Trial Of RTS Research Articles

Can incorporating genotyping data into efficacy estimators improve efficiency of early phase malaria vaccine trials?

BackgroundEarly 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 VEHR = 1–hazard ratio or VERR = 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: VEmolFOI, the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VEC, the vaccine-induced proportion reduction in mean number of infecting clones per exposure.MethodsPower of VEmolFOI and VEC was compared to that of VEHR and VERR 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.ResultsIn 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 VEC compared to VEHR for data like those from RTS,S, but VEC is less powerful than VEHR for trials in which the number of clones at first infection is not reduced. VEmolFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VEmolFOI. The primaquine VEmolFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VEmolFOI from improving power.ConclusionsThe 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.

Efficacy of Phase 3 Trial of RTS, S/AS01 Malaria Vaccine in infants: a systematic review and meta-analysis.

Although vaccines would be the ideal tool for control, prevention, elimination, and eradication of many infectious diseases, developing of parasites vaccines such as malaria vaccine is very complex. The most advanced malaria vaccine candidate is RTS,S, a pre-erythrocytic vaccine for which pivotal phase III trial design is underway. Few recent malaria vaccine review articles have attempted to outline of all clinical trials that have occurred globally and no meta-analysis was performed on efficacy of Phase 3 Trial of RTS, S/AS01 Malaria vaccine up to now in infants. Therefore, a systematic review and meta-analysis was carried out to review new and existing data on efficacy of Phase 3 Trial of RTS, S/AS01 Malaria Vaccine in infants. The electronic databases searched were Pubmed (1965-present) and Web of Science (1970-present) (Search date: May, 2016). After full-text review of the papers evaluating clinical/severe malaria in several well-designed phase III field efficacy trials, 5 were determined to meet the eligibility criteria for inclusion in the systematic review. Four out of the 5 publications dealing with efficacy of Phase 3 Trial of RTS, S/AS01 malaria vaccine were included in the qualitative analysis. Pooled estimate of vaccine efficacy in clinical and severe malaria in children aged 5-17mo was 29% (95% CL: 19%-46%) and 39% (95% CI 20%-74%), while this estimate vaccine in clinical and severe malaria in children aged 6-12mo was 19% (95% CI 14%-24%) and 21 (95% CI 19%-37%), respectively. On the other hand, higher VE was seen in both per- protocol and intention-to-treat population in children aged 5-17 than the children aged 6-12mo. The results of this meta-analysis suggest that this candidate malaria vaccine has relatively little efficacy, and the vaccine apparently will not meet the goal of malaria eradication by itself.

Models Predict Positive Public Health Effects for RTS,S Vaccine — with Qualifications

Phase III clinical trials of RTS,S/AS01 have shown modest vaccine efficacy against clinical malaria after three doses — 20% in infants (6–12 weeks) and 35% in children (5–17 months) during 32 months follow-up, with efficacy waning over time (NEJM JW Infect Dis Jun 2015 and Lancet 2015; 386:31). Given these results, should this vaccine be used and, if so, in which populations? To examine the vaccine's cost-effectiveness …

Costing RTS,S introduction in Burkina Faso, Ghana, Kenya, Senegal, Tanzania, and Uganda: A generalizable approach drawing on publicly available data

Recent results from the phase 3 trial of RTS,S/AS01 malaria vaccine show that the vaccine induced partial protection against clinical malaria in infants and children; given the high burden of the disease it is currently considered for use in malaria endemic countries. To inform adoption decisions the paper proposes a generalizable methodology to estimate the cost of vaccine introduction using routinely collected and publicly available data from the cMYP, UNICEF, and WHO-CHOICE. Costing is carried out around a set of generic activities, assumptions, and inputs for delivery of immunization services adapted to a given country and deployment modality to capture among other factors the structure of the EPI program, distribution model, geography, and demographics particular to the setting. The methodology is applied to estimate the cost of RTS,S introduction in Burkina Faso, Ghana, Kenya, Senegal, Tanzania, and Uganda. At an assumed vaccine price of $5 per dose and given our assumptions on coverage and deployment strategy, we estimate total economic program costs for a 6–9 months cohort within $23.11–$28.28 per fully vaccinated child across the 6 countries. Net of procurement, costs at country level are substantial; for instance in Tanzania these could add as much as $4.2 million per year or an additional $2.4 per infant depending on the level of spare capacity in the system. Differences in cost of vaccine introduction across countries are primarily driven by differences in cost of labour. Overall estimates generated with the methodology result in costs within the ranges reported for other new vaccines introduced in SSA and capture multiple sources of heterogeneity in costs across countries. Further validation with data from field trials will support use of the methodology while also serving as a validation for cMYP and WHO-CHOICE as resources for costing health interventions in the region.

