Scientists at the University of Washington have used mosquitoes as if they were hundreds of tiny flying syringes to deliver an unconventional vaccine against malaria. These mosquitoes are infected with the malaria-causing Plasmodium parasite, which has been genetically modified to be weakened and not make people sick but will nevertheless trigger an immune response that leads to the production of vital antibodies to keep the disease at bay when the parasite is encountered again.

Weakened parasite, strong immune system

Getting bitten by hundreds of mosquitoes sounds like the worst vaccine ever, but the point is not to inoculate people against malaria by getting bitten. The idea is to test whether exposure to weakened Plasmodium parasites leads to a robust immune response. If so, the weakened genetically modified parasite can be ultimately delivered with a single vaccine shot.

Only certain species of mosquitoes of the Anopheles genus — and only females of those species — can transmit malaria. According to the 2021 World Malaria Report, nearly half the world’s population lives in areas at risk of malaria transmission in 87 countries and territories. In 2020, malaria caused an estimated 241 million clinical cases, resulting in 627,000 deaths, 95% of which occurred in Africa.

Malaria is marked by disabling fever, chills, fatigue, and sweating. Although the disease can be treated with drugs and prevented with mosquito eradication programs, the high costs of these treatments and eradication methods consistently hamper efforts to reduce malaria’s prevalence.

Malaria-causing parasites are spread via a complex life cycle, which begins with a mosquito consuming blood from a host infected with Plasmodium parasites. These cells reach the insects’ gut, where they eventually form fertilized eggs that then squeeze through the gut’s lining and become encased in cysts in the insect’s body cavity. At this stage, the parasites undergo a furiously fast reproductive frenzy, making more and more copies of themselves until the cyst bursts and the parasites reach the salivary gland of the mosquito, from where they are expelled into a new host when the insect takes its next blood meal. Furthermore, when a ‘clean’ mosquito bites an infected human with malaria, the mosquito can get infected thereby restarting the grueling cycle.

Keeping malaria under control is a herculean challenge and downright impossible without vaccination. Thankfully, in 2021, the World Health Organization (WHO) endorsed the first malaria vaccine, known as RTS,S (trade name Mosquirix). The vaccine developed by GlaxoSmithKline was shown to be 30% to 40% effective against severe malaria in the first year in clinical trials.

Vaccination with RTS,S induces antibodies against the circumsporozoite protein (CSP), which is expressed by sporozoites, the infective form of Plasmodium that mosquitoes transmit. But this is just one of over 5,000 proteins the parasite expresses, so efficacy may suffer.

Other researchers have attempted to make a malaria vaccine by introducing a disarmed parasite. What the team at the University of Washington did differently was to make a harmless Plasmodium using CRISPR — a gene-editing tool that uses bacteria as a sort of molecular scissor to cut and paste bits of DNA. This way, people exposed to this disarmed version cannot get sick but will still produce antibodies against malaria.

To test this proof of concept, the researchers went really old school and had volunteers be bitten by mosquitoes infected with the weakened form of Plasmodium. Each volunteer had to place their arm over a mesh-covered container filled with over 200 mosquitoes whose bites delivered the genetically modified malaria parasite. After some time, half of the participants were exposed to a second round of mosquito bites, this time containing the real, unweakened malaria parasite. Out of the 14 participants exposed to malaria, seven came down with the disease and were quickly treated with anti-malaria medication, which all means the vaccine proved 50% effective. The protection didn’t last for more than a few months.

“We think we can obviously do better,” Stefan Kappe, an author of the study and parasitologist at the University of Washington Seattle and Seattle Children’s Research Institute, told NPR.

Some of the improvements they could pursue include using a stronger, more mature version of the parasite that could prime the body better against malaria. Once the configuration is dialed in, the plan is to have a more robust delivery method in place, preferably an injectable shot or patch of some kind.

The findings appeared in the journal Science Translational Medicine.