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Background & Aims Neutralising antibodies (NAbs) play a key role in clearance of HCV. NAbs have been isolated and mapped to several domains on the HCV envelope proteins. However, the immunodominance of these epitopes in HCV infection remains unknown, hindering efforts to elicit optimal epitope-specific responses. Furthermore, it remains unclear which epitope-specific responses are associated with broad NAb (bNAb) activity in primary HCV infection. The aim of this study was to define B cell immunodominance in primary HCV, and its implications on neutralisation breadth and clearance. Methods Using samples from 168 patients with primary HCV infection, the antibody responses targeted 2 immunodominant domains, termed domains B and C. Genotype 1 and 3 infections were associated with responses targeted towards different bNAb domains. Results No epitopes were uniquely targeted by clearers compared to those who developed chronic infection. Samples with bNAb activity were enriched for multi-specific responses directed towards the epitopes antigenic region 3, antigenic region 4, and domain D, and did not target non-neutralising domains. Conclusions This study outlines for the first time a clear NAb immunodominance profile in primary HCV infection, and indicates that it is influenced by the infecting virus. It also highlights the need for a vaccination strategy to induce multi-specific responses that do not target non-neutralising domains. Lay summary Neutralising antibodies will likely form a key component of a protective hepatitis C virus vaccine. In this work we characterise the predominant neutralising and non-neutralising antibody (epitope) targets in acute hepatitis C virus infection. We have defined the natural hierarchy of epitope immunodominance, and demonstrated that viral genotype can impact on this hierarchy. Our findings highlight key epitopes that are associated with broadly neutralising antibodies, and the deleterious impact of mounting a response towards some of these domains on neutralising breadth. These findings should guide future efforts to design immunogens aimed at generating neutralising antibodies with a vaccine candidate.

Introduction The pathophysiology of severe dengue is related to increased capillary permeability and plasma leakage into extracellular space. A simple, low cost risk prediction tool for plasma leakage will be useful for clinicians practicing in rural areas without imaging facilities. Study design A prospective observational study was carried out over 12 months at the National Hospital, Sri Lanka enrolling patients with confirmed diagnosis (via NS1 antigen testing) of early dengue infection. Clinical features on admission and investigation results on D3, D5 and D7 of the illness were recorded. Evidence of plasma leakage was confirmed by ultrasonography. Results A total of 179 patients met the inclusion criteria (males; 91, 50.8%, mean age: 31.6 years, SD ± 14.7). Sixty seven patients (67/173, 38.7%) had ultrasonographic evidence of plasma leakage. Several clinical features (severe vomiting, severe diarrhoea, abdominal pain and liver tenderness) as well as mean differences of some investigations were significantly associated with progression to plasma leakage. However, only liver tenderness on day 3 emerged as independent significant predictors of critical phase in the adjusted analysis (specificity: 93%, sensitivity: 44%). Conclusions Having liver tenderness by day 3 of the illness is helpful to identify a subgroup of patients at risk of plasma leakage.

Background Repurposing hydroxychloroquine (HCQ) and chloroquine (CQ) as antiviral agents is a re-emerging topic with the advent of new viral epidemics. Aims To summarize evidence from human clinical studies for using HCQ or CQ as antiviral agents for any viral infection. Sources PubMed, EMBASE, Scopus, Web of Science for published studies without time or language restrictions; Cochrane Clinical Trial Registry and Chinese Clinical Trials Registry for trials registered after 2015; MedRxiv for preprints within the last 12 months. Content Study eligibility criteria were interventional and prospective observational studies (with or without a control group). Participants were adults and children with a confirmed viral infection. Interventions included the use of CQ or HCQ as antiviral agent in one or more groups of the study. Two authors independently screened abstracts, and all authors agreed on eligible studies. A meta-analysis was planned if studies were available which were similar in terms of participants, intervention, comparator and outcomes. Nineteen studies (including two preprints) were eligible (HIV 8, HCV 2, dengue 2, chikungunya 1, COVID-19 6). Nine and ten studies assessed CQ and HCQ respectively. Benefits of either drug for viral load suppression in HIV are inconsistent. CQ is ineffective in curing dengue (high-certainty evidence) and may have little or no benefit in curing chikungunya (low-certainty evidence). The evidence for COVID-19 infection is rapidly evolving but at this stage we are unsure whether either CQ or HCQ has any benefit in clearing viraemia (very-low-certainty evidence). Implications Using HCQ or CQ for HIV/HCV infections is now clinically irrelevant as other effective antivirals are available for viral load suppression (HIV) and cure (HCV). There is no benefit of CQ in dengue, and the same conclusion is likely for chikungunya. More evidence is needed to confirm whether either HCQ or CQ is beneficial in COVID-19 infection.

Lack of a simple, high throughput antibody-dependent cellular phagocytosis (ADCP) assay has limited our understanding of its potential role of in hepatitis C (HCV) infection. Here, we optimised a flow-cytometry based ADCP assay using HCV envelope (E2)-protein coated microbeads that were opsonised with anti-E2 monoclonal IgG antibody (αE2 mAb) and the THP-1 monocyte cell line as effector cells. We found 1.5 × 109/ml microbeads opsonised with 5 μg/ml αE2 mAb and 1.6 × 106/ml THP-1 cells were optimal conditions to distinguish between healthy controls and patients with HCV. This optimised assay was then used to investigate ADCP in plasma obtained from 72 patients with chronic HCV infection and 15 healthy controls. We found that 75% of patients with genotype 1 and 87% of patients with genotype 3 HCV infection had significantly higher levels of ADCP compared to healthy controls. In patients, there was a significant correlation between increase in ADCP and higher concentrations of anti-E2 IgG antibodies in the plasma. Taken together, we established a simple, quick and high throughput ADCP assay for HCV infection that can readily be used for screening of large cohorts of patients and investigation of the role of ADCP in the pathogenesis or protection from this disease.

This review is on the pulmonary complications of snakebites, which can have fatal consequences. We identified three common themes as reported in the literature regarding envenomation: generalized neuromuscular paralysis affecting airway and respiratory muscles, pulmonary edema, and pulmonary hemorrhages or thrombosis due to coagulopathy. Respiratory paralysis and pulmonary edema can be due to either elapid or viper bites, whereas pulmonary complications of coagulopathy are exclusively reported with viper bites. The evidence for each complication, timeline of appearance, response to treatment, and details of pathophysiology are discussed.

This review concentrates on different aspects of malaria chemoprophylaxis, namely drug combinations, resistance, impact of malaria prevention in pregnancy and cost effectiveness. A MEDLINE search was performed for all articles with the key word ‘Malaria’ in the title field and ‘Prophylaxis’ in any field. The search was restricted to articles published in English within the last decade (1999–2009). Data sources included review articles published in core clinical journals, cohort studies, interventional studies, case control studies and cross sectional analyses. The mechanism of action, trial evidence of efficacy, side effects and geographical distribution of resistance is discussed for each prophylactic drug regimen. Impact of prophylaxis in pregnancy and the cost considerations are discussed under two separate sub topics.