1MMAPDPNANP NANPNANPNA NPNANPNANP NANPNANPNA NPNANPNANP51NANPNANPNA NPNANPNANP NANPNANPNA NPNKNNQGNG QGHNMPNDPN101RNVDENANAN NAVKNNNNEE PSDKHIEQYL KKIKNSISTE WSPCSVTCGN151GIQVRIKPGS ANKPKDELDY ENDIEKKICK MEKCSSVFNV VNSRPVTNME201NITSGFLGPL LVLQAGFFLL TRILTIPQSL DSWWTSLNFL GGSPVCLGQN251SQSPTSNHSP TSCPPICPGY RWMCLRRFII FLFILLLCLI FLLVLLDYQG301MLPVCPLIPG STTTNTGPCK TCTTPAQGNS MFPSCCCTKP TDGNCTCIPI351PSSWAFAKYL WEWASVRFSW LSLLVPFVQW FVGLSPTVWL SAIWMMWYWG401PSLYSIVSPF IPLLPIFFCL WVYI
203-400-Antigen CS (Plasmodium falciparum strain NF54 reduced), 203-L-methionine-204-L-methionine-205-L-alanine-206-L-proline-207-L-aspartic acid-210-L-alanine-211-L-asparagine-313-L-asparagine-329-L-glutamic acid-330-L-glutamine-333-L-lysine-336-L-lysine-339-L-isoleucine-373-L-glutamic acid-396-L-arginine-397-L-proline-398-L-valine-399-L-threonine-400-L-asparagine-, (400→1′)-protein with antigen (hepatitis B virus subtype adw small surface reduced) (9CI)
- Malaria vaccine RTS,S
Sequence Length: 424
Graphical depiction of circumsporozoite (CSP) and RTS,S structures. CSP comprises an N-terminal region containing a signal peptide sequence and Region I that binds heparin sulfate proteoglycans and has embedded within it a conserved five amino acid (KLKQP) proteolytic cleavage site sequence; a central region containing four-amino acid (NANP/NVDP) repeats; and a C-terminal region containing Region II [a thrombospondin (TSP)-like domain] and a canonical glycosylphosphatidylinositol (GPI) anchor addition sequence. The region of the CSP included in the RTS,S vaccine includes the last 18 NANP repeats and C-terminus exclusive of the GPI anchor addition sequence. Hepatitis B virus surface antigen (HBsAg) monomers self-assemble into virus-like particles and approximately 25% of the HBsAg monomers in RTS,S are genetically fused to the truncated CSP and serve as protein carriers. The CSP fragment in RTS,S contains three known T-cell epitopes: a highly variable CD4 + T-cell epitope before the TSP-like domain (TH2R), a highly variable CD8 + T-cell epitope within the TSP-like domain (TH3R), and a conserved “universal” CD4 + T cell epitope (CS.T3) at the C-terminus. (Figure courtesy of a recent publication16 and open access,
Example 1Recipe for component for a single pediatric dose of RTS, S malaria vaccine (2 vial formulation)Component AmountRTS,S 25μgNaCl 2.25mgPhosphate buffer (NaZK2) 1OmMMonothioglycerol 125μgWater for Injection Make volume to 250 μLThe above is prepared by adding RTS, S antigen to a mix of Water for Injection, NaCl 150OmM, phosphate buffer (NaZK2) 50OmM (pH 6.8 when diluted x 50) and an aqueous solution of monothioglycerol at 10%. Finally pH is adjusted to 7.0 ± 0.1.This may be provided as a vial together with a separate vial of adjuvant, for example a liposomal formulation of MPL and QS21Component Amount l,2-di-oleoyl-5/?-glycero-3-phosphocholine (DOPC) 500 μgCholesterol 125 μgMPL 25 μgQS21 25 μgNaCl 2.25mg Phosphate buffer (NaZK2) 1 OmMWater for Injection Make volume to250 μLFor administration the adjuvant formulation is added to the component formulation, for example using a syringe, and then shaken. Then the dose is administered in the usual way. The pH of the final liquid formulation is about 6.6 +/- 0.1.Example IAA final pediatric liquid formulation (1 vial) according to the invention may be prepared according to the following recipe.Component AmountRTS,S 25μgNaCl 4.5mgPhosphate buffer (NaZK2) 1OmMMonothioglycerol 125μg1 ,2-di-oleoyl-5/?-glycero-3-phosphocholine (DOPC) 500 μgCholesterol 125 μgMPL 25 μgQS21 25 μgWater for Injection Make volume to500 μLThe pH of the above liquid formulation is either adjusted to 7.0 +/- 0.1 (which is favorable for antigen stability, but not favorable at all for the MPL stability), or to 6.1 +/- 0.1 (which is favorable for MPL stability, but not favorable at all for RT S, S stability). Therefore this formulation is intended for rapid use after preparation.The above is prepared by adding RTS, S antigen to a mix of Water for Injection, NaCl 150OmM, phosphate buffer (NaZK2) 50OmM (pH 6.8 when diluted x 50) and an aqueous solution of monothioglycerol at 10%. Then a premix of liposomes containing MPL with QS21 is added, and finally pH is adjusted. Example IBA final adult dose (1 vial formulation) for the RTS, S according to the invention may be prepared as follows:Component AmountRTS,S 50μgNaCl 4.5mgPhosphate buffer (NaZK2) 1OmMMonothioglycerol 250μg1 ,2-di-oleoyl-5/?-glycero-3-phosphocholine (DOPC) 1000 μgCholesterol 250 μgMPL 50 μgQS21 50 μgWater for Injection Make volume to500 μLExample 1CExample 1C may prepared by putting Example 1, IA or IB in an amber vial, for example flushed with nitrogen before filing.
