How low is the risk of influenza A(H5N1) infection?

For over a decade, we have heard predictions that avian influenza A(H5N1) may be nearing pandemicity and that the pandemic will be catastrophic when it arrives. These predictions derive from a belief that A(H5N1) may be only a few mutations away from full adaptation to transmissibility [1] and from its allegedly high propensity to infect and to kill people. The World Health Organization (WHO) has recorded a case-fatality ratio of 59% among the 650 human cases reported to date [2], which some interpret to mean that approximately 60% of everyone infected by A(H5N1) will die. In the current climate of alarm, routine and decades-old virologic research approaches, such as examining the effects of engineered mutations on phenotypic properties like experimental virulence and transmissibility, recently termed “gain of function” studies, have been called “absolutely crazy” and “exceedingly dangerous” (Robert May, as quoted in Ref. [3]). Calls for curtailing research on potential pandemic pathogens [4] have prompted governments to exert greater oversight of influenza virus experimentation [5], framing a fundamentally important question about whether influenza research is more likely to prevent, or cause, influenza pandemics [6, 7]. Curiously ignored, however, is evidence that calls into question A(H5N1) viral doomsday scenarios; for example, after countless people (certainly at least hundreds of thousands, if not millions) have been intimately exposed to A(H5N1) inpoultry epizootics and live birdmarkets, almost none have been recognized as having mild infections, very few have A (H5N1) antibody at all, and, when detected, the antibody level is typically low and transient [8]. To understand human A (H5N1) pandemic risks, we need first to understand how a virus can expose enormous numbers of people over half the globe, for over 16 years, but infect as few as650of them, kill themajorityof those infected, and yet leave even the very closest contacts of these cases, as well as their countless coexposed coworkers andneighbors, mysteriously free of disease or even immune evidence of exposure. Can a panzootically circulating virus be so poorly adapted that it has difficulty infecting anyone, yet so deadly that it kills most of the few people it does infect? Do these paradoxes tell us anything about A(H5N1) risks? Gomaa et al address these questions in the current issue of The Journal of Infectious Diseases [9]. In a prospective study using stringent seroprevalence/seroincidence criteria (reciprocal neutralization titers of ≥80), they show that, in Egypt, A(H5N1) infection is (1) associated with intense exposure to poultry epizootics, (2) relatively common (2.1% baseline seropositivity), (3) clinically silent, (4) able to produce only transient low-level antibody responses (100% of persons with baseline A[H5N1] antibody had significant titer declines at 1 year, with titers for 92% of these falling to subthreshold levels, consistent with prospective data from Thailand [10,11]) and Nigeria [12]), and (5) not a function of serologic false positivity (an unexposed comparison group maintained a 0.0% antibody prevalence over the entire 3-year study). The study by Gomaa et al clarifies that A(H5N1) is much like other avian influenza viruses that seem to have difficulty infecting humans, such as A(H6N1), A(H7N9), and A(H10N8), but that can nevertheless cause mild or fatal infections in rare individuals. As has been appreciated for decades, this is a typical pattern of many animal viruses from various taxonomic families, such as West Nile virus: uncommon severe diseases occur in the midst of widespread asymptomatic or mild human infections. A(H5N1) might join most other avian influenza viruses as blips on the radar screen, if not for the fact that it has been spread around the globe to cause high-pathogenicity infections in many millions of chickens, thereby intensely exposing countless humans on farms and in markets, such as during the culling and handling of ill Received and accepted 18 September 2014; electronically published 29 October 2014. Correspondence: David M. Morens, MD, National Institutes of Health, Bldg 31, Rm 7A-03, 31 Center Dr, MSC 2520, Bethesda, MD 20892-2520 ([email protected]). The Journal of Infectious Diseases 2015;211:1364–6 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. Thiswork iswritten by (a) US Government employee(s) and is in the public domain in the US. DOI: 10.1093/infdis/jiu530