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Lancet (London, England) Dec 2023Malaria is resurging in many African and South American countries, exacerbated by COVID-19-related health service disruption. In 2021, there were an estimated 247... (Review)
Review
Malaria is resurging in many African and South American countries, exacerbated by COVID-19-related health service disruption. In 2021, there were an estimated 247 million malaria cases and 619 000 deaths in 84 endemic countries. Plasmodium falciparum strains partly resistant to artemisinins are entrenched in the Greater Mekong region and have emerged in Africa, while Anopheles mosquito vectors continue to evolve physiological and behavioural resistance to insecticides. Elimination of Plasmodium vivax malaria is hindered by impractical and potentially toxic antirelapse regimens. Parasitological diagnosis and treatment with oral or parenteral artemisinin-based therapy is the mainstay of patient management. Timely blood transfusion, renal replacement therapy, and restrictive fluid therapy can improve survival in severe malaria. Rigorous use of intermittent preventive treatment in pregnancy and infancy and seasonal chemoprevention, potentially combined with pre-erythrocytic vaccines endorsed by WHO in 2021 and 2023, can substantially reduce malaria morbidity. Improved surveillance, better access to effective treatment, more labour-efficient vector control, continued drug development, targeted mass drug administration, and sustained political commitment are required to achieve targets for malaria reduction by the end of this decade.
Topics: Pregnancy; Female; Animals; Humans; Antimalarials; Malaria; Malaria, Vivax; Plasmodium falciparum; Insecticides; Malaria, Falciparum; Drug Resistance
PubMed: 37924827
DOI: 10.1016/S0140-6736(23)01249-7 -
The Lancet. Infectious Diseases Aug 2023In October, 2021, WHO recommended that the RTS,S malaria vaccine, with its strong safety profile and high impact, be provided to children from age 5 months in regions... (Review)
Review
In October, 2021, WHO recommended that the RTS,S malaria vaccine, with its strong safety profile and high impact, be provided to children from age 5 months in regions with moderate to high Plasmodium falciparum malaria transmission. The evidence base included phase 3 trials in seven African countries and an ongoing malaria vaccine implementation programme (MVIP) in three African countries. We highlight problems with the MVIP mortality data, including potential confounding, inappropriate use of severe malaria as a surrogate marker, a statistically non-significant effect, and assessment after 2 years instead of the stipulated 4 years, which could have inflated the benefits and deflated the risks associated with the vaccine. We conclude that the claimed impact of the MVIP on mortality is not based on enough scientific evidence and that the MVIP findings do not rule out the possibility of increased mortality among vaccinated girls compared with vaccinated boys, as observed in the phase 3 studies. The MVIP should adhere fully to the planned analyses and the data should be made available for independent assessment. Roll-out of the vaccine elsewhere should include rigorous evaluation, especially of its safety.
Topics: Female; Humans; Infant; Male; Africa; Malaria; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; Child, Preschool
PubMed: 37086747
DOI: 10.1016/S1473-3099(23)00126-3 -
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 -
Virulence Dec 2023Infections with and cause over 600,000 deaths each year, concentrated in Africa and in young children, but much of the world's population remain at risk of infection.... (Review)
Review
Infections with and cause over 600,000 deaths each year, concentrated in Africa and in young children, but much of the world's population remain at risk of infection. In this article, we review the latest developments in the immunogenicity and pathogenesis of malaria, with a particular focus on , the leading malaria killer. Pathogenic factors include parasite-derived toxins and variant surface antigens on infected erythrocytes that mediate sequestration in the deep vasculature. Host response to parasite toxins and to variant antigens is an important determinant of disease severity. Understanding how parasites sequester, and how antibody to variant antigens could prevent sequestration, may lead to new approaches to treat and prevent disease. Difficulties in malaria diagnosis, drug resistance, and specific challenges of treating pose challenges to malaria elimination, but vaccines and other preventive strategies may offer improved disease control.
Topics: Child; Humans; Child, Preschool; Virulence; Malaria; Malaria, Falciparum; Plasmodium falciparum; Plasmodium vivax; Protozoan Proteins
PubMed: 36419237
DOI: 10.1080/21505594.2022.2150456 -
Science (New York, N.Y.) Dec 2023Last week, reflected on major achievements in science in 2023, from weight loss drugs and a malaria vaccine to exascale computing and advances in artificial...