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WHO recommends groundbreaking malaria vaccine for children at risk
Historic RTS,S/AS01 recommendation can reinvigorate the fight against malaria6 October 2021https://www.who.int/news/item/06-10-2021-who-recommends-groundbreaking-malaria-vaccine-for-children-at-risk
The World Health Organization (WHO) is recommending widespread use of the RTS,S/AS01 (RTS,S) malaria vaccine among children in sub-Saharan Africa and in other regions with moderate to high P. falciparum malaria transmission. The recommendation is based on results from an ongoing pilot programme in Ghana, Kenya and Malawi that has reached more than 800 000 children since 2019.
“This is a historic moment. The long-awaited malaria vaccine for children is a breakthrough for science, child health and malaria control,” said WHO Director-General Dr Tedros Adhanom Ghebreyesus. “Using this vaccine on top of existing tools to prevent malaria could save tens of thousands of young lives each year.”
Malaria remains a primary cause of childhood illness and death in sub-Saharan Africa. More than 260 000 African children under the age of five die from malaria annually.
In recent years, WHO and its partners have been reporting a stagnation in progress against the deadly disease.
“For centuries, malaria has stalked sub-Saharan Africa, causing immense personal suffering,” said Dr Matshidiso Moeti, WHO Regional Director for Africa. “We have long hoped for an effective malaria vaccine and now for the first time ever, we have such a vaccine recommended for widespread use. Today’s recommendation offers a glimmer of hope for the continent which shoulders the heaviest burden of the disease and we expect many more African children to be protected from malaria and grow into healthy adults.”
WHO recommendation for the RTS,S malaria vaccine
Based on the advice of two WHO global advisory bodies, one for immunization and the other for malaria, the Organization recommends that:
WHO recommends that in the context of comprehensive malaria control the RTS,S/AS01 malaria vaccine be used for the prevention of P. falciparum malaria in children living in regions with moderate to high transmission as defined by WHO. RTS,S/AS01 malaria vaccine should be provided in a schedule of 4 doses in children from 5 months of age for the reduction of malaria disease and burden.
Summary of key findings of the malaria vaccine pilots
Key findings of the pilots informed the recommendation based on data and insights generated from two years of vaccination in child health clinics in the three pilot countries, implemented under the leadership of the Ministries of Health of Ghana, Kenya and Malawi. Findings include:
- Feasible to deliver: Vaccine introduction is feasible, improves health and saves lives, with good and equitable coverage of RTS,S seen through routine immunization systems. This occurred even in the context of the COVID-19 pandemic.
- Reaching the unreached: RTS,S increases equity in access to malaria prevention.
- Data from the pilot programme showed that more than two-thirds of children in the 3 countries who are not sleeping under a bednet are benefitting from the RTS,S vaccine.
- Layering the tools results in over 90% of children benefitting from at least one preventive intervention (insecticide treated bednets or the malaria vaccine).
- Strong safety profile: To date, more than 2.3 million doses of the vaccine have been administered in 3 African countries – the vaccine has a favorable safety profile.
- No negative impact on uptake of bednets, other childhood vaccinations, or health seeking behavior for febrile illness. In areas where the vaccine has been introduced, there has been no decrease in the use of insecticide-treated nets, uptake of other childhood vaccinations or health seeking behavior for febrile illness.
- High impact in real-life childhood vaccination settings: Significant reduction (30%) in deadly severe malaria, even when introduced in areas where insecticide-treated nets are widely used and there is good access to diagnosis and treatment.
