Distinguishing immunological and behavioral effects of vaccination

The interpretation of vaccine efficacy estimands is subtle, even in randomized trials designed to quantify immunological effects of vaccination. In this article, we introduce terminology to distinguish between different vaccine efficacy estimands and clarify their interpretations. This allows us to explicitly consider immunological and behavioural effects of vaccination, and establish that policy-relevant estimands can differ substantially from those commonly reported in vaccine trials. We further show that a conventional vaccine trial allows identification and estimation of different vaccine estimands under plausible conditions, if one additional post-treatment variable is measured. Specifically, we utilize a ``belief variable'' that indicates the treatment an individual believed they had received. The belief variable is similar to ``blinding assessment'' variables that are occasionally collected in placebo-controlled trials in other fields. We illustrate the relations between the different estimands, and their practical relevance, in numerical examples based on an influenza vaccine trial

Home and away- the evolutionary dynamics of homing endonucleases

<p>Abstract</p> <p>Background</p> <p>Homing endonucleases (HEases) are a large and diverse group of site-specific DNAases. They reside within self-splicing introns and inteins, and promote their horizontal dissemination. In recent years, HEases have been the focus of extensive research due to their promising potential use in gene targeting procedures for the treatment of genetic diseases and for the genetic engineering of crop, animal models and cell lines.</p> <p>Results</p> <p>Using mathematical analysis and computational modeling, we present here a novel account for the evolution and population dynamics of HEase genes (HEGs). We describe HEGs as paradoxical selfish elements whose long-term persistence in a single population relies on low transmission rates and a positive correlation between transmission efficiency and toxicity.</p> <p>Conclusion</p> <p>Plausible conditions allow HEGs to sustain at high frequency through long evolutionary periods, with the endonuclease frequency being either at equilibrium or periodically oscillating. The predictions of our model may prove important not only for evolutionary theory but also for gene therapy and bio-engineering applications of HEases.</p

Polymorphisms Predicting Phylogeny in Hepatitis B Virus (HBV)

Hepatitis B viruses (HBV) are compact viruses with circular genomes of ∼3.2kb in length. Four genes (HBx, Core, Surface and Polymerase) generating seven products are encoded on overlapping reading frames. Ten HBV genotypes have been characterised (A-J), which may account for differences in transmission, outcomes of infection, and treatment response. However, HBV genotyping is rarely undertaken, and sequencing remains inaccessible in many settings. We used a machine learning approach based on random forest algorithms (RFA) to assess which amino acid (aa) sites in the genome are most informative for determining genotype. We downloaded 5496 genome-length HBV sequences from a public database, excluding recombinant sequences, regions with conserved indels, and genotypes I/J. Each gene was separately translated into aa, and the proteins concatenated into a single sequence (length 1614aa). Using RFA, we searched for aa sites predictive of genotype, and assessed co-variation among the sites with a Mutual Information (MI)-based method. We were able to discriminate confidently between genotypes A-H using 10 aa sites. 5/10 sites were identified in Polymerase (Pol), of which 4/5 were in the spacer domain, and a single site in reverse transcriptase. A further 4/10 sites were located in Surface protein, and a single site in HBx. There were no informative sites in Core. Properties of the aa were generally not conserved between genotypes at informative sites. Co-variation analysis identified 55 pairs of highly-linked sites. Three RFA-identified sites were represented across all pairs (two sites in spacer, and one in HBx). Residues that co-vary with these sites are concentrated in the small HBV surface gene. We also observe a cluster of sites adjacent to the Surface promoter region that co-vary with a spacer residue. Overall, we have shown that RFA analysis is a powerful tool for identifying aa sites that predict HBV lineage, with an unexpectedly high number of such sites in the spacer domain, which has conventionally been viewed as unimportant for structure or function. Our results improve ease of genotype prediction from limited regions of HBV sequence, and may have implications for understanding HBV evolution and the role of the spacer domain

