SEATTLE, Washington — In the United States, a mosquito bite is a nuisance. However, in parts of the developing world, it could be a death sentence. Each year, more than 200 million individuals contract malaria from the Plasmodium parasite in infected Anopheles mosquitoes. Africa alone accounted for 93% of malaria cases and 94% of malaria deaths in 2018, making the disease a serious impediment to developmental and economic progress on the continent, especially considering there is no malaria vaccine.
Malaria’s catastrophic toll has inspired many attempts to create a viable vaccine, but the genetic complexity of the malaria parasite has made vaccine development difficult. Only one vaccine, the RTS,S vaccine, has completed large-scale clinical testing and it only protected about 40% of recipients. In 2020, however, there have been three promising studies, each focusing on a novel approach to the malaria vaccine. These studies could open up new avenues in the fight against the disease.
Engineering a Cure
Traditionally, vaccine development focuses on attenuating a virus so that scientists can inject pieces of it into the body and jumpstart a protective immune response. However, the advent of genetic engineering creates the possibility for scientists to modify and amplify particular viral genes in order to improve vaccine efficacy. This is the approach that two groups of Dutch researchers pursued, as explained in the journal Science and Translational Medicine in May 2020.
Studies Using Genetic Modification
The first study genetically modified whole parasites of the species Plasmodium falciparum, the predominant malaria-causing pathogen in most of the world. This modified parasite lacked two genes involved in the parasite’s maturation and replication. They conducted a trial with 25 volunteers, each of whom received the modified parasite three times. The vaccine protected three of these volunteers from the malaria virus. The other 22 showed a delay in disease progression due to a vaccine-induced immune response.
The other study also utilized genetic engineering but honed in on a different species of the malaria parasite, P. berghei. This strain is not normally useful in vaccine discovery because it only affects mice. However, the researchers inserted the DNA for circumsporozoite. Circumsporozoite a protein found within P. falciparum that produces an immune response, into its genetic code. They inoculated 24 volunteers. While the vaccine did not fully protect from the virus, it did delay the detection of live parasites in the blood. The authors viewed the results positively, predicting that with some tweaks the vaccine could show greater efficacy.
Many in the scientific community have applauded both of these trials. Despite falling short of delivering full immunity to malaria, as proof-of-principle studies, they illustrate that genetically engineered malaria vaccines hold promise. In the years to come, such vaccines will likely be refined over the course of many trials. At the same time, the field will hopefully also be riding a boost from another important study released in July 2020.
A Breakthrough Down Under
Two months after the publication of the two genetically engineered vaccine trials, researchers at Australian National University published a study attempting to explain why so many previous trials have failed. The team analyzed data collected during a clinical trial in humans and conducted their own experiments using a mouse model. They focused on circumsporozoite protein, the same protein used in the rodent-strain vaccine trial, and the target of the RTS,S vaccine.
The authors sought to answer the question of why malaria vaccine candidates, including the RTS,S vaccine, are not able to generate sufficient levels of antibodies, the body’s main immune defense. They concluded that the antibodies themselves created a negative feedback loop that prevented sufficient immune production. Encouragingly, though, immune responses in the mice they tested were boosted when the mice received another immunization six months later. Altogether, the researchers suggested that the path forward in malaria vaccine discovery is targeting multiple proteins on the parasite’s surface. Such an approach would offer promise not only for a malaria vaccine but other complex diseases such as HIV.
Hope for the Future
Even with these promising results, a genetically engineered malaria vaccine that generates protective levels of antibodies is likely years away. Yet the expedited timeline for COVID-19 vaccine candidates, supported by billions of dollars of investment from governments, shows that exceptional progress can occur in a short amount of time when global health is an urgent priority. If countries applied such urgency to the search for a malaria vaccine, they could prevent millions of deaths. In addition, it would allow much of the developing world to flourish in the process.
– Jack Silvers