Diversifying Selection Analysis Predicts Antigenic Evolution of 2009 Pandemic H1N1 Influenza A Virus in Humans

Abstract

Although a large number of immune epitopes have been identified in the influenza A virus (IAV) hemagglutinin (HA) protein using various experimental systems, it is unclear which are involved in protective immunity to natural infection in humans. We developed a data mining approach analyzing natural H1N1 human isolates to identify HA protein regions that may be targeted by the human immune system and can predict the evolution of IAV. We identified 16 amino acid sites experiencing diversifying selection during the evolution of prepandemic seasonal H1N1 strains and found that 11 sites were located in experimentally de- IMPORTANCEThe WHO estimates that approximately 5 to 10% of adults and 20 to 30% of children in the world are infected by influenza virus each year. While an adaptive immune response helps eliminate the virus following acute infection, the virus rapidly evolves to evade the established protective memory immune response, thus allowing for the regular seasonal cycles of influenza virus infection. The analytical approach described here, which combines an analysis of diversifying selection with an integration of immune epitope data, has allowed us to identify antigenic regions that contribute to protective immunity and are therefore the key targets of immune evasion by the virus. This information can be used to determine when sequence variations in seasonal influenza virus strains have affected regions responsible for protective immunity in order to decide when new vaccine formulations are warranted.

Genome-Wide Analysis of Evolutionary Markers of Human Influenza A(H1N1)pdm09 and A(H3N2) Viruses May Guide Selection of Vaccine Strain Candidates

“…There were many studies that have attempted to track the evolution and evolutionary driving sites in influenza viruses, mostly by identifying those sites under selective pressure, using evolution-aware and statistically rigorous codon models that consider separately the non-synonymous and synonymous substitution rates and base/codon frequencies ( Plotkin et al 2002 ; Smith et al 2004 ; Drummond et al 2006 ; Strelkowa and Lassig 2012 ; Bhatt et al 2013 ; Bedford et al 2014 ; Lee et al 2015a ; Tharakaraman and Sasisekharan 2015 ). Moreover, some of these studies utilized whole-genome sequences of influenza viruses and modern software, such as FUBAR and PAML/CODEML ( Holmes et al 2005 ; Nelson and Holmes 2007 ; Nunes et al 2008 ; Murrell et al 2013 ; Vijaykrishna et al 2015 ).…”

“…Influenza vaccines have been developed to protect the general population and especially people at risk (young children, pregnant women, health professionals, and adults over 65 years of age) from developing severe disease ( Osterholm et al 2012 ). However, vaccines need to be reformulated each year owing to the rapid viral antigenic evolution ( Plotkin et al 2002 ; Smith et al 2004 ; Lee et al 2015a ). Twice a year, the World Health Organization (WHO) provides recommendations on influenza strains that should be included in vaccines for the upcoming influenza season, for southern and northern hemispheres ( www.who.int/influenza/vaccines/virus/recommendations/en/ ).…”

“…The WHO recommendations are based on phylogenetic and immunological analyses of influenza viruses from previous seasons ( http://apps.who.int/gb/pip/pdf_files/Fluvaccvirusselection.pdf?ua=1 ). However, the phylogenetic approaches are often limited to the analysis of the nucleotide sequences of viral hemagglutinin (HA) and neuraminidase (NA) ( Plotkin et al 2002 ; Smith et al 2004 ; Drummond et al 2006 ; Strelkowa and Lassig 2012 ; Bhatt et al 2013 ; Bedford et al 2014 ; Lee et al 2015a ; Tharakaraman and Sasisekharan 2015 ). However, newer studies increasingly utilized whole-genome sequences of influenza viruses, shedding new light on virus evolution and aiding vaccine strain selection process ( Holmes et al 2005 ; Nelson and Holmes 2007 ; Du et al 2012 ; Luksza and Lassig 2014 ; Neher et al 2014 ; Steinbruck et al 2014 ; Lee et al 2015b ; Neher and Bedford 2015 ; Vijaykrishna et al 2015 ).…”

Clinical Performance of the Allplex^TM Respiratory Panel 1 Test Compared to Simplexa^TM Flu A/B and RSV for Detection of Influenza Virus and Respiratory Syncytial Virus Infection Including Their Subtyping

“…Influenza occurs globally with an estimated annual attack rate of 5–10% in adults and 20–30% in children [2]. In 2009, pandemic influenza A (H1N1) caused 29,669 cases of infection, including 145 deaths, in 74 countries [3].…”

Hajj vaccinations—facts, challenges, and hope

“…An additional complexity with influenza viruses is their ability to undergo rapid antigenic evolutionary changes (drifts) that require the reformulation of the vaccine every year to accommodate the currently circulating viral strains. 82,83 However, the selection of the strains to be included in the vaccine is usually based on surveillance of the nucleotide sequences of the viral neuraminidase (NA) and haemagglutinin (HA) genes. [84][85][86][87][88] Recently, the analysis of whole-genome sequencing data derived from of a global collection of 3969 A(H1N1) and 4774 A(H3N2) strains circulating in the period between 2009 and 2015 demonstrated precedential amino acid changes (481 and 533 sites were identified in A(H1N1) and A(H3N2), respectively).…”