Malaria Vaccine Technology Roadmap Research Articles

Sterile protection and transmission blockade by a multistage anti-malarial vaccine in the pre-clinical study.

The Malaria Vaccine Technology Roadmap 2013 (World Health Organization) aims to develop safe and effective vaccines by 2030 that will offer at least 75% protective efficacy against clinical malaria and reduce parasite transmission. Here, we demonstrate a highly effective multistage vaccine against both the pre-erythrocytic and sexual stages of Plasmodium falciparum that protects and reduces transmission in a murine model. The vaccine is based on a viral-vectored vaccine platform, comprising a highly-attenuated vaccinia virus strain, LC16m8Δ (m8Δ), a genetically stable variant of a licensed and highly effective Japanese smallpox vaccine LC16m8, and an adeno-associated virus (AAV), a viral vector for human gene therapy. The genes encoding P. falciparum circumsporozoite protein (PfCSP) and the ookinete protein P25 (Pfs25) are expressed as a Pfs25–PfCSP fusion protein, and the heterologous m8Δ-prime/AAV-boost immunization regimen in mice provided both 100% protection against PfCSP-transgenic P. berghei sporozoites and up to 100% transmission blocking efficacy, as determined by a direct membrane feeding assay using parasites from P. falciparum-positive, naturally-infected donors from endemic settings. Remarkably, the persistence of vaccine-induced immune responses were over 7 months and additionally provided complete protection against repeated parasite challenge in a murine model. We propose that application of the m8Δ/AAV malaria multistage vaccine platform has the potential to contribute to the landmark goals of the malaria vaccine technology roadmap, to achieve life-long sterile protection and high-level transmission blocking efficacy.

Assessment of experimental malaria vaccine induced protection in pre-exposed populations

Efforts to control and further reduce morbidity and mortality caused by Plasmodium falciparum infections in all age groups will be substantially strengthened by development of efficacious malaria vaccines in malaria pre-exposed populations. 1 Moorthy VS Newman RD Okwo-Bele J-M Malaria vaccine technology roadmap. Lancet. 2013; 382: 1700-1701 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar Vaccine development against parasitic diseases represents a formidable challenge given the complexity of parasite life cycles and the intricate human host–parasite interactions. How to robustly assess vaccine-induced protection during clinical development is one of the key determinants driving successful vaccine development programmes. In the field of P falciparum malaria vaccine development, the availability of controlled human malaria infection (CHMI) model has helped to systematically select vaccine candidates, including the advanced subunit vaccines RTS,S 2 Sauerwein RW Roestenberg M Moorthy VS Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat Rev Immunol. 2011; 11: 57-64 Crossref PubMed Scopus (193) Google Scholar (now recommended by WHO), R21, 3 Datoo MS Natama MH Somé A et al. Efficacy of a low-dose candidate malaria vaccine, R21 in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: a randomised controlled trial. Lancet. 2021; 397: 1809-1818 Summary Full Text Full Text PDF PubMed Scopus (43) Google Scholar and the whole, live organism-based vaccine, PfSPZ Vaccine, 4 Seder RA Chang L-J Enama ME et al. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science. 2013; 341: 1359-1365 Crossref PubMed Scopus (507) Google Scholar for further clinical development. The PfSPZ Vaccine contains irradiation-attenuated, purified, vialed, cryopreserved sporozoites of P falciparum (strain NF54) and numerous studies have shown the vaccine to be safe and tolerable in east and west African volunteers in a broad range of age groups. 5 Jongo SA Urbano V Church LWP et al. Immunogenicity and protective efficacy of radiation-attenuated and chemo-attenuated PfSPZ Vaccines in Equatoguinean adults. Am J Trop Med Hyg. 2021; 104: 283-293 Crossref PubMed Google Scholar , 6 Jongo SA Church LWP Mtoro AT et al. Safety and differential antibody and t-cell responses to the Plasmodium falciparum sporozoite malaria vaccine, PfSPZ Vaccine, by age in Tanzanian adults, adolescents, children, and infants. Am J Trop Med Hyg. 2019; 100: 1433-1444 Crossref PubMed Scopus (29) Google Scholar Safety and efficacy of a three-dose regimen of Plasmodium falciparum sporozoite vaccine in adults during an intense malaria transmission season in Mali: a randomised, controlled phase 1 trialA three-dose regimen of PfSPZ Vaccine was safe, well tolerated, and conferred 51% vaccine efficacy against intense natural P falciparum transmission, similar to 52% vaccine efficacy reported for a five-dose regimen in a previous trial. Full-Text PDF

