the use of neuraminidase inhibitors (NAIs) are currently the front lines of defense against seasonal influenza. The activity of influenza vaccines and antivirals drugs such as the NAIs can be affected by mutations in the influenza hemagglutinin (HA) protein. Numerous HA substitutions have been identified in nonclinical NAI resistance-selection experiments as well as in clinical specimens from NAI treatment or surveillance studies. These mutations are listed in the prescribing information (package inserts) for FDA-approved NAIs, including oseltamivir, zanamivir, and peramivir.MethodsNAI treatment-emergent H1 HA mutations were mapped onto the H1N1 HA1 trimeric crystal structure and most of them localized to the HA antigenic sites predicted to be important for anti-influenza immunity. Recombinant A/California/04/09 (H1N1)-like viruses carrying HA V152I, G155E, S162 N, S183P, and D222G mutations were generated. We then evaluated the impact of these mutations on the immune reactivity and replication potential of the recombinant viruses in a human respiratory epithelial cell line, Calu− 3.ResultsWe found that the G155E and D222G mutations significantly increased viral titers ~ 13-fold compared to the wild-type virus. The hemagglutination and microneutralization activity of goat and ferret antisera, monoclonal antibodies, and human serum samples raised against pandemic A(H1N1)pdm09 viruses was ~ 100-fold lower against mutants carrying G155E or D222G compared to the wild-type virus.ConclusionsAlthough the mechanism by which HA mutations emerge during NAI treatment is uncertain, some NAI treatment-emergent HA mutations correlate with decreased immunity to influenza virus.
Highlights
Vaccination and the use of neuraminidase inhibitors (NAIs) are currently the front lines of defense against seasonal influenza
HA substitutions are generally included as NAI treatment-emergent mutations if they meet one of the following criteria: (i) selected in cell culture in the presence of NAI; (ii) observed as treatmentemergent in more than one patient, (iii) observed as treatment-emergent in a single patient at positions identified in cell culture as impacting drug susceptibility; and (iv) observed in surveillance or baseline clinical study samples at positions identified in cell culture as impacting susceptibility
It is worth noting that HA/NA substitutions observed at baseline in clinical studies or in surveillance samples are included in the approved drug product labels because there are examples of circulating amino acid polymorphisms that clearly reduce susceptibility of influenza virus to antivirals
Summary
Vaccination and the use of neuraminidase inhibitors (NAIs) are currently the front lines of defense against seasonal influenza. Numerous HA substitutions have been identified in nonclinical NAI resistance-selection experiments as well as in clinical specimens from NAI treatment or surveillance studies These mutations are listed in the prescribing information (package inserts) for FDA-approved NAIs, including oseltamivir, zanamivir, and peramivir. Many of the antiviral drug products that are either FDA-approved or in development for prophylaxis or treatment of influenza virus infection target the HA and/or NA glycoproteins and they include NA inhibitors (NAIs), monoclonal antibodies (mAbs), and vaccines. The activity of these drugs and vaccines may be affected by changes in the dynamic HA and NA molecules selected by the clinical use of these therapeutic agents. The present study demonstrates that NAI treatment-emergent HA mutations can result in altered antigenic profiles and may potentially impact antibodymediated virus inhibition
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