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Immunization with Plasmodium falciparum sporozoites under chemoprophylaxis can protect against controlled human malaria infection with the same strain for at least 10 weeks, and protection correlates with polyfunctional T-cell memory. The search for a malaria vaccine The best candidates for a malaria vaccine so far have been radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) inoculated by mosquitos, intravenous injection of radiation-attenuated, cryopreserved PfSPZ, and infectious PfSPZ inoculated by mosquitos in people taking chloroquine or mefloquine. Here Stephen Hoffman, Peter Kremsner and colleagues report that inoculation of volunteers taking chloroquine with direct intravenous injection of aseptic, cryopreserved, non-irradiated PfSPZ can induce protection against infection with the same strain for at least ten weeks. The authors show that protection correlates with polyfunctional T-cell memory. A highly protective malaria vaccine would greatly facilitate the prevention and elimination of malaria and containment of drug-resistant parasites 1 . A high level (more than 90%) of protection against malaria in humans has previously been achieved only by immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (PfSPZ) inoculated by mosquitoes 2 , 3 , 4 ; by intravenous injection of aseptic, purified, radiation-attenuated, cryopreserved PfSPZ (‘PfSPZ Vaccine’) 5 , 6 ; or by infectious PfSPZ inoculated by mosquitoes to volunteers taking chloroquine 7 , 8 , 9 , 10 or mefloquine 11 (chemoprophylaxis with sporozoites). We assessed immunization by direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated PfSPZ (‘PfSPZ Challenge’ 12 , 13 ) to malaria-naive, healthy adult volunteers taking chloroquine for antimalarial chemoprophylaxis (vaccine approach denoted as PfSPZ-CVac) 14 . Three doses of 5.12 × 10 4 PfSPZ of PfSPZ Challenge 12 , 13 at 28-day intervals were well tolerated and safe, and prevented infection in 9 out of 9 (100%) volunteers who underwent controlled human malaria infection ten weeks after the last dose (group III). Protective efficacy was dependent on dose and regimen. Immunization with 3.2 × 10 3 (group I) or 1.28 × 10 4 (group II) PfSPZ protected 3 out of 9 (33%) or 6 out of 9 (67%) volunteers, respectively. Three doses of 5.12 × 10 4 PfSPZ at five-day intervals protected 5 out of 8 (63%) volunteers. The frequency of Pf-specific polyfunctional CD4 memory T cells was associated with protection. On a 7,455 peptide Pf proteome array, immune sera from at least 5 out of 9 group III vaccinees recognized each of 22 proteins. PfSPZ-CVac is a highly efficacious vaccine candidate; when we are able to optimize the immunization regimen (dose, interval between doses, and drug partner), this vaccine could be used for combination mass drug administration and a mass vaccination program approach to eliminate malaria from geographically defined areas.

The RTS,S/AS01 malaria vaccine has completed phase 3 testing and rollout is being contemplated. Follow-up of children in a phase 2 trial of the vaccine up to 7 years showed evidence of an increased malaria-infection rate among vaccinees in areas with higher-than-average transmission. RTS,S/AS01 is a malaria vaccine candidate that has undergone phase 3 evaluation across several sites in Africa that have varying intensities of malaria transmission. During more than 48 months of follow-up, immunization with the RTS,S/AS01 vaccine was estimated to be associated with rates of protection against clinical malaria of 36.3% (95% confidence interval [CI], 31.8 to 40.5) among children 5 to 17 months of age who had received a fourth dose and 28.3% (95% CI, 23.3 to 32.9) among those who had not received a fourth dose. 1 The rates among young infants (6 to 12 weeks of age at the . . .