Final results from a pivotal phase 3 malaria vaccine trial

In The Lancet, the RTS,S Clinical Trials Partnership 1 RTS,S Clinical Trials PartnershipEfficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015; (published online April 24.)http://dx.doi.org/10.1016/S0140-6736(15)60721-8 Google Scholar report the most recent results from the pivotal phase 3 trial of RTS,S/AS01 malaria vaccine, the fourth major publication from this randomised controlled trial. 2 RTS,S Clinical Trials PartnershipFirst results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med. 2011; 365: 1863-1875 Crossref PubMed Scopus (653) Google Scholar , 3 RTS,S Clinical Trials PartnershipA phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med. 2012; 367: 2284-2295 Crossref PubMed Scopus (541) Google Scholar , 4 RTS,S Clinical Trials PartnershipEfficacy and safety of the RTS,S/AS01 malaria vaccine during 18 months after vaccination: a phase 3 randomized, controlled trial in children and young infants at 11 African sites. PLoS Med. 2014; 11: e1001685 Crossref PubMed Scopus (322) Google Scholar The trial enrolled 15 459 infants and young children at 11 centres in seven sub-Saharan African countries: Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and Tanzania. Two age groups were included: 6–12 weeks and 5–17 months at first dose. The schedule involved a primary series of three monthly doses, with a booster dose given 18 months later in one of the three trial groups. The partnership responsible for undertaking this trial, consisting of GlaxoSmithKline and PATH, are to be congratulated on the quality of the study. Industry involvement in malaria vaccine development has been crucial to the promising next-generation malaria vaccine work that is underway. The generous funding from the Bill & Melinda Gates Foundation to PATH for clinical trials of RTS,S/AS01 has been very important, as has the continued commitment of a large pharmaceutical company to this project despite the absence of a market for this product in high-income settings. GlaxoSmithKline and PATH worked with many of the leading scientists in sub-Saharan Africa in a clinical trial partnership model, through a committee in which many of the decisions were taken together with and by local investigators. The strengthening of clinical trial capacity in sub-Saharan Africa to support the trial has already left a strong legacy. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trialRTS,S/AS01 prevented a substantial number of cases of clinical malaria over a 3–4 year period in young infants and children when administered with or without a booster dose. Efficacy was enhanced by the administration of a booster dose in both age categories. Thus, the vaccine has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission. Full-Text PDF From work with men and boys to changes of social norms and reduction of inequities in gender relations: a conceptual shift in prevention of violence against women and girlsViolence perpetrated by and against men and boys is a major public health problem. Although individual men's use of violence differs, engagement of all men and boys in action to prevent violence against women and girls is essential. We discuss why this engagement approach is theoretically important and how prevention interventions have developed from treating men simply as perpetrators of violence against women and girls or as allies of women in its prevention, to approaches that seek to transform the relations, social norms, and systems that sustain gender inequality and violence. Full-Text PDF Pedro L Alonso: mapping out the future of malaria controlPedro L Alonso has pioneered many innovations in public health during his 30-year long career in malaria research and global health. Known as someone who thrives on a challenge, some think he faces one of his biggest challenges yet in his role as the Director of the WHO Global Malaria Programme , which he took up in October, 2014. Alonso and his team in Geneva coordinate WHO's work to control and eliminate malaria. Full-Text PDF

RTS,S Malaria Vaccine Efficacy Wanes over Time

In a phase II trial of RTS,S/AS01E in children vaccinated at age 5 to 17 months in Kenya and Tanzania, efficacy against a first malaria episode was 46%

First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children

First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children

A Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Infants

BackgroundThe candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial.MethodsWe administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed.ResultsThe incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, −7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222).ConclusionsThe RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.)

Addressing the bottleneck at clinical testing of candidate malaria vaccines

[Extract] Invited Commentary on 'Preerythrocytic and Blood-Stage Malaria Vaccines Can Be Assessed in Small Sporozoite Challenge Trials in Human Volunteers', Roestenberg et al., Journal of Infectious Diseases, 2012. Vaccines are a very effective health care intervention but are not available for many diseases, including malaria. Potential candidates have been identified in preclinical research studies and some have progressed through preclinical development to clinical trials (http://www.who.int/vaccine_research/links/Rainbow/en/index.html). However, the vaccine development pathway is long and expensive and there is a major bottleneck at the stage of clinical testing. For malaria, only a single candidate has advanced to Phase 3.1 Agnandji ST, Lell B, Soulanoudjingar SS, Fernandes JF, Abossolo BP, Conzelmann C, et al.. RTS,S Clinical Trials Partnership. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med. 2011;365(20):1863–75. Moreover, rodent malaria models exist but protection against challenge with the causative parasites of human malaria can only be assessed in humans, and there are no known correlates of protective immunity to malaria. Candidate vaccines that fail to meet defined go/no-go criteria in animals during development may nonetheless exhibit efficacy in humans. The testing of a larger portfolio of vaccine candidates in small numbers of volunteers in clinical research studies would be valuable.

