Malaria: New vaccine candidate shows efficacy in clinical trials

Malaria causes an estimated 627,000 Deaths worldwide in 2020, with almost 93% of all deaths from malaria occurring in sub-Saharan Africa. In addition, 80% of malaria-related deaths in Africa occurred in children under the age of 5.

Malaria is caused by unicellular parasites of the genus plasmodium transmitted by mosquito bites. Although five kinds of plasmodium can cause malaria in humans Plasmodium falciparum is the leading cause of serious illness and death.

When a plasmodium-infected female Anopheles mosquito bites a human who plasmodium Parasites enter the host’s bloodstream and eventually infect the liver.

This stage of infection with multiplication of the parasites in the liver lasts 7-10 days and is asymptomatic. They then re-enter the blood and invade red blood cells.

The parasites then multiply in red blood cells, causing them to rupture and infect other red blood cells. Red blood cell infection is responsible for the symptomatic stage of malaria.

At present, measures to combat malaria infection include preventive measures in the form of insecticides or treatment with antimalarial drugs.

The emergence of mosquitoes resistant to insecticides and plasmodium Parasites resistant to antimalarial drugs has highlighted the need for effective antimalarial vaccines.

However, developing vaccines against malaria has been challenging because of the complexity of the challenge plasmodium parasites. For example, the genome of P. falciparum is larger and more complex than viruses, consisting of more than 5,000 genes.

In addition, the complex life cycle of P. falciparumwhich involves several steps, poses a challenge for the selection of the appropriate target protein for vaccine development.

RTS, S/AS01also known as Mosquirix, has shown the most promise among vaccine candidates and was the first and only malaria vaccine approved by the World Health Organization (WHO) for use in medium- to high-risk settings.

The RTS,S/AS01 vaccine targets the life stages of the plasmodium Parasites that precede the invasion and infection of the red blood cells.

RTS,S/AS01 is a recombinant protein-based vaccine consisting of a truncated version of the circumsporozoite protein (CSP) fused to hepatitis B surface antigen.

The circumsporozoite protein is a major protein expressed on the parasite’s surface, and the RTS,S/AS01 vaccine trains the body to mount an immune response against this protein.

Hepatitis B surface antigen is a protein that coats the hepatitis B virus and can self-assemble into virus-like particles when expressed in yeast cells.

The RTS,S/AS01 vaccine uses hepatitis B surface antigen virus-like particles to act as a scaffold to present the circumsporozoite protein to the immune system and enhance the immune response.

However, studies conducted in sub-Saharan Africa have shown that the RTS,S/AS01 vaccine has modest efficacy. For example, a phase 3 clinical trial showed that four doses of the RTS,S/AS01 vaccine provided an efficacy of 36% over a follow-up period of 48 months in children aged 5-17 months.

Therefore, there is a need for more effective vaccines against malaria. Consequently, the WHO has set itself the goal of developing a malaria vaccine with an efficacy of at least 75% by 2030.

Therefore, researchers at the University of Oxford in the UK have now developed a new vaccine candidate called R21, which has an improved formula aimed at overcoming the problems that most likely led to lower efficacy in the case of RTS,S/AS01.

As part of a phase 1/2b clinical trial conducted in Burkina Faso, the study authors so far evaluated the efficacy of the R21/Matrix-M vaccine after 12 months of follow-up in children aged 5-17 months.

The clinical study consisted of 450 children who were randomized to receive 3 doses of R21 vaccine with a low dose of Matrix-M adjuvant (25 micrograms), R21 vaccine with a high dose of Matrix-M (50 micrograms), or rabies vaccine in the control group.

Matrix-M is designed to enhance the immune response against the CSP fusion protein.

In a previous report in The lancetthe authors found that the R21 vaccine candidate with the lower dose of Matrix-M adjuvant had 71% efficacy against symptomatic malaria and the R21 vaccine with the higher adjuvant dose had 77% efficacy over the 12-month follow-up would have. Recovery period after the primary three-dose therapy.

As part of the same clinical study, researchers gave a booster dose to 409 repeat participants 12 months after the first vaccination course. They examined the effectiveness of the vaccine during the 12-month follow-up period after the booster vaccination and the 24-month period after the first series of vaccinations.

Multiple episodes of malaria are common in the same person. Therefore, the researchers evaluated the vaccine’s effectiveness against the first and multiple episodes of symptomatic malaria.

During the 12-month period after the fourth booster dose, the low adjuvant dose R21 vaccine candidate had 71% efficacy against the first episode of symptomatic malaria, while vaccine efficacy in the group receiving the higher adjuvant dose R21 was was 80%.

The efficacy of the higher adjuvant dose R21 vaccine against first and multiple episodes of malaria during the 24-month period after the first dose was 75% and 78%, respectively.

The researchers also assessed the levels of antibodies against CSP present in blood samples taken 4 weeks after the first series of vaccinations and the booster vaccination.

Anti-CSP antibody levels after the primary and booster courses were correlated with the extent of protection against one or more malaria episodes at the first and second years of follow-up, respectively. Therefore, levels of antibodies against CSP could be used to assess the level of protection conferred by the vaccine.

Researchers also found a drop in anti-CSP antibody levels one year after the first vaccination series, and the booster dose restored antibody levels.

Prof Sir Brian Greenwood, a professor at the London School of Hygiene and Tropical Medicine who is not involved in this research, comments on the findings:

“The study did not include a group of children who received only the initial doses of vaccine, therefore it is not possible to infer from this paper how necessary booster doses of R21 vaccine are to maintain protection through the first five years of life or more in where children in many seasonal transmission areas are still at high risk of malaria. The marked decline in anti-CSP antibody titers in the months following the primary series as observed with the RTS,S/AS01 vaccine and the evidence presented in this and other studies that anti-CSP antibody titers are associated with protection , but suggest that booster doses are likely to be required to maintain protection.”

The R21/Matrix-M vaccine candidate was well tolerated and had acceptable side effects. However, the authors noted that the small size of the study sample could have prevented the characterization of less common side effects due to the vaccine.

As part of the ongoing Phase 1/2b clinical trial, the authors also intend to follow participants for a further two years to assess the long-term safety of the vaccine candidate and the potential need for booster doses.

dr Davidson Hamer, a professor of global health and medicine at Boston University, said Medical news todaythat one of the limitations of the study “is that this is a relatively small sample size per group and that other preventive measures were taking place in this community during this time – although this should have been evenly distributed among all three groups.”

“It will be important to follow this up with a larger, cross-country study in areas with different levels of malaria transmission, underlying child malnutrition and different levels of implementation of malaria control measures,” he added.

To further evaluate the efficacy and safety of the R21 vaccine candidate in a larger sample, researchers enrolled 4,800 children in a Phase 3 clinical trial.

The researchers have so far applied for and received ethical approval from the Comité d’Ethique pour la Recherche en Santé and the Agence National de Régulation Pharmaceutique in Burkina Faso and the Oxford Tropical Research Ethics Committee in the UK for all studies