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The Journal of Clinical Investigation Jan 2022
Review
Topics: Humans; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum
PubMed: 34981788
DOI: 10.1172/JCI156588 -
BioDrugs : Clinical Immunotherapeutics,... Nov 2023Malaria is a mosquito-borne disease caused by protozoan parasites of the genus Plasmodium. Despite significant declines in malaria-attributable morbidity and mortality... (Review)
Review
Malaria is a mosquito-borne disease caused by protozoan parasites of the genus Plasmodium. Despite significant declines in malaria-attributable morbidity and mortality over the last two decades, it remains a major public health burden in many countries. This underscores the critical need for improved strategies to prevent, treat and control malaria if we are to ultimately progress towards the eradication of this disease. Ideally, this will include the development and deployment of a highly effective malaria vaccine that is able to induce long-lasting protective immunity. There are many malaria vaccine candidates in development, with more than a dozen of these in clinical development. RTS,S/AS01 (also known as Mosquirix) is the most advanced malaria vaccine and was shown to have modest efficacy against clinical malaria in phase III trials in 5- to 17-month-old infants. Following pilot implementation trials, the World Health Organisation has recommended it for use in Africa in young children who are most at risk of infection with P. falciparum, the deadliest of the human malaria parasites. It is well recognised that more effective malaria vaccines are needed. In this review, we discuss malaria vaccine candidates that have progressed into clinical evaluation and highlight the most advanced candidates: Sanaria's irradiated sporozoite vaccine (PfSPZ Vaccine), the chemoattenuated sporozoite vaccine (PfSPZ-CVac), RTS,S/AS01 and the novel malaria vaccine candidate, R21, which displayed promising, high-level efficacy in a recent small phase IIb trial in Africa.
Topics: Infant; Animals; Child; Humans; Child, Preschool; Malaria Vaccines; Plasmodium falciparum; Malaria, Falciparum; Malaria; Sporozoites
PubMed: 37728713
DOI: 10.1007/s40259-023-00623-4 -
The New England Journal of Medicine Nov 2015
Topics: Female; Humans; Malaria Vaccines; Malaria, Falciparum; Male; Plasmodium falciparum
PubMed: 26488465
DOI: 10.1056/NEJMe1511955 -
Human Vaccines & Immunotherapeutics Nov 2021Malaria vaccines hold significant promise for life-saving benefit, especially to children who bear the major burden of malaria mortality. The RTS,S/AS01 malaria vaccine...
Malaria vaccines hold significant promise for life-saving benefit, especially to children who bear the major burden of malaria mortality. The RTS,S/AS01 malaria vaccine provides moderate efficacy and is being tested in implementation studies. In parallel, multiple strategies are being advanced to test next-generation malaria vaccines, including novel approaches that build on principles learned from RTS,S development, vaccination with radiation-attenuated sporozoites, and development of monoclonal antibodies targeting immunogenic peptides. Novel vaccine delivery approaches are also being advanced, including self-amplifying RNA vaccine delivery, self-assembling protein nanoparticle methods, circumsporozoite protein-based approaches, and whole organism vaccination. Techniques employed for COVID-19 vaccine development should also be considered for malaria vaccination, including sustained release polymer nanoparticle hydrogel vaccination and charge-altering releasable transporters. As vaccine science advances and new approaches optimize knowledge gained, highly effective malaria vaccines that provide sustained protection are within reach.
Topics: COVID-19; COVID-19 Vaccines; Child; Humans; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; SARS-CoV-2; Vaccination; Vaccine Development; Vaccines, Synthetic; mRNA Vaccines
PubMed: 34347570
DOI: 10.1080/21645515.2021.1947762 -
Current Opinion in Microbiology Dec 2022The complex Plasmodium life cycle offers different vaccine approaches with distinct parasitological and clinical effects. The approaches and their rationales were... (Review)
Review
The complex Plasmodium life cycle offers different vaccine approaches with distinct parasitological and clinical effects. The approaches and their rationales were established decades ago: vaccines targeting pre-erythrocytic (sporozoite and liver-stage) parasites prevent infection, those to blood-stage parasites reduce disease, and those to sexual-stage parasites or mosquito vector reduce transmission and eliminate malaria through herd immunity. The pre-erythrocytic RTS,S vaccine (Mosquirix, GlaskoSmithKline (GSK)), recommended by WHO in 2021, reduces clinical malaria in children. Knowledge of parasite biology, host-parasite interactions, and immune mechanisms is informing new concepts to improve on RTS,S and to target other parasite stages. This review emphasizes vaccine approaches and candidates currently in the clinic or likely to enter clinical testing soon.
Topics: Animals; Child; Humans; Malaria Vaccines; Sporozoites; Plasmodium; Malaria
PubMed: 36343566
DOI: 10.1016/j.mib.2022.102227 -
Lancet (London, England) Feb 2024Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites.
METHODS
We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5-36 months) were enrolled and randomly assigned (2:1) to receive 5 μg R21 plus 50 μg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on ClinicalTrials.gov, NCT04704830, and is ongoing.
