|Year : 2021 | Volume
| Issue : 1 | Page : 12-16
Malaria vaccine development: State of the art and beyond
Shuyang Guo, Wenbo Sai, Min Li
Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China
|Date of Web Publication||29-Oct-2021|
Center for Drug Evaluation, National Medical Products Administration, Beijing 100022
Source of Support: None, Conflict of Interest: None
According to the statistics of the World Health Organization, malaria is still one of the main diseases affecting human health, especially in Africa, and inflicts a heavy disease burden and a huge economic burden in endemic countries. At present, the widespread emergence of antimalarial drug resistance and unresolved drug availability issues have led researchers to turn their attention to the development of antimalarial vaccines. This review aims at highlighting the recent development of malaria vaccines and discussing the challenges.
Keywords: Malaria; Vaccines; Adjuvants
|How to cite this article:|
Guo S, Sai W, Li M. Malaria vaccine development: State of the art and beyond. One Health Bull 2021;1:12-6
| 1. Introduction|| |
Malaria is a life-threatening disease caused by parasites that are transmitted to humans through the bites of infected female Anopheles mosquitoes. According to the World Health Organization’s World Malaria Report 2020, malaria caused an estimated 229 million clinical episodes and 409 000 deaths in 2019. An estimated 94% of deaths were in the WHO African Region, children aged 5 years and under are the most vulnerable group affected by malaria, accounting for 67% (274 000) of the total malaria deaths. As the COVID-19 pandemic changed the health management behaviors of people last year, especially those who were experiencing fevers, 2020 is likely to be the first year in decades to see an increase in malaria-related deaths. Malaria poses a heavy burden on both individual patients and society. In 2019, the global investments for malaria elimination and control activities were estimated at around US $3 billion.
After decades of implementing integrated interventions, China has achieved a remarkable milestone in malaria elimination. On June 30, 2021, China was officially certified as a malaria-free country by the WHO. It is the first country in the WHO Western Pacific Region to be awarded a malaria free certification in more than three decades, a remarkable feat for a country that reported 30 million cases of the disease annually in the 1940s.
The resistance of Plasmodium (P.) falciparum to chloroquine, sulfadoxine-pyrimidine, and other antimalarial drugs, was reported in the 1970s and 1980s and had since become widespread. To achieve the goal of controlling and possibly eliminating malaria, there is a strong need to develop highly effective, long-lasting, and affordable malaria vaccines. Although there has been major recent progress in malaria vaccine development, substantial challenges remain for achieving highly efficacious and durable vaccines against P. falciparum. This review aims at highlighting the advanced clinical malaria vaccine candidates and discussing the challenges associated with these candidates.
| 2. Malaria vaccines|| |
2.1. Progress in malaria vaccine
There are 5 parasite species that cause malaria in humans, among them, P. vivax and P. falciparum are the most common. P. vivax is more widely distributed, but P. falciparum is the main species causing patient death. The P. falciparum life cycle in humans includes the pre-erythrocytic stage, which initiates the infection; the asexual blood stage, which causes disease; and the gametocyte stage, which infects mosquitoes that transmit the parasite. According to the life cycle of P. falciparum in humans, malaria vaccines can be divided into three types: pre-erythrocytic, blood-stage, and transmission-blocking vaccines (TBVs). Pre-erythrocytic stage or liver stage is the initial stage of infection and associated with significant changes in Plasmodium gene expression and morphology, this process generates tens of thousands of merozoites that are released into the blood from the infected hepatocytes. Therefore, targeting the malaria pre-erythrocytic stages, an obligatory and clinically silent phase of the parasite’s life cycle, is considered an ideal and attractive strategy for vaccination; The inhibition of parasitic infection and development of hepatocytes leads to elimination of disease-causing blood stages and gametocyte stages. Further, low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination. It follows that the research and development of vaccines targeting the pre-erythrocytic stage of malaria has been a priority in the field for the past few decades.
