February 16, 2022
With Mosquirix approved by WHO, hopes are high for a breakthrough in fight against Malaria
Mosquito-borne Malaria is one of the world’s major infectious illnesses, claiming between one and three million lives each year and affecting 40% of the world’s population in roughly 107 countries.
While antimalarial medications and other treatments have slowed the spread of the disease thus far, the rise of drug resistance to malaria has demanded a more permanent cure.
After more than 60 years of research and development, a potential breakthrough has taken shape as a recombinant protein-based malaria vaccine, RTS,S/AS01, also known as Mosquirix, which the World Health Organization (WHO) approved use for children in sub-Saharan Africa and other impacted regions on October 6, 2021.
COVID-19 boosted research in mRNA vaccines
Malaria is spread by female Anopheles mosquitoes. They feed on nectar but require blood for proliferation. When an infected mosquito inserts her needle-like mouth into an organism, the malaria parasite – plasmodium falciparum – enters the body with the mosquito’s saliva.
The parasite makes its way to the liver of the infected organism, where it replicates itself thousands of times before spilling out to infect red blood cells. It is when the parasite multiplies inside red blood cells that the infected individual will experience a variety of flu-like symptoms, including a fever, headache, sweats, and chills. If left untreated, many victims, especially children under the age of five, develop kidney or liver failure, fall into a coma, or die from severe anemia.
The difficulty of creating a malaria vaccine is attributed to one simple characteristic: malaria is caused not by a bacteria or virus, but a parasite. This seemingly minute difference makes the developmental process all the much harder – not to mention the fact there are over 200 species of malaria, only 5 of which can cause illness in humans.
To begin, the largest of viruses contain about 200 genes while the malaria parasite contains around 5,300. When the parasite multiplies, genes are moved across homologous chromosomes via a process known as recombination which results in genetic variations. According to a journal published by Professor and Chair of Molecular Parasitology at the University of Edinburgh, David E. Arnot, and referenced by the Wellcome Sanger Institute, this gene recombination occurs in approximately “0.2 percent of parasites after each 48-hour life cycle in the red blood cell”.
Although 0.2 percent may appear insignificant, it is worth noting that a typical infected individual will have roughly one billion parasites, offering an enormous opportunity for a parasite to develop new, recombined genes within each infected person.
With the fast proliferation of genetic variants, developing a vaccine capable of targeting malaria before it evolves and becomes resistant to its treatment has proven challenging.
The other challenge lies within the complicated life cycle of the malaria parasite.
When the mosquito bites a victim, the earliest form of the parasite, called sporozoites, are injected into the bloodstream with the saliva of the insect.
Sporozoites travel to the liver and for the next seven to ten days begin reproducing asexually, at such time generating no symptoms in the host. The sporozoites then mature into the second form of the parasite, schizonts, which rupture, releasing the third form, merozoites, into the bloodstream. Merozoites are a form of parasite that are capable of infecting red blood cells (called erythrocytes). As the parasite multiplies, the red blood cells burst, releasing more merozoites, and thus the parasite infects more erythrocytes. During this stage of infection, the host exhibits malarial symptoms.
Some merozoites mature into the fourth, pre-sexual form of the parasite known as gametocytes. These parasites circulate in the bloodstream of the infected organism and are injested by mosquitos that draw blood from it.
It is inside the the mosquitos where the gametocytes develop into gametes, the fifth, sexual form of the parasite, which then become ookinetes – sixth, actively moving form of the parasite – and ultimately become sporozoites. Thus the cycle is completed: sprotozites travel to spit glands of the mosquito and restart the entire cycle.
With so many varying stages that the malaria parasite undergoes, different vaccines are classified by the parasite’s current developmental stage: pre-erythrocytic vaccines attack the parasite while it is still in the liver, blood-stage vaccines attack the parasite after it has reached the circulation, and transmission-blocking vaccines attack the parasite during its growth and maturity.
Chloroquine, a synthetic drug discovered in the 1930s, was one of the first and most widely used treatments for malaria. By the late 1950s and early 1960s, however, a Chloroquine-resistant genetic variation of plasmodium falciparum had begun to develop in South East Asia, Oceania, and South America. Since then, the drug resistant strain of malaria spread to nearly all areas of the world where malaria was present and Chloroquine was no longer an effective treatment.
Similarly, Artemisinin-based Combination Therapies (ACTs), a treatment that contains a combination of two or more antimalarial drugs, has also proven ineffective in recent years, as malaria parasites resistant to artemisinin have emerged in the Greater Mekong Subregion (which includes Cambodia, Laos, Myanmar, Thailand, Vietnam, and parts of southern China).
As artemisinin-resistant malaria continues its spread across the world, the need for new treatments has become more pressing than ever.
The development of Mosquirix, the malaria vaccine, began in 1987 through a collaboration between GlaxoSmithKline (GSK), a UK-based global pharmaceutical company, and the Walter Reed Army Institute of Research (WRAIR), the largest biomedical research facility administered by the U.S. Department of Defense.
The vaccine is classified as a pre-erythrocytic vaccination and contains a small portion of protein from the malaria parasite. This means that the parasite within it is incapable of infecting the organism – an approach considered to be safer than vaccines produced from live malaria strains.
The presence of protein from the parasite triggers the body’s production of antibodies, thereby enabling the immune system to learn how to deal with the actual parasite when a vaccinated individual is bitten by an infected mosquito.
The vaccine, Mosquirix, teaches the immune system how to target the circumsporozoite protein on the sporozoite’s surface, which leads to the parasite being destroyed before it can reach the liver and infects its cells. Therefore, the entire infection is arrested in its first stage.
The Mosquirix vaccine has exhibited a 45.7% effectiveness against all clinical illness during an 18-month period in a field study of African children. This protection rate is not extremely high and varies according to the age of the individual receiving the vaccination, with infants receiving less protection than older children. For comparison, the Pfizer-BioNTech vaccine for Covid-19 has a 95% efficacy rate.
4.3 million malaria cases and 22,000 deaths in children younger than five years could be averted annually” with the use of Mosquirix.
Dr Alexandra B. Hogan, mathematical infectious disease modellar
Still, the vaccine will prove most effective when used alongside previous prevention methods, such as bed nets, chemical insecticides, and the artemisinin-combination treatment (ACT) in regions that have not developed resistance yet.
The most significant long-term problem is the rapid decrease in the protective immunity offered by Mosquirix, possibly due to the high rate of mutation in parasites causing malaria. Therefore, administration of regular booster doses might be required to control malaria, a task significantly increasing the financial and organisational difficulties of the fight against malaria.
There is, however, some support from other aspects of change to how our societies live. According to Jenny Liu, an assistant professor at the University of California, “the malaria map is rapidly shrinking. In 1900, endemic malaria was present in almost every country. Nowadays, the disease has been eliminated in 111 countries and 34 countries are advancing towards elimination”
Though the future of malaria is uncertain, new treatments, technological advancements, and global research will continue to move the disease towards eradication – the vaccine is just another step in that journey.