Malaria vaccine

A malaria vaccine is a vaccine that is used to prevent malaria. The only approved vaccine as of 2021 is RTS,S, known by the brand name Mosquirix. It requires four injections, and has a relatively low efficacy. Due to this low efficacy, the World Health Organization (WHO) does not recommend the routine use of the RTS,S vaccine in babies between 6 and 12 weeks of age.
Research continues with other malaria vaccines. The most effective malaria vaccine discovered so far is R21/Matrix-M, with 77% efficacy shown in initial trials, and significantly higher antibody levels than with the RTS,S vaccine. It is the first vaccine that meets the World Health Organization's goal of a malaria vaccine with at least 75% efficacy.
Approved vaccines.
RTS,S.
RTS,S (developed by PATH Malaria Vaccine Initiative (MVI) and GlaxoSmithKline (GSK) with support from the Bill and Melinda Gates Foundation) is the most recently developed recombinant vaccine. It consists of the "P. falciparum" circumsporozoite protein (CSP) from the pre-erythrocytic stage. The CSP antigen causes the production of antibodies capable of preventing the invasion of hepatocytes and additionally elicits a cellular response enabling the destruction of infected hepatocytes. The CSP vaccine presented problems in trials due to its poor immunogenicity. RTS,S attempted to avoid these by fusing the protein with a surface antigen from hepatitis B, hence creating a more potent and immunogenic vaccine. When tested in trials an emulsion of oil in water and the added adjuvants of monophosphoryl A and QS21 (SBAS2), the vaccine gave protective immunity to 7 out of 8 volunteers when challenged with "P. falciparum."
RTS,S/AS01 (commercial name Mosquirix), was engineered using genes from the outer protein of "P. falciparum" malaria parasite and a portion of a hepatitis B virus plus a chemical adjuvant to boost the immune response. Infection is prevented by inducing high antibody titers that block the parasite from infecting the liver. In November 2012 a Phase III trial of RTS,S found that it provided modest protection against both clinical and severe malaria in young infants.
, preliminary results of a phase III clinical trial indicated that RTS,S/AS01 reduced the number of cases among young children by almost 50 percent and among infants by around 25 percent. The study ended in 2014. The effects of a booster dose were positive, even though overall efficacy seem to wane with time. After four years reductions were 36 percent for children who received three shots and a booster dose. Missing the booster dose reduced the efficacy against severe malaria to a negligible effect. The vaccine was shown to be less effective for infants. Three doses of vaccine plus a booster reduced the risk of clinical episodes by 26 percent over three years, but offered no significant protection against severe malaria.
In a bid to accommodate a larger group and guarantee a sustained availability for the general public, GSK applied for a marketing license with the European Medicines Agency (EMA) in July 2014. GSK treated the project as a non-profit initiative, with most funding coming from the Gates Foundation, a major contributor to malaria eradication.
On 24 July 2015, Mosquirix received a positive opinion from the EMA on the proposal of the vaccine to be used to vaccinate children aged 6 weeks to 17 months outside the European Union. A pilot project for vaccination was launched on 23 April 2019 in Malawi, on 30 April 2019 in Ghana, and on 13 September 2019 in Kenya.
Agents under development.
A completely effective vaccine is not yet available for malaria, although several vaccines are under development. Multiple vaccine candidates targeting the blood-stage of the parasite's life cycle have been insufficient on their own. Several potential vaccines targeting the pre-erythrocytic stage are being developed, with RTS,S the only approved option so far.<ref name="doi10.1056/NEJMoa1208394"></ref>
R21/Matrix-M.
The most effective malaria vaccine discovered so far is R21/Matrix-M, with 77% efficacy shown in initial trials. It is the first vaccine that meets the World Health Organization's goal of a malaria vaccine with at least 75% efficacy. It was developed through a collaboration involving the University of Oxford, the Kenya Medical Research Institute, the London School of Hygiene & Tropical Medicine, Novavax, the Serum Institute of India, and the Institut de Recherche en Sciences de la Santé in Nanoro, Burkina Faso. The R21 vaccine uses a circumsporozoite protein (CSP) antigen, at a higher proportion than the RTS,S vaccine. It includes the Matrix-M adjuvant that is also utilized in the Novavax COVID-19 vaccine.
A Phase II trial was reported in April 2021, with a vaccine efficacy of 77% and antibody levels significantly higher than with the RTS,S vaccine. A Phase III trial is planned with 4,800 children across four African countries. If the vaccine is approved, over 200 million doses can be manufactured annually by the Serum Institute of India.