Polymorphisms predicting phylogeny in hepatitis B virus

Hepatitis B viruses (HBVs) are compact viruses with circular genomes of ∼3.2 kb in length. Four genes (HBx, Core, Surface, and Polymerase) generating seven products are encoded on overlapping reading frames. Ten HBV genotypes have been characterised (A-J), which may account for differences in transmission, outcomes of infection, and treatment response. However, HBV genotyping is rarely undertaken, and sequencing remains inaccessible in many settings. We set out to assess which amino acid (aa) sites in the HBV genome are most informative for determining genotype, using a machine learning approach based on random forest algorithms (RFA). We downloaded 5,496 genome-length HBV sequences from a public database, excluding recombinant sequences, regions with conserved indels, and genotypes I and J. Each gene was separately translated into aa, and the proteins concatenated into a single sequence (length 1,614 aa). Using RFA, we searched for aa sites predictive of genotype and assessed covariation among the sites with a mutual information-based method. We were able to discriminate confidently between genotypes A-H using ten aa sites. Half of these sites (5/10) sites were identified in Polymerase (Pol), of which 4/5 were in the spacer domain and one in reverse transcriptase. A further 4/10 sites were located in Surface protein and a single site in HBx. There were no informative sites in Core. Properties of the aa were generally not conserved between genotypes at informative sites. Among the highest co-varying pairs of sites, there were fifty-five pairs that included one of these 'top ten' sites. Overall, we have shown that RFA analysis is a powerful tool for identifying aa sites that predict the HBV lineage, with an unexpectedly high number of such sites in the spacer domain, which has conventionally been viewed as unimportant for structure or function. Our results improve ease of genotype prediction from limited regions of HBV sequences and may have future applications in understanding HBV evolution

West Nile virus transmission potential in Portugal

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.It is unclear whether West Nile virus (WNV) circulates endemically in Portugal. Despite the country's adequate climate for transmission, Portugal has only reported four human WNV infections so far. We performed a review of WNV-related data (1966-2020), explored mosquito (2016-2019) and land type distributions (1992-2019), and used climate data (1981-2019) to estimate WNV transmission suitability in Portugal. Serological and molecular evidence of WNV circulation from animals and vectors was largely restricted to the south. Land type and climate-driven transmission suitability distributions, but not the distribution of WNV-capable vectors, were compatible with the North-South divide present in serological and molecular evidence of WNV circulation. Our study offers a comprehensive, data-informed perspective and review on the past epidemiology, surveillance and climate-driven transmission suitability of WNV in Portugal, highlighting the south as a subregion of importance. Given the recent WNV outbreaks across Europe, our results support a timely change towards local, active surveillance.info:eu-repo/semantics/publishedVersio

Hepatitis B virus seroepidemiology data for Africa:Modelling intervention strategies based on a systematic review and meta-analysis