- Highly cost-effective: Modelling estimates that the vaccine is cost effective in areas of moderate to high malaria transmission.
Next steps for the WHO-recommended malaria vaccine will include funding decisions from the global health community for broader rollout, and country decision-making on whether to adopt the vaccine as part of national malaria control strategies.
Financing for the pilot programme has been mobilized through an unprecedented collaboration among three key global health funding bodies: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.
Note to editors:
- The malaria vaccine, RTS,S, acts against P. falciparum, the most deadly malaria parasite globally, and the most prevalent in Africa.
- The Malaria Vaccine Implementation Programme is generating evidence and experience on the feasibility, impact and safety of the RTS,S malaria vaccine in real-life, routine settings in selected areas of Ghana, Kenya and Malawi.
- Pilot malaria vaccine introductions are led by the Ministries of Health of Ghana, Kenya and Malawi.
- The pilot programme will continue in the 3 pilot countries to understand the added value of the 4th vaccine dose, and to measure longer-term impact on child deaths.
- The Malaria Vaccine Implementation Programme is coordinated by WHO and supported by in-country and international partners, including PATH, UNICEF and GSK, which is donating up to 10 million doses of the vaccine for the pilot.
- The RTS,S malaria vaccine is the result of 30 years of research and development by GSK and through a partnership with PATH, with support from a network of African research centres.
- The Bill & Melinda Gates Foundation provided catalytic funding for late-stage development of RTS,S between 2001 and 2015.
RTS,S/AS01 (trade name Mosquirix) is a recombinant protein-based malaria vaccine. In October 2021, the vaccine was endorsed by the World Health Organization (WHO) for “broad use” in children, making it the first malaria vaccine candidate, and first vaccine to address parasitic infection, to receive this recommendation.
The RTS,S vaccine was conceived of and created in the late 1980s by scientists working at SmithKline Beecham Biologicals (now GlaxoSmithKline (GSK) Vaccines) laboratories in Belgium. The vaccine was further developed through a collaboration between GSK and the Walter Reed Army Institute of Research in the U.S. state of Maryland and has been funded in part by the PATH Malaria Vaccine Initiative and the Bill and Melinda Gates Foundation. Its efficacy ranges from 26 to 50% in infants and young children.
Approved for use by the European Medicines Agency (EMA) in July 2015, it is the world’s first licensed malaria vaccine and also the first vaccine licensed for use against a human parasitic disease of any kind. On 23 October 2015, WHO’s Strategic Advisory Group of Experts on Immunization (SAGE) and the Malaria Policy Advisory Committee (MPAC) jointly recommended a pilot implementation of the vaccine in Africa. This 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.
Main article: Malaria vaccine
Potential malaria vaccines have been an intense area of research since the 1960s. SPf66 was tested extensively in endemic areas in the 1990s, but clinical trials showed it to be insufficiently effective. Other vaccine candidates, targeting the blood-stage of the malaria parasite’s life cycle, have also been insufficient on their own. Among several potential vaccines under development that target the pre-erythrocytic stage of the disease, RTS,S has shown the most promising results so far.
The EMA approved the RTS,S vaccine in July 2015, with a recommendation that it be used in Africa for babies at risk of getting malaria. RTS,S was the world’s first malaria vaccine to get approval for this use. Preliminary research suggests that delayed fractional dosing could increase the vaccine’s efficacy up to 86%.
On 17 November 2016, WHO announced that the RTS,S vaccine would be rolled out in pilot projects in three countries in sub-Saharan Africa. The pilot program, coordinated by WHO, will assess the extent to which the vaccine’s protective effect shown in advanced clinical trials can be replicated in real-life settings. Specifically, the programme will evaluate the feasibility of delivering the required four doses of the vaccine; the impact of the vaccine on lives saved; and the safety of the vaccine in the context of routine use.
Vaccinations by the ministries of health of Malawi, Ghana, and Kenya began in April and September 2019 and target 360,000 children per year in areas where vaccination would have the highest impact. The results are planned to be used by the World Health Organization to advise about a possible future deployment of the vaccine. In 2021 it was reported that the vaccine together with other anti-malaria medication when given at the most vulnerable season could reduce deaths and illness from the disease by 70%.
RTS,S has been funded, most recently, by the non-profit PATH Malaria Vaccine Initiative (MVI) and GlaxoSmithKline with funding from the Bill and Melinda Gates Foundation. The RTS,S-based vaccine formulation had previously been demonstrated to be safe, well tolerated, immunogenic, and to potentially confer partial efficacy in both malaria-naive and malaria-experienced adults as well as children.
