A phase 2b randomized, controlled trial of the efficacy of the GMZ2 malaria vaccine in African children.

: GMZ2 is a recombinant protein malaria vaccine, comprising two blood-stage antigens of Plasmodium falciparum, glutamate-rich protein and merozoite surface protein 3. We assessed efficacy of GMZ2 in children in Burkina Faso, Gabon, Ghana and Uganda. : Children 12-60months old were randomized to receive three injections of either 100μg GMZ2 adjuvanted with aluminum hydroxide or a control vaccine (rabies) four weeks apart and were followed up for six months to measure the incidence of malaria defined as fever or history of fever and a parasite density ⩾5000/μL. : A cohort of 1849 children were randomized, 1735 received three doses of vaccine (868 GMZ2, 867 control-vaccine). There were 641 malaria episodes in the GMZ2/Alum group and 720 in the control group. In the ATP analysis, vaccine efficacy (VE), adjusted for age and site was 14% (95% confidence interval [CI]: 3.6%, 23%, p-value=0.009). In the ITT analysis, age-adjusted VE was 11.3% (95% CI 2.5%, 19%, p-value=0.013). VE was higher in older children. In GMZ2-vaccinated children, the incidence of malaria decreased with increasing vaccine-induced anti-GMZ2 IgG concentration. There were 32 cases of severe malaria (18 in the rabies vaccine group and 14 in the GMZ2 group), VE 27% (95% CI -44%, 63%). : GMZ2 is the first blood-stage malaria vaccine to be evaluated in a large multicenter trial. GMZ2 was well tolerated and immunogenic, and reduced the incidence of malaria, but efficacy would need to be substantially improved, using a more immunogenic formulation, for the vaccine to have a public health role.<br/

Comparative Validation of Five Quantitative Rapid Test Kits for the Analysis of Salt Iodine Content: Laboratory Performance, User- and Field-Friendliness

<div><p>Background</p><p>Iodine deficiency has important health and development consequences and the introduction of iodized salt as national programs has been a great public health success in the past decades. To render national salt iodization programs sustainable and ensure adequate iodization levels, simple methods to quantitatively assess whether salt is adequately iodized are required. Several methods claim to be simple and reliable, and are available on the market or are in development.</p><p>Objective</p><p>This work has validated the currently available quantitative rapid test kits (quantRTK) in a comparative manner for both their laboratory performance and ease of use in field settings.</p><p>Methods</p><p>Laboratory performance parameters (linearity, detection and quantification limit, intra- and inter-assay imprecision) were conducted on 5 quantRTK. We assessed inter-operator imprecision using salt of different quality along with the comparison of 59 salt samples from across the globe; measurements were made both in a laboratory and a field setting by technicians and non-technicians. Results from the quantRTK were compared against iodometric titration for validity. An ‘ease-of-use’ rating system was developed to identify the most suitable quantRTK for a given task.</p><p>Results</p><p>Most of the devices showed acceptable laboratory performance, but for some of the devices, use by non-technicians revealed poorer performance when working in a routine manner. Of the quantRTK tested, the iCheck^® and I-Reader^® showed most consistent performance and ease of use, and a newly developed paper-based method (saltPAD) holds promise if further developed.</p><p>Conclusions</p><p>User- and field-friendly devices are now available and the most appropriate quantRTK can be selected depending on the number of samples and the budget available.</p></div

Summary of results from the ‘method’ validation of the different quantRTK’s.

<p>^a LoD, limit of detection; LoQ, limit of quantification; for the description of the calculations, refer to the description in the method section;</p><p>^b three iodine levels were used (15.0, 29.6, 59.1 mg/kg) and the three CV’s are given in the order of increasing iodine concentration;</p><p>^c Recovery A was calculated from the linearity assessment, and results are presented as mean recovery ± SD; Recovery B was calculated from the inter-operator precision exercise and comprises the observed/expected values from the samples with approximate KIO₃ concentrations of 15, 20, 30, 45, 60, and 90 mg/kg; results are shown with % SD.</p><p>^d the device gives results in mg/L and anything above 13mg/L is indicated as 'above measuring range'; assuming 1:5 dilution (factor 5.45), this corresponds to 65 mg/kg;</p><p>^e The device has set working ranges from 15–50 mg/kg and thus, LoD and LoQ could not be assessed; further, for intra- and inter-assay imprecision and recovery, the low level of salt (15.0 mg/kg) could not be assessed; the high level yielded results, because the device gave consistently lower readings; n/d thus, means not determined;</p><p>^f For the saltPAD, three types of interpretation of the results on the cards were done: interpretation by the operator, by an expert reader (a person from the device developer) and an image analysis software; for the device performance, the expert reader’s results only were used.</p><p>Summary of results from the ‘method’ validation of the different quantRTK’s.</p