FINDINGS
From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71-79; p<0·0001) at the seasonal sites and 68% (61-74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71-78; p<0·0001) at the seasonal sites and 67% (59-73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762-974) cases per 1000 children-years at seasonal sites and 296 (231-362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5-17 month age group compared with 18-36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73-84]; p<0·001) and standard (75% [65-83]; p<0·001) sites.
INTERPRETATION
R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa.
FUNDING
The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.
Topics: Child, Preschool; Female; Humans; Infant; Male; Antibodies, Viral; Burkina Faso; Double-Blind Method; Immunization; Malaria; Malaria Vaccines; Nanoparticles; Saponins
PubMed: 38310910
DOI: 10.1016/S0140-6736(23)02511-4 -
Clinical Infectious Diseases : An... Mar 2015Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an... (Review)
Review
Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease.
Topics: Antigens, Protozoan; Antimalarials; Biomedical Research; Female; Genetic Variation; Humans; Malaria; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; Pregnancy; Pregnancy Complications, Parasitic
PubMed: 25452593
DOI: 10.1093/cid/ciu954 -
F1000Research 2020Much of the gain in malaria control, in terms of regional achievements in restricting geographical spread and reducing malaria cases and deaths, can be attributed to... (Review)
Review
Much of the gain in malaria control, in terms of regional achievements in restricting geographical spread and reducing malaria cases and deaths, can be attributed to large-scale deployment of antimalarial drugs, insecticide-treated bed nets, and early diagnostics. However, despite impressive progress, control efforts have stalled because of logistics, unsustainable delivery, or short-term effectiveness of existing interventions or a combination of these reasons. A highly efficacious malaria vaccine as an additional tool would go a long way, but success in the development of this important intervention remains elusive. Moreover, most of the vaccine candidate antigens that were investigated in early-stage clinical trials, selected partly because of their immunogenicity and abundance during natural malaria infection, were polymorphic or structurally complex or both. Likewise, we have a limited understanding of immune mechanisms that confer protection. We reflect on some considerable technological and scientific progress that has been achieved and the lessons learned.
Topics: Antigens, Protozoan; Humans; Malaria; Malaria Vaccines
PubMed: 32399189
DOI: 10.12688/f1000research.22143.1 -
Medecine Tropicale Et Sante... Jun 2023Vaccination against malaria is an old dream that reemerged in 2015 with the European Medicines Agency's favourable opinion on a first antimalarial vaccine, RTS,S/ AS01....
Vaccination against malaria is an old dream that reemerged in 2015 with the European Medicines Agency's favourable opinion on a first antimalarial vaccine, RTS,S/ AS01. Six years later, the World Health Organization (WHO) is advising a wide deployment of this vaccine in sub-Saharan Africa and in regions with high and moderate transmission where circulates. This follows favourable results from the pilot programme in Ghana, Kenya and Malawi involving over 800,000 children since 2019. This article addresses the objectives and main vaccine candidates targeting the different stages of parasite development, highlighting the progress and limitations of these different approaches. The RTS,S saga has been a milestone in vaccine development, with a first-generation vaccine recommended by the WHO for use in children over 5 months of age in sub-Saharan Africa and other areas of moderate to high transmission of malaria, in combination with other prevention measures. Research efforts continue to better understand the correlates of protection. With advances in vaccine platforms, new multi-antigen, multi-stage, and even multi-species approaches might emerge and brighten the horizon for malaria control.
Topics: Child; Humans; Malaria Vaccines; Malaria; Malaria, Falciparum; Vaccination; Kenya
PubMed: 37525687
DOI: 10.48327/mtsi.v3i2.2023.325 -
Expert Review of Vaccines Feb 2021: The development of effective vaccines remains a major health priority to combat the global burden of malaria, a life-threatening disease caused by parasites.... (Review)
Review
: The development of effective vaccines remains a major health priority to combat the global burden of malaria, a life-threatening disease caused by parasites. Transmission-blocking vaccines (TBVs) elicit antibodies that neutralize the sexual stages of the parasite in blood meals ingested by the mosquito, interrupting parasite development in the vector host and preventing disease spread to other individuals.: The gametocyte surface antigens Pfs230, Pfs48/45, and Pfs47, the parasite ookinete surface protein Pfs25, and the male gametocyte specific protein PfHAP2 are leading TBV candidates, some of which are in clinical development. The recent expansion of methodology to study monoclonal antibodies isolated directly from humans and animal models, coupled with effective measures for parasite neutralization, has provided unprecedented insight into TBV efficacy and development.: Available structural and functional data on antigen-monoclonal antibody (Ag-mAb) complexes, as well as epitope classification studies, have identified neutralizing epitopes that may aid vaccine development and improve protection. Here, we review the clinical prospects of TBV candidates, progress in the development of novel vaccine strategies for TBVs, and the impact of structural vaccinology in TBV design.
Topics: Animals; Anopheles; Antibodies, Monoclonal; Antibodies, Protozoan; Antigens, Protozoan; Humans; Malaria Vaccines; Malaria, Falciparum; Mosquito Vectors; Plasmodium falciparum; Vaccinology
PubMed: 33430656
DOI: 10.1080/14760584.2021.1873135