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Field trials of malaria vaccines.

Malaria due to Plasmodium falciparum is probably the most important infectious disease in the tropical world. About 2000 million people live in areas exposed to malaria and 300 million individuals are infected every year. In Africa south of the Sahara alone, over 1 million children die annually as a result of malaria. It is a difficult parasitic disease both to diagnose and control. It does not provide sterile immunity even after long exposure periods. However, acquisition of partial immunity allows over 60 per cent of individuals with long exposure to carry the parasite in their blood without symptoms, posing difficulties for case definition, malaria attributable morbidity and deaths. Further, it is extremely difficult to establish the extent to which malaria has influence over the adverse outcome of other infectious disease like measles and malnutrition. The complex life cycle of the parasite involving human and vector mosquitos as well as its allelic diversity and antigenic variations makes the development and implementation of effective malaria control intervention problematic. It is now becoming evident that multi-intervention approach may be the most appropriate way of combating malaria in view of the increasing resistance of the parasite to antimalarial drugs as well as vector mosquitoes to insecticides. Malaria vaccines will therefore play a major role in future malaria interventions. New malaria vaccine candidates will require testing in malaria endemic countries. Sufficient sites for testing potential malaria vaccines must be prepared. In this paper we discuss the necessary preparations required for field testing of malaria vaccines in tropical countries.

Animals↗

Progress with new malaria vaccines.

Malaria is a parasitic disease of major global health significance that causes an estimated 2.7 million deaths each year. In this review we describe the burden of malaria and discuss the complicated life cycle of Plasmodium falciparum, the parasite responsible for most of the deaths from the disease, before reviewing the evidence that suggests that a malaria vaccine is an attainable goal. Significant advances have recently been made in vaccine science, and we review new vaccine technologies and the evaluation of candidate malaria vaccines in human and animal studies worldwide. Finally, we discuss the prospects for a malaria vaccine and the need for iterative vaccine development as well as potential hurdles to be overcome.

Animals↗

Genetically modified Plasmodium parasites as a protective experimental malaria vaccine.

Malaria is a mosquito-borne disease that is transmitted by inoculation of the Plasmodium parasite sporozoite stage. Sporozoites invade hepatocytes, transform into liver stages, and subsequent liver-stage development ultimately results in release of pathogenic merozoites. Liver stages of the parasite are a prime target for malaria vaccines because they can be completely eliminated by sterilizing immune responses, thereby preventing malarial infection. Using expression profiling, we previously identified genes that are only expressed in the pre-erythrocytic stages of the parasite. Here, we show by reverse genetics that one identified gene, UIS3 (upregulated in infective sporozoites gene 3), is essential for early liver-stage development. uis3-deficient sporozoites infect hepatocytes but are unable to establish blood-stage infections in vivo, and thus do not lead to disease. Immunization with uis3-deficient sporozoites confers complete protection against infectious sporozoite challenge in a rodent malaria model. This protection is sustained and stage specific. Our findings demonstrate that a safe and effective, genetically attenuated whole-organism malaria vaccine is possible.

Animals↗

Malaria vaccines.

Malaria kills one child in Africa every 30 s. After summarising the burden of malaria, the life-cycle of this parasite in humans and female Anopheles mosquitoes is outlined. Important differences between natural immunity and that induced by current candidate vaccines are discussed. In the main part of the review, the recent rapid expansion in evaluation of candidate malaria vaccines in clinical trials across the world is discussed. Subunit vaccine technologies are progressing rapidly with new delivery systems, vectors and antigens under evaluation as well as new polyepitope approaches. Combination vaccination regimens, improved adjuvants and genetic engineering of antigens are all improving the immunogenicity of candidate vaccines. We also discuss particular difficulties in vaccination against malaria, the conduct of field trials of malaria vaccines in non-industrialised countries and the need for even greater co-operation between researchers. Finally, the important concept of iterative vaccine development is raised and the prospects for effective malaria vaccination are discussed.

Animals↗

Malaria vaccines.

