A novel sequence-based antigenic distance measure for H1N1, with application to vaccine effectiveness and the selection of vaccine strains

BackgroundThe aim of this study was to analyse the genetic patterns of Hemagglutinin (HA) genes of influenza A strains circulating on Corsica Island during the 2006–2009 epidemic seasons and the 2009–2010 pandemic season.MethodsNasopharyngeal samples from 371 patients with influenza-like illness (ILI) were collected by General Practitioners (GPs) of the Sentinelles Network through a randomised selection routine.ResultsPhylogenetic analysis of HA revealed that A/H3N2 strains circulating on Corsica were closely related to the WHO recommended vaccine strains in each analyzed season (2006–2007 to 2008–2009). Seasonal Corsican influenza A/H1N1 isolated during the 2007–2008 season had drifted towards the A/Brisbane/59/2007 lineage, the A/H1N1 vaccine strain for the 2008–2009 season. The A/H1N1 2009 (A/H1N1pdm) strains isolated on Corsica Island were characterized by the S220T mutation specific to clade 7 isolates. It should be noted that Corsican isolates formed a separate sub-clade of clade 7 as a consequence of the presence of the fixed substitution D222E.The percentages of the perfect match vaccine efficacy, estimated by using the p epitope model, against influenza viruses circulating on Corsica Island varied substantially across the four seasons analyzed, and tend to be highest for A/H1N1 compared with A/H3N2 vaccines, suggesting that cross-immunity seems to be stronger for the H1 HA gene.ConclusionThe molecular analysis of the HA gene of influenza viruses that circulated on Corsica Island between 2006–2010 showed for each season the presence of a dominant lineage characterized by at least one fixed mutation. The A/H3N2 and A/H1N1pdm isolates were characterized by multiples fixation at antigenic sites. The fixation of specific mutations at each outbreak could be explained by the combination of a neutral phenomenon and a founder effect, favoring the presence of a dominant lineage in a closed environment such as Corsica Island.

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“…These two fitted models predict a vaccine effectiveness of 47% when p epitope = 0 for A/H3N2 and of 53% when p epitope = 0 for A/H1N1 [21], [23].…”

Section: Methodsmentioning

confidence: 99%

Genetic Structure of Human A/H1N1 and A/H3N2 Influenza Virus on Corsica Island: Phylogenetic Analysis and Vaccine Strain Match, 2006–2010

et al. 2011

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“…We selected these antigenic distance values to reflect ∼100% cross-reactivity of Abs to the conserved face epitope and ∼20% cross-reactivity of Abs to the polymorphic face epitope suggested in the monovalent vaccination results (47). In cases in which experimental data from a vaccination study are unavailable, the antigenic distance can be inferred from in vitro testing of serum samples (31) or estimated from epitope sequence identity (64,65). A third epitope-specific parameter, neutralization (r 1 and r 2 ), was set to 1.0 for both epitopes to reflect experimental data, which suggested that both epitopes have comparable neutralization characteristics (47).…”

Section: Overall Immune System Modelmentioning

confidence: 99%

Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1

Chaudhury

Reifman

Wallqvist

2014

The Journal of Immunology

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Polyvalent vaccines use a mixture of Ags representing distinct pathogen strains to induce an immune response that is cross-reactive and protective. However, such approaches often have mixed results, and it is unclear how polyvalency alters the fine specificity of the Ab response and what those consequences might be for protection. In this article, we present a coarse-grain theoretical model of B cell affinity maturation during monovalent and polyvalent vaccinations that predicts the fine specificity and cross-reactivity of the Ab response. We stochastically simulate affinity maturation using a population dynamics approach in which the host B cell repertoire is represented explicitly, and individual B cell subpopulations undergo rounds of stimulation, mutation, and differentiation. Ags contain multiple epitopes and are present in subpopulations of distinct pathogen strains, each with varying degrees of cross-reactivity at the epitope level. This epitope- and strain-specific model of affinity maturation enables us to study the composition of the polyclonal response in granular detail and identify the mechanisms driving serum specificity and cross-reactivity. We applied this approach to predict the Ab response to a polyvalent vaccine based on the highly polymorphic malaria Ag apical membrane antigen-1. Our simulations show how polyvalent apical membrane Ag-1 vaccination alters the selection pressure during affinity maturation to favor cross-reactive B cells to both conserved and strain-specific epitopes and demonstrate how a polyvalent vaccine with a small number of strains and only moderate allelic coverage may be broadly neutralizing. Our findings suggest that altered fine specificity and enhanced cross-reactivity may be a universal feature of polyvalent vaccines.

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“…Much of the evolution of influenza in both species involved substitutions of charged or hydrophobic amino acid residues or mutations that led to changes in glycosylation profile [18]. Influenza virus undergoing escape evolution in Guinea pigs also showed a tendency to substitute the amino acids in the epitope regions, which was also observed in human influenza [6], [27]. Consequently, the evolution of the virus in Guinea pigs represents a valuable model system for helping us to understand the escape evolution of human influenza virus.…”

Section: Discussionmentioning

confidence: 93%

Evolution of H3N2 Influenza Virus in a Guinea Pig Model

et al. 2011

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Studies of influenza virus evolution under controlled experimental conditions can provide a better understanding of the consequences of evolutionary processes with and without immunological pressure. Characterization of evolved strains assists in the development of predictive algorithms for both the selection of subtypes represented in the seasonal influenza vaccine and the design of novel immune refocused vaccines. To obtain data on the evolution of influenza in a controlled setting, naïve and immunized Guinea pigs were infected with influenza A/Wyoming/2003 (H3N2). Virus progeny from nasal wash samples were assessed for variation in the dominant and other epitopes by sequencing the hemagglutinin (HA) gene to quantify evolutionary changes. Viral RNA from the nasal washes from infection of naïve and immune animals contained 6% and 24.5% HA variant sequences, respectively. Analysis of mutations relative to antigenic epitopes indicated that adaptive immunity played a key role in virus evolution. HA mutations in immunized animals were associated with loss of glycosylation and changes in charge and hydrophobicity in and near residues within known epitopes. Four regions of HA-1 (75–85, 125–135, 165–170, 225–230) contained residues of highest variability. These sites are adjacent to or within known epitopes and appear to play an important role in antigenic variation. Recognition of the role of these sites during evolution will lead to a better understanding of the nature of evolution which help in the prediction of future strains for selection of seasonal vaccines and the design of novel vaccines intended to stimulated broadened cross-reactive protection to conserved sites outside of dominant epitopes.

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A novel sequence-based antigenic distance measure for H1N1, with application to vaccine effectiveness and the selection of vaccine strains

Cited by 55 publications

References 30 publications

Genetic Structure of Human A/H1N1 and A/H3N2 Influenza Virus on Corsica Island: Phylogenetic Analysis and Vaccine Strain Match, 2006–2010

Genetic Structure of Human A/H1N1 and A/H3N2 Influenza Virus on Corsica Island: Phylogenetic Analysis and Vaccine Strain Match, 2006–2010

Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1

Evolution of H3N2 Influenza Virus in a Guinea Pig Model

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