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Background Thresholds for SARS-CoV-2 antibody assays have typically been determined using samples from symptomatic, often hospitalised, patients. In this setting the sensitivity and specificity of the best performing assays can both exceed 98%. However, antibody assay performance following mild infection is less clear. Methods We assessed quantitative IgG responses in a cohort of healthcare workers in Oxford, UK, with a high pre-test probability of Covid-19, in particular the 991/11,475(8.6%) who reported loss of smell/taste. We use anosmia/ageusia and other risk factors as probes for Covid-19 infection potentially undiagnosed by immunoassays by investigating their relationship with antibody readings either side of assay thresholds. Results The proportion of healthcare workers reporting anosmia/ageusia increased at antibody readings below diagnostic thresholds using an in-house ELISA ( n  = 9324) and the Abbott Architect chemiluminescent microparticle immunoassay (CMIA;  n  = 11,324): 426/906 (47%) reported anosmia/ageusia with a positive ELISA, 59/449 (13.1%) with high-negative and 326/7969 (4.1%) with low-negative readings. Similarly, by CMIA, 518/1093 (47.4%) with a positive result reported anosmia/ageusia, 106/686 (15.5%) with a high-negative and 358/9563 (3.7%) with a low-negative result. Adjusting for the proportion of staff reporting anosmia/ageusia suggests the sensitivity of both assays in mild infection is lower than previously reported: Oxford ELISA 89.8% (95%CI 86.6–92.8%) and Abbott CMIA 79.3% (75.9–82.7%). Conclusion Following mild SARS-CoV-2 infection 10–30% of individuals may have negative immunoassay results. While lowered diagnostic thresholds may result in unacceptable specificity, our findings have implications for epidemiological analyses and result interpretation in individuals with a high pre-test probability. Samples from mild PCR-confirmed infections should be included in SARS-CoV-2 immunoassay evaluations.

The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4 + and/or CD8 + epitopes, including six immunodominant regions. Six optimized CD8 + epitopes were defined, with peptide–MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8 + T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design. Questions have arisen as to whether patients with severe COVID-19 disease can generate a T cell response against SARS-CoV-2. Tao Dong and colleagues report that convalescent patients with COVID-19 harbor functional memory CD4 + and CD8 + T cells that recognize multiple epitopes that span the viral proteome. CD4 + T cells predominated the memory response in patients with severe disease, whereas higher proportions of CD8 + T cells were found in patients with mild disease.

The immunogenicity of the candidate tuberculosis (TB) vaccine MVA85A may be enhanced by aerosol delivery. Intradermal administration was shown to be safe in adults with latent TB infection (LTBI), but data are lacking for aerosol-delivered candidate TB vaccines in this population. We carried out a Phase I trial to evaluate the safety and immunogenicity of MVA85A delivered by aerosol in UK adults with LTBI (NCT02532036). Two volunteers were recruited, and the vaccine was well-tolerated with no safety concerns. Aerosolised vaccination with MVA85A induced mycobacterium- and vector-specific IFN-γ in blood and mycobacterium-specific Th1 cytokines in bronchoalveolar lavage. We identified several important barriers that could hamper recruitment into clinical trials in this patient population. The trial did not show any safety concerns in the aerosol delivery of a candidate viral-vectored TB vaccine to two UK adults with Mycobacterium tuberculosis (M.tb) infection. It also systemically and mucosally demonstrated inducible immune responses following aerosol vaccination. A further trial in a country with higher incidence of LTBI would confirm these findings.

In a longitudinal study of seropositive and seronegative health care workers undergoing asymptomatic and symptomatic SARS-CoV-2 testing, the presence of anti-spike or anti-nucleocapsid IgG antibodies was associated with a substantially reduced risk of SARS-CoV-2 reinfection in the ensuing 6 months.

