A genetic technology known as a gene drive could help prevent malaria by spreading genes in wild mosquitoes that stop them transmitting the parasite. Tests in a lab in Tanzania have now confirmed that one potential gene drive should achieve this if it were released in the country.

“It would be a game-changing technology, that’s for sure,” says at Imperial College London.

A specific piece of DNA in the genome of an animal is normally passed on to only half its offspring, because a parent’s DNA is divided in half among egg or sperm. Gene drives increase this proportion, meaning a bit of DNA can spread rapidly through a population even if it provides no evolutionary benefit.

There are many natural gene drives that work via all kinds of mechanisms – perhaps even in some human populations – and in 2013, biologists developed artificial gene drives using CRISPR gene-editing technology, which works by copying pieces of DNA from one chromosome to another.

The idea is to use these drives to spread bits of DNA that block malaria transmission – but which bits? Christophides reported in 2022 that the development of malaria parasites inside mosquitoes can be greatly reduced by two tiny proteins, one derived from honeybees and the other from the African clawed frog. The added genes for these antimalarial proteins can be linked to the gene for an enzyme that helps mosquitoes digest blood, so the antimalarial proteins are made after a mosquito feeds and get secreted into its gut.

But these tests were done using lab strains of mosquitoes and malarial parasites collected decades ago, so it wasn’t clear if this approach would work in affected African countries today.

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Now, researchers including Christophides and at the Ifakara Health Institute in Tanzania have modified local Anopheles gambiae mosquitoes to produce the components of a gene drive based on this approach. The components were kept separate, meaning the gene drive cannot spread, and the mosquitoes were housed in a secure facility.

Tests show robust inhibition of malaria parasites taken from infected children, and also effective copying of the genes for the antimalarial proteins. “So we are now able to say that this technology could work in the field,” says Christophides.

The next step will be to release mosquitoes that produce the antimalarial proteins on an island in Lake Victoria, to see how they behave in the wild. The team is engaging with local communities there as well as carrying out risk assessments, says Lwetoijera. “To date, the political and public support has remained positive.”

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The hope is that the gene drive could help eliminate malaria from areas where A. gambiae is the only species spreading malaria, says Christophides. “A gene drive may turn the tide,” he says.

Several other groups are also working on gene drives for controlling malaria, and the technology is also being developed for controlling various pests.

Genetically modified mosquitoes are already being released to control wild mosquito populations in some countries, but these approaches rely on continually releasing very large numbers of the insects.

An experimental vaccine that targets a malaria parasite behind a relapsing form of the disease has shown some promise in a small trial. Researchers tested two vaccine candidates, finding that neither had any serious safety concerns, but only one induced a substantial immune response.

The parasite Plasmodium vivax is the second most common cause of malaria in the world, . Unlike Plasmodium falciparum, the parasite that most commonly causes malaria, no vaccine is approved for P. vivax, which can remain dormant in the body and cause a relapse of symptoms.

at the University of Oxford and her colleagues have developed two vaccines against P. vivax, which both target the so-called Plasmodium vivax Duffy binding protein.  in their red blood cells appear to be more resistant to P. vivax.

One of the vaccines, a viral vector vaccine, uses a modified virus to deliver the parasite’s genetic information to cells to induce an immune response. The other, a protein-based vaccine, does this by introducing some of the parasite’s proteins.

In a trial of 18 healthy volunteers – aged 18 to 45 – eight received the viral vector vaccine, while the other 10 received the protein-based vaccine. Due to the covid-19 pandemic disrupting the trial, the timing of different vaccine doses varied among the participants.

Between two and four weeks after their final vaccine dose, the participants were injected with blood containing P. vivax. The team also injected 13 people who weren’t given either vaccine to act as the control group.

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Both types of vaccine were well tolerated and no serious adverse effects were reported.

When it came to the immune response, this was much stronger in those who received the protein-based vaccine, but only in those with a long gap between their second and third doses. Of the 10 protein-vaccine recipients, six received their third dose 13 months after their second dose, compared with a one-month gap for the remaining four participants.