Summary of the results from the ‘system’ validation: inter-operator imprecision, expressed as coefficient of variation.

<p>^a three iodine levels were used (15.0, 29.6, 59.1 mg/kg) and the three CV’s are given in the order of increasing iodine concentration;</p><p>^b three iodine levels were used (20.0, 47.5, 90.4 mg/kg) and the three CV’s are given in the order of increasing iodine concentration;</p><p>^c outside of measuring range for more than one measurement and thus, n/d means not determined.</p><p>^d For the saltPAD, three types of interpretation of the results on the cards were done: interpretation by the operator, by an expert reader (a person from the device developer) and an image analysis software; the index provides the information which readings were used.</p><p>Summary of the results from the ‘system’ validation: inter-operator imprecision, expressed as coefficient of variation.</p

Schematic presentation of rating matrix employed.

<p>Schematic presentation of rating matrix employed.</p

Bland-Altman’s Limits of Agreement (LOA).

<p>^a Provides the number of samples with a valid quantitative result (i.e. not below or above the measuring range);</p><p>^b Difference between the reference method and the respective quantRTK;</p><p>^c Difference between the reference method and the quantRTK ±2 SD.</p><p>^d For the saltPAD, three types of interpretation of the results on the cards were done: interpretation by the operator, by an expert reader (a person from the device developer) and an image analysis software; the index provides the information which readings were used.</p><p>Bland-Altman’s Limits of Agreement (LOA).</p

Overall assessment of the quantRTK included in the validation, including objective and subjective parameters.

<p>^a Overall rating: (2*Analytical performance+user friendliness+field readiness+low resource setting suitability)/5;</p><p>^b These devices are not yet commercially available and under further development; thus, the scores are of transient nature.</p><p>Overall assessment of the quantRTK included in the validation, including objective and subjective parameters.</p

Evaluation of the routine implementation of pulse oximeters into integrated management of childhood illness (IMCI) guidelines at primary health care level in West Africa : the AIRE mixed-methods research protocol

Background: The AIRE operational project will evaluate the implementation of the routine Pulse Oximeter (PO) use in the integrated management of childhood illness (IMCI) strategy for children under-5 in primary health care centers (PHC) in West Africa. The introduction of PO should promote the accurate identification of hypoxemia (pulse blood oxygen saturation Sp02 < 90%) among all severe IMCI cases (respiratory and non-respiratory) to prompt their effective case management (oxygen, antibiotics and other required treatments) at hospital. We seek to understand how the routine use of PO integrated in IMCI outpatients works (or not), for whom, in what contexts and with what outcomes.Methods: The AIRE project is being implemented from 03/2020 to 12/2022 in 202 PHCs in four West African countries (Burkina Faso, Guinea, Mali, Niger) including 16 research PHCs (four per country). The research protocol will assess three complementary components using mixed quantitative and qualitative methods: a) context based on repeated cross-sectional surveys: baseline and aggregated monthly data from all PHCs on infrastructure, staffing, accessibility, equipment, PO use, severe cases and care; b) the process across PHCs by assessing acceptability, fidelity, implementation challenges and realistic evaluation, and c) individual outcomes in the research PHCs: all children under-5 attending IMCI clinics, eligible for PO use will be included with parental consent in a cross-sectional study. Among them, severe IMCI cases will be followed in a prospective cohort to assess their health status at 14 days. We will analyze pathways, patterns of care, and costs of care.Discussion: This research will identify challenges to the systematic implementation of PO in IMCI consultations, such as health workers practices, frequent turnover, quality of care, etc. Further research will be needed to fully address key questions such as the best time to introduce PO into the IMCI process, the best SpO2 threshold for deciding on hospital referral, and assessing the cost-effectiveness of PO use. The AIRE research will provide health policy makers in West Africa with sufficient evidence on the context, process and outcomes of using PO integrated into IMCI to promote scale-up in all PHCs.Trial registration: Trial registration number: PACTR202206525204526 retrospectively registered on 06/15/202