RTS,S: Toward a first landmark on the Malaria Vaccine Technology Roadmap

The Malaria Vaccine Technology Roadmap calls for a 2015 landmark goal of a first-generation malaria vaccine that has protective efficacy against severe disease and death, lasting longer than one year. This review focuses on product development efforts over the last five years of RTS,S, a pre-erythrocytic, recombinant subunit, adjuvanted, candidate malaria vaccine designed with this goal of a first-generation malaria vaccine in mind. RTS,S recently completed a successful pivotal Phase III safety, efficacy and immunogenicity study. Although vaccine efficacy was found to be modest, a substantial number of cases of clinical malaria were averted over a 3–4 years period, particularly in settings of significant disease burden. European regulators have subsequently adopted a positive opinion under the Article 58 procedure for an indication of active immunization of children aged 6 weeks up to 17 months against malaria caused by Plasmodium falciparum and against hepatitis B. Further evaluations of the benefit, risk, feasibility and cost-effectiveness of RTS,S are now anticipated through policy and financing reviews at the global and national levels.

Development of an in vitro Plasmodium parasite killing assay for the evaluation of cell-mediated immune responses following vaccination with pre-erythrocytic malaria vaccine candidates

Background Vaccination against liver stage malaria antigens can induce T cell-mediated immunity to the disease [1]. A viral vector vaccination regime undergoing Phase 2b clinical testing uses chimpanzee adenovirus 63 (ChAd63) and Modified Vaccinia virus Ankara (MVA) encoding liver stage antigen Thrombospondin-Related Adhesion Protein (TRAP) fused to a malaria multi-epitope string (ME). This regime induces high frequencies of antigen-specific T cells, providing 21% sterile protection and a delay to patent parasitaemia in a further 36% of vaccinees, following controlled human Plasmodium falciparum malaria infection (CHMI). Monofunctional IFNg-producing CD8 T cells correlate with vaccine-induced protection but the associated protective mechanisms remain unidentified [2]. Developing standardized immunological and functional assays is a research-specific aim of the WHO’s Malaria Vaccine Technology Roadmap, with emphasis on novel immunoassays for investigation of cellular products reflecting cellmediated malaria immunity [3]. Development of an in vitro parasite killing assay is underway, which quantifies cell-mediated killing of Plasmodium-infected human hepatocytes and investigates the underlying functional mechanisms. Additionally, the assay aims to compliment in vivo CHMI studies.

Implications of the licensure of a partially efficacious malaria vaccine on evaluating second-generation vaccines

BackgroundMalaria is a leading cause of morbidity and mortality, with approximately 225 million clinical episodes and >1.2 million deaths annually attributed to malaria. Development of a highly efficacious malaria vaccine will offer unparalleled possibilities for disease prevention and remains a key priority for long-term malaria control and elimination.DiscussionThe Malaria Vaccine Technology Roadmap’s goal is to 'develop and license a first-generation malaria vaccine that has protective efficacy of more than 50%’. To date, malaria vaccine candidates have only been shown to be partially efficacious (approximately 30% to 60%). However, licensure of a partially effective vaccine will create a number of challenges for the development and progression of new, potentially more efficacious, malaria vaccines in the future. In this opinion piece we discuss the methodological, logistical and ethical issues that may impact on the feasibility and implementation of superiority, non-inferiority and equivalence trials to assess second generation malaria vaccines in the advent of the licensure of a partially efficacious malaria vaccine.ConclusionsSelecting which new malaria vaccines go forward, and defining appropriate methodology for assessment in logistically challenging clinical trials, is crucial. It is imperative that the scientific community considers all the issues and starts planning how second-generation malaria vaccines will advance in the advent of licensure of a partially effective vaccine.