Malaria continues to be a major worldwide problem. Recent advances in our understanding of the parasite and the immune response to malarial infections has resulted in major advances in the progress toward an effective malaria vaccine. Owing to the complexity of the parasite's life cycle, an effective vaccine will most assuredly contain components selected to stimulate potent immune mechanisms directed at various points in the parasite's life cycle. Considering the increasing incidence of drug resistance, combined with the high case-fatality rate, most research efforts have focused on developing a vaccine against Plasmodium falciparum. A successful vaccine against P. falciparum would be a significant advance in medical science. One must not, however, forget the severe morbidity associated with the other three human malarial species. As information is gained in the effort against P. falciparum, it is rapidly incorporated into efforts against P. vivax, P. malariae, and P. ovale.

Animals↗

Prospects for a malaria vaccine.

Malaria infection is a worsening problem throughout the developing world where conventional methods of control and treatment are becoming ineffective. Recent discoveries using the tools of the new biology, monoclonal antibodies and gene cloning, have brought malaria vaccines to the brink of reality.

Animals↗

[Structural studies of malaria vaccine].

Malaria still remains a serious health problem in large areas of the world, and in this article, recent research progress mainly made by us toward malaria vaccine development has been reviewed. 1) Peptide vaccines (antigens) of immunodominant tetrapeptide repeats (NANP and NVDP) of the circumsporozoite surface protein of the malaria parasite, Plasmodium falciparum, were genetically produced in E. coli as a fusion protein with a part of human growth hormone, which has affected on the conformations and immunogenicities of the peptide vaccines. 2) Monoclonal antibodies against the peptide antigens were produced by fusion of mouse spleen cells with myeloma cells, and the F (ab's) obtained by partial digestion of the antibodies with papain were used for the measurement of the dissociation constants of the antigen-antibody complexes. The amino acid sequence of the Hv region in F(ab) domain was also deduced from its nucleotide sequence.

Amino Acid Sequence↗

Progress and challenges for malaria vaccines.

Malaria causes much physical and economic hardship in tropical regions, particularly in communities where medical care is rudimentary. Should a vaccine be developed, it is the residents of these areas that stand to benefit the most. But the vaccine, which has been promised to be 'just round the corner' for many years, remains elusive. It is important to ask why this is so, when effective vaccines exist for many other infectious diseases. What are the reasons for the slow rate of progress, and what has been learned from the first clinical trials of candidate malaria vaccines? What are the remaining challenges, and what strategies can be pursued to address them?

Animals↗

The main obstacle to a malaria vaccine: the malaria parasite.

The challenge to development of a malaria vaccine will be the variability of the sequences of target antigens. We discuss the variability in the T cell epitopes on the circumsporozoite protein of Plasmodium falciparum and the rapid selection of mutants after immunization with a protein from the asexual erythrocytic stage of P. knowlesi.

Animals↗

[Achievements and problems in the development of malaria vaccines].

Malaria continues as a public health problem in the world. The control strategy by insecticides against the vector arthropod and antimalaria drugs have not been enough to eradicate this illness, which is the cause of over a million deaths every year throughout the world. In the latest years the recombinant DNA technology and the synthesis of peptides for antimalaria vaccine elaboration has been used specially against Plasmodium falciparum, which is the most aggressive of the human species of Plasmodium. Encouraging results in this field have been obtained. Some molecules have been characterized and synthetized which are considered worthy vaccine candidates because of their suitable immunogenicity, safety and immunoprotective capacity. These molecules belong to sexual and merozoite phases of the parasite, meanwhile molecules isolated from the sporozoitic phase, such as circunsporozoitic protein, have posed the greatest problems for the vaccine development.

Amino Acid Sequence↗

Research toward malaria vaccines.

Malaria exacts a toll of disease to people in the Tropics that seems incomprehensible to those only familiar with medicine and human health in the developed world. The methods of molecular biology, immunology, and cell biology are now being used to develop an antimalarial vaccine. The Plasmodium parasites that cause malaria have many stages in their life cycle. Each stage is antigenically distinct and potentially could be interrupted by different vaccines. However, achieving complete protection by vaccination may require a better understanding of the complexities of B- and T-cell priming in natural infections and the development of an appropriate adjuvant for use in humans.

