- Disease Burden & Status of Malaria Control
- Background to RTS,S/AS01 vaccine candidate
- Other Approaches
- Second generation malaria vaccines
- Useful Links
International efforts to combat malaria have led to a scaling-up of the key existing malaria control measures over recent years.
The combination of WHO recommended tools and methods to combat malaria now includes long-lasting insecticidal nets (LLIN), access to artemisinin-based combination therapy (ACT) and parasitological diagnosis, supported in specific settings by indoor residual spraying of insecticide (IRS) and intermittent preventive treatment in pregnancy and infants (IPT).
For regularly updated information on malaria disease burden and the status of malaria control, see WHO's World Malaria Reports.
The agents of human malaria are four species of Plasmodium protozoa: P. falciparum, P. vivax, P. malariae and P. ovale. All are transmitted by Anopheles mosquitoes. There is increasing recognition in south-east Asia of zoonotic transmission of the simian parasite P. knowlesi in specific areas. P. falciparum causes the greatest number of deaths, whereas P. vivax has the greatest geographic distribution. All strains of Plasmodium have a complex life cycle that begins when a female Anopheline mosquito injects sporozoites into the human host when taking a blood meal. Within 2 hours sporozoites migrate to the liver via the bloodstream and invade hepatocytes. Sporozoites mature in the liver where they give rise to tens of thousands of merozoites over a period of 6–16 days. Merozoites enter into the bloodstream and invade erythrocytes where they multiply and mature over a period of 48–72 hours through ring stages, trophozoites to form schizonts which consist of many newly formed merozoites. Infected red blood cells (RBC) then lyse and liberate the merozoites which immediately proceed to invade new RBCs over a few seconds to repeat the asexual cycle. The classical signs of malaria, acute febrile episodes and rigors that occur every 48 to 72 hours, coinciding with the synchronized lysis of infected RBCs releasing merozoites. Some of the merozoites differentiate into sexual-stage gametocytes. If a male and female gametocyte are taken up by the same anopheline mosquito during a blood feed, the male can fertilise the female leading to development of mosquito stages which culminate in the development of new sporozoites in the salivary glands, thus completing the cycle.
Some new refinements to this traditional life cycle have been elucidated with several studies detailing the skin stage of infection and showing that injected sporozoites migrate within the skin for up to 2 hours, and that some sporozoites migrate actively or passively as components within antigen-presenting cells to regional lymph nodes. In a P. yoelii rodent model further detail on the transition between the liver and blood stages has been discovered (of unproven relevance to human malaria). Small packets of 100-200 merozoites are released from the liver as merosomes surrounded by host cell membrane and thus are protected from the action of liver phagocytes. These merosomes lodge in the lung where merozoites enter into the blood stream. It is also now known that certain schizonts contain only parasites which are committed to sexual stage differentiation.
The complete nucleotide sequences of both the P. falciparum parasite and of the Anopheles gambiae vector have been determined.
The major malaria vaccine funding agencies include USAID, NIAID and the PATH Malaria Vaccine Initiative (MVI, a program of PATH in the USA), the Wellcome Trust in the UK and the European Union – either directly, through the European and Developing Countries Clinical Trials Partnership (EDCTP) or through the European Vaccine Initiative (EVI). MVI is funded predominantly by the Bill & Melinda Gates Foundation, which also provides some direct malaria vaccine related funding. The Gates Foundation also funded the Malaria Clinical Trials Alliance which has provided substantial support to strengthen malaria drug and vaccine field trial sites. The African Malaria Network Trust (AMANET) was established to build African capacity to plan and coordinate malaria vaccine trials in Africa.
Several lines of evidence suggest that a prophylactic malaria vaccine for humans is feasible. Firstly, immunization with irradiated sporozoites was shown to confer about 90% protection against experimental infection following laboratory-bred, sporozoite-infected mosquito bites in naïve human volunteers, albeit with small numbers of volunteers. Secondly, naturally acquired immunity progressively builds up during the first two decades of life in people living in malaria-endemic countries, firstly to mortality related to malaria, then to severe disease and then to uncomplicated morbid episodes. Naturally acquired immunity does not confer sterile protection, such that immune individuals will tend to harbour asymptomatic blood stage parasites. This immunity appears to be linked to antigenic stimulation and is likely to act in large part by prevention of sequestration of parasites to vascular endothelium. Whilst waning does occur when exposure ceases, the precise nature of this waning has not been well documented. Understanding of the molecular basis of naturally acquired immunity is still in its relatively early stages. Thirdly, protection has been elicited by passive transfer of hyperimmune immunoglobulins from malaria-immune adults into malaria-naïve human volunteers.
Key obstacles to the development of a vaccine include the lack of immune correlates of protection, the lack of predictive animal models, in vitro immunoassays or functional assays, the antigenic diversity of the parasite and the stage-specificity of many induced immune responses. In addition there are major economic hurdles related to the lack of effective markets. Much work has been done to determine which protective antigens or epitopes should be used in the construction of recombinant or synthetic malaria vaccines. The Plasmodium genome is A-T rich, unlike most of the microbial organisms or animal cells used to express recombinant antigens, and it also shows quite different codon usage. Enhanced expression of recombinant Plasmodium antigens therefore requires specific techniques such as codon harmonization. Many of the protective immune responses are targeted against conformation-dependent epitopes and so correct conformational expression is important, another challenge for many plasmodial proteins.