BACKGROUND: International Sustainable Development Goals (SDGs) for elimination of hepatitis B virus (HBV) infection set ambitious targets for 2030. In African populations, infant immunisation has been fundamental to reducing incident infections in children, but overall population prevalence of chronic hepatitis B (CHB) infection remains high. In high-prevalence populations, adult catch-up vaccination has sometimes been deployed, but an alternative Test and Treat (T&T) approach could be used as an intervention to interrupt transmission. Universal T&T has not been previously evaluated as a population intervention for HBV infection, despite high-profile data supporting its success with human immunodeficiency virus (HIV). METHODS AND FINDINGS: We set out to investigate the relationship between prevalence of HBV infection and exposure in Africa, undertaking a systematic literature review in November 2019. We identified published seroepidemiology data representing the period 1995-2019 from PubMed and Web of Science, including studies of adults that reported prevalence of both hepatitis B surface antigen (HBsAg; prevalence of HBV infection) and antibody to hepatitis B core antigen (anti-HBc; prevalence of HBV exposure). We identified 96 studies representing 39 African countries, with a median cohort size of 370 participants and a median participant age of 34 years. Using weighted linear regression analysis, we found a strong relationship between the prevalence of infection (HBsAg) and exposure (anti-HBc) (R2 = 0.45, p < 0.001). Region-specific differences were present, with estimated CHB prevalence in Northern Africa typically 30% to 40% lower (p = 0.007) than in Southern Africa for statistically similar exposure rates, demonstrating the need for intervention strategies to be tailored to individual settings. We applied a previously published mathematical model to investigate the effect of interventions in a high-prevalence setting. The most marked and sustained impact was projected with a T&T strategy, with a predicted reduction of 33% prevalence by 20 years (95% CI 30%-37%) and 62% at 50 years (95% CI 57%-68%), followed by routine neonatal vaccination and prevention of mother to child transmission (PMTCT; at 100% coverage). In contrast, the impact of catch-up vaccination in adults had a negligible and transient effect on population prevalence. The study is constrained by gaps in the published data, such that we could not model the impact of antiviral therapy based on stratification by specific clinical criteria and our model framework does not include explicit age-specific or risk-group assumptions regarding force of transmission. CONCLUSIONS: The unique data set collected in this study highlights how regional epidemiology data for HBV can provide insights into patterns of transmission, and it provides an evidence base for future quantitative research into the most effective local interventions. In combination with robust neonatal immunisation programmes, ongoing PMTCT efforts, and the vaccination of high-risk groups, diagnosing and treating HBV infection is likely to be of most impact in driving advances towards elimination targets at a population level

The metabolic, virulence and antimicrobial resistance profiles of colonising Streptococcus pneumoniae shift after PCV13 introduction in urban Malawi

Streptococcus pneumoniae causes substantial mortality among children under 5-years-old worldwide. Polysaccharide conjugate vaccines (PCVs) are highly effective at reducing vaccine serotype disease, but emergence of non-vaccine serotypes and persistent nasopharyngeal carriage threaten this success. We investigated the hypothesis that following vaccine, adapted pneumococcal genotypes emerge with the potential for vaccine escape. We genome sequenced 2804 penumococcal isolates, collected 4-8 years after introduction of PCV13 in Blantyre, Malawi. We developed a pipeline to cluster the pneumococcal population based on metabolic core genes into “Metabolic genotypes” (MTs). We show that S. pneumoniae population genetics are characterised by emergence of MTs with distinct virulence and antimicrobial resistance (AMR) profiles. Preliminary in vitro and murine experiments revealed that representative isolates from emerging MTs differed in growth, haemolytic, epithelial infection, and murine colonisation characteristics. Our results suggest that in the context of PCV13 introduction, pneumococcal population dynamics had shifted, a phenomenon that could further undermine vaccine control and promote spread of AMR

The metabolic, virulence and antimicrobial resistance profiles of colonising Streptococcus pneumoniae shift after PCV13 introduction in urban Malawi.

Streptococcus pneumoniae causes substantial mortality among children under 5-years-old worldwide. Polysaccharide conjugate vaccines (PCVs) are highly effective at reducing vaccine serotype disease, but emergence of non-vaccine serotypes and persistent nasopharyngeal carriage threaten this success. We investigated the hypothesis that following vaccine, adapted pneumococcal genotypes emerge with the potential for vaccine escape. We genome sequenced 2804 penumococcal isolates, collected 4-8 years after introduction of PCV13 in Blantyre, Malawi. We developed a pipeline to cluster the pneumococcal population based on metabolic core genes into "Metabolic genotypes" (MTs). We show that S. pneumoniae population genetics are characterised by emergence of MTs with distinct virulence and antimicrobial resistance (AMR) profiles. Preliminary in vitro and murine experiments revealed that representative isolates from emerging MTs differed in growth, haemolytic, epithelial infection, and murine colonisation characteristics. Our results suggest that in the context of PCV13 introduction, pneumococcal population dynamics had shifted, a phenomenon that could further undermine vaccine control and promote spread of AMR

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal coronavirus disease (COVID-19) outcomes is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses, and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to intensive care units (ICU) with fatal COVID-19 outcomes, but not in individuals with non-fatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to ICU with fatal and non-fatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an original antigenic sin type-response