Symptomatic malaria cases reflect only a small proportion of all Plasmodium spp infections. Many infected individuals are asymptomatic, and persistent asymptomatic Plasmodium falciparum infections are common in endemic settings. We aimed to quantify the contribution of symptomatic and asymptomatic infections to P falciparum transmission in Tororo, Uganda. We did a longitudinal, observational cohort study in Tororo district, Uganda. We recruited participants of all ages from randomly selected households within this district. Participants were eligible if the selected household had no more than nine permanent residents and at least two members younger than 10 years, and the household was their primary residence, and they agreed to come to the study clinic for any fever episode and avoid antimalarial medications outside the study. Participants were followed-up by continuous passive surveillance for the incidence of symptomatic infections; routine assessments (ie, standardised clinical evaluation and blood samples) were done at baseline and at routine visits every 4 weeks for 2 years. P falciparum parasite density, gametocyte density, and genetic composition were determined molecularly using quantitative PCR (qPCR), quantitative reverse transcriptase PCR (qRT-PCR), and amplicon deep sequencing, respectively. Membrane feeding assays were also done to assess infectivity to mosquitoes. The contribution of different populations to the infectious reservoir was estimated for symptomatic infections, asymptomatic but microscopically detected infections, and asymptomatic but qPCR-detected infections; and for age groups younger than 5 years, 5–15 years, and 16 years or older. Between Oct 4, 2017, and Oct 31, 2019, 531 individuals were enrolled from 80 randomly selected households and were followed-up for 2 years. At baseline, P falciparum was detected in 28 (5·3%) of 531 participants by microscopy and an additional 64 (12·1%) by qPCR and declined thereafter. In 538 mosquito feeding experiments on 107 individuals, 446 (1·2%) of 37 404 mosquitoes became infected, with mosquito infection rates being strongly associated with gametocyte densities (β=2·11, 95% CI 1·62–2·67; p<0·0001). Considering both transmissibility of infections and their relative frequency, the estimated human infectious reservoir consisted primarily of asymptomatic microscopy-detected infections (83·8%), followed by asymptomatic submicroscopic infections (15·6%), and symptomatic infections (0·6%). Children aged 5–15 years accounted for more than half of the infectious reservoir (58·7%); individuals younger than 5 years (25·8%) and those 16 years or older (15·6%) contributed less. Samples from four children contribued to 279 (62·6%) of 446 infected mosquitoes after multiple mosquito-feeding assays. Individuals with asymptomatic infections were important drivers of malaria transmission. School-aged children contributed to more than half of all mosquito infections, with a small minority of asymptomatic children being highly infectious. Demographically targeted interventions, aimed at school-aged children, could further reduce transmission in areas under effective vector control. US National Institutes of Health, Bill & Melinda Gates Foundation, and the European Research Council.

There is a tremendous need for a malaria vaccine. By means of a sieve analysis, the RTS,S/AS01 candidate vaccine, which is in advanced clinical development, was shown to have improved vaccine efficacy against genetically matched versus mismatched infecting malaria strains. Malaria induces substantial morbidity and mortality worldwide 1 and has proved to be a challenge for vaccine-development efforts. The recently renewed effort to control, eliminate, and hopefully eradicate malaria will have a greater likelihood of success if a vaccine can be combined with other intervention methods, such as drug-administration campaigns and insect-vector control. 2 , 3 The most advanced candidate vaccine for protection against Plasmodium falciparum malaria infection, RTS,S/AS01, is a monovalent recombinant protein vaccine that targets a fragment of the circumsporozoite protein parasite antigen. RTS,S/AS01 was evaluated in a large randomized, controlled, phase 3 trial, conducted at 11 study sites in Africa . . .

Efforts to develop a live-attenuated malaria vaccine are advancing. In this report, an engineered sporozoite-based vaccine is presented in a human challenge model, with associated immunologic assessments.

