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Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 56% efficacy over 12 months in African children. We therefore assessed a new candidate vaccine for safety and efficacy., info:eu-repo/semantics/published

Background: Stalled progress in controlling Plasmodium falciparum malaria highlights the need for an effective and deployable vaccine. RTS,S/AS01, the most effective malaria vaccine candidate to date, demonstrated 55·8% (97·5% confidence interval [CI], 51-60) efficacy over 12 months in African children. Methods: We conducted a double-blind, randomised, controlled trial of a low-dose circumsporozoite protein-based vaccine, R21, with two different doses of adjuvant, Matrix-M™ (MM), in children aged 5-17 months in Nanoro, Burkina Faso, a highly seasonal malaria transmission setting. Three vaccinations were administered at 4-week intervals prior to the malaria season with a fourth dose one year later. Vaccine safety, immunogenicity and efficacy were evaluated over one year. Findings: 450 children were randomised to receive the R21/MM vaccine or a control rabies vaccine. R21/MM had a 43 favourable safety profile and was well-tolerated. At 6 months, 43/146 (29·5%) who received R21/MM with low44 dose adjuvant, 38/146 (26%) who received R21/MM with high-dose adjuvant, and 105/147 (71·4%) who received the rabies vaccine developed clinical malaria. Vaccine efficacy (VE) was 74% (95% CI, 63-82) and 77% (95% CI, 67-84) in the low- and high-dose adjuvant groups, respectively. At 1 year, VE remained high at 77% (95% CI, 67-84) in the high-dose adjuvant group. Participants vaccinated with R21/MM showed high titres of malaria-specific anti-NANP antibodies 28 days after the third vaccination, which were almost doubled with the higher adjuvant dose. Titres waned but were boosted to levels similar to peak titres following the primary series of vaccinations after a fourth dose administered one year later. Interpretation: R21/Matrix-M appears safe and very immunogenic in African children, and demonstrates promising high-level efficacy. Trial Registration: ClinicalTrials.gov number: NCT03896724. Funding: The European & Developing Countries Clinical Trials Partnership (EDCTP), The Wellcome Trust and the NIHR Oxford Biomedical Research Centre. Declaration of Interest: AVSH and KJE are named as co-inventors on patent applications related to R21. GG, LF, JR and PP-A are employees of Novavax, developers of the Matrix-M adjuvant, and US is an employee of the Serum Institute of India Private Ltd, co-developer of the R21/MM vaccine. Other authors declare no competing interests. Ethical Approval: The trial was approved by the Comite d’Ethique pour la Recherche en Sante, Burkina Faso (CERS, reference number 2019-01-012), and by the national regulatory authority, Agence National de Regulation Pharmaceutique, Burkina Faso (ANRP, reference number 5005420193EC0000). Ethical approval was also granted in the United Kingdom by the Oxford Tropical Research Ethics Committee (OxTREC reference number 19-19).

Background: Cases of Middle East respiratory syndrome coronavirus (MERS-CoV) infection continue to rise in the Arabian Peninsula 7 years after it was first described in Saudi Arabia. MERS-CoV poses a significant risk to public health security because of an absence of currently available effective countermeasures. We aimed to assess the safety and immunogenicity of the candidate simian adenovirus-vectored vaccine expressing the full-length spike surface glycoprotein, ChAdOx1 MERS, in humans. Methods: This dose-escalation, open-label, non-randomised, uncontrolled, phase 1 trial was done at the Centre for Clinical Vaccinology and Tropical Medicine (Oxford, UK) and included healthy people aged 18–50 years with negative pre-vaccination tests for HIV antibodies, hepatitis B surface antigen, and hepatitis C antibodies (and a negative urinary pregnancy test for women). Participants received a single intramuscular injection of ChAdOx1 MERS at three different doses: the low-dose group received 5 × 109 viral particles, the intermediate-dose group received 2·5 × 1010 viral particles, and the high-dose group received 5 × 1010 viral particles. The primary objective was to assess safety and tolerability of ChAdOx1 MERS, measured by the occurrence of solicited, unsolicited, and serious adverse events after vaccination. The secondary objective was to assess the cellular and humoral immunogenicity of ChAdOx1 MERS, measured by interferon-γ-linked enzyme-linked immunospot, ELISA, and virus neutralising assays after vaccination. Participants were followed up for up to 12 months. This study is registered with ClinicalTrials.gov, NCT03399578. Findings: Between March 14 and Aug 15, 2018, 24 participants were enrolled: six were assigned to the low-dose group, nine to the intermediate-dose group, and nine to the high-dose group. All participants were available for follow-up at 6 months, but five (one in the low-dose group, one in the intermediate-dose group, and three in the high-dose group) were lost to follow-up at 12 months. A single dose of ChAdOx1 MERS was safe at doses up to 5 × 1010 viral particles with no vaccine-related serious adverse events reported by 12 months. One serious adverse event reported was deemed to be not related to ChAdOx1 MERS. 92 (74% [95% CI 66–81]) of 124 solicited adverse events were mild, 31 (25% [18–33]) were moderate, and all were self-limiting. Unsolicited adverse events in the 28 days following vaccination considered to be possibly, probably, or definitely related to ChAdOx1 MERS were predominantly mild in nature and resolved within the follow-up period of 12 months. The proportion of moderate and severe adverse events was significantly higher in the high-dose group than in the intermediate-dose group (relative risk 5·83 [95% CI 2·11–17·42], p Interpretation: ChAdOx1 MERS was safe and well tolerated at all tested doses. A single dose was able to elicit both humoral and cellular responses against MERS-CoV. The results of this first-in-human clinical trial support clinical development progression into field phase 1b and 2 trials.

