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Finding the Missing Piece — the Limits of the Current Malaria Vaccine and How We Can Improve Future Vaccine Design

With hundreds of millions of infections worldwide, malaria continues to be a global health threat and burden to vulnerable populations. For decades, researchers have dedicated work to stamping out this illness, which is caused by the parasite Plasmodium falciparum, and a vaccine was recently licensed for prevention of the disease. The vaccine, called RTS,S/AS01, has the potential to reduce the number of infections, especially in young children, in endemic countries. The trouble lies in the vaccine’s efficacy — results have been mixed, with a protection rate ranging from 22 to 74.6 percent (the average is 36.3 percent) in children receiving three doses plus a booster. It can easily be argued that even a 30 percent reduction in malaria cases could save at least thousands of lives, and a vaccine that provides protection to only a fraction of people is still worth putting on the market. But it is important to continue to look ahead, and try to understand limitations of the current vaccine to improve and inform further vaccine development strategies.

The current RTS,S/AS01 vaccine uses a recombinant protein combined with an adjuvant — a compound included in many vaccine formulations that helps to stimulate a more potent immune response — called AS01 to immunize against a key malarial protein known as circumsporozoite protein (CSP). The protein is called recombinant because it is a special lab-engineered form in which the most immunostimulatory portions of the protein have been fused to a hepatitis B protein — again, with the aim of boosting immune cells’ responses to the protein. This essentially trains the immune system to recognize and rapidly respond to an encounter with the pathogen by targeting the response to easily recognizable proteins found on the surface of the parasite, so that if an infected mosquito bites someone, the immune system is able to respond quickly and fight off any incoming parasites. The adjuvant gives the immune system the extra nudge it needs to recognize the recombinant protein as “foreign” so that immunity can build. This vaccine formulation was engineered based off of the protein from one strain of Plasmodium falciparum, 3D7, which is a lab-adapted strain that researchers can easily use in a laboratory setting. However, just like any other species, the global population of malaria is made up of many different genetic variants of the parasite. In previous studies, researchers found that unmatched vaccine and field haplotypes — or a set of genetic variants found in nature that are frequently inherited together — can reduce vaccine efficacy by about 20 percent. Patients who have malaria may also be infected by multiple genetically distinct forms of the parasite, which indicates that the parasites may have originated from multiple mosquito bites and could influence vaccine efficacy.

New Research, More Questions

A recent paper published by Ph.D. candidate Julia Pringle, who works in the lab of Doug Norris at the Johns Hopkins Bloomberg School of Public Health, focused on the role of the parasite haplotypes represented in the current vaccine and how this could influence efficacy. Working with collaborators at the Johns Hopkins Southern and Central Africa International Center of Excellence in Malaria Research, the researchers found that few isolates identified in Zambia and the Democratic Republic of Congo perfectly matched the vaccine strain, with most patient infections having multiple parasite clones. Further, Pringle compared the sequences obtained from her field isolate samples to sequences in a worldwide database, including from other African countries and Asian countries. Through these analyses, she identified that malarial parasites from the different continents are genetically distinct in the region targeted by the new vaccine.

Pringle first focused on samples from the Nchelenge District in Zambia. Zambia has a high prevalence of malaria throughout the country, though it has implemented various malaria prevention techniques such as indoor residual spraying — a method of preventative insecticide spraying of walls of households, so that when mosquitoes land they are hit with a dose of insecticide. The Nchelenge District has an especially high prevalence in children younger than 5 — over 50 percent. Samples were also collected in the nearby Democratic Republic of Congo, just across the Zambian border, where there are very few, if any, antimalarial campaigns. Pringle and colleagues collected dried blood spot samples taken from randomly selected households, and extracted DNA. This parasite DNA could then be analyzed to determine variability in the CSP protein.

Using next-generation sequencing, Pringle identified multiple variants present in blood samples from Zambia and the Democratic Republic of Congo. Of the samples containing P. falciparum DNA, only 5.2 percent perfectly matched the vaccine strain sequence. This indicates a significant diversity in malaria parasites present in the field relative to the single strain represented in the vaccine, which could result in reduced vaccine efficacy. Pringle then compared her sequences to those in global databases, analyzing a total of over 4,000 sequences. Among these, she identified 393 unique haplotypes, though about 50 percent of all samples fell into one of seven central haplotypes. The team then compared the African isolates to database sequences of Asian isolates to understand the variation in haplotypes around the world. Asian haplotypes were even more diverse than those in Africa, with the 3D7 vaccine haplotype only present in 0.2 percent of samples. This suggests that the CSP protein sequence is very diverse, both locally and globally, but key haplotypes are pervasive in populations. This could allow researchers to better tailor future malaria vaccine efforts based off of several CSP haplotypes, rather than only one.

Designing Vaccines By Region

Overall, this study indicates there is a significant gap between the vaccine strain haplotype of CSP and those found in the field, which could lead to reduced efficacy in populations plagued by malaria. Nevertheless, this should further inspire researchers to improve future vaccine efforts using tools such as those Pringle and colleagues used. It is possible to identify the major haplotypes within a geographic region, and include several of their CSP haplotypes in vaccine design. This would diversify the CSP “portfolio” in the vaccine, and likely provide better protection by training immune systems to better recognize naturally occurring versions of the parasite that people would be more likely to come in contact with. Further, this could allow adjusting of vaccine design to specific regions, such as Africa or Asia, with distinct parasite populations. The paper by Pringle and colleagues aptly demonstrates the power of genome sequencing to better understand malaria, and how to use this information to fight the parasite using vaccines, as we move forward in our goal to eliminate this disease.

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