Antigens, Protozoan↗

Malaria vaccine development: recent progress towards a sporozoite vaccine.

Malaria affects the lives of hundreds of millions of people. Drug therapy is becoming less effective, a vaccine has yet to be developed, and one to two million children die annually as a result of malaria. In the last 10 years, however, there has been great progress towards a vaccine. A number of important antigens have been cloned, including the circumsporozoite (CS) protein which covers the sporozoite and which is a target for antibody and cytotoxic T lymphocytes. In laboratory models, successful vaccination has been achieved with some CS constructs. Although successful immunization with irradiated sporozoites has been achieved in the laboratory, the lack of immunity following natural exposure to sporozoites in endemic countries is puzzling. Parasite variation, host genetic factors and immunological tolerance may each contribute to this situation. Identification of other important antigens and a better understanding of host immune responses to sporozoite and liver stage antigens should be important steps towards rational vaccine design.

Antigens, Protozoan↗

[Malaria vaccine].

Malaria affects many millions throughout the world. Though the exact number of cases is unknown, experts agree that the total is enormous and that the disease is an important factor in keeping the Third World poor and deprived. Yet efforts to attack malaria by drugs and mosquito eradication may well be failing. Most efforts to develop a vaccine have been directed at those forms of the malarial parasite that linger in the blood. But the group at New York University led by Dr. Ruth Nussenzweig has been concentrating on parasites in the form called sporozoites, which are found in the salivary glands of infected mosquitoes.

Humans↗

[Research on malaria vaccine].

Malaria is an important public health problem in developing countries. The production of a good vaccine needs a better knowledge of different mechanisms which control the immune system. Results from donors show a higher frequency of antigens HLA: A2, B35, CW4, CW6, DRW52, DQW1 and DQW3. The lymphoproliferation in vitro of mononuclear cells, T cells and CD4+ and CD8+ subsets T cells with merozoite extracts is not so clear to establish a correlation between HLA phenotypes and T cells response.

Adult↗

Phase 1 evaluation of 3 highly immunogenic prime-boost regimens, including a 12-month reboosting vaccination, for malaria vaccination in Gambian men.

Successful vaccination against intracellular pathogens, including liver-stage Plasmodium falciparum, will require induction of strong antigen-specific T lymphocyte responses. The multiple epitope (ME)-thrombospondin-related adhesion protein (TRAP) construct includes CD8(+) and CD4(+) T cell epitopes from pre-erythrocytic P. falciparum antigens fused in-frame to the entire pre-erythrocytic antigen TRAP. Three carriers for this construct--plasmid DNA and 2 recombinant nonreplicating poxviruses (modified vaccinia virus Ankara [MVA] and fowlpox strain 9 [FP9])--were administered at 3-week intervals in a heterologous prime-boost combination to 29 Gambian men aged 18-45 years. Doses of DNA ME-TRAP, MVA ME-TRAP, and FP9 ME-TRAP were 2 mg and 1.5x10(8) and 1x10(8) plaque-forming units, respectively. DNA ME-TRAP was injected intramuscularly; MVA ME-TRAP and FP9 ME-TRAP were injected intradermally. There were no clinically relevant laboratory abnormalities and no severe or serious adverse events related to vaccination. DNA/MVA and FP9/MVA regimens were the most potent inducers of circulating effector T cells seen to date in sub-Saharan Africa. Twelve months after the final vaccination, a single booster vaccination expanded the effector T cell pool to a similar or higher magnitude than that after the primary vaccinations. These results highlight optimized combination regimens with general relevance to the development of vaccines targeting intracellular pathogens.

Adolescent↗

Current Status and Prospects of Malaria Vaccines.