Summary Background Development of an effective vaccine against the pathogenic blood-stage infection of human malaria has proved challenging, and no candidate vaccine has affected blood-stage parasitemia following controlled human malaria infection (CHMI) with blood-stage Plasmodium falciparum. Methods We undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the P. falciparum reticulocyte-binding protein homolog 5 (RH5), formulated in AS01B adjuvant. We assessed safety, immunogenicity, and efficacy against blood-stage CHMI. Trial registered at ClinicalTrials.gov, NCT02927145. Findings The RH5.1/AS01B formulation was administered using a range of RH5.1 protein vaccine doses (2, 10, and 50 μg) and was found to be safe and well tolerated. A regimen using a delayed and fractional third dose, in contrast to three doses given at monthly intervals, led to significantly improved antibody response longevity over ∼2 years of follow-up. Following primary and secondary CHMI of vaccinees with blood-stage P. falciparum, a significant reduction in parasite growth rate was observed, defining a milestone for the blood-stage malaria vaccine field. We show that growth inhibition activity measured in vitro using purified immunoglobulin G (IgG) antibody strongly correlates with in vivo reduction of the parasite growth rate and also identify other antibody feature sets by systems serology, including the plasma anti-RH5 IgA1 response, that are associated with challenge outcome. Conclusions Our data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease. Funding This study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC., Graphical abstract, Highlights The RH5.1/AS01B vaccine is safe, well tolerated, and immunogenic in healthy adults A delayed fractional third dose significantly improves antibody response longevity In vivo blood-stage P. falciparum growth rate is significantly lower in vaccinees In vitro IgG-mediated growth inhibition activity is associated with challenge outcome, Context and significance A highly effective vaccine against the human malaria parasite Plasmodium falciparum is urgently needed. One vaccine strategy aims to prevent parasite growth in the blood, protecting against clinical disease; however, this has proved exceptionally challenging. Here we show that a candidate vaccine (reticulocyte-binding protein homolog 5.1 [RH5.1]/AS01B) is safe in a phase I/IIa clinical trial and identify a vaccination regimen that improves the durability of the human antibody response, which is critical for long-term protection. Following experimental challenge of vaccinated adults with malaria, we observed that the vaccine could reduce parasite growth in the blood and identified immune responses that could predict how well the vaccine performs. These data will help guide the design of improved vaccines in the future., Minassian et al. report that the RH5.1/AS01B vaccine against blood-stage Plasmodium falciparum malaria is safe and immunogenic in a phase I/IIa clinical trial. They demonstrate a significantly reduced blood-stage parasite growth rate in vaccinees following controlled human malaria infection and identify that in vitro antibody-mediated growth inhibition activity is associated with challenge outcome.

The amount of construction and demolition waste has increased considerably over the last few decades due to growing construction industries. There has been an increasing trend toward the use of sustainable materials and reduce the consumption of non-renewable natural resources. Recycling and reuse of demolition concrete in construction is one potential solution to minimise the natural resources. Recently the main use of recycled concrete aggregate (RCA) is for non-structural applications such as in road sub-bases. However, research studies suggest that the natural aggregates can be partially or fully substituted by RCA if well graded and good quality RCA is guaranteed. The RCA concrete has a lower elastic modulus, compressive and tensile strength, and ductility and greater water absorption than natural aggregate (NA) concrete. Furthermore, the age of the concrete used as RCA has a vital effect on the mechanical properties of the recycled aggregate concrete. However, adding steel fibres (SFs) into RCA mix may improve its mechanical properties. The purpose of this study is to evaluate the percentage of RCA replacement and the age of original concrete on the compressive and tensile strength RCA at 7-, 14- and 28- days. Furthermore, this research will investigate the effect of steel fibre percentage and hook geometry on the compressive and tensile strength of NA to anticipate the effect of steel fibres on the mechanical properties of concrete made from RCA. To achieve that, a number of concrete cubes, cylinders with different percentage of RCA replacements and 3D and 5D hooked end SFs are casted to assess the compressive and tensile strength.

The implementation of audit in most hospital departments in the UK has been instigated by the guidelines set out by the Royal Colleges. This paper aims to demonstrate the results of regular subregional audit meetings in the ENT departments involving three District Hospitals in East Anglia. We report the effects of audit meetings in improving the management of epistaxis, whereby a protocol for treatment and discharge was established, the duration of the nasal pack left in situ was reduced, and the material of the pack was changed.