Last week, reflected on major achievements in science in 2023, from weight loss drugs and a malaria vaccine to exascale computing and advances in artificial intelligence. These are all impressive developments and provide yet more testimony to the power of science to continually expand the quality of our lives while deepening our understanding of the world. Even so, it's hard to end the year without some worries about 2024. Wars in Ukraine and Gaza will grind on in the new year, and the United States is headed toward perhaps the most consequential and divisive presidential election in more than 160 years. These events-and similar ones around the world-will challenge the cohesiveness and determination of the scientific community as never before.
PubMed: 38127749
DOI: 10.1126/science.adn5404 -
Nature Immunology Sep 2023Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where...
Malaria is caused by Plasmodium species transmitted by Anopheles mosquitoes. Following a mosquito bite, Plasmodium sporozoites migrate from skin to liver, where extensive replication occurs, emerging later as merozoites that can infect red blood cells and cause symptoms of disease. As liver tissue-resident memory T cells (Trm cells) have recently been shown to control liver-stage infections, we embarked on a messenger RNA (mRNA)-based vaccine strategy to induce liver Trm cells to prevent malaria. Although a standard mRNA vaccine was unable to generate liver Trm or protect against challenge with Plasmodium berghei sporozoites in mice, addition of an agonist that recruits T cell help from type I natural killer T cells under mRNA-vaccination conditions resulted in significant generation of liver Trm cells and effective protection. Moreover, whereas previous exposure of mice to blood-stage infection impaired traditional vaccines based on attenuated sporozoites, mRNA vaccination was unaffected, underlining the potential for such a rational mRNA-based strategy in malaria-endemic regions.
Topics: Animals; Mice; Memory T Cells; Malaria; Liver; Malaria Vaccines; Plasmodium berghei; CD8-Positive T-Lymphocytes
PubMed: 37474653
DOI: 10.1038/s41590-023-01562-6 -
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 -
The Medical Clinics of North America Nov 2023Global immunization programs have saved tens of millions of lives over the last 2 decades. Now, the recent successes of COVID-19 vaccines having saved more than 3... (Review)
Review
Global immunization programs have saved tens of millions of lives over the last 2 decades. Now, the recent successes of COVID-19 vaccines having saved more than 3 million lives in North America during the pandemic may open the door to accelerate technologies for other emerging infection vaccines. New vaccines for respiratory syncytial virus, norovirus, influenza, herpes simplex virus, shingles, dengue fever, enteric bacterial infections, malaria, and Chagas disease are advancing through clinical development and could become ready for delivery over the next 5 years. The successful delivery of these new vaccines may require expanded advocacy and communications efforts.
Topics: Humans; Vaccination; COVID-19 Vaccines; Vaccine-Preventable Diseases; Vaccination Hesitancy; COVID-19; Vaccines; Influenza Vaccines
PubMed: 37806729
DOI: 10.1016/j.mcna.2023.05.012 -
Pathogens (Basel, Switzerland) Aug 2023Recent advances in malaria genetics and genomics have transformed many aspects of malaria research in areas of molecular evolution, epidemiology, transmission,... (Review)
Review
Recent advances in malaria genetics and genomics have transformed many aspects of malaria research in areas of molecular evolution, epidemiology, transmission, host-parasite interaction, drug resistance, pathogenicity, and vaccine development. Here, in addition to introducing some background information on malaria parasite biology, parasite genetics/genomics, and genotyping methods, we discuss some applications of genetic and genomic approaches in vaccine development and in studying interactions with microbiota. Genetic and genomic data can be used to search for novel vaccine targets, design an effective vaccine strategy, identify protective antigens in a whole-organism vaccine, and evaluate the efficacy of a vaccine. Microbiota has been shown to influence disease outcomes and vaccine efficacy; studying the effects of microbiota in pathogenicity and immunity may provide information for disease control. Malaria genetics and genomics will continue to contribute greatly to many fields of malaria research.
PubMed: 37624021
DOI: 10.3390/pathogens12081061