Nanoparticle enhancement of RTS,S.
In 2015, researchers used a repetitive antigen display technology to engineer a nanoparticle that displayed malaria specific B cell and T cell epitopes. The particle exhibited icosahedral symmetry and carried on its surface up to 60 copies of the RTS,S protein. The researchers claimed that the density of the protein was much higher than the 14% of the GSK vaccine.
PfSPZ vaccine.
The PfSPZ vaccine is a candidate malaria vaccine developed by Sanaria using radiation-attenuated sporozoites to elicit an immune response. Clinical trials have been promising, with trials taking place in Africa, Europe, and the US protecting over 80% of volunteers. It has been subject to some criticism regarding the ultimate feasibility of large-scale production and delivery in Africa, since it must be stored in liquid nitrogen.
The PfSPZ vaccine candidate was granted fast track designation by the U.S. Food and Drug Administration in September 2016.
In April 2019, a phase 3 trial in Bioko was announced, scheduled to start in early 2020.
saRNA vaccine against PMIF.
A patent was published in February 2021 for a Self-amplifying RNA (saRNA) vaccine that targets the protein PMIF, which is produced by the plasmodium parasite to inhibit the body's T-cell response. The vaccine has been tested in mice and is described as, "probably the highest level of protection that has been seen in a mouse model" according to Richard Bucala, co-inventor of the vaccine. There are plans for phase one tests in humans later in 2021.
Considerations.
The task of developing a preventive vaccine for malaria is a complex process. There are a number of considerations to be made concerning what strategy a potential vaccine should adopt.
Parasite diversity.
"P. falciparum" has demonstrated the capability, through the development of multiple drug-resistant parasites, for evolutionary change. The "Plasmodium" species has a very high rate of replication, much higher than that actually needed to ensure transmission in the parasite's life cycle. This enables pharmaceutical treatments that are effective at reducing the reproduction rate, but not halting it, to exert a high selection pressure, thus favoring the development of resistance. The process of evolutionary change is one of the key considerations necessary when considering potential vaccine candidates. The development of resistance could cause a significant reduction in efficacy of any potential vaccine thus rendering useless a carefully developed and effective treatment.
Choosing to address the symptom or the source.
The parasite induces two main response types from the human immune system. These are anti-parasitic immunity and anti-toxic immunity.
Taking this information into consideration an ideal vaccine candidate would attempt to generate a more substantial cell-mediated and antibody response on parasite presentation. This would have the benefit of increasing the rate of parasite clearance, thus reducing the experienced symptoms and providing a level of consistent future immunity against the parasite.
Potential targets.
By their very nature, protozoa are more complex organisms than bacteria and viruses, with more complicated structures and life cycles. This presents problems in vaccine development but also increases the number of potential targets for a vaccine. These have been summarised into the life cycle stage and the antibodies that could potentially elicit an immune response.
The epidemiology of malaria varies enormously across the globe, and has led to the belief that it may be necessary to adopt very different vaccine development strategies to target the different populations. A Type 1 vaccine is suggested for those exposed mostly to "P. falciparum" malaria in sub-Saharan Africa, with the primary objective to reduce the number of severe malaria cases and deaths in infants and children exposed to high transmission rates. The Type 2 vaccine could be thought of as a 'travellers' vaccine', aiming to prevent all cases of clinical symptoms in individuals with no previous exposure. This is another major public health problem, with malaria presenting as one of the most substantial threats to travellers' health. Problems with the current available pharmaceutical therapies include costs, availability, adverse effects and contraindications, inconvenience and compliance, many of which would be reduced or eliminated entirely if an effective (greater than 85–90%) vaccine was developed. 
The life cycle of the malaria parasite is particularly complex, presenting initial developmental problems. Despite the huge number of vaccines available at the current time, there are none that target parasitic infections. The distinct developmental stages involved in the life cycle present numerous opportunities for targeting antigens, thus potentially eliciting an immune response. Theoretically, each developmental stage could have a vaccine developed specifically to target the parasite. Moreover, any vaccine produced would ideally have the ability to be of therapeutic value as well as preventing further transmission and is likely to consist of a combination of antigens from different phases of the parasite's development. More than 30 of these antigens are currently being researched by teams all over the world in the hope of identifying a combination that can elicit immunity in the inoculated individual. Some of the approaches involve surface expression of the antigen, inhibitory effects of specific antibodies on the life cycle and the protective effects through immunization or passive transfer of antibodies between an immune and a non-immune host. The majority of research into malarial vaccines has focused on the "Plasmodium falciparum" strain due to the high mortality caused by the parasite and the ease of a carrying out in vitro/in vivo studies. The earliest vaccines attempted to use the parasitic circumsporozoite protein (CSP). This is the most dominant surface antigen of the initial pre-erythrocytic phase. However, problems were encountered due to low efficacy, reactogenicity and low immunogenicity. 
