Two residues in the hemagglutinin of A/Fujian/411/02-like influenza viruses are responsible for antigenic drift from A/Panama/2007/99

103

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Influenza vaccines must be frequently reformulated to account for antigenic changes in the viral envelope protein, hemagglutinin (HA). The rapid evolution of influenza virus under immune pressure is likely enhanced by the virus's genetic diversity within a host, although antigenic change has rarely been investigated on the level of individual infected humans. We used deep sequencing to characterize the between-and within-host genetic diversity of influenza viruses in a cohort of patients that included individuals who were vaccinated and then infected in the same season. We characterized influenza HA segments from the predominant circulating influenza A subtypes during the 2012-2013 (H3N2) and 2013-2014 (pandemic H1N1; H1N1pdm) flu seasons. We found that HA consensus sequences were similar in nonvaccinated and vaccinated subjects. In both groups, purifying selection was the dominant force shaping HA genetic diversity. Interestingly, viruses from multiple individuals harbored low-frequency mutations encoding amino acid substitutions in HA antigenic sites at or near the receptor-binding domain. These mutations included two substitutions in H1N1pdm viruses, G158K and N159K, which were recently found to confer escape from virusspecific antibodies. These findings raise the possibility that influenza antigenic diversity can be generated within individual human hosts but may not become fixed in the viral population even when they would be expected to have a strong fitness advantage. Understanding constraints on influenza antigenic evolution within individual hosts may elucidate potential future pathways of antigenic evolution at the population level. IMPORTANCEInfluenza vaccines must be frequently reformulated due to the virus's rapid evolution rate. We know that influenza viruses exist within each infected host as a "swarm" of genetically distinct viruses, but the role of this within-host diversity in the antigenic evolution of influenza has been unclear. We characterized here the genetic and potential antigenic diversity of influenza viruses infecting humans, some of whom became infected despite recent vaccination. Influenza virus between-and within-host genetic diversity was not significantly different in nonvaccinated and vaccinated humans, suggesting that vaccine-induced immunity does not exert strong selective pressure on viruses replicating in individual people. We found low-frequency mutations, below the detection threshold of traditional surveillance methods, in nonvaccinated and vaccinated humans that were recently associated with antibody escape. Interestingly, these potential antigenic variants did not reach fixation in infected people, suggesting that other evolutionary factors may be hindering their emergence in individual humans. S easonal influenza A epidemics cause an estimated 3 to 5 million cases of severe respiratory illness each year, resulting in approximately 250,000 to 500,000 deaths worldwide (1). Available influenza vaccines only provide moderate protection against infection and illness...

Section: Figmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Deep Sequencing Reveals Potential Antigenic Variants at Low Frequencies in Influenza A Virus-Infected Humans

Dinis

Florek

Fatola

et al. 2016

103

121

“…The N158D (V2 and V3) and the K193N (V11) changes at antigenic site B and the R220S (V10) change at antigenic site D affected viral antigenicity of the H7N9 virus. The 158 residue has previously been shown to alter viral antigenicity in seasonal H3N2 and H1N1pdm viruses (38,51).…”

Section: Discussionmentioning

confidence: 99%

Development of a High-Yield Live Attenuated H7N9 Influenza Virus Vaccine That Provides Protection against Homologous and Heterologous H7 Wild-Type Viruses in Ferrets

Chen

Baz

et al. 2014

Self Cite

IMPORTANCEIn response to the recent avian H7N9 influenza virus infection in humans, we developed a live attenuated H7N9 influenza vaccine (LAIV) with two amino acid substitutions in the viral HA protein that improved vaccine yield by 10-fold in chicken embryonated eggs, the substrate for vaccine manufacture. The two amino acids also improved the antigen yield for inactivated H7N9 vaccines, demonstrating that this finding could great facilitate the efficiency of H7N9 vaccine manufacture. The candidate H7N9 LAIV was immunogenic and protected ferrets against homologous and heterologous wild-type H7 virus challenge, making it suitable for use in protecting humans from H7 infection.

“…The ability for hemagglutinin to escape the binding action of an antibody by means of a small number of substitutions was demonstrated both experimentally and computationally (16,41).…”

Section: Characteristics Of Antibody Binding In Influenza a Virus Hemmentioning

confidence: 99%

Analysis of Antigenically Important Residues in Human Influenza A Virus in Terms of B-Cell Epitopes

Lees

Moss

Shepherd

2011

In this paper we undertake an analysis of the antigenicity of influenza A virus hemagglutinin. We developed a novel computational approach to the identification of antigenically active regions and showed that the amino acid substitutions between successive predominant seasonal strains form clusters that are consistent, in terms of both their location and their size, with the properties of B-cell epitopes in general and with those epitopes that have been identified experimentally in influenza A virus hemagglutinin to date. Such an interpretation provides a biologically plausible framework for an understanding of the location of antigenically important substitutions that is more specific than the canonical "antigenic site" model and provides an effective basis for deriving models that predict antigenic escape in the H3N2 subtype. Our results support recent indications that antibodies binding to the "stalk" region of hemagglutinin are found in the human population and exert evolutionary pressure on the virus. Our computational approach provides a possible method for identifying antigenic escape through evolution in this region, which in some cases will not be identified by the hemagglutinin inhibition assay.