Malaria vaccine

Considerations

Parasite diversity

Choosing to address the symptom or the source

• "Anti-parasitic immunity" addresses the source; it consists of an antibody response and a cell-mediated immune response. Ideally a vaccine would enable the development of anti-plasmodial antibodies in addition to generating an elevated cell-mediated response. Potential antigens against which a vaccine could be targeted will be discussed in greater depth later. Antibodies are part of the specific immune response. They exert their effect by activating the complement cascade, stimulating phagocytic cells into endocytosis through adhesion to an external surface of the antigenic substances, thus 'marking' it as offensive. Humoral or cell-mediated immunity consists of many interlinking mechanisms that essentially aim to prevent infection entering the body and then kill any micro-organisms or foreign particles that succeed in penetration. The cell-mediated component consists of many white blood cells that target foreign bodies by a variety of different mechanisms. In the case of malaria both systems would be targeted to attempt to increase the potential response generated, thus ensuring the maximum chance of preventing disease.
• "Anti-toxic immunity" addresses the symptoms; it refers to the suppression of the immune response associated with the production of factors that either induce symptoms or reduce the effect that any toxic by-products have on the development of disease. For example, it has been shown that Tumor necrosis factor-alpha has a central role in generating the symptoms experienced in severe P. falciparum malaria. Thus a therapeutic vaccine could target the production of TNF-a, preventing respiratory distress and cerebral symptoms. This approach has serious limitations as it would not reduce the parasitic load; rather it only reduces the associated pathology. As a result, there are substantial difficulties in evaluating efficacy in human trials.

Potential targets

• The initial stage in the life cycle, following inoculation, is a relatively short "pre-erythrocytic" or "hepatic" phase. A vaccine at this stage must have the ability to protect against sporozoites invading and possibly inhibiting the development of parasites in the hepatocytes. However, if any sporozoites evaded the immune system they would then have the potential to be symptomatic and cause the clinical disease.
• The second phase of the life cycle is the "erythrocytic" or blood phase. A vaccine here could prevent merozoite multiplication or the invasion of red blood cells. This approach is complicated by the lack of MHC molecule expression on the surface of erythrocytes. Instead, malarial antigens are expressed, and it is this towards which the antibodies could potentially be directed. Another approach would be to attempt to block the process of erythrocyte adherence to blood vessel walls. It is thought that this process is accountable for much of the clinical syndrome associated with malarial infection; therefore a vaccine given during this stage would be therapeutic and hence administered during clinical episodes to prevent further deterioration.
• The last phase of the life cycle that has the potential to be targeted by a vaccine is the "sexual stage". This would not give any protective benefits to the individual inoculated but would prevent further transmission of the parasite by preventing the gametocytes from producing multiple sporozoites in the gut wall of the mosquito. It therefore would be used as part of a policy directed at eliminating the parasite from areas of low prevalence or to prevent the development and spread of vaccine-resistant parasites. This type of transmission-blocking vaccine is potentially very important. The evolution of resistance in the malaria parasite occurs very quickly, potentially making any vaccine redundant within a few generations. This approach to the prevention of spread is therefore essential.
• Another approach is to target the protein kinases, which are present during the entire lifecycle of the malaria parasite. Research is underway on this, yet production of an actual vaccine targeting these protein kinases may still take a long time.
• Report of a new candidate of vaccine capable to neutralize all tested strains of Plasmodium falciparum, the most deadly form of the parasite causing malaria, was published in Nature Communications by a team of scientists from the University of Oxford in 2011. The viral vectored vaccine, targeting a full-length P. falciparum reticulocyte-binding protein homologue 5 was found to induce an antibody response in an animal model. The results of this new vaccine confirmed the utility of a key discovery reported from scientists at the Wellcome Trust Sanger Institute, published in Nature. The earlier publication reported P. falciparum relies on a red blood cell surface receptor, known as 'basigin', to invade the cells by binding a protein PfRH5 to the receptor. Unlike other antigens of the malaria parasite which are often genetically diverse, the PfRH5 antigen appears to have little genetic diversity. It was found to induce very low antibody response in people naturally exposed to the parasite. The high susceptibility of PfRH5 to the cross-strain neutralizing vaccine-induced antibody demonstrated a significant promise for preventing malaria in the long and often difficult road of vaccine development. According to Professor Adrian Hill, a Wellcome Trust Senior Investigator at the University of Oxford, the next step would be the safety tests of this vaccine. At the time it was projected that if these proved successful, the clinical trials in patients could begin within two to three years.
• PfEMP1, one of the proteins known as variant surface antigens produced by Plasmodium falciparum, was found to be a key target of the immune system's response against the parasite. Studies of blood samples from 296 mostly Kenyan children by researchers of Burnet Institute and their cooperators showed that antibodies against PfEMP1 provide protective immunity, while antibodies developed against other surface antigens do not. Their results demonstrated that PfEMP1 could be a target to develop an effective vaccine which will reduce risk of developing malaria.
• Plasmodium vivax is the common malaria species found in India, Southeast Asia and South America. It is able to stay dormant in the liver and reemerge years later to elicit new infections. Two key proteins involved in the invasion of the red blood cells by P. vivax are potential targets for drug or vaccine development. When the Duffy binding protein of P. vivax binds the Duffy antigen on the surface of RBC, process for the parasite to enter the RBC is initiated. Structures of the core region of DARC and the receptor binding pocket of DBP have been mapped by scientists at the Washington University in St. Louis. The researchers found that the binding is a two-step process which involves two copies of the parasite protein acting together like a pair of tongs which 'clamp two copies of DARC. Antibodies that interfere with the binding, by either targeting the key region of the DARC or the DBP will prevent the infection.
• Antibodies against the Schizont Egress Antigen-1 were found to disable the parasite ability to rupture from the infected red blood cells thus prevent it from continuing with its life cycle. Researchers from Rhode Island Hospital identified Plasmodium falciparum'' PfSEA-1, a 244 kd malaria antigen expressed in the schizont-infected RBCs. Mice vaccinated with the recombinant PfSEA-1 produced antibodies which interrupted the schizont rupture from the RBCs and decreased the parasite replication. The vaccine protected the mice from lethal challenge of the parasite. Tanzanian and Kenyan children who have antibodies to PfSEA-1 were found to have fewer parasites in their blood stream and milder case of malaria. By blocking the schizont outlet, the PfSEA-1 vaccine may work synergistically with vaccines targeting the other stages of the malaria life cycle such as hepatocyte and RBC invasion.

