Quantitative Approach To Assess Influenza A Virus Fitness and Transmission in Guinea Pigs

Influenza pandemics occur when an IAV from nonhuman hosts enters the human population and adapts to give rise to a lineage capable of sustained transmission among humans. Despite recurring zoonotic infections involving avian- or swine-adapted IAVs, influenza pandemics occur infrequently because IAVs typically exhibit low fitness in a new host species. ABSTRACT Efforts to estimate the risk posed by potentially pandemic influenza A viruses (IAVs) and to understand the mechanisms governing interspecies transmission have been hampered by a lack of animal models that yield relevant and statistically robust measures of viral fitness. To address this gap, we monitored several quantitative measures of fitness in a guinea pig model: infectivity, magnitude of replication, kinetics of replication, efficiency of transmission, and kinetics of transmission. With the goal of identifying metrics that distinguish human- and nonhuman-adapted IAVs, we compared strains derived from humans to those circulating in swine and canine populations. Influenza A/Panama/2007/99 (H3N2), A/Netherlands/602/2009 (H1N1), A/swine/Kansas/77778/2007 (H1N1), A/swine/Spain/53207/2004 (M1 P41A) (H1N1), and A/canine/Illinois/41915/2015 (H3N2) viruses were evaluated. Our results revealed higher infectivity and faster kinetics of viral replication and transmission for human and canine strains compared to the swine viruses. Conversely, peak viral titers and efficiency of transmission were higher for human strains relative to both swine and canine IAVs. Total viral loads were comparable among all strains tested. When analyzed together, data from all strains point to peak viral load as a principal driver of transmission efficiency and replication kinetics as a major driver of transmission kinetics. While the dose initiating infection did not strongly impact peak viral load, dose was found to modulate the kinetics of viral replication and, in turn, the timing of transmission. Taken together, our results point to peak viral load and transmission efficiency as key metrics differentiating human and nonhuman IAVs and suggest that high peak viral load precipitates robust transmission. IMPORTANCE Influenza pandemics occur when an IAV from nonhuman hosts enters the human population and adapts to give rise to a lineage capable of sustained transmission among humans. Despite recurring zoonotic infections involving avian- or swine-adapted IAVs, influenza pandemics occur infrequently because IAVs typically exhibit low fitness in a new host species. Anticipating when a zoonosis might lead to a pandemic is both critical for public health preparedness and extremely challenging. The approach to characterizing IAVs reported here is designed to aid risk assessment efforts by generating rigorous and quantitative data on viral phenotypes relevant for emergence. Our data suggest that the ability to replicate to high titers and transmit efficiently irrespective of the initial dose are key characteristics distinguishing IAVs that have established sustained circulation in the human population from IAVs that circulate in nonhuman mammalian hosts.