A Malaria Vaccine: Promising Results, but Not There Yet

Research Article| March 01 2012 A Malaria Vaccine: Promising Results, but Not There Yet AAP Grand Rounds (2012) 27 (3): 26. https://doi.org/10.1542/gr.27-3-26 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation A Malaria Vaccine: Promising Results, but Not There Yet. AAP Grand Rounds March 2012; 27 (3): 26. https://doi.org/10.1542/gr.27-3-26 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: malaria, malaria vaccines, vaccines Source: The RTS,S Clinical Trials Partnership. First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med. 2011; 365(20): 1863– 1875; doi: https://doi.org/10.1056/NEJMoa1102287 An international group of researchers performed this double-blind, randomized trial involving eleven centers in seven African countries to determine the efficacy, safety, and immunogenicity of RTS,S/AS01, a candidate malaria vaccine in infants and young children. The vaccine is a recombinant vaccine in which the malaria protein is fused to the hepatitis B surface antigen. After enrollment in the study, children were divided into two age groups: 6 to 12 weeks (6,537 participants) and 5 to 17 months (8,923 participants). Children in each group were then randomly assigned to three doses of the vaccine at one-month intervals; a control group received a non-malaria vaccine. In the 6 to 12 weeks age group, the control... You do not currently have access to this content.

First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children

An ongoing phase 3 study of the efficacy, safety, and immunogenicity of candidate malaria vaccine RTS,S/AS01 is being conducted in seven African countries. From March 2009 through January 2011, we enrolled 15,460 children in two age categories--6 to 12 weeks of age and 5 to 17 months of age--for vaccination with either RTS,S/AS01 or a non-malaria comparator vaccine. The primary end point of the analysis was vaccine efficacy against clinical malaria during the 12 months after vaccination in the first 6000 children 5 to 17 months of age at enrollment who received all three doses of vaccine according to protocol. After 250 children had an episode of severe malaria, we evaluated vaccine efficacy against severe malaria in both age categories. In the 14 months after the first dose of vaccine, the incidence of first episodes of clinical malaria in the first 6000 children in the older age category was 0.32 episodes per person-year in the RTS,S/AS01 group and 0.55 episodes per person-year in the control group, for an efficacy of 50.4% (95% confidence interval [CI], 45.8 to 54.6) in the intention-to-treat population and 55.8% (97.5% CI, 50.6 to 60.4) in the per-protocol population. Vaccine efficacy against severe malaria was 45.1% (95% CI, 23.8 to 60.5) in the intention-to-treat population and 47.3% (95% CI, 22.4 to 64.2) in the per-protocol population. Vaccine efficacy against severe malaria in the combined age categories was 34.8% (95% CI, 16.2 to 49.2) in the per-protocol population during an average follow-up of 11 months. Serious adverse events occurred with a similar frequency in the two study groups. Among children in the older age category, the rate of generalized convulsive seizures after RTS,S/AS01 vaccination was 1.04 per 1000 doses (95% CI, 0.62 to 1.64). The RTS,S/AS01 vaccine provided protection against both clinical and severe malaria in African children. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619 .).

Correction: Randomized Controlled Trial of RTS,S/AS02Dand RTS,S/AS01EMalaria Candidate Vaccines Given According to Different Schedules in Ghanaian Children

Correction: Randomized Controlled Trial of RTS,S/AS02_Dand RTS,S/AS01_EMalaria Candidate Vaccines Given According to Different Schedules in Ghanaian Children

Gene-expression analysis for prediction of RTS,S-induced protection in humans

Evaluation of: Vahey MT, Wang Z, Kester KE et al. Expression of genes associated with immunoproteasome processing of major histocompatibility complex peptides is indicative of protection with adjuvanted RTS,S malaria vaccine. J. Infect. Dis. 201(4), 580–589 (2010).Vaccines have been most successful in combating infectious diseases in mankind and animals. However, we understand little regarding how effective vaccines stimulate robust protective immune responses. One of the major challenges during development of novel vaccines is to prospectively determine vaccine efficacy and to arrive at hypotheses driving rational vaccine development pathways. The RTS,S candidate malaria vaccine has demonstrated efficacy against malaria in a number of Phase IIa and Phase IIb clinical trials. In 2009, a multicenter, multicountry Phase III clinical trial of RTS,S/AS01 began with results anticipated in 2012. The immunologic basis of how this vaccine protects approximately 50% of volunteers from malaria remains uncertain. The paper under evaluation describes a system biology approach to define gene signatures in peripheral blood that may predict protection in Phase IIa trials in a fraction of volunteers.

