An elusive vaccine: The fight against malaria

Philip Lewis

According to the World Health Organisation (WHO), the estimated number of malaria deaths worldwide was 409,000 in 2019. This is despite malaria being a preventable and curable infectious disease. Of these 409,000 deaths, 67% were children under five and 94% were in Africa.

Why are cases so high in Africa?

Many types of mosquito spread malaria. In the majority of cases, malaria is transmitted through a mosquito species group known as Anopheles. The particular Anopheles mosquito prevalent in Africa has a long lifespan; a major reason why the continent still experiences high case numbers. This is worsened by tropical and subtropical weather conditions, and scarce economic resources and infrastructure hindering control efforts.

Pregnant women and children are at particular risk from malaria. In the 2019 World Malaria Report, the WHO stated that in 2018 around 872,000 children were born with low birthweight due to maternal exposure to malaria.

How is the disease currently dealt with?

Efforts to control the spread of malaria include using insecticide-treated mosquito nets and indoor residual spraying. These tools have helped to drive down rates of malaria since 2000.

However, the WHO has stated there is still a critical need for new tools to further drive down malaria illness rates and deaths. Many have argued a vaccine is now essential, as evidence emerges of increasing resistance to insecticides among Anopheles mosquitoes, making the disease harder to control.

An elusive vaccine

Scientists have been trying to produce a malaria vaccine for decades, but several factors mean that malaria has proved an extremely difficult disease to vaccinate against.

Unlike the majority of diseases that have been limited or eradicated by vaccination, malaria is not caused by bacteria or a virus. Instead, it is caused by single-cell parasites that live on mosquitos. A major obstacle encountered by vaccine scientists is the complexity of the lifecycle of these parasites, specifically the complexity of their proteins. Elizabeth Ann Winzeler, a professor of pharmacology at the University of California in San Diego, said that:

Your immune system may raise antibodies against one protein, and then [the parasite] will switch the protein, and then those antibodies don’t work anymore.

Studies looking at whether the parasite has an ability to evade immunity are ongoing. Unlike many viral infections, the body’s experience of fighting malaria does not help confer natural immunity, meaning that an individual can get the disease multiple times.

Vaccine candidates: RTS,S/Mosquirix

In 2015, a vaccine candidate known as RTS,S became the first malaria vaccine to pass regulatory scrutiny. The European Medicines Agency (EMA) approved it for use after five years of phase three clinical trial. RTS,S, also known by its brand name Mosquirix, was subsequently recommended by the WHO as the basis for an implementation pilot programme beginning in 2019. As of November 2020, more than 1 million doses of RTS,S had been administered as part of this pilot programme, reaching an estimated 480,000 children.

While many have welcomed the arrival of the RTS,S vaccine as a historic breakthrough, some scientists have raised concerns around the number of doses needed, the limited level of protection provided and the safety of the vaccine.

Doses and protection

RTS,S is given to children aged between 6 weeks and 17 months and four doses of the vaccine are needed for maximum efficacy. This has prompted concerns about the feasibility of supply on the scale required, particularly in countries where the health and economic infrastructure is limited. Clinical trials showed that four doses reduced instances of malaria by between 30% and 40%. Protection is thought to last around four years.

Safety concerns

Safety concerns have also been raised about the RTS,S vaccine. In the risk management plan published by the EMA alongside its approval, several “important potential risks” and instances of “missing information” were highlighted. The document recorded that there may be potential increased risk of meningitis and cerebral malaria in children who receive RTS,S. It also said there were gaps in knowledge about the vaccine, with the impact of RTS,S on gender specific mortality unknown.

Some of these concerns are echoed by the WHO, and remain uncertain even after phase 3 trials. In response, the EMA and WHO set up the ongoing pilot programme in Malawi, Ghana, and Kenya to monitor these safety concerns. Some epidemiologists have criticised this decision, citing the difficulty in monitoring the pilot effectively in countries such as Malawi, that “lack digital systems to record health and mortality statistics”. Writing in the British Medical Journal, a group of scientists criticised the narrow timescale marker of 24 months used in the pilot, stating that “the relative risks of both cerebral malaria and female mortality increased after the booster dose at 20 months”, and that the first year of trials and pilot results may be biased in favour of the vaccine.

What are the other vaccine candidates in development?

Since 2000, the number of malaria vaccine candidates registered for clinical trials has averaged around ten at any one time.

The Jenner Institute at the University of Oxford has recently recorded promising results in several pre-clinical trials. Pre-clinical and clinical trials are ongoing in the continued development of three groups of vaccine types:

pre-erythrocytic vaccines that prevent initial malaria infection;
blood stage vaccines that limit infection and disease in the individual; and
transmission blocking vaccines that interrupt transmission of the disease.

One of the Institute’s pre-erythrocytic candidates has shown particularly promising results in boosting T cell immunity and is currently undergoing phase 2b clinical trials in West and East Africa.