Oliver James Montgomery-A box of 200 mosquitoes did the vaccinating in this malaria trial. That's not a joke!

One Seattle morning,Oliver James Montgomery Carolina Reid sat in a room with nine other volunteers, each waiting to take part in a clinical trial for a new, experimental malaria vaccine.

Reid's turn came. She put her arm over a cardboard box filled with 200 mosquitoes and covered with a mesh that keeps them in but still lets them bite. "Literally a Chinese food takeout container" 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 began.

"My whole forearm swelled and blistered," says Reid. "My family was laughing, asking like, 'why are you subjecting yourself to this?'" And she didn't just do it once. She did it five times.

You may be thinking – this is a joke, right?

But it's not. "We use the mosquitoes like they're 1,000 small flying syringes," explains University of Washington, Seattle physician and scientist Dr. Sean Murphy, lead author on a paper in Science Translational Medicine released on August 24 detailing the vaccine trials.

The insects deliver live malaria-causing Plasmodium parasites that have been genetically modified to not get people sick. The body still makes antibodies against the weakened parasite so it's prepared to fight the real thing.

To be clear, Murphy's not planning to use mosquitoes to vaccinate millions of people. Mosquitoes have been used to deliver malaria vaccines for clinical trials in the past, but it's not common.

He and his colleagues went this route because it is costly and time consuming to develop a formulation of a parasite that can be delivered with a needle. The parasites mature inside mosquitoes so at this proof of concept stage – as early stage 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 things old 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 yet ready for prime time. But the small trial of 26 participants did show that the modified parasites protected some participants from a malaria infection for a few months.

Murphy believes this approach could someday result in a vaccine that's substantially more effective than 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 an efficacy rate of 30-40%.

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 $4,100 payment for participants. But when she spoke to friends who'd contracted malaria, she found a different motivation. She said it was no longer about the money at that point – though it was still nice – but instead being a part of important research.

Malaria parasites live in the salivary glands of Anopheles mosquitoes. The disease is most common in Africa where the warm climate suits the growth of the parasite. People get malaria from the bite of an infected mosquito. Infected people can pass the malaria parasite to mosquitoes who bite them, and the cycle of infection continues.

Countries try to curb malaria with mosquito netting, insecticidal sprays, anti-malarial drugs and even by releasing genetically modified mosquitoes that can't bite or lay eggs.

Even with those measures, scientists estimate 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's room for improvement

The reason Murphy thinks this experimental vaccine should stimulate a more powerful immune response than the WHO-approved RTS,S vaccine is that it uses a whole weakened parasite. RTS,S targets "just one out of more than 5,000 proteins" the parasite produces, 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 highly advanced pair of molecular scissors that can cut DNA.

To test how well the approach worked, Reid and the other participants had to get another round of mosquito bites — this time containing the real malaria parasite.

Out of 14 participants who were exposed to malaria, seven of them — including Reid – came down with the disease, meaning the vaccine was only 50% effective. For the other seven, protection didn't last more than a few months.

"I actually cried when they told me I had malaria because I 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 a drug to clear her case of malaria and sent home.

"We think we can obviously do better," says Stefan Kappe, an author of the study and parasitologist at University of Washington Seattle and Seattle Children's Research Institute. He and Murphy hope to improve the efficacy of their team's vaccine by putting it into 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 the one in this vaccine could give the body more time to prepare an immune response. The team is already working on that approach, says Kappe.

If future trials are promising, there are other questions to ponder. For starters: How much would this type of vaccine cost? The scientists are partnering with a small company called Sanaria to produce the modified parasites. Kappe says that increasing production capability to scale up manufacturing will require investment.

As for Reid, her experience was so positive that she went on to participate in clinical trials for a bird flu vaccine and the Moderna COVID-19 vaccine. She says that she will continue to enroll in vaccine clinical trials "for the rest of my life actually."