Plasmodium falciparum-Specific Cellular Immune Responses after Immunization with the RTS,S/AS02D Candidate Malaria Vaccine in Infants Living in an Area of High Endemicity in Mozambique

Results from clinical trials in areas where malaria is endemic have shown that immunization with RTS,S/AS02A malaria vaccine candidate induces partial protection in adults and children and cellular effector and memory responses in adults. For the first time in a malaria vaccine trial, we sought to assess the cell-mediated immune responses to RTS,S antigen components in infants under 1 year of age participating in a clinical phase I/IIb trial of RTS,S/AS02D in Mozambique. Circumsporozoite protein (CSP)-specific responses were detected in approximately half of RTS,S-immunized infants and included gamma interferon (IFN-gamma), interleukin-2 (IL-2), and combined IL-2/IL-4 responses. The median stimulation indices of cytokine-producing CD4(+) and CD8(+) cells were very low but significantly higher in RTS,S-immunized infants than in infants that received the comparator vaccine. Protection against subsequent malarial infection tended to be associated with a higher percentage of individuals with CSP-specific IL-2 in the supernatant (P = 0.053) and with higher CSP-specific IFN-gamma-producing CD8(+) T-cell responses (P = 0.07). These results report for the first time the detection of malaria-specific cellular immune responses after vaccination of infants less than 1 year of age and pave the way for future field studies of cellular immunity to malaria vaccine candidates.

WITHDRAWN: Vaccines for preventing malaria.

Four types of malaria vaccine, SPf66 and MSP/RESA vaccines (against the asexual stages of the Plasmodium parasite) and CS-NANP and RTS,S vaccines (against the sporozoite stages), have been tested in randomized controlled trials in endemic areas. To assess malaria vaccines against Plasmodium falciparum, P. vivax, P. malariae and P ovale in preventing infection, disease and death. We searched the Cochrane Infectious Diseases Group Specialized Register (April 2004), CENTRAL (The Cochrane Library Issue 2, 2004), MEDLINE (1966 to April 2004), EMBASE (1980 to April 2004), Science Citation Index (1981 to April 2004), and reference lists of articles. We also contacted organizations and researchers in the field. Randomized controlled trials comparing vaccines against Plasmodium falciparum, P. vivax, P. malariae or P. ovale with placebo or routine antimalarial control measures in people of any age receiving a challenge malaria infection. Two reviewers independently assessed trial quality and extracted data. Eighteen efficacy trials involving 10,971 participants were included. There were ten trials of SPf66 vaccine, four trials of CS-NANP vaccines, two trials of RTS,S vaccine, and two of MSP/RESA vaccine. Results with SPf66 in reducing new malaria infections (P. falciparum) were heterogeneous: it was not effective in four African trials (Peto odds ratio (OR) 0.96, 95% confidence interval (CI) 0.81 to 1.14), but in five trials outside Africa the number of first attacks was reduced (Peto OR 0.77, 95% CI 0.67 to 0.88). Trials to date have not indicated any serious adverse events with SPf66 vaccine. In three trials of CS-NANP vaccines, there was no evidence for protection by these vaccines against P. falciparum malaria (Peto OR 1.12, 95% CI 0.64 to 1.93). In a small trial in non-immune adults in the USA, RTS,S gave strong protection against experimental infection with P. falciparum. In a trial in an endemic area of the Gambia in semi-immune people, there was a reduction in clinical malaria episodes in the second year of follow up, corresponding to a vaccine efficacy of 66% (CI 14% to 85%). In a trial in Papua New Guinea, MSP/RESA had no protective effect against episodes of clinical malaria. There was evidence of an effect on parasite density, but this differed according to whether the participants had been pretreated with sulfadoxine/pyrimethamine or not. The prevalence of infections with the parasite subtype of MSP2 in the vaccine was reduced compared with the other subtype (Peto OR 0.35, CI 0.23 to 0.53). There is no evidence for protection by SPf66 vaccines against P. falciparum in Africa. There is a modest reduction in attacks of P. falciparum malaria following vaccination with SPf66 in other regions. Further research with SPf66 vaccines in South America or with new formulations of SPf66 may be justified. There was not enough evidence to evaluate the use of CS-NANP vaccines. The RTS,S vaccine showed promising result, as did the MSP/RESA vaccine, but it should include the other main allelic form of MSP2. The MSP/RESA trial demonstrated that chemotherapy during a vaccine trial may reduce vaccine efficacy, and trials should consider very carefully whether this practice is justified.