Malaria is an ancient disease, but so far, there is still no effective way to eradicate this disease. According to the WHO, in 2019, malaria took 409,000 lives worldwide. What’s concerning is 274,000 deaths were children under 5 years of age.
Malaria occurs in more than 100 countries and territories around the world, including large regions of Africa and South Asia, parts of Central, South America, the Caribbean, the Middle East and Oceania
Malaria is caused by four parasitic species from the genus Plasmodium, including Plasmodium falciparum. The symptoms of this disease range from flu-like illness, severe anaemia, jaundice, respiratory distress, to cerebral malaria.
This disease can also cause asymptomatic infections, partial immunity, or multi-organ failure leading to death.
An essential carrier of malaria is the Anopheles mosquito, which grow well in the tropics and subtropics throughout the world. Nonetheless, the actual cause behind this disease is a parasite.
For decades, scientists have been looking for an effective strategy to stop this disease. But not until recently, there is a hope that a new vaccine could become the key for defeating malaria.
Why defeating malaria is hard?
Defeating malaria is relatively difficult because:
- The complicated life stages of the parasites requiring two different hosts: human and mosquitoes.
- The immunity against malaria is only partial—reinfection can occur after a person recovers from the illness.
After repeated infection, a person who lives in a particular region with widespread malaria cases may be ‘semi-immune’—with no typical malaria symptoms. In addition, she or he develops anti-malaria immunity to kill the parasite and inhibit its replication. However, this partial immunity only occurs for older children and adults.
As the infants and younger children grow and continue to be exposed to the parasites, they gradually acquire protective immune responses (Matuschewski & Mueller, 2007). However, younger children, pregnant women, first time travelers to the endemic areas, and people with another disease, such as HIV/AIDS, are vulnerable to this disease.
Therefore, many studies are in progress to develop an effective approach to defeat malaria, particularly for developing a malaria vaccine.
Why do we need a malaria vaccine?
Many efforts have been made to defeat malaria, including the use of antimalarial drugs and insecticides. Unfortunately, these strategies currently encounter some growing issues, so an efficacious malaria vaccine would be essential to help overcome this disease.
Below are some reasons why a malaria vaccine is important:
- The emergence of antimalarial drug resistance.
- The drug discovery cannot keep up with the drug resistance.
- The increasing resistance to insecticides.
- Vaccines offer an efficient and cost-effective tool to prevent illness and death for those people who belong to high-risk populations.
A vaccine with high efficacy rate could protect many people from this life threatening disease and reduce the transmission of the parasites at the same time.
Life cycle and transmission
Malaria is transmitted by a mosquito, which carries parasites. The parasite needs two hosts to finish its life cycle: a mosquito and a human.
Inside a mosquito, the parasites undergo sexual reproduction to multiply. After biting a person, the mosquito transmits the parasites into the human bloodstream. Inside the human body, the parasites invade cells, grow, and complete the asexual reproduction.
Figure 1. The life cycle of the Plasmodium parasite.
In figure 1 above, you can see the complete life cycle of the Plasmodium parasite. When the infected mosquito bites a person, the parasites enter her or his liver cells in the form of sporozoites. First, sporozoites grow and multiply in the liver cells during the liver stage infection. When the liver cells rupture, these cells release merozoites.
During the blood stage infection, the merozoites invade blood cells, and multiply until the cells rupture. Some of the merozoites undergo asexual multiplication, whereas others develop into sexual forms, called gametocytes.
After a mosquito takes a blood meal, the gametocytes enter the mosquito’s body. Inside the mosquito, the gametocytes develop into mature sex cells and differentiate into male and female gametes. After the gametes fuse, the zygotes enter the mosquito’s gut and develop into oocysts. In the gut cells, the oocysts grow and release sporozoites, which enter the mosquito’s salivary glands. Afterward, the cycle starts again when the mosquito bites another person.
What are the immune responses to malaria?
Inside human body, immune responses to malaria could target any different life stages of the parasites, from the sporozoites to the merozoites.
Typically, there are two types of immune responses against the parasites: innate immune responses and adaptive immune responses. An innate immune response is the first line of defense triggered by the parasite, when they enter a human body. Then, the parasite infection activates an adaptive immune response.
Innate Immune Responses
An innate immune response is an immune response activated without any prior exposures to an antigen. Some cells involved in the innate immune responses are neutrophils, monocytes, macrophages, and natural killer cells.