Mix of antigenic components.
Increasing the potential immunity generated against "Plasmodia" can be achieved by attempting to target multiple phases in the life cycle. This is additionally beneficial in reducing the possibility of resistant parasites developing. The use of multiple-parasite antigens can therefore have a synergistic or additive effect.
One of the most successful vaccine candidates currently in clinical trials consists of recombinant antigenic proteins to the circumsporozoite protein. (This is discussed in more detail below.)
Delivery system.
The selection of an appropriate system is fundamental in all vaccine development, but especially so in the case of malaria. A vaccine targeting several antigens may require delivery to different areas and by different means in order to elicit an effective response. Some adjuvants can direct the vaccine to the specifically targeted cell type—e.g. the use of Hepatitis B virus in the RTS,S vaccine to target infected hepatocytes—but in other cases, particularly when using combined antigenic vaccines, this approach is very complex. Some methods that have been attempted include the use of two vaccines, one directed at generating a blood response and the other a liver-stage response. These two vaccines could then be injected into two different sites, thus enabling the use of a more specific and potentially efficacious delivery system.
To increase, accelerate or modify the development of an immune response to a vaccine candidate it is often necessary to combine the antigenic substance to be delivered with an adjuvant or specialised delivery system. These terms are often used interchangeably in relation to vaccine development; however in most cases a distinction can be made. An adjuvant is typically thought of as a substance used in combination with the antigen to produce a more substantial and robust immune response than that elicited by the antigen alone. This is achieved through three mechanisms: by affecting the antigen delivery and presentation, by inducing the production of immunomodulatory cytokines, and by affecting the antigen presenting cells (APC). Adjuvants can consist of many different materials, from cell microparticles to other particulated delivery systems (e.g. liposomes).
Adjuvants are crucial in affecting the specificity and isotype of the necessary antibodies. They are thought to be able to potentiate the link between the innate and adaptive immune responses. Due to the diverse nature of substances that can potentially have this effect on the immune system, it is difficult to classify adjuvants into specific groups. In most circumstances they consist of easily identifiable components of micro-organisms that are recognised by the innate immune system cells. The role of delivery systems is primarily to direct the chosen adjuvant and antigen into target cells to attempt to increase the efficacy of the vaccine further, therefore acting synergistically with the adjuvant.
There is increasing concern that the use of very potent adjuvants could precipitate autoimmune responses, making it imperative that the vaccine is focused on the target cells only. Specific delivery systems can reduce this risk by limiting the potential toxicity and systemic distribution of newly developed adjuvants.
Studies into the efficacy of malaria vaccines developed to date have illustrated that the presence of an adjuvant is key in determining any protection gained against malaria. A large number of natural and synthetic adjuvants have been identified throughout the history of vaccine development. Options identified thus far for use combined with a malaria vaccine include mycobacterial cell walls, liposomes, monophosphoryl lipid A and squalene.
History.
Individuals who are exposed to the parasite in endemic countries develop acquired immunity against disease and death. Such immunity does not however prevent malarial infection; immune individuals often harbour asymptomatic parasites in their blood. This does, however, imply that it is possible to create an immune response that protects against the harmful effects of the parasite.
Research shows that if immunoglobulin is taken from immune adults, purified and then given to individuals who have no protective immunity, some protection can be gained.
Irradiated mosquitoes.
In 1967, it was reported that a level of immunity to the "Plasmodium berghei" parasite could be given to mice by exposing them to sporozoites that had been irradiated by x-rays. Subsequent human studies in the 1970s showed that humans could be immunized against "Plasmodium vivax" and "Plasmodium falciparum" by exposing them to the bites of significant numbers of irradiated mosquitos.
From 1989 to 1999, eleven volunteers recruited from the United States Public Health Service, United States Army, and United States Navy were immunized against "Plasmodium falciparum" by the bites of 1001–2927 mosquitoes that had been irradiated with 15,000 rads of gamma rays from a Co-60 or Cs-137 source. This level of radiation is sufficient to attenuate the malaria parasites so that, while they can still enter hepatic cells, they cannot develop into schizonts nor infect red blood cells. Over a span of 42 weeks, 24 of 26 tests on the volunteers showed that they were protected from malaria.