Hepatitis C virus (HCV) exhibits high genetic diversity, characterized by regional variations in genotype prevalence. This poses a challenge to the improved development of vaccines and pan-genotypic treatments, which require the consideration of global trends in HCV genotype prevalence. Here we provide the first comprehensive survey of these trends. To approximate national HCV genotype prevalence, studies published between 1989 and 2013 reporting HCV genotypes are reviewed and combined with overall HCV prevalence estimates from the Global Burden of Disease (GBD) project. We also generate regional and global genotype prevalence estimates, inferring data for countries lacking genotype information. We include 1,217 studies in our analysis, representing 117 countries and 90% of the global population. We calculate that HCV genotype 1 is the most prevalent worldwide, comprising 83.4 million cases (46.2% of all HCV cases), approximately one-third of which are in East Asia. Genotype 3 is the next most prevalent globally (54.3 million, 30.1%); genotypes 2, 4, and 6 are responsible for a total 22.8% of all cases; genotype 5 comprises the remaining <1%. While genotypes 1 and 3 dominate in most countries irrespective of economic status, the largest proportions of genotypes 4 and 5 are in lower-income countries. Conclusion: Although genotype 1 is most common worldwide, nongenotype 1 HCV cases—which are less well served by advances in vaccine and drug development—still comprise over half of all HCV cases. Relative genotype proportions are needed to inform healthcare models, which must be geographically tailored to specific countries or regions in order to improve access to new treatments. Genotype surveillance data are needed from many countries to improve estimates of unmet need. (Hepatology 2015;61:77–87)

Currently no vaccine exists for hepatitis C virus (HCV), a major pathogen thought to infect 170 million people globally. Many studies suggest that host T cell responses are critical for spontaneous resolution of disease, and preclinical studies have indicated a requirement for T cells in protection against challenge. We aimed to elicit HCV-specific T cells with the potential for protection using a recombinant adenoviral vector strategy in a Phase I study of healthy human volunteers. Two adenoviral vectors expressing NS proteins from HCV genotype 1B were constructed based on rare serotypes (Human Adenovirus 6 (Ad6) and Chimpanzee Adenovirus 3 (ChAd3)). Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A). HCV-specific T cells consisted of both CD4+ and CD8+ T cells subsets, secreted IL-2, IFNγ, and TNFα, and could be sustained for at least a year after boosting with the heterologous adenoviral vector. Studies using MHC peptide tetramers revealed long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity. These data indicate that an adenoviral vector strategy can induce sustained T cell responses of a magnitude and quality associated with protective immunity, and open the way for studies of prophylactic and therapeutic vaccines for HCV.

Abstract* "This manuscript has been accepted for publication in Science Translational Medicine. This version has not undergone final editing.Please refer to the complete version of record at www.sciencetranslationalmedicine.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS."To whom correspondence should be addressed: ellie.barnes@ndm.ox.ac.uk E Barnes Peter Medawar Building, South Parks Rd, Oxford, UK OX1 3SY . + joint author contributions Author contributions: E.B., S. Capone, S. Colloca, J.H., A.F., R.C., C.K., A.N., and P.K. designed the study/protocols; L. Swadling, S. Capone., R.A., A.B., R.R., E.N., J.H., C.K., D.B., J.F., A.K., V.A., M.D.S., F.G., M.L.E., L. Siani., C.T., A.H., M.D., A.F., E.B., and P.K., performed the research and analysis; L. Swadling., E.B., A.F., S. Capone, and P.K. wrote the manuscript; E.B. was the principal investigator. Europe PMC Funders Group Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsA protective vaccine against hepatitis C virus (HCV) remains an unmet clinical need. HCV infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular cancer. Animal challenge experiments, immunogenetics studies and assessment of host immunity during acute infection highlight the critical role that effective T-cell immunity plays in viral control. In this first-in-man study we have induced antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection, and improved upon a vaccine based on adenoviral vectors alone. We assessed a heterologous prime-boost vaccination strategy based on a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A and NS5B proteins of HCV genotype-1b.Analysis employed single cell mass cytometry (CyTOF), and HLA class-I peptide tetramer technology in healthy human volunteers. We show that HCV specific T-cells induced by ChAd3 are optimally boosted with MVA, and generate very high levels of both CD8+ and CD4+ HCV specific T-cells targeting multiple HCV antigens. Sustained memory and effector T-cell populations are generated and T-cell memory evolved over time with improvement of quality (proliferation and polyfunctionality) following heterologous MVA boost.We have developed a HCV vaccine strategy, with durable, broad, sustained and balanced T-cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine.

Extension of the interval between vaccine doses for the BNT162b2 mRNA vaccine was introduced in the UK to accelerate population coverage with a single dose. At this time, trial data was lacking, and we addressed this in a study of UK healthcare workers. The first vaccine dose induced protection from infection from the circulating alpha (B.1.1.7) variant over several weeks. In a sub-study of 589 individuals, we show that this single dose induces SARS-CoV-2 neutralizing antibody (NAb) responses and a sustained B and T cell response to spike protein. NAb levels were higher after the extended dosing interval (6-14 weeks) compared to the conventional 3-4 week regimen, accompanied by enrichment of CD4 + T cells expressing IL2. Prior SARS-CoV-2 infection amplified and accelerated the response. These data on dynamic cellular and humoral responses indicate that extension of the dosing interval is an effective, immunogenic protocol.