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BACKGROUNDThe biology of Plasmodium vivax is markedly different from that of P. falciparum; how this shapes the immune response to infection remains unclear. To address this shortfall, we inoculated human volunteers with a clonal field isolate of P. vivax and tracked their response through infection and convalescence.METHODSParticipants were injected intravenously with blood-stage parasites and infection dynamics were tracked in real time by quantitative PCR. Whole blood samples were used for high dimensional protein analysis, RNA sequencing, and cytometry by time of flight, and temporal changes in the host response to P. vivax were quantified by linear regression. Comparative analyses with P. falciparum were then undertaken using analogous data sets derived from prior controlled human malaria infection studies.RESULTSP. vivax rapidly induced a type I inflammatory response that coincided with hallmark features of clinical malaria. This acute-phase response shared remarkable overlap with that induced by P. falciparum but was significantly elevated (at RNA and protein levels), leading to an increased incidence of pyrexia. In contrast, T cell activation and terminal differentiation were significantly increased in volunteers infected with P. falciparum. Heterogeneous CD4+ T cells were found to dominate this adaptive response and phenotypic analysis revealed unexpected features normally associated with cytotoxicity and autoinflammatory disease.CONCLUSIONP. vivax triggers increased systemic interferon signaling (cf P. falciparum), which likely explains its reduced pyrogenic threshold. In contrast, P. falciparum drives T cell activation far in excess of P. vivax, which may partially explain why falciparum malaria more frequently causes severe disease.TRIAL REGISTRATIONClinicalTrials.gov NCT03797989.FUNDINGThe European Union's Horizon 2020 Research and Innovation programme, the Wellcome Trust, and the Royal Society.

Since its discovery, COVID-19 has rapidly spread across the globe and has had a massive toll on human health, with infection mortality rates as high as 10%, and a crippling impact on the world economy. Despite numerous advances, there remains an urgent need for accurate and rapid point-of-care diagnostic tests and better therapeutic treatment options. To contribute chemically distinct, non-protein-based affinity reagents, we report here the identification of modified DNA-based aptamers that selectively bind to the S1, S2, or receptor-binding domain of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Several aptamers inhibit the binding of the spike protein to its cell-surface receptor angiotensin-converting enzyme 2 (ACE2) and neutralize authentic SARS-CoV-2 virus in vitro , including all variants of concern. With a high degree of nuclease resistance imparted by the base modifications, these reagents represent a new class of molecules with potential for further development as diagnostics or therapeutics., Competing Interests: A.D.G., C.Z., B.E.R., C.N.C, M.R.O., D.J.S., and N,J, are employees and shareholders of SomaLogic, Inc., (© 2023 The Authors.)

Background: Evaluation of susceptibility to emerging SARS-CoV-2 variants of concern (VOC) requires rapid screening tests for neutralising antibodies which provide protection., Methods: Firstly, we developed a receptor-binding domain-specific haemagglutination test (HAT) to Wuhan and VOC (alpha, beta, gamma and delta) and compared to pseudotype, microneutralisation and virus neutralisation assays in 835 convalescent sera. Secondly, we investigated the antibody response using the HAT after two doses of mRNA (BNT162b2) vaccination. Sera were collected at baseline, three weeks after the first and second vaccinations from older (80-99 years, n  = 89) and younger adults (23-77 years, n  = 310) and compared to convalescent sera from naturally infected individuals (1-89 years, n  = 307)., Results: Here we show that HAT antibodies highly correlated with neutralising antibodies (R = 0.72-0.88) in convalescent sera. Home-dwelling older individuals have significantly lower antibodies to the Wuhan strain after one and two doses of BNT162b2 vaccine than younger adult vaccinees and naturally infected individuals. Moverover, a second vaccine dose boosts and broadens the antibody repertoire to VOC in naïve, not previously infected older and younger adults. Most (72-76%) older adults respond after two vaccinations to alpha and delta, but only 58-62% to beta and gamma, compared to 96-97% of younger vaccinees and 68-76% of infected individuals. Previously infected older individuals have, similarly to younger adults, high antibody titres after one vaccination., Conclusions: Overall, HAT provides a surrogate marker for neutralising antibodies, which can be used as a simple inexpensive, rapid test. HAT can be rapidly adaptable to emerging VOC for large-scale evaluation of potentially decreasing vaccine effectiveness., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