Lancet Infect Dis

Background PRIMVAC is a VAR2CSA-derived placental malaria vaccine candidate aiming to prevent serious clinical outcomes of Plasmodium falciparum infection during pregnancy. We assessed the safety and immunogenicity of PRIMVAC adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) in French and Burkinabe women who were not pregnant. Methods This first-in-human, randomised, double-blind, placebo-controlled, dose escalation trial was done in two staggered phases, a phase 1A trial in 18–35-year-old women who were malaria naive in a hospital in France and a subsequent phase 1B trial in women who were naturally exposed to P falciparum and nulligravid in the clinical site of a research centre in Burkina Faso. Volunteers were recruited into four sequential cohorts receiving PRIMVAC intramuscularly at day 0, 28, and 56: two cohorts in France receiving 20 μg or 50 μg of PRIMVAC and then two in Burkina Faso receiving 50 μg or 100 μg of PRIMVAC. Volunteers were randomly assigned (1:1) to two groups (PRIMVAC adjuvanted with either Alhydrogel or GLA-SE) in France and randomly assigned (2:2:1) to three groups (PRIMVAC adjuvanted with either Alhydrogel, GLA-SE, or placebo) in Burkina Faso. Randomisation was centralised, using stratification by cohort and blocks of variable size, and syringes were masked by opaque labels. The primary endpoint was the proportion of participants with any grade 3 or higher adverse reaction to vaccination up until day 35. Safety at later time points as well as humoral and cellular immunogenicity were assessed in secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02658253. Findings Between April 19, 2016, and July 13, 2017, 68 women (18 in France, 50 in Burkina Faso) of 101 assessed for eligibility were included. No serious adverse event related to the vaccine occurred. PRIMVAC antibody titres increased with each dose and seroconversion was observed in all women vaccinated with PRIMVAC (n=57). PRIMVAC antibody titres reached a peak (geometric mean 11 843·0, optical density [OD] 1·0, 95% CI 7559·8–18 552·9 with 100 μg dose and GLA-SE) 1 week after the third vaccination (day 63). Compared with Alhydrogel, GLA-SE tended to improve the PRIMVAC antibody response (geometric mean 2163·5, OD 1·0, 95% CI 1315·7–3557·7 with 100 μg dose and Alhydrogel at day 63). 1 year after the last vaccination, 20 (71%) of 28 women who were vaccinated with PRIMVAC/Alhydrogel and 26 (93%) of 28 women who were vaccinated with PRIMVAC/GLA-SE still had anti-PRIMVAC antibodies, although antibody magnitude was markedly lower (452·4, OD 1·0, 95% CI 321·8–636·1 with 100 μg dose and GLA-SE). These antibodies reacted with native homologous VAR2CSA expressed by NF54-CSA infected erythrocytes (fold change from baseline at day 63 with 100 μg dose and GLA-SE: 10·74, 95% CI 8·36–13·79). Limited cross-recognition, restricted to sera collected from women that received the 100 μg PRIMVAC dose, was observed against heterologous VAR2CSA variants expressed by FCR3-CSA (fold change from baseline at day 63: 1·49, 95% CI 1·19–1·88) and 7G8-CSA infected erythrocytes (1·2, 1·08–1·34). Interpretation PRIMVAC adjuvanted with Alhydrogel or GLA-SE had an acceptable safety profile, was immunogenic, and induced functional antibodies reacting with the homologous VAR2CSA variant expressed by NF54-CSA infected erythrocytes. Cross-reactivity against heterologous VAR2CSA variants was limited and only observed in the higher dose group. An alternate schedule of immunisation, antigen dose, and combinations with other VAR2CSA-based vaccines are envisaged to improve the cross-reactivity against heterologous VAR2CSA variants. Funding Bundesministerium für Bildung und Forschung, through Kreditanstalt für Wiederaufbau, Germany; Inserm, and Institut National de Transfusion Sanguine, France; Irish Aid, Department of Foreign Affairs and Trade, Ireland