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Safe and effective antimalarial drugs with new methods of action are urgently needed. Fosmidomycin inhibits the synthesis of isoprenoid by Plasmodium falciparum, and suppresses the growth of multidrug-resistant strains in vitro. Our aim was to assess the efficacy and tolerability of fosmidomycin in adults with malaria in Gabon. We administered the drug for 5, 4, or 3 days (1·2 g every 8 h), in nine, eight, and ten evaluable patients, respectively. All treatment regimens were well tolerated. Cure rates by day 14 were 89% (eight of nine), 88% (seven of eight), and 60% (six of ten), for treatment durations of 5, 4, and 3 days, respectively. These data suggest that fosmidomycin is a safe and effective treatment for uncomplicated malaria if given for 4 days or more. [Copyright &y& Elsevier]

Hepatitis B virus (HBV) infection remains one of the major neglected health issues worldwide. In sub-Saharan Africa (SSA), HBV endemicity is high, with more than 8% of the population being chronic HBV carriers. Recently, WHO recommended that all infants should receive their first dose of the HBV vaccine as soon as possible after birth. Unfortunately, the incorporation of a birth dose of HBV in the expanded programme immunization (EPI) has not occurred in the majority of countries in SSA. From April to September 2017, a cross-sectional survey was conducted in two vaccine units located in southern Benin. We assessed the sustained anti-HBs antibody response in infants induced by a standard scheme of 3 doses of HBV vaccination (6, 10, 14 weeks) in comparison to a scheme of 4 doses with a birth dose included (0, 6, 10, 14 weeks). Blood samples were systematically collected in the first 140 children aged 9 months and their mothers who had consented to participate for the detection of HBs antigen and the quantification of anti-HBs antibodies. The prevalence of HBV infection among infants and mothers was 2.2% and 7.1%, respectively. Infants who received 4 doses of HBV vaccine had a significantly higher level of anti-HBs antibody than those who received 3 doses of vaccine (557.9 UI/L vs. 386.9 UI/L, respectively, P = 0.03). We also showed that the scheme of 4 doses was associated with a significantly higher sustained protective response in comparison to the scheme of 3 doses (aOR 2.49, 95% CI 1.03–6.03, P = 0.04). This result provides further evidence of the importance of administering HBV vaccine at birth, but also highlights the importance for the prevention of vertical transmissions. Additional studies are needed to better establish the cost-effectiveness of such a 4 doses immunization strategy before implementing the HBV vaccination at birth in the EPI. [ABSTRACT FROM AUTHOR]

Background The antigen VAR2CSA plays a pivotal role in the pathophysiology of pregnancy-associated malaria (PAM) caused by Plasmodium falciparum . A VAR2CSA-based vaccine candidate, PAMVAC, is under development by an EU-funded multi-country consortium (PlacMalVac project). As part of PAMVAC's clinical development, we quantified naturally acquired vaccine antigen-specific memory B and T cell responses in Beninese primigravidae recruited at the beginning of pregnancy and followed up to delivery and beyond. Methods Clinical and parasitological histories were compiled from monthly clinic visits. On 4 occasions (first and fifth month of pregnancy, delivery, 6 months post-delivery) peripheral blood mononuclear cells were isolated for in vitro assays. PAMVAC-specific memory B cells as well as those specific for a PAM unrelated P. falciparum antigen (PfEMP1-CIDR1a) and for tetanus toxoid were quantified by ELISpot. Memory T cell responses were assessed by quantifying cytokines (IL-5, IL-6, IL-10, IL-13, IFN-γ, TNF-α) in supernatants of cells stimulated in vitro either with PAMVAC, or mitogen (PHA). Results Both tetanus toxoid- and PAMVAC-specific memory B cell frequencies increased to reach peak levels in the 5th month and at delivery, respectively and persisted post-delivery. The frequency of CIDR1a-specific memory B cells was stable during pregnancy, but declined post-delivery. The cumulated prevalence of infection with P. falciparum during pregnancy was 61% by microscopy. In women with a history of such infections, a significantly higher frequency of PAMVAC-specific memory B cells was observed at delivery. PAMVAC-specific pro-inflammatory (IFN-γ, TNF) responses tended to be higher at delivery in those with a history of infection. Mitogen-induced IL-5/IL-13 responses were significantly enhanced in the same women. Conclusions PAMVAC-specific memory B cells are induced during first pregnancies and are maintained post-delivery. Women with a T helper cell profile biased towards production of Th2-type cytokines have a greater risk of infection with P. falciparum. [ABSTRACT FROM AUTHOR]

Background 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. Methods Children 12–60 months old were randomized to receive three injections of either 100 μg 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. Results 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%). Conclusions 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. [ABSTRACT FROM AUTHOR]

Abstract: Background: Helminth infections are highly prevalent in the tropics and may have an effect on immune responses to vaccines due to their immunomodulatory effect. The prevalence of helminth infections in young children, the target group for malaria and most other vaccines, is high. Therefore we assessed the influence of helminth infection on vaccine-induced immune responses in a phase I clinical trial of the malaria vaccine candidate GMZ2. Methods: Twenty Gabonese preschool-age children were vaccinated with GMZ2, a blood stage malaria vaccine candidate. Humoral immune response against the vaccine antigens and parasitological status were assessed. Vaccine-specific antibody concentrations and memory B-cell numbers were compared in worm infected and non-infected participants. Results: Antibody response to GMZ2 was 3.4-fold (95% confidence interval: 1.6, 7.4) higher in Trichuris trichiura negative subjects compared to positive participants, whereas immunoglobulin subclass distribution was similar. Memory B-cell response was moderately increased in T. trichiura negative individuals, although the difference was not significant. Conclusions: Future malaria vaccine development programs need to account for worm-mediated hyporesponsiveness of immune reactions. [Copyright &y& Elsevier]

