Broad anti-hepatitis C virus (HCV) antibody responses are associated with improved clinical disease parameters in chronic HCV infection

During hepatitis C virus (HCV) infection broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glycoproteins are generated in many individuals. It is unclear if these antibodies play a protective or a pathogenic role during chronic infection. In this study, we investigated whether bNAb responses in individuals with chronic infection were associated with differences in clinical presentation. Patient-derived purified serum IgG was used to assess the breadth of HCV E1E2 binding and neutralization activity of HCV pseudoparticles. Two panels were compared, bearing viral envelope proteins representing either an inter-genotype or an intra-genotype (gt) 1 group. We found that HCV viral load was negatively associated with strong cross-genotypic E1E2 binding (P=0.03). Overall we observed only modest correlation between total E1E2 binding and neutralizing ability. The breadth of inter-genotype neutralization did not correlate with any clinical parameters, however, analysis of individuals with gt 1 HCV infection (n=20), using an intra-genotype pseudoparticle panel, found a strong association between neutralization breadth and reduced liver fibrosis (P=0.006). Broad bNAb response in our chronic cohort was associated with a single nucleotide polymorphism (SNP) in the HLA-DQB1 gene (P=0.038) as previously reported in an acute cohort. Furthermore bNAbs in these individuals targeted more than one region of E2 neutralizing epitopes as assessed through cross-competition of patient bNAbs with well-characterized E2 antibodies. We conclude that bNAb responses in chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses. IMPORTANCE: Globally there are 130-150 million people with chronic HCV infection. Typically the disease is progressive and is a major cause of severe liver cirrhosis and hepatocellular carcinoma. While it is known that neutralizing antibodies have a role in spontaneous clearance during acute infection, little is known about their role in chronic infection. In the present work we investigate the antibody response in a cohort of chronically infected individuals and find that a broad neutralizing antibody response is protective, with reduced levels of liver fibrosis and cirrhosis. We also find an association with SNPs in class II HLA genes and the presence of a broad neutralizing response indicating that antigen presentation may be important for production of HCV neutralizing antibodies

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS): Prospective, national surveillance, United Kingdom and Ireland, 2020

Background: Paediatric Multisystem Inflammatory Syndrome temporally associated with SARS-CoV-2 (PIMS-TS), first identified in April 2020, shares features of both Kawasaki disease (KD) and toxic shock syndrome (TSS). The surveillance describes the epidemiology and clinical characteristics of PIMS-TS in the United Kingdom and Ireland. Methods: Public Health England initiated prospective national surveillance of PIMS-TS through the British Paediatric Surveillance Unit. Paediatricians were contacted monthly to report PIMS-TS, KD and TSS cases electronically and complete a detailed clinical questionnaire. Cases with symptom onset between 01 March and 15 June 2020 were included. Findings: there were 216 cases with features of PIMS-TS alone, 13 with features of both PIMS-TS and KD, 28 with features of PIMS-TS and TSS and 11 with features of PIMS-TS, KD and TSS, with differences in age, ethnicity, clinical presentation and disease severity between the phenotypic groups. There was a strong geographical and temporal association between SARS-CoV-2 infection rates and PIMS-TS cases. Of those tested, 14.8% (39/264) children had a positive SARS-CoV-2 RT-PCR, and 63.6% (75/118) were positive for SARS-CoV-2 serology. In total 44·0% (118/268) required intensive care, which was more common in cases with a TSS phenotype. Three of five children with cardiac arrest had TSS phenotype. Three children (1·1%) died. Interpretation: the strong association between SARS-CoV-2 infection and PIMS-TS emphasises the importance of maintaining low community infection rates to reduce the risk of this rare but severe complication in children and adolescents. Close follow-up will be important to monitor long-term complications in children with PIMS-T

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The neutralizing antibody responses of individuals that spontaneously resolve hepatitis C virus infection

Hepatitis C virus (HCV) infection is a major global health problem. In the majority of cases the virus is not cleared by the host immune response and progresses to chronic infection. Studies of the neutralizing antibody responses in individuals that naturally clear infection are limited. Understanding what constitutes a successful antibody response versus one that has ‘failed’ and resulted in chronic infection is important to understand what type of antibody response would need to be elicited by a protective vaccine. Samples from spontaneous clearers are difficult to obtain therefore studies are often limited. In our study through HCV Research UK, we had access to a cohort of over 200 samples. We identified the samples that contained HCV neutralizing antibodies using ELISA and HCV pseudoparticle (HCVpp) assays. We then utilised mutagenesis and cross-competition analysis to determine the profile of the neutralizing antibody responses. In addition, we analysed a cohort of samples from chronic infection using the same techniques to enable direct comparison of the antibody profiles observed in both cohorts. We conclude that similar profiles are present in both cohorts indicating that it is not the neutralizing antibody response per se that determines the outcome of infection. These data will provide useful information for future HCV vaccine design

Broad Anti-Hepatitis C Virus (HCV) Antibody Responses Are Associated with Improved Clinical Disease Parameters in Chronic HCV Infection

During hepatitis C virus (HCV) infection,broadly neutralizing antibody (bNAb) responses targeting E1E2 envelope glyco proteins are generated in many individuals.It is unclear if these antibodies play a protective or a pathogenic role during chronic infection. In this study, we investigated whether bNAb responses inindividuals with chronic infection we reassociated with differences in clinical presentation. Patient-derived purified serum IgG was used to assess the breadth of HCV E1E2 binding and the neutralization activity of HCV pseudoparticles. The binding and neutralization activity results for two panels bearing viral envelope proteins representing either an intergenotype or an intragenotype 1 group were compared. We found that the HCV load was negatively associated with srong cross-genotypic E1E2 binding (P=0.03). Overall,we observed only a modest correlation between total E1E2 binding and neutralization ability. The breadth of intergeno type neutralization did not correlate with any clinical parameters;however,analysis of individuals with genotype1(gt1) HCVinfection(n=20),using an intrageno type pseudop article panel,found a stronga ssociation between neutralization breadth and reduced liver fibrosis(P=0.006).Abroad bNAb response in our cohort with chronic infection was associated with a single nucleotide polymorphism (SNP) in the HLA DQB1 gene (P=0.038),as previously reported in a cohort with acute disease. Furthermore,the bNAbs in these individuals targeted more than one region of E2-neutralizing epitopes, as assessed through cross-competition of patient bNAbs with well-characterized E2 antibodies. We conclude that the bNAb responses inpatients with chronic gt1 infection are associated with lower rates of fibrosis and host genetics may play a role in the ability to raise such responses

The DNA sequence of the human X chromosome

The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence

Risk of COVID-19 after natural infection or vaccinationResearch in context

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health