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The efficacy of a Vi polysaccharide typhoid conjugate vaccine (Vi-TCV) was assessed in 28,130 Malawian children who were 9 months to 12 years of age. The incidence of blood culture–confirmed typhoid fever was significantly lower among children who received Vi-TCV than among those who received a control vaccine.

Malaria remains a leading cause of mortality among children in Africa, and recent advances in control have stagnated. Although new vaccines are available, protective efficacy is not optimum. Monoclonal antibodies targeting the Plasmodium falciparum circumsporozoite protein have potential to simplify prevention. We assessed the safety, pharmacokinetics, and protective efficacy of MAM01, a monoclonal antibody preferentially directed against the conserved Asn-Ala-Asn-Pro (NANP) central repeat region of circumsporozoite protein. This phase 1, dose-escalation, double-blind, placebo-controlled, adaptive trial was done at the Center for Vaccine Development and Global Health, University of Maryland, Baltimore, MD, USA. Adults aged 18–50 years, with no previous malaria vaccinations or infections, and BMI of 18–30 kg/m2, were recruited sequentially, assigned to dose cohorts, and randomly assigned to receive the monoclonal antibody MAM01 (at 1·5, 5, 10, or 40 mg/kg intravenously or 5 mg/kg subcutaneously) or to placebo (identical buffer solution), with dose escalation staggered by 2-week intervals. Randomisation was done using an interactive response technology system. Participants and investigators were masked to treatment assignments. An untreated infectivity control was enrolled to support evaluation of protective efficacy. Participants from the MAM01 and control groups underwent controlled human malaria infection via the bites of five mosquitoes infected with P falciparum NF54 strain 18–26 weeks after monoclonal antibody or placebo administration. After malaria challenge, participants were followed up daily for ultra-sensitive PCR-based malaria detection on days 6–17, with continued follow-up of participants remaining aparasitaemic on days 20, 23, and 27. Participants who tested positive were treated with atovaquone–proguanil or artemether–lumefantrine; those who remained negative were empirically treated at day 27. A second dose of 5 mg/kg subcutaneously was administered to the cohorts that received 5 mg/kg subcutaneously or intravenously 2–4 weeks after completion of the controlled human malaria infection. The primary outcome was safety and tolerability of MAM01 at each dose level, and after second MAM01 dosing. Secondary outcomes included pharmacokinetic properties and protective efficacy (ie, presence of confirmed parasitaemia) after controlled human malaria infection. Safety was assessed in all participants who received trial intervention (MAM01 or placebo), as well as in participants who underwent controlled human malaria infection. This trial is complete and is registered with ClinicalTrials.gov, NCT05891236. Between Aug 14, 2023, and Dec 13, 2024, 63 participants were assessed for eligibility, 38 were enrolled, and 37 were randomly assigned. After review of sentinel group safety data (1·5 mg/kg [n=1] and placebo [n=1]), 29 participants were assigned to receive MAM01 at doses of 1·5 mg/kg (n=5), 5 mg/kg (n=6), 10 mg/kg (n=6), or 40 mg/kg (n=6) intravenously or 5 mg/kg subcutaneously (n=6) and six were assigned to the placebo group. One participant was included as an untreated infectivity control. MAM01 administration was well tolerated. No treatment-related serious adverse events occurred after one or two doses. After controlled human malaria infection, six of six participants in the control group and 18 of 22 participants in the MAM01 group developed parasitaemia. None of three participants in the 40 mg/kg intravenous dose group developed parasitaemia. Pharmacokinetic analysis showed that serum MAM01 concentrations greater than 88 μg/mL protected against malaria challenge. MAM01 was well tolerated, met safety targets, and showed clinical proof-of-principle by eliciting protection in malaria-naive adults using the controlled human malaria infection model. Progress driving down the cost of goods coupled with dose selection within target populations will dictate the feasibility of malaria monoclonal antibody deployment. Gates Foundation.

