Mosquitoes are often associated with serious diseases such as malaria, dengue fever and yellow fever. However, researchers from Leiden University Medical Center (LUMC) and Radboud University in the Netherlands may have discovered a valuable new role for insects: as vaccine distributors.

Their scientists say they have successfully engineered mosquitoes to deliver a vaccine that has the potential to significantly boost immunity against malaria.

The World Health Organization’s latest World Malaria Report shows that an estimated 597,000 people will die from malaria globally in 2023, with African countries bearing the brunt, accounting for 95% of malaria deaths.

Scientists estimate that more than 240 million cases of malaria occur worldwide each year. Children and pregnant women are the most vulnerable to this disease.

How do mosquito-borne vaccines work?

The vaccine uses a weakened strain of Plasmodium falciparum, the parasite that causes the deadliest form of malaria in humans.

“We have removed an important gene in the malaria parasite but still allow the parasite to infect humans without making them sick,” explains vaccinologist Meta Roestenberg., Professor of Vaccinology and Clinical Director of the Human Infection Control Center at LUMC.

Typically, malaria parasites are transmitted to humans through bites. Mosquitoes use their long, needle-like mouths called proboscis to pierce the skin, inject saliva into the bloodstream, and then suck the blood. Parasites in saliva travel directly to the liver, multiply rapidly there, and then leave the liver to infect red blood cells with malaria. This can cause symptoms such as fever, chills, and sweating.

In clinical trials, the team used mosquitoes carrying modified parasites to deliver the vaccine through bites, which mirrors the natural spread of malaria. Goal: To generate a strong immune response in the liver and protect against malaria infection.

“Because the gene is turned off, the parasite cannot complete its development in the liver, cannot enter the bloodstream, and therefore does not cause disease symptoms,” Rothenberg said. “At least in theory.”

How is the trial conducted?

The first trial tested an injectable malaria vaccine derived from a genetically modified parasite called PfSPZ GA1. The study, a collaboration with Sanara, the US biotech company developing the vaccine, involved 67 participants from two Dutch cities: Leiden and Nijmegen.

research results, publish An article published in the journal Science Translational Medicine in May 2020 showed that the GA1 vaccine was safe to use and delayed the onset of malaria, but did not prevent participants from contracting the disease.

In a second trial, participants who had not had malaria before received mosquito-borne versions of two vaccines – GA1 and a modified GA2. After administration of the GA1 vaccine, the parasite can replicate in the liver within 24 hours. With the GA2 vaccine, the parasite can multiply for a longer period of time (up to a week), which gives the immune system more time to recognize it and start fighting it.

The researchers first tested doses of the GA2 vaccine on participants to determine its safety and tolerability. Participants were then divided into three groups: two tested the GA1 and GA2 vaccines, and one received a placebo.

Across three games, participants were bitten 50 times: eight by GA1-infected mosquitoes, nine by GA2-infected mosquitoes, and three by uninfected mosquitoes. Participants who completed the immunization phase were subsequently bitten five times by mosquitoes carrying malaria parasites.

What was the result?

result study Published in the New England Journal of Medicine in November.

According to the trial, 13% of the GA1-infected group and 89% of the GA2-infected group developed immunity to malaria. No one in the placebo group developed immunity.

Is further research needed?

Experts say that due to the small sample size of the clinical trial (20 participants), the GA2 vaccine still needs to be tested in larger studies.

More research is needed to determine how well the GA2 vaccine strengthens the immune system over a longer period of time and whether it can protect against different strains of the malaria parasite in areas where the disease is common.

“Using mosquitoes as vectors is an easier and faster way to transmit malaria sporozoites,” explains Rostberg. “Of course, this is not sustainable in the long term, so the product has to be developed as a vial vaccine and then rolled out in Africa.”

“It is not possible to use mosquitoes for mass immunization. This is only feasible in the context of clinical trials,” she added.

Have insects ever been used to deliver vaccines?

Japan, 2010

In 2010, Japanese scientists genetically modified mosquitoes to carry in their salivary glands a vaccine against leishmaniasis, a parasitic disease commonly spread by sandflies. The vaccine is secreted through saliva during a mosquito bite.

Studies have shown that rodents bitten by “flying vaccinators” developed antibodies against the parasite. However, researchers have yet to determine whether the resulting immune response is sufficient to prevent infection.

“After being bitten, a protective immune response is induced, just like a traditional vaccination, but without the pain and cost,” lead researcher Shigeto Yoshida of Autonomous Medical University said in a statement.

United States, 2022

A September 2022 study in Seattle, Washington, involving 26 participants, explored the potential of mosquitoes as vaccinators.

In a trial similar to one conducted in the Netherlands, mosquitoes served as vectors for malaria-causing Plasmodium parasites that had been genetically weakened using CRISPR gene-editing technology. This is the first major clinical trial to use mosquitoes as a direct vaccine delivery system for genetically modified parasites.

Participants were first vaccinated against malaria and then given the malaria virus to see if the vaccine protected them from contracting malaria.

The mosquito-borne vaccine was 50% effective, with seven of 14 participants contracting the disease.