At present, the leading candidate malaria vaccines mainly include subunit vaccines such as RTS,S and R21/Matrix-M and whole sporozoite vaccines represented by attenuated sporozoites.
2.2. Subunit vaccines
2.2.1. RTS,S/AS01 vaccine (Mosquirix™)
RTS,S vaccine development was initiated in 1987 as part of a collaboration between GlaxoSmithKline (GSK) and the Walter Reed Army Institute of Research (WRAIR). Following nearly thirty years’ effort and hundreds of millions of dollars’ investment, the RTS,S vaccine program was brought to the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) for review and approval. EMA performed a scientific evaluation of the vaccine and issued a positive opinion in July 2015, indicating that the risk/benefit assessment is favorable. Since the efficacy of the vaccine from phase 3 studies was suboptimal, WHO decided to conduct a large-scale pilot program beginning in 2019 to introduce the vaccines to three African countries (Ghana, Kenya, and Malawi) with moderate-to-high malaria transmission. The pilot program will conduct pharmacovigilance and evaluate the impact of the vaccine on the disease burden. The findings will inform the WHO and country level decision makers whether to expand the vaccine introduction.
RTS,S vaccine is based on the truncated circumsporozoite protein (CSP) displayed on the hepatitis B surface antigen (HBsAg) virus-like particles (VLP). The truncated SCP contains the central repeat region and the C terminal region that contains three known T-cell epitopes and a conserved “universal” CD4+ T cell epitope (CS.T3). The vaccine uses a new adjuvant system AS01, which may be crucial for the efficacy of the vaccine.
In the naming of the RTS,S vaccine, the “R” represents the central repeat region, a single polypeptide chain corresponding to a highly-conserved tandem repeat tetrapeptide Asn-Ala-Asn-Pro (NANP) amino acid sequence, and the “T” represents T-lymphocyte epitopes separated by immunodominant CD4+ and CD8+ epitopes (Th2R and Th3R). The combined RT peptide is genetically fused to the N-terminal of HBsAg, the “S” (Surface) portion when co-expressed in yeast cells, yielding VLPs that display both CSP and S at their surfaces. A second “S” portion is an unfused HBsAg that spontaneously fuses to the RTS component.
Multiple adjuvants have been tested with RTS,S in the initial clinical trials, which found AS04 to be more highly immunogenic and protective against controlled human malaria infection (CHMI). Subsequent clinical trials in rhesus monkeys showed that AS02A provided superior antibody and protection in CHMI. Stability studies prompted development of a lyophilized RTS,S formulation for reconstitution with AS02A. With the development of a newer adjuvant system AS01, a CHMI study demonstrated greater efficacy and increased anti-CSP antibody and CD4+ T cell response for AS01 compared with AS02. Subsequently, the RTS,S/AS01 vaccine was advanced to Phase III testing.
In a phase III clinical study of RTS,S/AS01 vaccine, 6 537 infants aged 6-12 weeks and 8 923 children aged 5-17 months were randomized to receive three doses of RTS,S/AS01 vaccine or comparator vaccine. Clinical malaria primary case was defined as an illness accompanied by a temperature ≥37.5 °C and P. falciparum asexual parasitemia at a density of 5 000 parasites/μL. Clinical malaria secondary case was defined as an illness accompanied by a temperature≥37.5 °C and P. falciparum asexual parasitemia at a density of 0 parasites/μL. Vaccine efficacy against clinical malaria in children during the 18 months after vaccine dose 3 was 46% (95% CI 42-50). Vaccine efficacy during the 20 months was 45% (95% CI 41-49), but there was no significant protection against severe malaria, malaria hospitalization, or all-cause hospitalization[ 11]. Vaccine efficacy was higher in children than in infants, but even at modest levels of vaccine efficacy, the number of malaria cases averted could be substantial. It was thought that RTS,S/AS01 could be an important supplement to current malaria control in malaria endemic areas.