The parasite’s multiplication rate was 51 per cent lower in these six participants than in the control group. This led to these vaccine recipients developing malaria symptoms around a week after everyone else. However, the symptoms weren’t less severe, says Hou. Among the four participants with a one-month dosing interval, the team found no difference in their parasites’ multiplication rate compared with the unvaccinated controls.

Protein-based vaccines generally stimulate antibody responses more effectively than vector-based ones, says Hou. Meanwhile, the increased success rate of the protein-containing vaccine when given with a delayed dosing interval has been seen in other vaccines, she says. “We don’t understand how it works in detail, but it’s probably related to giving the immune system more time to develop a good response.”

The researchers are now testing the vaccine in a larger trial. They also plan to use the study’s results to create a new vaccine that is even more effective at preventing the parasite from replicating in the blood. “I think one of the really happy things about seeing these results is that we can actually induce an effect,” says Hou. “It might not be strong enough yet, but we know that it’s possible.”

Ghana is the first country to approve a new, highly effective malaria vaccine called R21/Matrix-M. The decision marks a milestone in the efforts to combat a disease that killed in 2021, most of them young children.

The country’s Food and Drugs Authority authorised the shot on 13 April for children between the ages of 3 and 5 years old – the age group most vulnerable to dying from malaria in areas with high transmission rates. A majority of countries in Africa, including Ghana, account for 95 per cent of all malaria cases worldwide, and 96 per cent of deaths. Children under 5 account for 80 per cent of deaths in the region, according to the World Health Organization (WHO).

Immunisation with the recently approved vaccine involves three primary doses followed by a booster shot one year later. While the vaccine’s phase III trial is still ongoing, an earlier phase II trial conducted in 2019 found it was 77 per cent effective at preventing infection. The only other approved malaria vaccine – Mosquirix, manufactured by UK pharmaceutical company GSK – is about 30 per cent effective at protecting against severe illness.

R21/Matrix-M is the first vaccine to exceed the WHO’s malaria vaccine efficacy goal of . The WHO has not yet approved it, but according the , the organisation is reviewing data from the ongoing phase III trial involving 4800 children. The drug’s developer, the University of Oxford, is expected to report data on that trial later this year.

The drug’s manufacturer, the Serum Institute of India, said in that it has the capacity to produce more than 200 million doses of the drug annually – significantly more than the yearly doses of Mosquirix promised by GSK.

“Malaria is a life-threatening disease that disproportionately affects the most vulnerable populations in our society and remains a leading cause of death in childhood,” said at the Serum Institute of India in a press release. “The licensure of the R21/Matrix-M for use in Ghana is a significant milestone in our efforts to combat malaria worldwide.”

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An invasive species of mosquito from Asia has been linked to a malaria outbreak in Ethiopia earlier this year. These insects persist even through the dry season, when other mosquitoes lack the outdoor water sources needed to lay their eggs, and are now invading neighbouring countries.

Most malaria infections in Africa are spread through the mosquito Anopheles gambiae, but Anopheles stephensi has taken a foothold on the continent’s east coast. The spread of this invasive species could complicate the effort to eradicate malaria, a mosquito-borne disease that kills around .

A. stephensi lays eggs in water and feeds on blood to reproduce, and the species was first confirmed in Djibouti in 2012 when the nation was close to eliminating malaria. Now, the country has thousands of cases each year.

Over the last decade, the species has spread to Ethiopia, Sudan, Somalia, Yemen and Nigeria. In spring 2022, the city of Dire Dawa in eastern Ethiopia saw an increase in malaria from around 200 cases per year to around 2400 cases, says ‪ at Armauer Hansen Research Institute in Ethiopia.

“There was a huge increase in cases, but there was no formal investigation of what caused the increase,” he says. “So, we decided to jump in and investigate.”

