One Seattle morning, Carolina Reid sat in a room with nine other volunteers, each waiting to take part in a clinical trial for an experimental new malaria vaccine.
Reid’s turn has come. She put her arm on a cardboard box filled with 200 mosquitoes and covered with a net that holds them back but still lets them bite. “Literally, a container of Chinese food to go,” is how she remembers it. A scientist then covered her arm with a black cloth, because mosquitoes like to bite at night.
Then the feeding frenzy started.
“My whole forearm swelled up and blistered,” Reid says. “My family was laughing and asking me, ‘Why are you submitting to this?'” And she didn’t just do it once. She did it five times.
You might be thinking – this is a joke, right?
But it’s not. “We use mosquitoes as if they were 1,000 little flying syringes,” says University of Washington, Seattle physician and scientist Dr Sean Murphy, lead author of a paper in Science Translational Medicine released August 24 detailing vaccine trials.
Insects deliver live Plasmodium parasites that cause malaria that have been genetically engineered not to make people sick. The body is still making antibodies against the weakened parasite, so it is ready to fight the real parasite.
To be clear, Murphy does not plan to use mosquitoes to vaccinate millions of people. Mosquitoes have been used to deliver malaria vaccines for clinical trials in the past, but this is not common.
He and his colleagues took this route because it is expensive and time-consuming to develop a formulation of a parasite that can be delivered with a needle. Parasites mature inside mosquitoes, so at this stage of proof of concept – as early trials are called – it makes sense to use them for delivery.
“They went old school with this one,” says Dr. Kirsten Lyke, a physician and vaccine researcher at the University of Maryland School of Medicine who was not involved in the study. “All old things become new again.”
She calls the use of a genetically modified live parasite “a total game changer” for vaccine development.
This type of vaccine is of course not ready for prime time yet. But the small trial of 26 participants showed that the modified parasites protected some participants from malaria infection for a few months.
Murphy thinks this approach could one day result in a vaccine significantly more effective than the the world’s first malaria vaccine, the RTS,S vaccine from drugmaker GlaxoSmithKline. The World Health Organization approved it last year, but it only has a 30-40% effectiveness rate.
Mosquitoes and malaria – a toxic relationship
Reid was looking for work when she joined the trial in 2018. “The first thing that caught my eye was the money,” she says – a payment of $4,100 for participants. But when she spoke to friends who had contracted malaria, she found a different motivation. She said it wasn’t about the money anymore – although that was still nice – but more about being part of an important search.
Malaria parasites live in the salivary glands of Anopheles mosquitoes. The disease is more common in Africa where the warm climate is suitable for the growth of the parasite. People catch malaria through the bite of an infected mosquito. Infected people can transmit the malaria parasite to mosquitoes that bite them, and the cycle of infection continues.
Even with these measures, scientists estimate that there are over 240 million cases of malaria a year and over 600,000 deaths – which is why vaccines are needed.
A promising start – but there is room for improvement
The reason Murphy thinks this experimental vaccine should stimulate a stronger immune response than the WHO-approved RTS,S vaccine is that it uses a weakened whole parasite. RTS,S targets “just one of more than 5,000 proteins” produced by the parasite, he says.
Others have attempted to make a malaria vaccine from disarmed parasites. What’s new is that this team did the disarming with CRISPR – a pair of highly advanced molecular scissors that can cut DNA.
To test the effectiveness of the approach, Reid and the other participants had to endure another round of mosquito bites, this time containing the real malaria parasite.
Of 14 participants exposed to malaria, seven of them, including Reid, caught the disease, meaning the vaccine was only 50% effective. For the other seven, the protection did not last more than a few months.
“I actually cried when they told me I had malaria because I had developed such a close relationship with the nurses,” Reid says. She wanted to continue through the trials, but her infection made her ineligible. She was given medicine to clear her case of malaria and sent home.
“We think we can obviously do better,” says Stefan Kappe, study author and parasitologist at the University of Washington Seattle and the Seattle Children’s Research Institute. He and Murphy hope to improve the effectiveness of their team’s vaccine by putting it in syringes instead of using mosquitoes so they can get the dosage right. A higher initial dose could lead to greater protection for a longer period of time.
Lyke says some scientists think using a slightly more mature version of the parasite than this vaccine could give the body more time to mount an immune response. The team is already working on this approach, Kappe says.
If future trials are promising, there are other questions to ask. To start: How much would this type of vaccine cost? Scientists are partnering with a small company called Sanaria to produce the modified parasites. Kappe says increasing production capacity to scale up manufacturing will require investment.
As for Reid, her experience was so positive that she later participated in clinical trials for an avian flu vaccine and the Moderna COVID-19 vaccine. She says she will continue to enroll in vaccine clinical trials “for the rest of my life, in fact.”
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