Predicting Hotspots for Influenza Virus Reassortment

Trevon L. Fuller

, Marius Gilbert, Vincent Martin, Julien Cappelle, Parviez Hosseini, Kevin Y. Njabo, Soad Abdel Aziz, Xiangming Xiao, Peter Daszak, and Thomas B. Smith

Author affiliations: University of California, Los Angeles, California, USA (T.L. Fuller, K.Y. Njabo, T.B. Smith); Université Libre de Bruxelles, Brussels, Belgium (M. Gilbert); Food and Agriculture Organization of the United Nations, Beijing, People’s Republic of China (V. Martin); Centre de Cooperation International en Recherche Agronomique pour le Developpement, Montpellier, France (J. Cappelle); EcoHealth Alliance, New York, New York, USA (P. Hosseini, P. Daszak); National Laboratory for Quality Control on Poultry Production, Dokki, Giza, Egypt (S.A. Aziz); University of Oklahoma, Oklahoma City, Oklahoma, USA (X. Xiao)

Abstract

The 1957 and 1968 influenza pandemics, each of which killed ≈1 million persons, arose through reassortment events. Influenza virus in humans and domestic animals could reassort and cause another pandemic. To identify geographic areas where agricultural production systems are conducive to reassortment, we fitted multivariate regression models to surveillance data on influenza A virus subtype H5N1 among poultry in China and Egypt and subtype H3N2 among humans. We then applied the models across Asia and Egypt to predict where subtype H3N2 from humans and subtype H5N1 from birds overlap; this overlap serves as a proxy for co-infection and in vivo reassortment. For Asia, we refined the prioritization by identifying areas that also have high swine density. Potential geographic foci of reassortment include the northern plains of India, coastal and central provinces of China, the western Korean Peninsula and southwestern Japan in Asia, and the Nile Delta in Egypt.

Simultaneous infection with multiple influenza virus strains can affect virus fitness components, such as virus growth performance, and thus affect virus pathogenicity, transmission, or recombination (1). In a host infected with 2 closely related influenza viruses, the stains can reassort, exchanging gene segments to produce new strains, some of which might have increased virulence. Virulence might also trade off with transmission such that more pathogenic viruses spread more slowly (2). However, in some instances, a reassortant virus can have high transmissibility and high pathogenicity. For example, reassortment between influenza viruses of humans and birds resulted in the 1957 and 1968 pandemic viruses, each of which is estimated to have killed ≈1 million persons (3,4). The exchange of genes between pairs of influenza virus subtypes increased virulence in animal models, including reassortment between subtypes H9N2 and H1N1, between H5N1 and H1N1, and between H3N2 and H5N1 (5,6). We focus on reassortment between subtypes H3N2 and H5N1 because extensive data are available, but given sufficient data, our approach could be extended to other subtypes.
For seasonal influenza virus A subtype H3N2, person-to-person transmissibility and prevalence among humans are high (7). Furthermore, subtype H5N1, which is primarily found in birds, can be highly pathogenic; the fatality rate among humans is 60% (8). In mice, ≈8% of reassortant viruses formed from human subtype H3N2 and avian subtype H5N1 resulted in increased virulence and a mortality rate of 100% (5). This finding among mice raises the possibility that among humans reassortment events between subtypes H3N2 and H5N1 could generate a novel influenza virus that could spread rapidly, resulting in many deaths. To prioritize areas where future reassortment is most likely to occur, we analyzed surveillance data for subtype H5N1 among poultry in the People’s Republic of China and Egypt and subtype H3N2 among humans. We chose China and Egypt because both countries have had recent outbreaks of subtype H5N1 infection among poultry, human deaths from subtype H5N1 infection, and extensive spatial data on cases of infection with subtype H5N1. This information would help decision makers implement policies to reduce spillover in these areas (9). Areas with high risk for co-occurrence of these 2 influenza virus subtypes along with high densities of susceptible hosts, such as swine, quail, or turkeys, could benefit from enhanced monitoring and farm and market biosecurity.