The radiation-attenuated Plasmodium falciparum sporozoite (PfSPZ) vaccine provides protection against P. falciparum infection in malaria-naïve adults. Preclinical studies show that T cell-mediated immunity is required for protection and is readily induced in humans after vaccination. However, previous malaria exposure can limit immune responses and vaccine efficacy (VE) in adults. We hypothesized that infants with less previous exposure to malaria would have improved immunity and protection. We conducted a multi-arm, randomized, double-blind, placebo-controlled trial in 336 infants aged 5–12 months to determine the safety, tolerability, immunogenicity and efficacy of the PfSPZ Vaccine in infants in a high-transmission malaria setting in western Kenya ( NCT02687373 ). Groups of 84 infants each received 4.5 × 10 5 , 9.0 × 10 5 or 1.8 × 10 6 PfSPZ Vaccine or saline three times at 8-week intervals. The vaccine was well tolerated; 52 (20.6%) children in the vaccine groups and 20 (23.8%) in the placebo group experienced related solicited adverse events (AEs) within 28 d postvaccination and most were mild. There was 1 grade 3-related solicited AE in the vaccine group (0.4%) and 2 in the placebo group (2.4%). Seizures were more common in the highest-dose group (14.3%) compared to 6.0% of controls, with most being attributed to malaria. There was no significant protection against P. falciparum infection in any dose group at 6 months (VE in the 9.0 × 10 5 dose group = −6.5%, P  = 0.598, the primary statistical end point of the study). VE against clinical malaria 3 months after the last dose in the highest-dose group was 45.8% ( P  = 0.027), an exploratory end point. There was a dose-dependent increase in antibody responses that correlated with VE at 6 months in the lowest- and highest-dose groups. T cell responses were undetectable across all dose groups. Detection of Vδ2 + Vγ9 + T cells, which have been correlated with induction of PfSPZ Vaccine T cell immunity and protection in adults, were infrequent. These data suggest that PfSPZ Vaccine-induced T cell immunity is age-dependent and may be influenced by Vδ2 + Vγ9 + T cell frequency. Since there was no significant VE at 6 months in these infants, these vaccine regimens will likely not be pursued further in this age group. The PfSPZ Vaccine does not protect infants from infection with Plasmodium falciparum , the major cause of malaria.

This trial assessed the efficacy of the vaccine RTS,S/AS01 E as compared with chemoprevention in preventing malaria. The protective efficacy of RTS,S/AS01 E was noninferior to that of chemoprevention, and the combination of RTS,S/AS01 E and chemoprevention was more effective than either intervention alone.

Each year, about 225 million persons have malaria, with some 781,000 associated deaths. In a preliminary report of a phase 3 trial in African children, the RTS,S/AS01 malaria vaccine had about 50% efficacy against incident malaria and 34% efficacy against severe disease. Each year, malaria occurs in approximately 225 million persons worldwide, and 781,000 persons, mostly African children, die from the disease. 1 During the past decade, the scale-up of malaria-control interventions has resulted in considerable reductions in morbidity and mortality associated with malaria in parts of Africa. 2 , 3 However, malaria continues to pose a major public health threat. A malaria vaccine, deployed in combination with current malaria-control tools, could play an important role in future control and eventual elimination of malaria in Africa. 4 The RTS,S vaccine that targets the circumsporozoite protein and is given with an adjuvant system (AS01 or AS02) has . . .

RTS,S/AS01E has been tested in a phase 3 malaria vaccine study with partial efficacy in African children and infants. In a cohort of 1028 subjects from one low (Bagomoyo) and two high (Nanoro, Kintampo) malaria transmission sites, we analysed IgG plasma/serum concentration and avidity to CSP (NANP-repeat and C-terminal domains) after a 3-dose vaccination against time to clinical malaria events during 12-months. Here we report that RTS,S/AS01E induces substantial increases in IgG levels from pre- to post-vaccination ( p  < 0.001), higher in NANP than C-terminus (2855 vs 1297 proportional change between means), and higher concentrations and avidities in children than infants ( p  < 0.001). Baseline CSP IgG levels are elevated in malaria cases than controls ( p  < 0.001). Both, IgG magnitude to NANP (hazard ratio [95% confidence interval] 0.61 [0.48–0.76]) and avidity to C-terminus (0.07 [0.05–0.90]) post-vaccination are significantly associated with vaccine efficacy. IgG avidity to the C-terminus emerges as a significant contributor to RTS,S/AS01E-mediated protection. RTS,S/AS01E has been tested in a phase 3 malaria vaccine trial and has shown partial efficacy in children and infants. Here, the authors analyze IgG concentration and avidity to CSP in ~1000 participants and show that IgG avidity to the C-terminus of CSP is significantly associated with vaccine-mediated protection.