Year: 2018
Type: article
Abstract: (See the Major Article by Ning et al on pages 19–25.) Integrated genetic and antigenic methods to characterize seasonal influenza viruses are increasingly being used to support surveillance, vaccine strain selection, and estimates of vaccine effectiveness [1, 2]. Advances in these methods and increased characterization of circulating viruses has also allowed identification of single-site mutations in the surface hemagglutinin (HA) and neuraminidase (NA) proteins that contribute to the influenza virus’ ability to escape the immunity of human populations [3, 4]. At the same time, ongoing global surveillance of seasonal human influenza viruses and emerging avian influenza viruses has meticulously documented the evolutionary trajectories of HA and NA. In this issue of The Journal of Infectious Diseases, Ning et al study mutations in the HA of influenza A(H7N9) viruses that have accumulated over the last 5 years, with the goal of identifying changes that might affect the virus’s antigenicity [5]. Influenza A(H7N9) virus is an avian virus that was first detected in humans in 2013 [6]. It has since resulted in at least 1625 infections and 623 deaths across 6 epidemic waves in China [7]. The frequency of infections and resulting deaths make this virus a serious pandemic threat; however, the virus still does not transmit efficiently from human to human [8]. The vast majority of infected individuals had contact with poultry, and other than a few cases linked to travel, infections have been limited to China. Notably, the 2016–2017 influenza A(H7N9) epidemic wave was the largest since this virus emerged, accounting for about one third of all infections and deaths to date. Mass immunization of Chinese poultry with a bivalent influenza A(H7N9) and A(H5N1) vaccine began in September 2017, and subsequently, only 3 human infections have been detected in the 2017–2018 sixth wave [7]. While A(H7N9) viruses evolve from year to year, like A(H3N2) and A(H1N1) viruses, most of the evolution happens in avian host species. Early isolates in 2013 demonstrated the circulation of genetically similar viruses from a common source [9]. Since then, influenza A(H7N9) viruses have diversified into a large number of clades that are dispersed to varying degrees across China [8]. The selection pressures driving the virus’s evolution in birds are unclear, particularly given that vaccines had not been used until recently. Most viruses contain G186V and Q226L/I substitutions in the HA gene, which mediate increased affinity for human sialic acid receptors [10]. Many also have substitutions in the PB2 protein, which is known to increase pathogenicity in mammalian hosts [11]. Concerningly, the fifth wave saw the emergence of viruses with a polybasic motif in HA characteristic of highly pathogenic avian influenza viruses. The ongoing evolution of influenza A(H7N9) virus and the large number of cases in the fifth wave have put human vaccine development and strain selection front and center. With the goal of understanding how the evolution may complicate strain selection for vaccines, Ning et al assessed the antigenic effects of specific influenza A(H7N9) virus mutations [5]. Using publicly available HA sequences of influenza A (H7N9) viruses isolated from humans, they identified 53 single amino acid substitutions relative to the ancestral A/Anhui/1/2013 virus that were found at high frequencies (>5%) or were located in a putative antigenic or receptor binding site. They then generated a panel of A/Anhui-derived pseudoviruses with these single amino acid substitutions and assessed the ability of sera from A/Anhui-vaccinated guinea pigs to neutralize each one. They identified 3 amino acid substitutions—A143V, A143T, and R148K—that resulted in a 4-fold reduction in neutralization by A/Anhui antisera. Viruses containing both the A143V and R148K substitutions had a 10-fold reduction in susceptibility to neutralization. Importantly, this pairing of amino acid substitutions defined the major clade of influenza A(H7N9) viruses isolated in 2016–2017, representing about three quarters of human infections during the fifth wave. The A143V and R148K mutations both appear to have arisen in early 2014 at the root of a clade that dominated the fifth wave [12]. This explains their high frequency in the authors’ study but not what drove their emergence. Given their presence in antigenic sites, the authors frame the problem as one of antigenic drift. However, these mutations are unlikely to have arisen under human immune selection and have not been observed under selection with monoclonal antibodies targeting the H7 globular head and receptor binding site [13, 14]. Similarly, it is unclear whether current poultry husbandry practices in China would drive selection of antigenic variants, whether through vaccination or not. Although Ning et al assay each of these mutations alone or in combination, both A143V and R148K likely interact with other mutations in fifth wave viruses to alter their antigenicity [15]. It is more likely that these mutations emerged under selection for some other phenotype or even by chance. Mutations in or near the HA receptor binding site have been associated with increased receptor binding and transmissibility. Indeed, the initial spread of influenza A (H7N9) viruses into human populations has been linked to the impact of the G186V and Q226L/I substitutions on receptor binding, and at least 3 additional sites are known to influence the binding affinity and species tropism of H7 [16]. However, a recent study of recombinant HA corresponding to fifth wave viruses suggests that neither A143V nor R148K significantly influence the affinity of these viruses for human receptors [15]. This does not exclude a potential role in avian receptor tropism, transmissibility, or virulence. The A143V and R148K substitutions have been found in influenza A(H7N9) isolates with both low and high pathogenicity and could certainly be important for transmission [17]. Although the significance is unclear, it is notable that in an aerosol transmission experiment involving 3 pairs of ferrets, the R148K mutation was identified in a single recipient [18]. Despite these uncertainties, this study is timely and important. While influenza A(H7N9) vaccines are currently in development, none have yet been approved for use in humans. Following the first influenza A(H7N9) outbreak, in 2013, the World Health Organization identified the A/Anhui/1/2013 virus as a vaccine candidate, based on the ability of the antibodies it elicited to neutralize the majority of circulating viruses that were tested [19]. Additional vaccine candidate viruses have since been identified, including the A/Hong Kong/125/2017 virus, which contains the A143V and R148K substitutions found to be important in this study. It should be noted that even with a 10-fold reduction in neutralization activity, the antibodies elicited by an A/Anhui-containing vaccine would likely have protected against each of the viruses evaluated in this study. Not unexpectedly, influenza A(H7N9) viruses have continued to evolve since they first began infecting humans. This has resulted in antigenic changes in the viruses that infect humans and increased virulence in avian species. The degree to which poultry vaccination has limited recent human infection and how the vaccination program will further shape the genetic and antigenic characteristics of these viruses remain open questions. Therefore, integrated genetic and antigenic monitoring of these viruses in humans and birds remains essential for informing public health interventions, human vaccine development, and pandemic preparedness. Potential conflicts of interest. Both authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Authors: Joshua G Petrie, Adam S Lauring
Institutions: University of Michigan, Michigan Medicine
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2884398010