MALVAC 2012 scientific forum: accelerating development of second-generation malaria vaccines

The World Health Organization (WHO) convened a malaria vaccines committee (MALVAC) scientific forum from 20 to 21 February 2012 in Geneva, Switzerland, to review the global malaria vaccine portfolio, to gain consensus on approaches to accelerate second-generation malaria vaccine development, and to discuss the need to update the vision and strategic goal of the Malaria Vaccine Technology Roadmap. This article summarizes the forum, which included reviews of leading Plasmodium falciparum vaccine candidates for pre-erythrocytic vaccines, blood-stage vaccines, and transmission-blocking vaccines. Other major topics included vaccine candidates against Plasmodium vivax, clinical trial site capacity development in Africa, trial design considerations for a second-generation malaria vaccine, adjuvant selection, and regulatory oversight functions including vaccine licensure.

Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial

The RTS,S/AS01(E) 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/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) 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/AS01(E) 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. 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 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/AS01(E) 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). 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. Program for Appropriate Technology in Health Malaria Vaccine Initiative; GlaxoSmithKline Biologicals.

Clinical trials to estimate the efficacy of preventive interventions against malaria in paediatric populations: a methodological review

BackgroundRecent years have seen publication of a considerable number of clinical trials of preventive interventions against clinical malaria in children. There has been variability in the specification of end-points, case definitions, analysis methods and reporting and the relative lack of standardization complicates the ability to make comparative evaluations between trials.MethodsTo prepare for a WHO consultation on design issues in malaria vaccine trials, controlled trials of preventive interventions against malaria in children in endemic countries were identified in which clinical malaria, or death, had been one of the main end-points. Trials were included that evaluated the impact of vaccines, insecticide-treated bed nets (ITN), intermittent presumptive or preventive therapy in infants (IPTi) or, in one instance, vitamin A supplementation. Methods that had been used in these trials were summarized and compared in order to identify issues that were directly relevant to the design of malaria vaccine trials.Results29 controlled trials of preventive malaria interventions were identified, of which eight were vaccine trials. Vaccine trials that were designed to detect an effect on clinical malaria all reported the incidence rate of first episodes of clinical malaria as their primary endpoint. Only one trial of a preventive intervention (of ITN) was identified that was designed to detect an effect on severe malaria. A group of larger trials were designed to detect an effect of impregnated bed nets or curtains on all-cause mortality as the primary end-point. Key methodological and reporting differences between trials are noted in the text. Two issues have been identified that are of some concern. Firstly, the choice of primary endpoint is not stated in the reports of a number of the trials and, secondly, the relationship between pre-specified analysis plans and trial reports is rarely made clear.ConclusionThis article reports an investigation into the ways in which trial design and reporting could be improved and standardized to enable comparative evaluation of the relative merits of malaria control measures, and specifically with respect to the design of malaria vaccine trials. The need for standardization of clinical trial design, conduct, analysis and reporting has been also affirmed as a priority area by the Malaria Vaccine Technology Roadmap.

Malaria vaccines: immunity, models and monoclonal antibodies

Although experts in the field have agreed on the malaria vaccine technology roadmap that should be followed (http://www.malariavaccineroadmap.net/), the path towards an effective malaria vaccine remains littered with intellectual and practical pot-holes. The animal models that are currently available are problematic, and current understanding of the exact mechanisms and targets of protective immune responses is incomplete. However, recent technological advances might help overcome some of these hurdles.