  Mix of antigenic components

Delivery system

Agents under development

• The CSP was a vaccine developed that initially appeared promising enough to undergo trials. It is also based on the circumsporozoite protein, but additionally has the recombinant 2-Leu-Arg protein covalently bound to a purified Pseudomonas aeruginosa toxin. However at an early stage a complete lack of protective immunity was demonstrated in those inoculated. The study group used in Kenya had an 82% incidence of parasitaemia whilst the control group only had an 89% incidence. The vaccine intended to cause an increased T-lymphocyte response in those exposed, this was also not observed.
• The NYVAC-Pf7 multi-stage vaccine attempted to use different technology, incorporating seven P.falciparum antigenic genes. These came from a variety of stages during the life cycle. CSP and sporozoite surface protein 2 were derived from the sporozoite phase. The liver stage antigen 1, three from the erythrocytic stage and one sexual stage antigen were included. This was first investigated using Rhesus monkeys and produced encouraging results: 4 out of the 7 antigens produced specific antibody responses. Later trials in humans, despite demonstrating cellular immune responses in over 90% of the subjects, had very poor antibody responses. Despite this following administration of the vaccine some candidates had complete protection when challenged with P.falciparum. This result has warranted ongoing trials.
• In 1995 a field trial involving 19-5.1 proved to be very successful. Out of 194 children vaccinated none developed symptomatic malaria in the 12-week follow up period and only 8 failed to have higher levels of antibody present. The vaccine consists of the schizont export protein and 19 repeats of the sporozoite surface protein . Limitations of the technology exist as it contains only 20% peptide and has low levels of immunogenicity. It also does not contain any immunodominant T-cell epitopes.

  Nanoparticle enhancement of RTS,S

PfSPZ vaccine

History

Irradiated mosquitoes