The authors believe that although the efficacy and persistence of the immune response of RTS,S vaccine are still suboptimal, it is the world’s first, and to date the only malaria vaccine evaluated in these countries has shown to provide partial protection against malaria, which helps to reduce the incidence of clinical malaria and reduce the incidence of severe malaria in young children.
The efficacy against clinical malaria for RTS,S given with the AS01 adjuvant system is higher than previous adjuvants. AS01 activity to enhance adaptive responses depends on synergistic activities of a saponin molecule extracted from the bark of the South American tree Quillaja saponaria Molina, fraction 21(QS-21) and 3-O-desacyl-4’-monophosphoryl lipid A(MPL). AS01 is effective in promoting CD4+T cell-mediated immune responses and is an appropriate candidate adjuvant for inclusion in vaccines targeting intracellular pathogens (such as P. falciparum).
At present, the first-generation vaccine known as RTS,S/AS01 has demonstrated the potential to protect against malaria. In addition to RTS,S, GSK has been already working on second-generation malaria vaccines with better safety, efficacy and long-lasting protection.
2.2.2. R21 /Matrix-M™ vaccine
R21 is another pre-erythrocytic candidate malaria vaccine candidate being developed by the Jenner Institute at Oxford University, the Serum Institute of India Pvt Ltd, and Novavax Inc, etc. The adjuvant is Novavax’s patented saponin-based Matrix-M™ adjuvant, R21. Like RTS,S, R21 uses the same CSP antigen fused to the HBsAg self-assemble into VLPs in yeast. Compared with RTS,S, which contains only 20% of the fusion protein part and the remaining 80% is separately expressed HBsAg monomer, R21 is completely composed of the fusion protein formed by two components. R21 achieves a much higher proportion of CSP displayed on the antigen surface, and consequently induces a greater anti-CSP antibody response and lower anti-HBsAg antibody response.
Following preclinical studies of R21 using multiple adjuvants, Matrix-M was selected for clinical development based on its superior adjuvant activity. Matrix-M is a saponin-based liposomal adjuvant that stimulates both humoral and cellular immune responses to vaccines.
In 2019, a double-blind, randomized, controlled phase 2b trial was undertaken, vaccine R21 with different doses of adjuvant Matrix-M was given to 450 children aged 5–17 months. Before the malaria season, three vaccinations were administered at 4-week intervals, and the fourth dose was finished 1 year later. The primary objective assessed protective efficacy of R21 plus Matrix-M (R21/MM) from 14 days after the third vaccination to 6 months. At 6 months, the vaccine efficacy of group 1 (5 μg R21 plus 25 μg Matrix-M) and group 2 (5 μg R21 plus 50 μg Matrix-M) were 74% and 77%, respectively. At 1 year, vaccine efficacy remained high, at 71% in group 1 and 77% in group 2.
R21/MM has reached the WHO-specified efficacy goal of 75% or more in the target population of African children. In addition, R21/ MM had a favourable safety profile and was well tolerated. Follow-up of this phase 2 trial is currently continuing for a second malaria season to determine the durability of the vaccine efficacy.
An important advantage of R21/MM relates to its potential for large-scale manufacturing, and the R21 pediatric dose is just 5 μg antigen. The saponin adjuvant, MM, lacks the monophosphoryl lipid A adjuvant component, which is found in Mosquirix™ and is less complex to manufacture, and this may enable largescale and low-cost supply of R21/MM.
2.3. Whole sporozoite vaccines
Ruth Nussenzweig and co-workers demonstrated in 1967 that immunization with irradiation-attenuated sporozoites (IAS) could elicit sterile protective immunity against sporozoite challenge in murine models, thus confirming the possibility of developing such malaria vaccines. Although this class of vaccines has been continuously explored and studied, and preliminary data on the protective efficacy have been obtained[16-19], the progress of this class of malaria vaccines is relatively slow due to the problems such as formidable challenges in scaling up production (whole sporozoite vaccine strategy currently requires sporozoite production in live mosquitoes), difficulty in storing and transporting the vaccine for carrying out clinical trials, etc.
