Transmission of Pandemic H1N1 Influenza Virus and Impact of Prior Exposure to Seasonal Strains or Interferon Treatment

Novel swine-origin influenza viruses of the H1N1 subtype were first detected in humans in April 2009. As of 12 August 2009, 180,000 cases had been reported globally. Despite the fact that they are of the same antigenic subtype as seasonal influenza viruses circulating in humans since 1977, these viruses continue to spread and have caused the first influenza pandemic since 1968. Here we show that a pandemic H1N1 strain replicates in and transmits among guinea pigs with similar efficiency to that of a seasonal H3N2 influenza virus. This transmission was, however, partially disrupted when guinea pigs had preexisting immunity to recent human isolates of either the H1N1 or H3N2 subtype and was fully blocked through daily intranasal administration of interferon to either inoculated or exposed animals. Our results suggest that partial immunity resulting from prior exposure to conventional human strains may blunt the impact of pandemic H1N1 viruses in the human population. In addition, the use of interferon as an antiviral prophylaxis may be an effective way to limit spread in at-risk populations.A pandemic of novel swine-origin influenza virus (H1N1) is developing rapidly. As of 12 August 2009, nearly 180,000 cases had been reported to the WHO from around the globe (36). Sustained human-to-human transmission has furthermore been observed in multiple countries, prompting the WHO to declare a public health emergency of international concern and to raise the pandemic alert level to phase 6 (7).Swine are a natural host of influenza viruses, and although sporadic incidences of human infection with swine influenza viruses occur (8, 9, 14, 29, 35), human-to-human transmission is rare. H1N1 influenza viruses have likely circulated in swine since shortly after the 1918 human influenza pandemic (38). From the 1930s, when a swine influenza virus was first isolated, to the late 1990s, this classical swine lineage has remained relatively stable antigenically (34). In the late 1990s, however, genetic reassortment between a human H3N2 virus, a North American avian virus, and a classical swine influenza virus produced a triple reassortant virus, which subsequently spread among North American swine (34). Further reassortment events involving human influenza viruses led to the emergence in pigs of triple reassortants of the H1N1 and H1N2 subtypes (34). None of these swine viruses have demonstrated the potential for sustained human-to-human transmission.The swine-origin influenza viruses now emerging in the human population possess a previously uncharacterized constellation of eight genes (28). The NA and M segments derive from a Eurasian swine influenza virus lineage, having entered pigs from the avian reservoir around 1979, while the HA, NP, and NS segments are of the classical swine lineage and the PA, PB1, and PB2 segments derive from the North American triple reassortant swine lineage (13). This unique combination of genetic elements (segments from multiple swine influenza virus lineages, some of them derived from avian and human influenza viruses) may account for the improved fitness of pandemic H1N1 viruses, relative to that of previous swine isolates, in humans.Several uncertainties remain about how this outbreak will develop over time. Although the novel H1N1 virus has spread over a broad geographical area, the number of people known to be infected remains low in many countries, which could be due, at least in part, to the lack of optimal transmission of influenza viruses outside the winter season; thus, it is unclear at this point whether the new virus will become established in the long term. Two major factors will shape the epidemiology of pandemic H1N1 viruses in the coming months and years: the intrinsic transmissibility of the virus and the degree of protection offered by previous exposure to seasonal human strains. Initial estimates of the reproductive number (R₀) have been made based on the epidemiology of the virus to date and suggest that its rate of spread is intermediate between that of seasonal flu and that of previous pandemic strains (3, 11). However, more precise estimates of R₀ will depend on better surveillance data in the future. The transmission phenotype of pandemic H1N1 viruses in a ferret model was also recently reported and was found to be similar to (16, 27) or less efficient (25) than that of seasonal H1N1 strains. The reason for this discrepancy in the ferret model is unclear.Importantly, in considering the human population, the impact of immunity against seasonal strains on the transmission potential of pandemic H1N1 viruses is not clear. According to conventional wisdom, an influenza virus must be of a hemagglutinin (HA) subtype which is novel to the human population in order to cause a pandemic (18, 38). Analysis of human sera collected from individuals with diverse influenza virus exposure histories has indicated that in those born in the early part of the 20th century, neutralizing activity against A/California/04/09 (Cal/04/09) virus is often present (16). Conversely, serological analyses of ferret postinfection sera (13) and human pre- and postvaccination sera (4a) revealed that neutralizing antibodies against recently circulating human H1N1 viruses do not react with pandemic H1N1 isolates. These serological findings may explain the relatively small number of cases seen to date in individuals greater than 65 years of age (6). Even in the absence of neutralizing antibodies, however, a measure of immune protection sufficient to dampen transmission may be present in a host who has recently experienced seasonal influenza (10). If, on the other hand, transmission is high and immunity is low, then pandemic H1N1 strains will likely continue to spread rapidly through the population. In this situation, a range of pharmaceutical interventions will be needed to dampen the public health impact of the pandemic.Herein we used the guinea pig model (4, 21-24, 26, 30) to assess the transmissibility of the pandemic H1N1 strains Cal/04/09 and A/Netherlands/602/09 (NL/602/09) relative to that of previous human and swine influenza viruses. To better mimic the human situation, we then tested whether the efficiency of transmission is decreased by preexisting immunity to recent human H1N1 or H3N2 influenza viruses. Finally, we assessed the efficacy of intranasal treatment with type I interferon (IFN) in limiting the replication and transmission of pandemic H1N1 viruses.