For example, natural killer cells act as the sensors and they are also actively defend the body from the parasites (Rochford & Kazura, 2019). The natural killer cells are blood cells, which show cytotoxic activity and produce proinflammatory cytokines—contributing in the clearance of parasites and the removal of infected liver and blood cells.This mechanism often produces a toxic substance to kill the infected cells.
Adaptive Immune Responses
An adaptive immune response occurs after exposure to an antigen, either by infection or vaccination.
There are two types of adaptive immune response against malaria: cellular immune responses and antibody responses, which include the activity of T-cells, B-cell, and antibodies (Loiseau et al., 2019).
For example, cell-mediated immune responses led by T cells predominates during the liver stage infection—leading to the migration of T-cells to the liver and the elimination of parasite-infected hepatocytes.
However, as the parasites move on to the blood cells, antibodies are the main key player of the adaptive immune responses, probably by recruiting additional immune cells to fight the parasites or by blocking the parasites from binding and invading new cells (Teo et al., 2016).
What can be a good target for a potential malaria vaccine?
There are three potential targets for a malaria vaccine focusing on different stages of the parasite life cycle:
Transmission blocking vaccines incorporate surface antigens of the mosquito sexual stage, such as gametes and zygotes (Duffy & Gorres, 2020). The targets of theses type of vaccines are to induce antibodies and kill parasites entering the mosquito body after it bites infected human. During the development of these vaccines, the challenges include adequate adaptive immune responses and widespread coverage to reach herd immunity. Some examples of transmission blocking vaccines are Pfs25, Pfs230, Pfs48/45, and Pvs230.
Blood stage vaccines target parasites growing and multiplying in the blood cells (Duffy & Gorres, 2020). During the development of this type of vaccines, the challenges are the short time when merozoites are accessible to antibodies, the antigenic polymorphism, and the large number of parasite. Some examples of these vaccines are AMA1-RON2, PfRH5, PfSEA1, VAR2CSA.
Pre-erythrocytic vaccines or pre-erythrocytic vaccines use antigens from the sporozoites during the liver stages (Duffy & Gorres, 2020). The targets of this type of vaccines are to clear sporozoites entering the human body, block them from invading the liver cells, and induce T-cells to attack infected liver cells. Some examples are PfSPZ, RTS.S/AS01, R21/MM vaccine.
Due to the complex life stages of the parasites, there is also a possibility that in the future the highly effective vaccines are likely to include more than one approach (Hill, 2011). However, the current vaccine candidates were developed as stand-alone vaccines.
What is the current status for potential malaria vaccines?
For a malaria vaccine, the WHO set a goal of 75 percent efficacy. The efficacy rate is the reduction in disease frequency in vaccinated people, when compared to unvaccinated people in one trial. Two potential vaccines are currently in the clinical trials.
The world’s first licensed malaria vaccine, RTS, S/AS01, produced by The GlaxoSmithKline vaccine company. The brand name for this vaccine is MosquirixTM.This vaccine targets the Plasmodium falciparum circumsporozoite protein (CSP) to prevent the parasites from infecting the liver cells. Although the efficacy for this vaccine in Phase 3 trials showed around 56 percent, it is currently used to protect children in several sub-Saharan countries. Unfortunately, after four years post immunization, immunized children showed the vaccine only prevented around 36 percent of malaria cases and 29 percent of severe cases.
Recently, researchers at the University of Oxford’s Jenner Institute developed a new malaria vaccine, called R21/MM. Both R21/MM and MosquirixTM are pre-erythrocytic vaccines, which contain Plasmodium falciparum CSP central repeat fused to hepatitis B surface (HBsAg) antigen.The only difference is R21/MM contains an improved version of MosquirixTM protein moieties. The R21/MM vaccine also contains an adjuvant Matrix-MTM to induce strong immune response.
In a small clinical trial, the R21/MM vaccine had up to 77 percent efficacy. Therefore, the R21/MM vaccine is the first potential malaria vaccine to pass the WHO efficacy goal, although the trial only had a small number of samples (450 children). In the future, this vaccine will be tested in a large Phase 3 trial, which include 4,800 children across four African countries.
While waiting for the results of the trial, we can only hope that the new vaccine could be the right answer to defeat malaria in the future.
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