Surface antigens of pathogens are commonly targeted by vaccine-elicited antibodies but antigenic variability, notably in RNA viruses such as influenza, HIV and SARS-CoV-2, pose challenges for control ...by vaccination. For example, influenza A(H3N2) entered the human population in 1968 causing a pandemic and has since been monitored, along with other seasonal influenza viruses, for the emergence of antigenic drift variants through intensive global surveillance and laboratory characterisation. Statistical models of the relationship between genetic differences among viruses and their antigenic similarity provide useful information to inform vaccine development, though accurate identification of causative mutations is complicated by highly correlated genetic signals that arise due to the evolutionary process. Here, using a sparse hierarchical Bayesian analogue of an experimentally validated model for integrating genetic and antigenic data, we identify the genetic changes in influenza A(H3N2) virus that underpin antigenic drift. We show that incorporating protein structural data into variable selection helps resolve ambiguities arising due to correlated signals, with the proportion of variables representing haemagglutinin positions decisively included, or excluded, increased from 59.8% to 72.4%. The accuracy of variable selection judged by proximity to experimentally determined antigenic sites was improved simultaneously. Structure-guided variable selection thus improves confidence in the identification of genetic explanations of antigenic variation and we also show that prioritising the identification of causative mutations is not detrimental to the predictive capability of the analysis. Indeed, incorporating structural information into variable selection resulted in a model that could more accurately predict antigenic assay titres for phenotypically-uncharacterised virus from genetic sequence. Combined, these analyses have the potential to inform choices of reference viruses, the targeting of laboratory assays, and predictions of the evolutionary success of different genotypes, and can therefore be used to inform vaccine selection processes.
Influenza viruses undergo continual antigenic evolution allowing mutant viruses to evade host immunity acquired to previous virus strains. Antigenic phenotype is often assessed through pairwise ...measurement of cross-reactivity between influenza strains using the hemagglutination inhibition (HI) assay. Here, we extend previous approaches to antigenic cartography, and simultaneously characterize antigenic and genetic evolution by modeling the diffusion of antigenic phenotype over a shared virus phylogeny. Using HI data from influenza lineages A/H3N2, A/H1N1, B/Victoria and B/Yamagata, we determine patterns of antigenic drift across viral lineages, showing that A/H3N2 evolves faster and in a more punctuated fashion than other influenza lineages. We also show that year-to-year antigenic drift appears to drive incidence patterns within each influenza lineage. This work makes possible substantial future advances in investigating the dynamics of influenza and other antigenically-variable pathogens by providing a model that intimately combines molecular and antigenic evolution. DOI: http://dx.doi.org/10.7554/eLife.01914.001.
Determining phenotype from genetic data is a fundamental challenge. Identification of emerging antigenic variants among circulating influenza viruses is critical to the vaccine virus selection ...process, with vaccine effectiveness maximized when constituents are antigenically similar to circulating viruses. Hemagglutination inhibition (HI) assay data are commonly used to assess influenza antigenicity. Here, sequence and 3-D structural information of hemagglutinin (HA) glycoproteins were analyzed together with corresponding HI assay data for former seasonal influenza A(H1N1) virus isolates (1997-2009) and reference viruses. The models developed identify and quantify the impact of eighteen amino acid substitutions on the antigenicity of HA, two of which were responsible for major transitions in antigenic phenotype. We used reverse genetics to demonstrate the causal effect on antigenicity for a subset of these substitutions. Information on the impact of substitutions allowed us to predict antigenic phenotypes of emerging viruses directly from HA gene sequence data and accuracy was doubled by including all substitutions causing antigenic changes over a model incorporating only the substitutions with the largest impact. The ability to quantify the phenotypic impact of specific amino acid substitutions should help refine emerging techniques that predict the evolution of virus populations from one year to the next, leading to stronger theoretical foundations for selection of candidate vaccine viruses. These techniques have great potential to be extended to other antigenically variable pathogens.
Catheter associated urinary tract infections are one of the most common infections acquired in hospital. A recent randomised control study demonstrated the benefit of using chlorhexidine (0.1%) for ...meatal cleaning prior to urinary catheter insertion, by reducing both catheter associated asymptomatic bacteriuria and infection. These findings raise the important question of whether a decision to switch from saline to chlorhexidine was likely to be cost-effective. The aim of this paper was to evaluate the cost-effectiveness of adopting routine use of chlorhexidine for meatal cleaning prior to urinary catheter insertion
The outcomes of this cost-effectiveness study are changes to health service costs in $AUD and changes to quality adjusted life years from a decision to adopt 0.1% chlorhexidine for meatal cleaning prior to urinary catheter insertion as compared to saline. Effectiveness outcomes for this study were taken from a 32 week stepped wedge randomised controlled study conducted in three Australian hospitals.