Introduction As populations on antiretroviral therapy (ART) in sub-Saharan Africa are aging, hypertension has become an increasingly important comorbidity among people living with HIV (PLHIV). To address a paucity of data from sub-Saharan Africa on the incidence of hypertension among PLHIV, we conducted a cohort study in Malawi to assess the frequency and correlates of incident hypertension among PLHIV established on ART. Methods In this prospective cohort study nested in a clinical trial, we followed participants without prevalent hypertension at enrolment and routinely screened their blood pressure (BP). In the parent study, clinically stable adult (≥ 18 years) PLHIV on ART with HIV-RNA ≤ 400 copies/mL and CD4 count ≥ 250/mm3 were randomized to daily trimethoprim-sulfamethoxazole (TS), weekly chloroquine (CQ), or no prophylaxis. We defined hypertension as systolic BP of ≥ 140 mmHg and diastolic BP ≥ 90 mmHg obtained on two consecutive clinic visits. Poisson regression analysis was used to determine the incidence of hypertension, using univariate and multivariate analyses designed based on a Directed Acyclic Graph to identify key predictors of hypertension. Results 1,240 PLHIV (76.4% female, median age 37 years, median duration on ART 3 years, 92.2% on efavirenz-based regimens) were followed from December 2012 to July 2018, accumulating 3,676 person-years of observation (PYO). The incidence of hypertension was 36.9 per 1,000 PYO (95% confidence interval [CI]: 31.0, 43.8), with 40% of diagnoses made before the age of 40 years and the highest incidence observed in the first calendar year of the study. Higher age (incidence rate ratio [IRR] = 1.05, 95%-CI 1.03, 1.07), male sex (IRR = 1,49, 95%-CI 1, 02–2,15; p  = 0.029), being overweight (aIRR = 2.55, 95%-CI: 1.27, 5.47) and obese (aIRR = 5.08, 95%-CI; 2.12, 12.18) and being on a non-efavirenz-based ART regimen (aIRR = 2.25, 95%-CI: 1.37, 3.53) were predictors of incident hypertension. Receiving TS (aIRR = 0.42, 95%-CI 0.26, 0.65) compared to receiving no prophylaxis reduced risk of incident hypertension. Conclusions The incidence of hypertension among PLHIV who were stable on longer-term ART was high, justifying routine BP screening at ART clinics. Identified predictors may help targeting screening. A newly observed protective effect of TS prophylaxis on incident hypertension needs confirmation.

•rCSP/GLA-LSQ malaria vaccine was associated with only mild/moderate adverse events.•Geometric mean (GM) anti-CSP IgG rose > 4-fold 28 days after 1st dose in all groups.•rCSP/GLA-LSQ resulted in ~90-fold rise GM anti-CSP IgG 28 days after 3rd dose.•GLA-LSQ, a novel adjuvant, showed favorable safety and immunostimulatory results. Plasmodium falciparum circumsporozoite protein (CSP) is a major sporozoite surface protein and a key target of pre-erythrocytic malaria subunit vaccines. A full-length recombinant CSP (rCSP) based strategy could be advantageous, as this antigen includes a region critical to sporozoite cell attachment and hepatocyte invasion. The adjuvant Glucopyranosyl Lipid A-liposome Quillaja saponaria 21 (GLA-LSQ) functions as a TLR4 agonist, promotes antigen-specific TH1 responses and stimulates cytotoxic T cell production. To date, one study has reported the clinical acceptability of GLA-LSQ. We present interim results of a phase 1 first-in-human dose-escalation clinical trial of full-length rCSP vaccine given with or without GLA-LSQ adjuvant. Participants experienced only mild to moderate related solicited adverse events. The lowest adjuvanted vaccine dose achieved >90-fold rise in geometric mean anti-CSP IgG antibody titer. These favorable safety and immunogenicity results confirm the immunostimulatory capacity of this relatively new adjuvant and support next steps in clinical product development. Trial registration: ClinicalTrials.gov Identifier NCT03589794 (registered 18 July 2018)

In Bandiagara, Mali, children experience on average two clinical malaria episodes per year. However, even in the same transmission area, the number of uncomplicated symptomatic infections, and their parasitemia, can vary dramatically among children. We simultaneously characterize host and parasite gene expression profiles from 136 Malian children with symptomatic falciparum malaria and examine differences in the relative proportion of immune cells and parasite stages, as well as in gene expression, associated with infection and or patient characteristics. Parasitemia explains much of the variation in host and parasite gene expression, and infections with higher parasitemia display proportionally more neutrophils and fewer T cells, suggesting parasitemia-dependent neutrophil recruitment and/or T cell extravasation to secondary lymphoid organs. The child’s age also strongly correlates with variations in gene expression: Plasmodium falciparum genes associated with age suggest that older children carry more male gametocytes, while variations in host gene expression indicate a stronger innate response in younger children and stronger adaptive response in older children. These analyses highlight the variability in host responses and parasite regulation during P. falciparum symptomatic infections and emphasize the importance of considering the children’s age when studying and treating malaria infections. Here the authors use dual RNA sequencing to characterize host and parasite gene expression from 136 Malian children with symptomatic Plasmodium falciparum infection. They find that parasitemia levels correlate with neutrophil and T cell levels and that the child’s age correlates with innate immune gene expression as well as gametocyte levels.