Summary: Background: The RTS,S/AS01E candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01E when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. Methods: We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6–10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01E at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. Findings: 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01E 0, 1, 2 month group (34%, 95% CI 27–41), 47 in the 0, 1, 7 month group (28%, 21–35), and 49 (29%, 22–36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01E groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site-adjusted according-to-protocol analysis) was 53% (95% CI 26–70; p=0·0012) against first malaria episodes and 59% (36–74; p=0·0001) against all malaria episodes. For the entire study period, (total vaccinated cohort) vaccine efficacy against all malaria episodes was higher with the 0, 1, 2 month schedule (57%, 95% CI 33–73; p=0·0002) than with the 0, 1, 7 month schedule (32% CI 16–45; p=0·0003). 1 year after dose three, vaccine efficacy against first malaria episodes was similar for both schedules (0, 1, 2 month group, 61·6% [95% CI 35·6–77·1], p<0·001; 0, 1, 7 month group, 63·8% [40·4–78·0], p<0·001, according-to-protocol cohort). Interpretation: Vaccine efficacy was consistent with the target put forward by the WHO-sponsored malaria vaccine technology roadmap for a first-generation malaria vaccine. The 0, 1, 2 month vaccine schedule has been selected for phase 3 candidate vaccine assessment. Funding: Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals. [Copyright &y& Elsevier]

Abstract: Malaria is still one of the major public health threats in sub-Saharan Africa. An effective vaccine could be a sustainable control measure that can be integrated into existing health infrastructures. The malaria vaccine candidate GMZ2 is a recombinant fusion protein of conserved parts of Plasmodium falciparum Glutamate Rich Protein and Merozoite Surface Protein 3 adjuvanted with aluminium hydroxide. GMZ2 is immunogenic and well tolerated in malaria-naive adults from Germany. To assess safety and immunogenicity in malaria-exposed individuals, 40 adults from Lambaréné, Gabon were randomly assigned to receive either 100μg GMZ2 or a rabies control vaccine three times in monthly intervals. Both vaccines were well tolerated. One month after a full course of vaccination, GMZ2-vaccinated individuals had 1.4-fold (95% confidence interval: [1.1, 1.7]) higher baseline-corrected anti-GMZ2 antibody levels and more GMZ2-specific memory B-cells compared to the rabies group (p =0.039), despite a high prevalence of GMZ2-specific immune reactivity due to previous intense exposure to P. falciparum. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this paper is to explore attitudes of mothers towards childhood vaccinations and reasons for non-attendance and non-adherence to mother–child clinics (MCCs). Forty in-depth interviews with mothers of children under 5 years of age revealed positive attitudes towards vaccination that seem at odds with the region''s observed low vaccination coverage. Important reasons for MCC non-attendance included distance to the MCC, transport costs, negative experiences at MCCs (such as interactions with unfriendly staff) and mothers’ feeling of shame provoked by different, often poverty-associated reasons such as attending the clinic with a dirty or poorly clothed child. [Copyright &y& Elsevier]

Abstract: Clindamycin is safe and effective for the treatment of Plasmodium falciparum malaria, but its use as monotherapy is limited by unacceptably slow initial clinical response rates. To investigate whether the protracted action is due to an accumulative, time of exposure-dependent or a delayed effect on parasite growth, we studied the in vivo and in vitro pharmacodynamic profiles of clindamycin against P. falciparum. In vivo, elimination of young, circulating asexual parasite stages during treatment with clindamycin displayed an unusual biphasic kinetic: a plateau phase was followed by a precipitated decline of asexual parasite densities to nearly undetectable levels after 72 and 60h in adult patients and asymptomatic children, respectively, suggesting an uninhibited capacity to establish a second, but not third, infectious cycle. In vitro, continuous exposure of a laboratory-adapted P. falciparum strain to clindamycin with concentrations of up to 100μM for two replication cycles (96h) did not produce inhibitory effects of >50% compared with drug-free controls as measured by the production of P. falciparum histidine-rich protein II (PfHRP2). PfHRP2 production was completely arrested after the second cycle (96–144h) (>10,000-fold decrease of mean half-inhibitory concentrations measured at 96–144h compared to 48–96h). Furthermore, incubation with clindamycin during only the first (0–48h) versus three (0–144h) parasite replication cycles led to comparable inhibition of PfHRP2 production in the third infectious cycle (96–144h) (mean IC99 of 27 and 22nM, respectively; P =0.2). When parasite cultures were exposed to different concentrations of clindamycin ranging from 50 to 1,000nM for 72h and followed up in an experiment designed to simulate a typical 3-day treatment regimen, parasitaemia was initially suppressed below the microscopic detection threshold. Nonetheless, parasites reappeared in a dose-dependent manner after removal of drug at 72h but not in continuously drug-exposed controls. The delayed, but potent, antimalarial effect of clindamycin appears to be of greatest potential benefit in new combinations of clindamycin with rapidly acting antimalarial combination partners. [Copyright &y& Elsevier]