The changes in health costs from switching from saline to 0.1% chlorhexidine per 100,000 catheterisations would save hospitals AUD$387,909 per 100,000 catherisations, prevent 70 cases of catheter associated urinary tract infections, release 282 bed days and provide a small improvement in health benefits of 1.43 quality adjusted life years. Using a maximum willingness to pay for a marginal quality adjusted life year threshold of AUD$28,000 per 100,000 catherisations, suggests that adopting chlorhexidine would be cost effective and potentially cost-saving.
The findings from our work provide evidence to health system administrators and those responsible for drafting catheter associated urinary tract infections prevention guidelines that investing in switching from saline to chlorhexidine is not only clinically effective but also a sensible decision in the context of allocating finite healthcare resources.
The evolution of human influenza viruses Hay, Alan J.; Gregory, Victoria; Douglas, Alan R. ...
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
12/2001, Volume:
356, Issue:
1416
Journal Article
Peer reviewed
Open access
The evolution of influenza viruses results in (i) recurrent annual epidemics of disease that are caused by progressive antigenic drift of influenza A and B viruses due to the mutability of the RNA ...genome and (ii) infrequent but severe pandemics caused by the emergence of novel influenza A subtypes to which the population has little immunity. The latter characteristic is a consequence of the wide antigenic diversity and peculiar host range of influenza A viruses and the ability of their segmented RNA genomes to undergo frequent genetic reassortment (recombination) during mixed infections. Contrasting features of the evolution of recently circulating influenza AH1N1, AH3N2 and B viruses include the rapid drift of AH3N2 viruses as a single lineage, the slow replacement of successive antigenic variants of AH1N1 viruses and the co-circulation over some 25 years of antigenically and genetically distinct lineages of influenza B viruses. Constant monitoring of changes in the circulating viruses is important for maintaining the efficacy of influenza vaccines in combating disease.
Influenza A (H5N1) viruses infected humans in Hong Kong between May and December, 1997. Sixteen viruses, including 6 from fatal cases, were isolated during this outbreak. Molecular analysis of the ...surface proteins genes encoding the hemagglutinin (HA) and neuraminidase (NA) of these H5N1 isolates, of a subtype not previously known to infect humans, are presented. The 16 human H5 HA sequences contain multiple basic amino acids adjacent to the cleavage site, a motif associated with highly pathogenic avian influenza A viruses. The phylogenetic relationship among both avian and human H5 hemagglutinins indicates that the human isolates are related directly to isolates that circulated among chickens in the live poultry markets in Hong Kong prior to and during the outbreak in humans. HA sequences from the human isolates and a recent chicken isolate represent a separate clade, within which there are two subgroups that are distinguishable antigenically and by the presence of a potential glycosylation site. Likewise the N1 neuraminidases of the human H5 isolates represent a clade that is evolutionarily distinct from previously characterized N1 neuraminidases. The recent human H5N1 virus NA genes are avian-like, indicating direct introduction from an avian source rather than evolution of a human N1 NA. All of the 16 human NA genes encode a shortened stalk due to a 19-amino acid deletion, also found in the recent avian H5N1 isolates from Hong Kong. Two unique amino acids were identified in the N1 NAs of the recent human isolates; however, it is not known if these residues influence host range. Neither the HA nor the NA genes of the human H5N1 virus isolates show evidence of adaptive changes during the outbreak. Although analyses of the surface protein genes of the H5N1 viruses from this outbreak did not provide immediate answers regarding the molecular basis for virulence, the analyses provided clues to potentially important areas of the genes worth further investigation.
While influenza surveillance has increased in most developing countries in the last few years, little influenza surveillance has been carried out in sub-Saharan Africa and no information is available ...in Central Africa. The objective of this study was to assess the prevalence of influenza viruses circulating in Yaounde, Cameroon and determine their antigenic and genetic characteristics.
Throat and/or nasal swabs were collected from November 2007 to October 2008 from outpatients with influenza-like illness (ILI) in Yaounde, Cameroon and analyzed by two different techniques: a one-step real time reverse transcription-polymerase chain reaction (RT-PCR) and virus isolation in MDCK cells. Typing and subtyping of virus isolates was performed by hemagglutination inhibition (HI), and viruses were sent to the WHO Collaborating Centre in London, UK for further characterization and analyses of antiviral resistance by enzyme inhibition assay and nucleotide sequencing.
A total of 238 patients with ILI were sampled. During this period 70 (29%) samples were positive for influenza by RT-PCR, of which only 26 (11%) were positive by virus isolation. By HI assay, 20 of the 26 isolates were influenza type A (10 H3N2 and 10 H1N1) and 6 were influenza type B (2 B/Victoria/2/87 lineage and 4 B/Yagamata/16/88 lineage). Seven (70%) of the H1N1 isolates were shown to be resistant to oseltamivir due to a H275Y mutation.
This study confirmed the circulation of influenza A(H1N1), A(H3N2) and B viruses in the human population in Central Africa and describes the emergence of oseltamivir-resistant A(H1N1) viruses in Central Africa.
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