Abstract Background Typhoid fever is an acute infection characterized by prolonged fever following the ingestion and subsequent invasion of Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen. The incidence of typhoid fever has been most reported in children 5–15 years of age, but is increasingly recognized in children younger than 5 years old. There has been a recent expansion of multidrug-resistant typhoid fever globally. Prior typhoid vaccines were not suitable for use in the youngest children in countries with a high burden of disease. This study aims to determine the efficacy of a typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization, by testing it in children 9 months through 12 years of age in Blantyre, Malawi. Methods In this Phase III, individually randomized, controlled, double-blind trial of the clinical efficacy of TCV, 28 000 children 9 months through 12 years of age will be enrolled and randomized in a 1:1 ratio to receive either Vi-TCV or a meningococcal serogroup A conjugate vaccine. A subset of 600 of these children will be further enrolled in an immunogenicity and reactogenicity sub-study to evaluate the safety profile and immune response elicited by Vi-TCV. Recruiting began in February 2018. Results All children will be under passive surveillance for at least 2 years to determine the primary outcome, which is blood culture–confirmed S. Typhi illness. Children enrolled in the immunogenicity and reactogenicity sub-study will have blood drawn before vaccination and at 2 timepoints after vaccination to measure their immune response to vaccination. They will also be followed actively for adverse events and serious adverse events. Conclusions The introduction of a single-dose, efficacious typhoid vaccine into countries with high burden of disease or significant antimicrobial resistance could have a dramatic impact, protecting children from infection and reducing antimicrobial usage and associated health inequity in the world’s poorest places. This trial, the first of a TCV in Africa, seeks to demonstrate the impact and programmatic use of TCVs within an endemic setting. Clinical Trials Registration NCT03299426.

Background The World Health Organization (WHO) has called for new malaria vaccines with > 90% efficacy against Plasmodium falciparum infection to expand the anti-disease benefit provided by the RTS,S/AS01 and R21/Matrix M subunit vaccines currently administered to infants and young children in sub-Saharan Africa. Attenuated P. falciparum sporozoites (PfSPZ) are being developed as a traveller’s vaccine and to fulfill WHO’s call for high-level efficacy in endemic countries to support malaria elimination. Methods PfSPZ Vaccine, comprised of radiation-attenuated PfSPZ, was compared with normal saline placebo in a randomized, double-blind trial targeting 60 malaria-naive US adults to assess safety, tolerability, immunogenicity, and efficacy against heterologous controlled human malaria infection three and twelve weeks after immunization. Pharmacists provided syringes to blinded clinicians using 3:1 (vaccine:placebo) blocked randomization, for administration by direct venous inoculation on days 1 and 8 (multidose prime) and day 29 (boost), a condensed regimen with superior efficacy. Primary outcomes included adverse events and antibody responses to the P. falciparum circumsporozoite protein (PfCSP). Results 31 participants were screened, randomized and immunized twice (V1, V2) 5–7 days apart, with one withdrawal after an intercurrent adverse event. A vial issue, later traced to the vial manufacturer, halted further immunizations. Solicited local and systemic adverse events recorded for 2 and 7 days after immunizations, respectively, occurred with equal frequency and severity in the 23 vaccinees and 7 controls receiving two immunizations, as did unsolicited adverse events recorded for 28 days and laboratory abnormalities 1 and 5 weeks after V2. Four of 23 vaccinees and one of 7 controls (p = 1.00) developed grade 2 adverse events including subjective fever, headache, malaise, fatigue, rigors, arthralgia and myalgia after V2 but not V1, these symptoms generally resolving within 24 h. Twenty-two of 23 (96%) vaccinees developed IgG (median 99-fold increase over baseline) and IgM (median 1,110-fold increase) antibodies to PfCSP one week after V2. Antibody responses were not associated with reactogenicity. Conclusions The two-dose priming immunization regimen was safe, well tolerated and highly immunogenic. Larger studies may better define the adverse event profile of condensed regimens of PfSPZ Vaccine in malaria-naive adults. Trial registration number: clinicaltrial.gov NCT05604521.

Background Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as VE HR  = 1–hazard ratio or VE RR  = 1–risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: VE molFOI , the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VE C , the vaccine-induced proportion reduction in mean number of infecting clones per exposure. Methods Power of VE molFOI and VE C was compared to that of VE HR and VE RR by simulations and analytic derivations, and the four VE methods were applied to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax , primaquine reduces subsequent reactivations after treatment completion. Results In the trial of RTS,S vaccine, a significantly reduced number of clones at first infection was observed, but this was not the case in trials of PfSPZ Vaccine or primaquine, although the PfSPZ trial lacked power to show a reduction. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VE C compared to VE HR for data like those from RTS,S, but VE C is less powerful than VE HR for trials in which the number of clones at first infection is not reduced. VE molFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VE molFOI . The primaquine VE molFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VE molFOI from improving power. Conclusions The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, these estimators are not recommended as primary endpoints for small trials unless supported by targeted data analysis. Trial registrations: NCT00866619, NCT02663700, NCT02143934.

Plasmodium parasites caused 241 million cases of malaria and over 600,000 deaths in 2020. Both P . falciparum and P . ovale are endemic to Mali and cause clinical malaria, with P . falciparum infections typically being more severe. Here, we sequenced RNA from nine pediatric blood samples collected during infections with either P . falciparum or P . ovale , and characterized the host and parasite gene expression profiles. We found that human gene expression varies more between individuals than according to the parasite species causing the infection, while parasite gene expression profiles cluster by species. Additionally, we characterized DNA polymorphisms of the parasites directly from the RNA-seq reads and found comparable levels of genetic diversity in both species, despite dramatic differences in prevalence. Our results provide unique insights into host-pathogen interactions during malaria infections and their variations according to the infecting Plasmodium species, which will be critical to develop better elimination strategies against all human Plasmodium parasites.