Components and mechanism
The RTS,S vaccine is based on a protein construct first developed by GlaxoSmithKline in 1986. It was named RTS because it was engineered using genes from the repeat (‘R’) and T-cell epitope (‘T’) of the pre-erythrocytic circumsporozoite protein (CSP) of the Plasmodium falciparum malaria parasite together with a viral surface antigen (‘S’) of the hepatitis B virus (HBsAg). This protein was then mixed with additional HBsAg to improve purification, hence the extra “S”. Together, these two protein components assemble into soluble virus-like particles similar to the outer shell of a hepatitis B virus.
A chemical adjuvant (AS01, specifically AS01E) was added to increase the immune system response. Infection is prevented by inducing humoral and cellular immunity, with high antibody titers, that block the parasite from infecting the liver.
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|Target||P. falciparum; to a lesser extent Hepatitis B|
|Vaccine type||Protein subunit|
|intramuscular injection (0.5 mL)|
|Legal status||In general: ℞ (Prescription only)|
A poster advertising trials of the RTS,S vaccine
Research continues with other malaria vaccines. The most effective malaria vaccine is R21/Matrix-M, with a 77% efficacy rate 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 (WHO) goal of a malaria vaccine with at least 75% efficacy.
Main article: 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 the trial stage, 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.
As of October 2013, 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 seems 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 European Medicines Agency (EMA) on the proposal for 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 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.
The most effective malaria vaccine 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.
Main article: 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.
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.
- SPf66 is a synthetic peptide based vaccine developed by Manuel Elkin Patarroyo team in Colombia, and was tested extensively in endemic areas in the 1990s. Clinical trials showed it to be insufficiently effective, with 28% efficacy in South America and minimal or no efficacy in Africa.
- The CSP (Circum-Sporozoite Protein) 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 (Asn-Ala-Pro15Asn-Val-Asp-Pro)2-Leu-Arg(R32LR) protein covalently bound to a purified Pseudomonas aeruginosa toxin (A9). 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 (called PfSSP2) were derived from the sporozoite phase. The liver stage antigen 1 (LSA1), three from the erythrocytic stage (merozoite surface protein 1, serine repeat antigen and AMA-1) and one sexual stage antigen (the 25-kDa Pfs25) were included. This was first investigated using Rhesus monkeys and produced encouraging results: 4 out of the 7 antigens produced specific antibody responses (CSP, PfSSP2, MSP1 and PFs25). 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 [NANP]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 (5.1) and 19 repeats of the sporozoite surface protein [NANP]. 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.
- A chemical compound undergoing trials for treatment of tuberculosis and cancer—the JmJc inhibitor ML324 and the antitubercular clinical candidate SQ109—is potentially a new line of drugs to treat malaria and kill the parasite in its infectious stage. More tests still need to be carried out before the compounds would be approved as a viable treatment.
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.
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.
- “Anti-parasitic immunity” addresses the source; it consists of an antibody response (humoral immunity) 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 (through external barriers or hostile internal environments) and then kill any micro-organisms or foreign particles that succeed in penetration. The cell-mediated component consists of many white blood cells (such as monocytes, neutrophils, macrophages, lymphocytes, basophils, mast cells, natural killer cells, and eosinophils) 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 (of micro-organism presence) 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.
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.
See also: PfSPZ Vaccine
|Sporozoite||Hepatocyte invasion; direct anti-sporozite|
|Asexual erythrocytic||Anti-host erythrocyte, antibodies blocking invasion; anti receptor ligand, anti-soluble toxin|
|Gametocytes||Anti-gametocyte. Anti-host erythrocyte, antibodies blocking fertilisation, antibodies blocking egress from the mosquito midgut.|
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 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, 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 being researched[when?] 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.
- 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 (through inducing cytotoxic T-lymphocytes that can destroy the infected liver cells). 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 vaccine candidate 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 vector vaccine, targeting a full-length P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) 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 (2011) 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 (VSAs) 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 (RBC) by P. vivax are potential targets for drug or vaccine development. When the Duffy binding protein (DBP) of P. vivax binds the Duffy antigen (DARC) 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 (PfSEA-1) were found to disable the parasite ability to rupture from the infected red blood cells (RBCs) 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
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 in clinical trials[which?][when?] consists of recombinant antigenic proteins to the circumsporozoite protein. (This is discussed in more detail below.)[where?]
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[when?] 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.
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.
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.
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|Screened cup of malaria-infected mosquitoes which will infect a volunteer in a clinical trial|
|Vaccine type||Protein subunit|
|Legal status||EU: Rx-only |
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