Malaria is a parasitic disease caused by four Plasmodium species infecting humans, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. The parasite is transmitted by the Anopheles mosquitoes that flourish in warm climates. These vectors thus are present in many tourist areas of the world, including Africa, Asia, and South America. Known in China, as far back as 2700 BC, malaria was controlled by medicinal plants or drugs. This was until drug resistance occurred, beginning in Asia with chloroquine in the 1960s and spreading quickly all over the world. Today, the status of malaria drug resistance is critical and has lead to the appearance of virulent and deadly P. falciparum strains that are difficult to control. In addition, the number of cases of malaria has increased owing in part to an increase in the spread of malaria caused by another flying vector: the airplane. Airplanes can carry not only infected travelers, but also, sometimes, mosquitoes. As an example, more that 1000 cases of imported malaria were reported in 1992 in the United States, where malaria had previously been eradicated. The mosquito vector (personal communication, Centers for Disease Control, Atlanta, GA) still exists in the U.S., and recent acquisitions of malaria among persons living in New Jersey and Texas, who had no risk factors for malaria, underscores the potential for imported malaria to affect the nonimmune host population in any country in the world.

Journal Article↗

Vaccines for preventing malaria.

BACKGROUND: Despite continued efforts to control the disease, malaria remains a major health problem in many regions of the world, especially sub-Saharan Africa, and new ways to control or eradicate the disease are urgently needed. Two types of vaccine, SPf66 vaccine against the asexual stages, and NANP vaccines against the sporozoite stages of the Plasmodium parasite, have been tested in randomised clinical trials in endemic areas. OBJECTIVES: To assess the effects of malaria vaccines. SEARCH STRATEGY: The Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase and reference lists of articles were searched. Organisations and researchers in the field were contacted. SELECTION CRITERIA: Randomised trials comparing vaccines against Plasmodium falciparum, P. vivax, P. malariae or P. ovale, and placebo. DATA COLLECTION AND ANALYSIS: Two independent reviewers assessed trial quality and conducted data extraction. MAIN RESULTS: Thirteen efficacy trials involving about 7700 people were included. There were nine trials of the Spf66 vaccine and four trials of the NANP vaccines. There was large heterogeneity between trials when investigating the effect of SPf66 in reducing incidence of the first attack of P. falciparum malaria. When trials were subcategorised by location, there was no evidence for effect of SPf66 in reducing incidence of P. falciparum in four African trials conducted in children under 5 years of age (Peto odds ratio [OR] = 0.96, 95% confidence interval [CI] 0.81 to 1.14). In five trials outside Africa with participants aged 2 years to adult, there was a reduction in incidence by SPf66 vaccine (Peto OR = 0.77, 95% CI 0.67 to 0.88, fixed effects model). Significant heterogeneity remained between trials conducted outside Africa. Using a random effects model for these five trials, the OR was 0.74 (95% CI 0.54 to 1.01). In five trials, there was no evidence for effect of the SPf66 vaccine on the incidence of the first attack of P. vivax malaria (OR 1.01, 95% CI 0.87 to 1.17). Trials to date have not indicated any severe adverse effects of SPf66 vaccine. In three trials of NANP-based vaccines, there was no evidence for protection by these vaccines against P. falciparum malaria (OR 1.12, 95% CI 0.64 to 1.93). REVIEWER'S CONCLUSIONS: 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 may be justified. Trials to date have not been of sufficient size to evaluate the effect of malaria vaccines on mortality or on severe malaria requiring admission to hospital. There was not enough evidence to evaluate the use of NANP vaccines.

Adult↗

Modeling malaria vaccines. II: Population effects of stage-specific malaria vaccines dependent on natural boosting.

Population effects of malaria vaccination programs will depend on the stage specificity of the vaccine, its duration of effectiveness, whether it is responsive to natural boosting, the proportion vaccinated, and the preexisting endemic conditions. This paper develops models of infection-blocking (sporozoite), disease-modifying (merozoite), and transmission-blocking (gametic) vaccines. It explores numerically their different effects on prevalence of infection and disease when utilized in different types of immunization programs at various levels of coverage. Simulations show that possible qualitative consequences of malaria vaccination programs include decreased prevalence of infection and disease and decreased prevalence of infection without a corresponding decrease in prevalence of disease. Epidemics, either one-time or cyclical, could occur. These effects could be accompanied by changes in the age distribution of disease. Finally, vaccination could contribute to elimination of transmission. The duration of effectiveness of the malaria vaccine relative to the duration of natural immunity could have important consequences for the unvaccinated. The problem of predicting a threshold for elimination of transmission is discussed.

Animals↗