A Single Amino Acid in the Stalk Region of the H1N1pdm Influenza Virus HA Protein Affects Viral Fusion, Stability and Infectivity

Cotter, Christopher R.; Jin, Hong; Chen, Zhongying

doi:10.1371/journal.ppat.1003831

Cited by 138 publications

(151 citation statements)

References 35 publications

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“…Surveillance reports after the 2009 pandemic identified another HA-stabilizing mutation (HA2-E47K) that may have played a role in adaptation of pH1N1 to humans (29,30). Other viral genes may also contribute to pandemic capacity.…”

Section: Discussionmentioning

confidence: 99%

Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein

Russier

Yang

Rehg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

210

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Influenza pandemics require that a virus containing a hemagglutinin (HA) surface antigen previously unseen by a majority of the population becomes airborne-transmissible between humans. Although the HA protein is central to the emergence of a pandemic influenza virus, its required molecular properties for sustained transmission between humans are poorly defined. During virus entry, the HA protein binds receptors and is triggered by low pH in the endosome to cause membrane fusion; during egress, HA contributes to virus assembly and morphology. In 2009, a swine influenza virus (pH1N1) jumped to humans and spread globally. Here we link the pandemic potential of pH1N1 to its HA acid stability, or the pH at which this one-time-use nanomachine is either triggered to cause fusion or becomes inactivated in the absence of a target membrane. In surveillance isolates, our data show HA activation pH values decreased during the evolution of H1N1 from precursors in swine (pH 5.5–6.0), to early 2009 human cases (pH 5.5), and then to later human isolates (pH 5.2–5.4). A loss-of-function pH1N1 virus with a destabilizing HA1-Y17H mutation (pH 6.0) was less pathogenic in mice and ferrets, less transmissible by contact, and no longer airborne-transmissible. A ferret-adapted revertant (HA1-H17Y/HA2-R106K) regained airborne transmissibility by stabilizing HA to an activation pH of 5.3, similar to that of human-adapted isolates from late 2009–2014. Overall, these studies reveal that a stable HA (activation pH ≤ 5.5) is necessary for pH1N1 influenza virus pathogenicity and airborne transmissibility in ferrets and is associated with pandemic potential in humans.

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Section: Discussionmentioning

confidence: 99%

Molecular requirements for a pandemic influenza virus: An acid-stable hemagglutinin protein

Russier

Yang

Rehg

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

210

View full text Add to dashboard Cite

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“…54 A stabilising mutation present in more recent pH1N1 isolates but not the earliest strains from 2009 was associated with greater infectivity in the ferret nasal tract. 55 O'Donnell et al 56 demonstrated that viruses reassorted to contain "Ann Arbor" internal genes became less pH stable than their wild-type counterparts due to cold-adapting mutations in the viral M gene. This reduction in stability could have greater impact on infectivity of pH1N1, which may already exist closer to the threshold for inactivation in the upper respiratory tract.…”

Section: (Iii)biological Characteristics Of the Ph1n1 Virus (A)reducementioning

confidence: 99%

“…60 In response to this, vaccine manufacturers took the initiative to update the pH1N1 component of LAIV in their 2015/16 product to include the HA from a more recent pH1N1 isolate (A/Bolivia/559/2013) that contains a known HA stabilising mutation 55 . In addition, measures were taken to improve maintenance of the cold chain.…”

Section: (B)reduced Thermostability Of the Ph1n1 Componentmentioning

confidence: 99%

Urgent challenges in implementing live attenuated influenza vaccine

Singanayagam

Zambon

Lalvani

et al. 2018

The Lancet Infectious Diseases

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SummaryConflicting reports have emerged about the effectiveness of the live attenuated influenza vaccine (LAIV). LAIV appears to be protecting particularly poorly against currently circulating H1N1 viruses that are derived from the 2009 pandemic H1N1 (pH1N1) viruses. During the 2015/16 influenza season, when pH1N1 was the predominant virus, studies from the United States (US) reported a complete lack of effectiveness of LAIV in children. This led to a critical decision in the US to recommend that LAIV not be used in 2016/17 and to switch to the inactivated influenza vaccine. Other countries, including the UK, Canada and Finland, have continued to recommend use of LAIV. This policy divergence and uncertainty has far reaching implications for the entire global community, given the importance of LAIV production capability for pandemic preparedness. In this Personal View, we discuss possible explanations for the observed reduced effectiveness of LAIV and highlight underpinning scientific questions. Further research to understand the reasons for these observations is essential to enable informed public health policy and commercial decisions about vaccine production and development in coming years. 3 IntroductionInfluenza vaccination remains the main strategy to control the burden of seasonal influenza disease that affects 5-10% of adults and 20-30% of children, resulting in 250,000-500,000 deaths worldwide each year. 1,2 In the US, 140 million doses of vaccine are distributed each year and vaccination is estimated to prevent nearly a quarter of predicted influenza-associated deaths. 3 Vaccination is also the primary public health response to a global influenza pandemic.Influenza vaccines contain a mixture of three or four components designed to protect against the different viruses that circulate contemporaneously as seasonal influenza viruses. Currently, these are two influenza A viruses (H1N1 and H3N2 subtypes) and two influenza B viruses (Victoria and Yamagata lineages). Vaccine components are reviewed and updated regularly by the WHO in line with observed antigenic drift of influenza viruses.The traditional inactivated influenza vaccine (IIV) was introduced in the 1940s. IIV is administered by intramuscular/intradermal injection, is licensed for use in all ages and has a good safety record. However, effectiveness rates vary, averaging around 50-60%. 4,5 More recently, live attenuated influenza vaccine (LAIV) was demonstrated to have greater efficacy than IIV in children, with absolute efficacy rates of 75-80%. [6][7][8] Internal genes of LAIV viruses are derived from a cold-adapted, attenuated strain of virus, either Ann Arbor/1960 (from the US) or Leningrad/1957 (from Russia). Haemagglutinin (HA) and neuraminidase (NA) surface antigens are engineered to be representative of currently circulating strains. LAIV is nasally administered and vaccine viruses replicate only in the air-cooled environment of the human upper respiratory tract. This results in a mild and self-limiting infection; virus cannot replicate at t...

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“…Potential interference among viruses included in the LAIV4 cannot be excluded but is not consistent with the results reported when the immunogenicity of LAIV4 was compared with that of LAIV3. 75 Heat susceptibility may have played a role, at least for the poor vaccine effectiveness in 2013-2014. During that influenza season, LAIV was prepared with the A/California/7/ 2009pdm09 strain.…”

Section: Characteristicsmentioning

confidence: 99%