TITLE: Influenza A (H7N9) virus evolution: Which genetic mutations are antigenically important?

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1 TITLE: Influenza A (H7N9) virus evolution: Which genetic mutations are antigenically important? AUTHORS: Joshua G. Petrie 1, Adam S. Lauring 2,3 AFFILIATIONS: 1 Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor; 2 Department of Microbiology and Immunology, University of Michigan, Ann Arbor; 3 Department of Internal Medicine, Division of Infectious Diseases, University of Michigan, Ann Arbor 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) is an avian virus that was first detected in humans in 2013 [6]. It has since resulted in at least 1,625 infections and 623 deaths across six 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 H7N9 epidemic wave was the largest since its emergence, accounting for about a 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 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, 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 known to increase pathogenicity in mammalian hosts [11]. Concerningly, the 5 th wave saw the emergence of viruses with a polybasic motif in HA characteristic of highly pathogenic avian influenza The Author(s) Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, journals.permissions@oup.com.

2 viruses. The ongoing evolution of A (H7N9) and the large number of cases in the 5 th 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 identify 3 amino acid substitutions, A143V, A143T, and R148K, which 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 , 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 5 th 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 haven t 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. While Ning et al. assay each of these mutations alone or in combination, both A143V and R148K likely interact with other mutations in 5 th 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 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 three additional sites are known to influence the binding affinity and species tropism of H7 [16]. However, a recent study of recombinant HA corresponding to 5 th wave viruses suggests that neither A143V nor R148K significantly impact 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 both low pathogenic and high pathogenic A (H7N9) isolates, and could certainly be important for transmission [17]. Although the significance is unclear, it is notable that in an aerosol transmission experiment involving three 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 has 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

3 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. J. G. P. and A. S. L. report no potential conflicts. All 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.

4 References 1. World Health Organization (WHO). WHO Recommended composition of influenza virus vaccines for use in the northern hemisphere influenza season [Internet] [cited 2018 Jun 20]. Available from: 2. Flannery B, Zimmerman RK, Gubareva LV, et al. Enhanced Genetic Characterization of Influenza A(H3N2) Viruses and Vaccine Effectiveness by Genetic Group, J Infect Dis. 2016; 214(7): Linderman SL, Chambers BS, Zost SJ, et al. Potential antigenic explanation for atypical H1N1 infections among middle-aged adults during the influenza season. Proc Natl Acad Sci U S A. 2014; 111(44): Zost SJ, Parkhouse K, Gumina ME, et al. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proc Natl Acad Sci. 2017; 114(47): Ning T, Nie J, Huang W, et al. Antigenic Drift of H7N9 Viral Hemagglutinin. J Infect Dis. 2018; In Press. 6. Gao H-N, Lu H-Z, Cao B, et al. Clinical findings in 111 cases of influenza A (H7N9) virus infection. N Engl J Med. 2013; 368(24): Food and Agriculture Organization of the United Nations (FAO). FAO H7N9 situation update [Internet] [cited 2018 Jun 25]. Available from: 8. Su S, Gu M, Liu D, et al. Epidemiology, Evolution, and Pathogenesis of H7N9 Influenza Viruses in Five Epidemic Waves since 2013 in China. Trends Microbiol. 2017; 25(9): Lam TT-Y, Zhou B, Wang J, et al. Dissemination, divergence and establishment of H7N9 influenza viruses in China. Nature. 2015; 522(7554): Xiong X, Martin SR, Haire LF, et al. Receptor binding by an H7N9 influenza virus from humans. Nature. 2013; 499(7459): Quan C, Shi W, Yang Y, et al. New Threats from H7N9 Influenza Virus: Spread and Evolution of Highand Low-Pathogenicity Variants with High Genomic Diversity in Wave Five. J Virol. 2018; 92(11):e Neher RA, Bedford T. nextflu: real-time tracking of seasonal influenza virus evolution in humans. Bioinformatics. 2015; 31(21): Chen Z, Wang J, Bao L, et al. Human monoclonal antibodies targeting the haemagglutinin glycoprotein can neutralize H7N9 influenza virus. Nat Commun. 2015; 6:6714.

5 14. Tan GS, Leon PE, Albrecht RA, et al. Broadly-Reactive Neutralizing and Non-neutralizing Antibodies Directed against the H7 Influenza Virus Hemagglutinin Reveal Divergent Mechanisms of Protection. PLOS Pathog. 2016; 12(4):e Yang H, Carney PJ, Chang JC, Guo Z, Stevens J. Structural and Molecular Characterization of the Hemagglutinin from the Fifth Epidemic Wave A(H7N9) Influenza Viruses. J Virol. 2018; :JVI Vries RP de, Peng W, Grant OC, et al. Three mutations switch H7N9 influenza to human-type receptor specificity. PLOS Pathog. 2017; 13(6):e Monne I, Fusaro A, Nelson MI, et al. Emergence of a Highly Pathogenic Avian Influenza Virus from a Low-Pathogenic Progenitor. J Virol. 2014; 88(8): Xu L, Bao L, Deng W, et al. Novel Avian-Origin Human Influenza A(H7N9) Can Be Transmitted Between Ferrets via Respiratory Droplets. J Infect Dis. 2014; 209(4): World Health Organization (WHO). WHO Candidate vaccine viruses for avian influenza A(H7N9) [Internet] [cited 2018 Jun 19]. Available from:

What is influenza virus? 13,000 base RNA genome: 1/ the size of the human genome

What is influenza virus? 13,000 base RNA genome: 1/246153 the size of the human genome CDC Principles of Virology, 4e Neumann et al. Nature. 2009. Influenza virus is one of the most deadly viral pathogens