The traditional approach to develop malaria vaccines has been the targeting of the different stages of parasite development (pre-erythrocytic, asexual and sexual stages).
Pre-erythrocytic vaccine strategies aim to generate an antibody response that will neutralize sporozoites and prevent them from invading the hepatocyte, and/or to elicit a cell-mediated immune response that will inhibit intra-hepatic parasites. This type of vaccine would be ideal for travelers because it would prevent the advent of clinical disease if completely efficacious. A partially efficacious pre-erythrocytic vaccine would be expected to reduce the incidence of new blood stage infections. This in itself may reduce the incidence of morbid episodes.
Asexual blood-stage (erythrocytic) vaccine strategies aim to elicit antibodies that will inactivate merozoites and/or target malarial antigens expressed on the RBC surface, thus inducing antibody-dependent cellular cytotoxicity and complement lysis; they also are intended to elicit T-cell responses that will inhibit the development of the parasite in RBCs. This type of vaccine would mostly serve as a disease-reduction vaccine in endemic countries by decreasing the exponential multiplication of merozoites.
Vaccines targeting the sexual stage of the parasite or mosquito stages do not aim to prevent illness or infection in the vaccinated individual, but to prevent or decrease transmission of the parasite to new hosts. Ultimately it is the indirect effect of vaccination on transmission which may have the greatest public health benefit particularly in the context of elimination planning. Pre-erythrocytic and asexual stage vaccines may also have as yet poorly characterized indirect effects on transmission. Other novel approaches being currently taken include the development of combination multicomponent vaccines, irradiated and genetically attenuated sporozoite vaccine approaches, and an anti-parasite toxin vaccine. This type of potential anti-disease vaccine would target parasite toxins contributing to the disease, such as the glycosylphosphatidyl inositol (GPI) anchor.
The most advanced and well-documented pre-erythrocytic vaccine candidate is derived from the circumsporozoite protein (CSP) that is found at the surface of the sporozoite and of the infected hepatocyte. This candidate vaccine, RTS,S/AS01, developed by GSK with close collaboration of Walter Reed Army Institute of Research, comprises the antigenic C-terminus (amino acids 207–395) of the CSP from P. falciparum fused to the hepatitis B surface antigen and expressed in the form of virus-like particles in Saccharomyces cerevisiae. An initial Phase I clinical trial of RTS,S formulated with GSK AS02 adjuvant (containing MPL, QS21 and an oil-in-water emulsion) showed protection against malaria challenge in six out of seven volunteers. Subsequent Phase IIa studies showed an overall protective efficacy of 30-40% among over 100 vaccinees. Efficacy against deferred re-challenge appeared lower. Trials in Gambian adults, supported by the European Union, demonstrated a 30% protection against infection over 15 weeks; the results of this study appeared to indicate waning of efficacy after 9 weeks. Volunteers who received a fourth dose of the vaccine the following year, prior to the onset of the malaria season, again exhibited a 47% protection against infection over a 9-week follow-up period.
Paediatric clinical development in Africa has been sponsored by GSK in partnership with PATH Malaria Vaccine Initiative (MVI) with funding from the Bill & Melinda Gates Foundation to MVI. Field testing on 2022 children aged 1-4 years in Mozambique showed that efficacy of three doses of RTS,S/AS02 at reducing the rate of the first malaria clinical episode was about 30%, with a 37% decrease in blood parasitemia prevalence at six months, and a 57% overall decrease of severe disease incidence. This protection was sustained for 18 months. Longer-term follow-up is consistent with waning beyond 18 months though the low rates of disease in the older age groups make any such estimates imprecise. A study of RTS,S/AS01 (using liposomes rather than oil-in-water in the adjuvant preparation) in Kenya and Tanzania of over 800 infants aged 5-17 months showed efficacy of 55% against all episodes of clinical malaria over 8 months of follow-up. Again severe malaria efficacy looked promising with only 1 episode in the vaccine group and 8 in the controls. Long-term follow-up will be important in assessing the full significance of this study. The pivotal multi-country Phase 3 registration trial of RTS,S/AS01 started in May 2009 and includes sites in Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique and Tanzania. Data will be available to make decisions about possible policy recommendation in 2015, should the vaccine be registered and show appropriate safety, non-inferiority and efficacy. RTS,S is a potential product with a well developed path towards licensure and access.
Over 30 other malaria vaccine projects have reached the clinical evaluation stage. Readers are referred to the regularly updated WHO tables of malaria vaccine projects globally, which is the most comprehensive publicly available source of information for malaria vaccine activity at the advanced pre-clinical and clinical stages.
WHO launched the malaria vaccine technology roadmap in 2006. This was an extensive consultative process involving many stakeholders. The roadmap has a landmark goal of a vaccine with 50% efficacy against severe disease and death to be developed by 2015. RTS,S/AS01 may achieve this goal. The longer-term community goal is for a vaccine with 80% efficacy against clinical malaria and a duration of protection of at least 4 years to be developed by 2025. This should be technically feasible but will depend upon mobilization of sufficient funding and information-sharing between stakeholders who work together in a collaborative framework to avoid unnecessary overlaps and increase efficiencies. Development of standardized assay and trial read-outs is also highly desirable to achieve the 2025 goal. These will enable comparative evaluation and increase the quality of data for decision-making in vaccine development. In order for the 2025 vaccine to contribute to malaria elimination and eradication efforts its impact on malaria transmission will be a key performance metric. Clinical and regulatory strategies for transmission-reducing malaria vaccines require establishment as a priority.