The trajectories of acquired immunity to severe acute respiratory syndrome coronavirus 2 infection are not fully understood. We present a detailed longitudinal cohort study of UK healthcare workers prior to vaccination, presenting April-June 2020 with asymptomatic or symptomatic infection. Here we show a highly variable range of responses, some of which (T cell interferon-gamma ELISpot, N-specific antibody) wane over time, while others (spike-specific antibody, B cell memory ELISpot) are stable. We use integrative analysis and a machine-learning approach (SIMON - Sequential Iterative Modeling OverNight) to explore this heterogeneity. We identify a subgroup of participants with higher antibody responses and interferon-gamma ELISpot T cell responses, and a robust trajectory for longer term immunity associates with higher levels of neutralising antibodies against the infecting (Victoria) strain and also against variants B.1.1.7 (alpha) and B.1.351 (beta). These variable trajectories following early priming may define subsequent protection from severe disease from novel variants., (© 2022. The Author(s).)

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants., (© 2021. The Author(s).)

COVID-19, caused by the novel coronavirus SARS-CoV-2, is a global health issue with more than 2 million fatalities to date. Viral replication is shaped by the cellular microenvironment, and one important factor to consider is oxygen tension, in which hypoxia inducible factor (HIF) regulates transcriptional responses to hypoxia. SARS-CoV-2 primarily infects cells of the respiratory tract, entering via its spike glycoprotein binding to angiotensin-converting enzyme 2 (ACE2). We demonstrate that hypoxia and the HIF prolyl hydroxylase inhibitor Roxadustat reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication in lung epithelial cells via an HIF-1α-dependent pathway. Hypoxia and Roxadustat inhibit SARS-CoV-2 RNA replication, showing that post-entry steps in the viral life cycle are oxygen sensitive. This study highlights the importance of HIF signaling in regulating multiple aspects of SARS-CoV-2 infection and raises the potential use of HIF prolyl hydroxylase inhibitors in the prevention or treatment of COVID-19., Competing Interests: Declaration of interests E.J.H. is employed under the Cambridge Experimental Medicine Initiative, which is partly funded by AstraZeneca, although they have not been involved in this project. P.J.R. is a scientific cofounder of, and holds equity in, ReOx, a university spin-out company that seeks to develop therapeutic inhibitors of HIF hydroxylases. He is also a non-executive director of Immunocore Holdings. The other authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Numerous physical modalities have been used in attempts to augment the healing process, including ultrasound, low- energy light therapy, and electrical stimulation (ES). ES has been shown to benefit tissue repair in a variety of wound types, but variations in study designs, administration, and parameters render its application in clinical practice somewhat unconventional. A dressing was designed to generate an electric potential of 0.6 V to 0.7 V in the presence of moisture, thereby delivering a sustained micro-current without the need for an external power source. The purpose of this study was to examine the effects of this bio-electric dressing (BED) on deep, partial-thickness wounds using six female specific pathogen-free animals and a well established porcine model for wound healing. Wounds (10 mm x 7 mm x 0.5 mm) were created in paravertebral and thoracic areas of these animals using a specialized electrokeratome and covered with the active polyester BED and a polyurethane film dressing (n = 30) (treatment) or an inactive polyester and film dressing (n = 30). Using an epidermal migration assay, wounds were assessed daily from day 4 through day 8 post-wounding. Differences in the proportion of wounds healed were statistically significant (P <0.001) on days 5 and 6 post-wounding. These results show BED is more effective than a control dressing treatment with moisture-retentive dressings in this animal model. Controlled clinical studies are warranted to elucidate the potential clinical implications of this treatment modality.

During the past two decades of the HIV/AIDS pandemic, several recruitment campaigns were designed to generate community involvement in preventive HIV vaccine clinical trials. These efforts utilized a blend of advertising and marketing strategies mixed with public relations and community education approaches to attract potential study participants to clinical trials (integrated marketing communications). Although more than 30,000 persons worldwide have participated in preventive HIV vaccine studies, no systematic analysis of recruitment campaigns exists. This content analysis study was conducted to examine several United States and Canadian recruitment campaigns for one of the largest-scale HIV vaccine trials to date (the "Step Study"). This study examined persuasive features consistent with the Elaboration Likelihood Model (ELM) including message content, personal relevance of HIV/AIDS and vaccine research, intended audiences, information sources, and other contextual features. The results indicated variation in messages and communication approaches with gay men more exclusively targeted in these regions. Racial/ethnic representations also differed by campaign. Most of the materials promote affective evaluation of the information through heuristic cueing. Implications for subsequent campaigns and research directions are discussed.