Mouse after mouse slurped down the experimental malaria vaccine, but the result was always the same: hardly any immune response at all. Frustrated, malaria vaccine researcher Sean Murphy and his team at the University of Washington tried altering the schedule and dosing of the vaccine to no avail.
Then a just vaccinated mouse let out a soft sneeze on the benchtop.
“There were some mice that when we gave it orally, they kind of snorted,” said Murphy. Unlike their less sniffly neighbors, these mice mounted a huge immune response to the vaccine. “We thought, ‘Well, gosh, maybe a very small amount is getting up in their nose,’” said Murphy. “That was a big eureka moment.”
With the clue from their snuffling mice and the help of some edible algae, Murphy’s team recently reported that a nasally delivered and orally boosted vaccine protected mice from malaria infection, setting the stage for future vaccine trials in humans (1).
The Holy Grail of malaria treatment is a safe and effective vaccine. After more than 40 years of research, the World Health Organization (WHO) approved the very first vaccine for malaria in 2021. While the vaccine works, it is only 31 to 56 percent effective (2). “One of the things that is pretty clear about it is it needs booster doses to sustain those antibody levels,” said Murphy.
Mosquitos infected with malaria-causing Plasmodium parasites transmit the parasites when they bite. At this stage in their lifecycle, the parasites are called sporozoites. The sporozoites travel from the skin to the bloodstream and eventually to the liver. There, they infect liver cells and develop into new lifecycle forms. Eventually, the parasites invade and kill red blood cells, causing malaria symptoms.
The WHO-approved malaria vaccine uses the Plasmodium falciparum circumsporozoite protein (PfCSP) to prompt the immune system to create antibodies to prevent sporozoites from traveling to and infecting the liver. Of the five Plasmodium species that cause malaria, P. falciparum causes more than 90 percent of malaria cases worldwide and causes the most severe and deadly cases of the disease (3).
Malaria is most common in sub-Saharan Africa, India, and parts of Oceania. Getting injectable vaccine doses to some remote and resource poor areas most affected by malaria is difficult. Refrigeration and trained personnel to administer the needle-based vaccines are often not available. So, when one of Murphy’s colleagues told him about spirulina, edible and protein-rich algae that scientists can engineer to express vaccine antigens, the little blue-green cells seemed like the perfect solution.
“What first impressed me about spirulina was that people could eat it. It's an alga, and it's just a bioreactor for the vaccine. But most bioreactors, you can't eat it. Nobody's going to give you cake of other bacteria and say, ‘Why don’t you eat this?’” said Murphy.
Because spirulina are edible, scientists can simply dry them out to form a powder. The biologics expressed by these dried out spirulina remain stable at temperatures as high as 42°C for at least six months (4). Once the spirulina powder gets to its vaccination site, health workers can resuspend it in liquid to administer orally or nasally. Working with the spirulina researchers at the biotechnology company Lumen Bioscience, Murphy’s team engineered spirulina to express virus-like particles displaying the same PfCSP antigen as the WHO approved malaria vaccine.
When the researchers delivered their spirulina PfCSP vaccine intranasally followed by either two or three oral booster doses, the mice developed a stronger antibody response compared to when the team only delivered the vaccine orally.
The real test came when the researchers challenged the vaccinated mice with actual parasites. Two weeks after the final oral booster dose, the researchers injected mice with Plasmodiumyoelii sporozoites, a laboratory model of malaria, expressing PfCSP. They found that their vaccine completely protected 80 percent of female mice and 100 percent of male mice from infection. The protective effects were also long lasting: When the researchers infected female mice with sporozoites three months after their third oral booster vaccination, the vaccine protected 87.5 percent of the mice.
“What they're reporting on is very interesting, and potentially quite exciting. When we think about what our requirements are for a malaria vaccine, the most important requirement is protective efficacy,” said Stephen Hoffman, a malaria vaccine researcher at the biotechnology company Sanaria who was not involved in the study but who does often collaborate with Murphy. “To get this degree of protection against a parasitic infection is unique.”
Matthew Laurens, a malaria vaccine researcher at the University of Maryland School of Medicine who did not take part in the study, agreed with Hoffman. He added that the results are “very compelling in terms of an alternate strategy for malaria vaccine development, and it definitely addresses the major drawback of the current malaria vaccines that are requiring refrigeration and needle syringe delivery.”
Murphy is eager to continue testing his team’s vaccine candidate under conditions that better represent the natural route of malaria infection. Instead of injecting parasites directly into mice, they plan to expose the vaccinated mice to bites from parasite-infected mosquitos.
They will also test their nasal and oral boosted vaccine in larger mammals, including nonhuman primates. “Mice are not tiny humans,” said Murphy. They hope to take their vaccine to clinical trials in the future.
“The prospect of vaccinating someone and then removing them from the at risk category of people is really exciting,” said Murphy. “If you reduce the burden of malaria, people's educational attainment goes up, their socioeconomic status goes up, tourism increases. All kinds of good things happen. The idea that a vaccine could precipitate those kinds of changes is really what motivates us. Hopefully, in our lifetimes, we'll get to see one like that.”
- Saveria, T. et al. Needle-free, spirulina-produced Plasmodium falciparum circumsporozoite vaccination provides sterile protection against pre-erythrocytic malaria in mice. npj Vaccines 7, 113 (2022).
- RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. The Lancet 386, 31-45 (2015).
- Zekar, L. and Sharman, T. Plasmodium Falciparum Malaria. [Updated 2022 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing (2022).
- Jester, B.W. et al. Development of spirulina for the manufacture and oral delivery of protein therapeutics. Nat Biotechnol 40, 956-964 (2022).