Blood-stage malaria vaccine candidate RH5.1/Matrix-M in healthy Tanzanian adults and children; an open-label, non-randomised, first-in-human, single-centre, phase 1b trial.

BACKGROUND: A blood-stage Plasmodium falciparum malaria vaccine would provide a second line of defence to complement partially effective or waning immunity conferred by the approved pre-erythrocytic vaccines. RH5.1 is a soluble protein vaccine candidate for blood-stage P falciparum, formulated with Matrix-M adjuvant to assess safety and immunogenicity in a malaria-endemic adult and paediatric population for the first time. METHODS: We did a non-randomised, phase 1b, single-centre, dose-escalation, age de-escalation, first-in-human trial of RH5.1/Matrix-M in Bagamoyo, Tanzania. We recruited healthy adults (aged 18-45 years) and children (aged 5-17 months) to receive the RH5.1/Matrix-M vaccine candidate in the following three-dose regimens: 10 µg RH5.1 at 0, 1, and 2 months (Adults 10M), and the higher dose of 50 µg RH5.1 at 0 and 1 month and 10 µg RH5.1 at 6 months (delayed-fractional third dose regimen; Adults DFx). Children received either 10 µg RH5.1 at 0, 1, and 2 months (Children 10M) or 10 µg RH5.1 at 0, 1, and 6 months (delayed third dose regimen; Children 10D), and were recruited in parallel, followed by children who received the dose-escalation regimen (Children DFx) and children with higher malaria pre-exposure who also received the dose-escalation regimen (High Children DFx). All RH5.1 doses were formulated with 50 µg Matrix-M adjuvant. Primary outcomes for vaccine safety were solicited and unsolicited adverse events after each vaccination, along with any serious adverse events during the study period. The secondary outcome measures for immunogenicity were the concentration and avidity of anti-RH5.1 serum IgG antibodies and their percentage growth inhibition activity (GIA) in vitro, as well as cellular immunogenicity to RH5.1. All participants receiving at least one dose of vaccine were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT04318002, and is now complete. FINDINGS: Between Jan 25, 2021, and April 15, 2021, we recruited 12 adults (six [50%] in the Adults 10M group and six [50%] in the Adults DFx group) and 48 children (12 each in the Children 10M, Children 10D, Children DFx, and High Children DFx groups). 57 (95%) of 60 participants completed the vaccination series and 55 (92%) completed 22 months of follow-up following the third vaccination. Vaccinations were well-tolerated across both age groups. There were five serious adverse events involving four child participants during the trial, none of which were deemed related to vaccination. RH5-specific T cell and serum IgG antibody responses were induced by vaccination and purified total IgG showed in vitro GIA against P falciparum. We found similar functional quality (ie, GIA per µg RH5-specific IgG) across all age groups and dosing regimens at 14 days after the final vaccination; the concentration of RH5.1-specific polyclonal IgG required to give 50% GIA was 14·3 µg/mL (95% CI 13·4-15·2). 11 children were vaccinated with the delayed third dose regimen and showed the highest median anti-RH5 serum IgG concentration 14 days following the third vaccination (723 µg/mL [IQR 511-1000]), resulting in all 11 who received the full series showing greater than 60% GIA following dilution of total IgG to 2·5 mg/mL (median 88% [IQR 81-94]). INTERPRETATION: The RH5.1/Matrix-M vaccine candidate shows an acceptable safety and reactogenicity profile in both adults and 5-17-month-old children residing in a malaria-endemic area, with all children in the delayed third dose regimen reaching a level of GIA previously associated with protective outcome against blood-stage P falciparum challenge in non-human primates. These data support onward efficacy assessment of this vaccine candidate against clinical malaria in young African children. FUNDING: The European and Developing Countries Clinical Trials Partnership; the UK Medical Research Council; the UK Department for International Development; the National Institute for Health and Care Research Oxford Biomedical Research Centre; the Division of Intramural Research, National Institute of Allergy and Infectious Diseases; the US Agency for International Development; and the Wellcome Trust.

Household factors associated with access to insecticide-treated nets and house modification in Bagamoyo and Ulanga districts, Tanzania.

BACKGROUND: Insecticide-treated nets (ITNs) and house modifications are proven vector control tools, yet in most regions, full coverage has not been achieved. This study investigates household factors associated with access to ITNs and house modification in Tanzania. METHODS: Baseline cross-sectional survey data from previous studies on spatial repellants and indoor residual spray evaluation was analysed from 6757 households in Bagamoyo (60 km north of Dar es Salaam) and 1241 households in Ulanga (a remote rural area in southeast Tanzania), respectively. Regression models were used to estimate the associations between the outcomes: population access to ITNs, access to ITN per sleeping spaces, window screens and closed eaves, and the covariates household size, age, gender, pregnancy, education, house size, house modification (window screens and closed eaves) and wealth. RESULTS: Population access to ITNs (households with one ITN per two people that stayed in the house the previous night of the survey) was 69% (n = 4663) and access to ITNs per sleeping spaces (households with enough ITNs to cover all sleeping spaces used the previous night of the survey) was 45% (n = 3010) in Bagamoyo, 3 years after the last mass campaign. These findings are both lower than the least 80% coverage target of the Tanzania National Malaria Strategic Plan (Tanzania NMSP). In Ulanga, population access to ITNs was 92% (n = 1143) and ITNs per sleeping spaces was 88% (n = 1093), 1 year after the last Universal Coverage Campaign (UCC). Increased household size was significantly associated with lower access to ITNs even shortly after UCC. House modification was common in both areas but influenced by wealth. In Bagamoyo, screened windows were more common than closed eaves (65% vs 13%), whereas in Ulanga more houses had closed eaves than window screens (55% vs 12%). CONCLUSION: Population access to ITNs was substantially lower than the targets of the Tanzania NMSP after 3 years and lower among larger households after 1 year following ITN campaign. House modification was common in both areas, associated with wealth. Improved access to ITNs and window screens through subsidies and Behaviour Change Communication (BCC) strategies, especially among large and poor households and those headed by people with a low level of education, could maximize the uptake of a combination of these two interventions.