Serological detection of antibodies to SARS-CoV-2 is essential for establishing rates of seroconversion in populations, and for seeking evidence for a level of antibody that may be protective against COVID-19 disease. Several high-performance commercial tests have been described, but these require centralised laboratory facilities that are comparatively expensive, and therefore not available universally. Red cell agglutination tests do not require special equipment, are read by eye, have short development times, low cost and can be applied at the Point of Care. Here we describe a quantitative Haemagglutination test (HAT) for the detection of antibodies to the receptor binding domain of the SARS-CoV-2 spike protein. The HAT has a sensitivity of 90% and specificity of 99% for detection of antibodies after a PCR diagnosed infection. We will supply aliquots of the test reagent sufficient for ten thousand test wells free of charge to qualified research groups anywhere in the world. Serological detection of antibodies against SARS-CoV-2 can help establish rates of seroconversion. Here the authors develop a red cell agglutination test to detect antibodies against the receptor binding domain for distribution free of charge to qualified research groups.

People who inject drugs (PWID) are at increased risk of co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Uncontrolled HCV infection contributes to ongoing transmission among PWID, underscoring the urgent need to expand access to treatment as a public health priority. Despite the availability of highly effective direct-acting antiviral therapy, access remains limited, particularly in remote areas where stigma and structural barriers complicate care delivery. Implementing integrated and differentiated HCV care models in these settings may help address this gap. This study evaluated a novel care model in remote areas in which general practitioners delivered integrated HCV and HIV care, supported by specialist telemonitoring, community health workers, and peer educators. We assessed treatment outcomes and associated predictors. Routine program data from the HCV treatment register were used to assess treatment completion and sustained viral response (SVR) among PWID. SVR12 was defined as an undetectable HCV viral load at 12 weeks after treatment completion. Patients who achieved SVR12 were invited for retesting at one year to calculate the one-year SVR rate (SVR64). Logistic regression analyses were performed to identify predictors of both SVR12 and SVR64. Among 314 HIV-HCV co-infected PWID who initiated HCV treatment, 69.7% (219 of 314) achieved SVR12, and after one year, 57.5% (126 of 219) achieved SVR64, based on intention-to-treat analysis. Participants aged ≥ 25 years were significantly more likely to achieve both SVR12 and SVR64. Methadone maintenance therapy (aOR: 2.6; 95% CI: 1.5-4.4), not being an active PWID (aOR: 1.5; 95% CI: 1.0-2.5), and advanced liver disease: fibrosis (aOR: 2.3; 95% CI: 1.2-4.2) and cirrhosis (aOR: 2.9; 95% CI: 1.3-6.3), were independently associated with SVR64 (p ≤ 0.05). A novel care model involving general practitioners, specialist telemonitoring, and support from community health workers and peer educators demonstrated effectiveness in achieving SVR among HIV-HCV co-infected PWID in remote settings. Further qualitative research is warranted to better understand the factors influencing HCV treatment outcomes.

With the continued emergence of SARS-CoV-2 variants and concerns of waning immunity, there is a need for better defined correlates of protection to aid future vaccine and therapeutic developments. Whilst neutralising antibody titres are associated with protection, these are typically determined in the absence of the complement system, which has the potential to enhance neutralisation titres and strengthen correlates with protection in vivo. Here we show that replenishment of the complement system in neutralisation assays can significantly enhance neutralisation titres, with up to an ~83-fold increase in neutralisation of the BA.1.1.529 strain using cross-reactive sera from vaccination against the ancestral strain. The magnitude of enhancement significantly varies between individuals, viral strains (wild-type/VIC01 and Omicron/BA.1), and cell lines (Vero E6 and Calu-3), and is abrogated following heat-inactivation of the complement source. Utilising ACE2 competition assays, we show that the mechanism of action is partially mediated by reducing ACE2-spike interactions. Through the addition of compstatin (a C3 inhibitor) to live virus neutralisation assays, the complement protein C3 is shown to be required for maximum efficiency. These findings further our understanding of SARS-CoV-2 immunity and neutralisation, with implications for protection against emerging variants and assessing future vaccine and therapeutic developments. It is important to understand the correlates of protection against SARS-CoV-2 and its variants for future vaccine design. Here, the authors show that the complement system enhances the antibody-mediated neutralisation of SARS-CoV-2 via increased inhibition of virus-host interactions.

A 35 year old HIV positive patient from Hong Kong presented with a fever, cough and a skin rash in association with a lung mass, all of which were due to disseminated Penicillium marneffeiinfection. He made a good response to antifungal therapy. The lung mass is a previously undescribed pulmonary manifestation of disseminated Penicillium marneffei infection. Infections with this fungus should be suspected in any patient with HIV and respiratory symptoms who has visited southeast Asia.