When residents sought medical care for malaria at two local clinics in Dire Dawa, Tadesse and his team screened the patients’ close contacts for the disease and looked for mosquitoes within a 100-metre radius of each household. Their study spanned April to June 2022 and included around 1000 participants.

As Tadesse expected, they found a close link between the presence of A. stephensi and the rate of malaria in the city. Around 97 per cent of the mosquitoes the team found were A. stephensi.

People living in households with water storage containers, where the insects could lay eggs, were more than three times as likely to test positive for a malaria infection than those without. Tadesse presented these results at a meeting of the American Society of Tropical Medicine and Hygiene in Seattle on 1 November.

Because A. stephensi prefers to lay eggs in residents’ water storage containers in addition to outdoor water sources, it can persist throughout the dry season. “Instead of two or three months, [malaria season] will be 12 months a year,” says at the University of Khartoum in Sudan, who was not involved in the work. Without significant investment in preventing the insects’ spread, says Ahmen, “catastrophe is coming”.

Malaria-carrying mosquitoes have been genetically modified in a way that slows the development of any malaria parasites inside them and also reduces the lifespan of the mosquitoes. The result is that the modified insects die before they can spread the disease.

Lab studies and computer models suggest this could completely stop the spread of the deadly parasite, says team member at Imperial College London.

“The combination of the two will eliminate malaria transmission,” he says.

For the approach to work, something called a gene drive would have to be used to spread the required genetic modification throughout wild mosquito populations. This is a mechanism that leads to a specific piece of DNA being inherited by all offspring, rather than just half as usually happens. The gene drive makes that piece of DNA spread in a population even if it is disadvantageous.

No engineered gene drive has yet been used in the wild – although naturally occurring versions exist – but CRISPR-based gene drives have been successfully tested in caged mosquitoes.

Researchers in Tanzania are now altering local mosquitoes in the same way as the researchers in London to see how well the modification works against local malaria parasites. If these studies are a success, the teams hope to collaborate on field trials in Tanzania, but for now the work is confined to labs.

“We are not releasing anything,” says Christophides.

The new work relies on the fact that it takes between 10 and 12 days for malaria parasites to develop within a mosquito and reach its salivary glands. Only at that point can mosquito bites infect people, yet in the wild Anopheles gambiae mosquitoes, which can carry malaria, typically live for just 10 days.

“So you can crash the entire transmission cycle by delaying parasite development,” says Christophides.

To do this, his team genetically modified A. gambiae mosquitoes so that cells in their guts secrete two small proteins previously shown to delay parasite development. One of these proteins comes from the African clawed frog, the other from honeybees.

When the modified mosquitoes are infected, it takes a few days longer before malarial parasites can be detected in the heads of the mosquitoes, the team has shown. What’s more, the change also shortens the lives of mosquitoes by a couple of days, says Christophides, further reducing the chances of any mosquitoes surviving long enough to become infectious.

There are two potential problems with the approach. As a gene drive spreads the modification, there would be a risk of malarial parasites evolving resistance to the two proteins. To avoid this, it will be important to spread the modification among mosquitoes as much as possible, says Christophides. The faster a parasite population collapses, the lower the odds of resistance evolving.

It is also possible that mosquitoes evolve in a way that stops the gene drive working. The gene drive would be designed to minimise this risk, says Christophides.

Other groups are working on gene drives designed to wipe out mosquito populations, for instance by making all female offspring infertile while males remain fertile and continue spreading the gene drive.

These two approaches could potentially be used together. For instance, a killer drive could be used to wipe out mosquitoes in a region and then any that survive or come in from another area could be modified by another drive to prevent them spreading malaria.

“We believe that both of them can contribute,” says Christophides.

In Brazil, are already being released to reduce wild mosquito numbers. These GM mosquitoes carry a gene that kills the offspring of any female mosquitoes they mate with. There is no evidence that this gene persists in the wild.

Malaria still kills nearly half a million people every year, mainly children. Last year, a malaria vaccine was approved for the first time and another one could be approved soon, but these are only partially effective.

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