In 2021, the National Institutes of Health (NIH) reported phase I trial results of two chemo-attenuated vaccines [(PfSPZ-CVac(PYR) and PfSPZ-CVac(CQ)] developed by Sanaria Inc.. P. falciparum 7G8 strain originated from Brazil which is used for heterologous CHMI is more divergent at the levels of the genome, proteome and CD8 T cell immune responses. This type of inoculation procedure is divided into two steps. First, participants are immunized by direct venous inoculation of aseptic, purified, cryopreserved infectious PfSPZ CVac, then, a few days later, anti-sporozoite drugs [pyrimethamine (PYR) or chloroquine (CQ)] were given after the first PfSPZ inoculation to prevent malaria caused by vaccination.
The principle of this whole-parasite vaccine strategy called chemoprophylaxis vaccination (CVac) is related to the malaria life cycle. After being bitten by an infected mosquito, the parasite enters the bloodstream in a form called a sporozoite, it reaches the liver where it resides inside hepatocytes. The parasite develops and multiplies in the liver. At this stage there are no symptoms. Over the next week, they return to the bloodstream and infect red blood cells. In the blood stage, parasites further replicate rapidly and cause illness. In the CVac trials, anti-malarial drug is administered to kill parasites, pyrimethamine to kill liver-stage parasites, and chloroquine to kill blood stage parasites.
Infectious PfSPZ were inoculated under prophylactic cover with pyrimethamine (PYR) or chloroquine (CQ), which kill pre-erythrocytic and blood-stage parasites, respectively, and vaccine efficacy against homologous and heterologous CHMI three months after immunization were assessed. The vaccine efficacy of PfSPZ-CVac(PYR) were 87.5% (7/8) and 77.8% (7/9) against homologous and heterologous CHMI, respectively. PfSPZ-CVac(CQ) provided 100% (6/6) vaccine efficacy against heterologous CHMI. 100% protection for three months against heterologous CHMI is unprecedented for any malaria vaccine in development.
In general, the phase I trial results show markedly improved protection against both homologous and heterologous CHMI, the dose and protective effect of the vaccine still need to be further verified by high-quality, large sample size clinical trials. In addition, such vaccines require sporozoite production in live mosquitoes, and therefore face considerable regulatory, manufacturing (scaling up production), and technical challenges.
| 3. Outlook and future developments|| |
At present, although the development of malaria vaccines has had remarkable achievements in the past decade, there is a series of difficult efficacy, engineering, manufacturing, and optimization problems that have to be solved when taking a complex biological product like malaria vaccine from research to reality. The WHO Malaria Vaccine Technology Roadmap (2013 update) was released in 2013 with the strategic goal to license vaccines targeting P. falciparum and P. vivax with a protective efficacy of at least 75% against clinical malaria with a duration of protection of at least 2 years and booster doses to be required no more frequently than annually by 2030. The development of malaria vaccines has had remarkable achievements in the past decade. At present, there is still a long way to go before such a vaccine becomes a reality. Nonetheless, we could see a ray of hope to achieve this goal in R21/MM and PfSPZ-CVac vaccines. Achieving this next-generation vaccine goal will necessitate building on the success of current pre-erythrocytic subunit and whole sporozoite-based vaccines, as well as other new strategies such as anti-gamete transmission blocking vaccines. New adjuvants and new combinations of adjuvants (Adjuvant Systems) have opened the door to the delivery of improved and new vaccines with long-lasting antibody titers and protection, which is a major barrier of malaria vaccine development. As the portfolio advances in development of malaria vaccine, the coming years promise to be an exciting time that should engender hope that a highly effective malaria vaccine may be within reach.
Conflict of interest statement
The authors declare that there is no conflict of interest.
Guo SY was responsible for literature collection and writing the draft of this article. Sai WB reviewed the development process of each malaria vaccine and evaluated the advantage and disadvantage of each vaccine. As the corresponding author, Li M controlled the content of the whole review.
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