Insights into Long-Lasting Protection Induced by RTS,S/AS02A Malaria Vaccine: Further Results from a Phase IIb Trial in Mozambican Children

Background: The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S. Methodology/Principal Findings: The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5-56.3; p = 0.029) over the double-blind phase and of 9.0% (230.6-36.6; p = 0.609) during the single-blind phase. Conclusions/Significance: Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia

Impact of RTS,S/AS02A and RTS,S/AS01B on Genotypes of P. falciparum in Adults Participating in a Malaria Vaccine Clinical Trial

Objective:RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals\u27 proprietary Adjuvant Systems AS02A or AS01B. A recent trial of the RTS,S/AS02A and RTS,S/AS01B vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02A and RTS,S/AS01B on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias.Design:The distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in break-through infections from vaccinated individuals and from those receiving a non-malarial vaccine.Setting:The study was conducted in Kombewa District, western Kenya.Participants:Semi-immune adults from the three study arms provided isolates at baseline and during break-through infections.Outcome:Parasite isolates used for determining MOI and divergence of csp T cell–epitopes were 191 at baseline and 87 from break-through infections.Results:Grouping recipients of RTS,S/AS01A and RTS,S/AS02B together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/AS01B group, but not the RTS,S/AS02A group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339 were less common among pooled RTS,S/AS vaccine recipients than among recipients of rabies vaccine, whereas parasites with D371 were more common among the RTS,S/AS groups.Conclusions:It is concluded that both RTS,S/AS vaccines reduce multiplicity of infection. Our results do not support the hypothesis that RTS,S/AS vaccines elicit preferential effects against pfcsp alleles with sequence similarity to the 3D7 pfcsp sequence employed in the vaccine construct

Efficacy, Safety, and Tolerability of Three Regimens for Prevention of Malaria: A Randomized, Placebo-Controlled Trial in Ugandan Schoolchildren

BACKGROUND: Intermittent preventive treatment (IPT) is a promising malaria control strategy; however, the optimal regimen remains unclear. We conducted a randomized, single-blinded, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of a single course of sulfadoxine-pyrimethamine (SP), amodiaquine + SP (AQ+SP) or dihydroartemisinin-piperaquine (DP) among schoolchildren to inform IPT. METHODS: Asymptomatic girls aged 8 to 12 years and boys aged 8 to 14 years enrolled in two primary schools in Tororo, Uganda were randomized to receive one of the study regimens or placebo, regardless of presence of parasitemia at enrollment, and followed for 42 days. The primary outcome was risk of parasitemia at 42 days. Survival analysis was used to assess differences between regimens. RESULTS: Of 780 enrolled participants, 769 (98.6%) completed follow-up and were assigned a treatment outcome. The risk of parasitemia at 42 days varied significantly between DP (11.7% [95% confidence interval (CI): 7.9, 17.1]), AQ+SP (44.3% [37.6, 51.5]), and SP (79.7% [95% CI: 73.6, 85.2], p<0.001). The risk of parasitemia in SP-treated children was no different than in those receiving placebo (84.6% [95% CI: 79.1, 89.3], p = 0.22). No serious adverse events occurred, but AQ+SP was associated with increased risk of vomiting compared to placebo (13.0% [95% CI: 9.1, 18.5] vs. 4.7% [95% CI: 2.5, 8.8], respectively, p = 0.003). CONCLUSIONS: DP was the most efficacious and well-tolerated regimen tested, although AQ+SP appears to be a suitable alternative for IPT in schoolchildren. Use of SP for IPT may not be appropriate in areas with high-level SP resistance in Africa. TRIAL REGISTRATION: ClinicalTrials.gov NCT00852371

Latin American immigrants in Indianapolis: Perceptions of prejudice and discrimination

The article focuses on immigrants’ interactions with the Indiana natives, with emphasis in the city of Indianapolis and its suburbs. More specifically, this study aims at providing an understanding of the experiences of Latin American immigrants with special attention to perceptions of prejudice and discrimination and to feelings of social exclusion. A substantial proportion of Latin American immigrants interviewed indicated that they considered Indiana natives to be prejudiced and that they had personally experienced discrimination. The study reveals specific examples of discrimination experienced by the immigrants at the work place, in housing, in stores, restaurants and by various service providers. The results of the study demonstrate the relevance of the normative and power resource theories to explain prejudice and discrimination

Immunological mechanisms underlying protection mediated by RTS,S: a review of the available data

The RTS,S/AS candidate malaria vaccine has demonstrated efficacy against a variety of endpoints in Phase IIa and Phase IIb trials over more than a decade. A multi-country phase III trial of RTS,S/AS01 is now underway with submission as early as 2012, if vaccine safety and efficacy are confirmed. The immunologic basis for how the vaccine protects against both infection and disease remains uncertain. It is, therefore, timely to review the information currently available about the vaccine with regard to how it impacts the human-Plasmodium falciparum host-pathogen relationship. In this article, what is known about mechanisms involved in partial protection against malaria induced by RTS,S is reviewed

Malaria vaccines and their potential role in the elimination of malaria

Research on malaria vaccines is currently directed primarily towards the development of vaccines that prevent clinical malaria. Malaria elimination, now being considered seriously in some epidemiological situations, requires a different vaccine strategy, since success will depend on killing all parasites in the community in order to stop transmission completely

Adenovirus-5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part B: Safety, Immunogenicity and Protective Efficacy of the CSP Component

Background: A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge.\ud \ud Methodology/Principal Findings: NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at 1x1010 particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected.\ud \ud Significance: The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection

The Lid Domain of Caenorhabditis elegans Hsc70 Influences ATP Turnover, Cofactor Binding and Protein Folding Activity

Hsc70 is a conserved ATP-dependent molecular chaperone, which utilizes the energy of ATP hydrolysis to alter the folding state of its client proteins. In contrast to the Hsc70 systems of bacteria, yeast and humans, the Hsc70 system of C. elegans (CeHsc70) has not been studied to date

Tree diversity and species identity effects on soil fungi, protists and animals are context dependent

Plant species richness and the presence of certain influential species (sampling effect) drive the stability and functionality of ecosystems as well as primary production and biomass of consumers. However, little is known about these floristic effects on richness and community composition of soil biota in forest habitats owing to methodological constraints. We developed a DNA metabarcoding approach to identify the major eukaryote groups directly from soil with roughly species-level resolution. Using this method, we examined the effects of tree diversity and individual tree species on soil microbial biomass and taxonomic richness of soil biota in two experimental study systems in Finland and Estonia and accounted for edaphic variables and spatial autocorrelation. Our analyses revealed that the effects of tree diversity and individual species on soil biota are largely context dependent. Multiple regression and structural equation modelling suggested that biomass, soil pH, nutrients and tree species directly affect richness of different taxonomic groups. The community composition of most soil organisms was strongly correlated due to similar response to environmental predictors rather than causal relationships. On a local scale, soil resources and tree species have stronger effect on diversity of soil biota than tree species richness per se