A global programme that aims to modify mosquitoes so they are unable to transmit malaria has received a grant to fund its next phase of expansion.

The Transmission Zero programme, led by Imperial College London in the UK, and the Ifakara Health Institute and National Institute of Medical Research in Tanzania, has received a grant for US$15 million from the Bill & Melinda Gates Foundation.

By moving forward with urgency, we treat malaria as the emergency that it is Dr Nikolai Windbichler

Half of the world’s population is at risk of contracting malaria, a disease caused by parasites that are transmitted from one person to another through bites from Anopheles mosquitoes. In 2021 alone, there were over 247 million cases and 619,000 deaths from malaria, mostly children under five years old in sub-Saharan Africa.

With current measures failing to halt disease transmission, new ways to control the spread of malaria are desperately needed. Transmission Zero is a global programme led by scientists at Imperial College London (Imperial) and the Ifakara Health Institute (IHI) of Tanzania, in partnership with the Tanzanian National Institute of Medical Research (NIMR), which aims to modify specific species of mosquitoes so that they are unable to transmit the disease.

The group has already successfully created and tested such a mosquito strain in Imperial’s labs, and recently announced the first transgenic (genetically modified) mosquito strain ever to be made in Africa by IHI researchers.

The new funding will be used to substantially expand the operations of Transmission Zero both in the UK and in Tanzania, building increased research and supporting activities as the programme scales up.

The Transmission Zero programme is co-led by Professor George Christophides and Dr Nikolai Windbichler from the Department of Life Sciences at Imperial.

Dr Windbichler said: "We are excited about the potential of the gene drive technologies we are developing and by moving forward with urgency, we treat malaria as the emergency that it is."

Professor Christophides added: “We want to move fast, but we also have to do this the right way so that everyone is on board, from senior policymakers to local community members, and we can demonstrate that the technology is effective and safe.”

Expanding research

The research programme includes deeper research into the team’s lead malaria-resistant mosquito strain, the development of new strains and tools for driving malaria resistance in wild mosquitoes in the laboratory, and work to identify new anti-malarial agents that could be used in further interventions to curb the spread of the disease.

This will bring the project closer toward eventual field trials involving controlled releases of the modified mosquitoes. The team has identified possible sites for trial releases, and will now profile the environment for each, including the insect population and disease dynamics. This will inform models of the spread of the modification and its impact on disease transmission.

The team will also seek regulatory approval and, importantly, buy-in from local communities for research activities and field trials, for which they will develop a stakeholder engagement plan. This will include both workshops and conferences with high-level stakeholders, policymakers, and journalists, alongside dedicated community meetings, workshops and outreach events to foster a two-way dialogue between Transmission Zero and local communities in Tanzania.

Lengthening the odds

Malaria spreads when a female mosquito bites a person who is infected with the parasite that causes the disease. Inside the mosquito, the parasite goes through several life stages before it's ready to infect another person when the mosquito bites again.

But not all mosquitoes live long enough for the parasite to become infectious. To make it even harder for the parasite, the team found a way to slow down its growth inside the mosquito. They did this by introducing a modification to the main mosquito species responsible for spreading malaria in sub-Saharan Africa, known as Anopheles gambiae.

When this genetically modified mosquito feeds on blood, it produces two immune molecules in its gut, which were originally derived from honeybees and frogs. These molecules delay the parasite’s development and, at the same time, reduce the mosquito's lifespan. Consequently, most mosquitoes would die before having the chance to transmit the disease.

A model developed by collaborators of Transmission Zero from the Institute for Disease Modeling found that the modification could be a powerful tool for bringing down cases of malaria even where transmission is high.

Dr Dina Vlachou, a Transmission Zero senior scientist from Imperial, said: “We know we can stop parasites cultured in the lab from growing in this modified mosquito. But we need to understand this process better and see if it works just as well in the real world, stopping parasites taken from people naturally infected with malaria from being able to transmit through the mosquitoes.”

Spreading a modification

To use the genetic modification to prevent malaria spread in the real world, it must be transferred from laboratory-bred mosquitoes to wild ones. Normal breeding could spread the modification to some degree, but because it comes with the drawback of reducing the mosquito's lifespan, natural selection would likely remove the genetic modification from the mosquito population rather quickly.

That's where a genetic modification technique called a ‘gene drive' comes in. When added to the mosquito, a gene drive ensures that the antimalarial modification is efficiently passed on to the next generation, allowing it to spread quickly and widely among natural mosquito populations.

Since this approach is quite new and carries potential risks, it requires careful planning before any field trials can be carried out. For example, the mosquito modifications may not be effective against wild strains of malaria parasite or may lead to unintended (off-target) effects on transmission of other diseases.

The Transmission Zero team is therefore pioneering a cautious, stepwise approach. They are developing two separate but compatible strains of modified mosquitoes: one with the antimalarial modification and another with the gene drive.

We've taken the first step, and we're not stopping here. Dr Tibebu Habtewold

Their plan is to first test the effectiveness and safety of the antimalarial modification alone. If there are any issues with the modified mosquitoes, these will naturally die out and be removed from the population without the presence of the gene drive, providing an off-ramp and ensuring safety.

They will only introduce the gene drive if this modification proves to be effective and safe, helping to reduce malaria transmission as intended.

The new phase of the project will span the next three years, resulting in a regulatory dossier for stage 1 and 2 field trials of the lead mosquito strain by the end of 2026. Stage 1 field trials could therefore begin at the start of 2027, starting with only the antimalarial modification.

Towards elimination

This fundamental research coupled with the establishment of a facility at IHI to generate and handle genetically modified mosquitoes puts the Transmission Zero team in a strong position to progress towards the first stage of such field trials.

Dr Tibebu Habtewold, a key member of the Transmission Zero team who played a central role in creating the first genetically modified mosquito strain in Tanzania, highlighted the importance of Africans leading the way in developing this technology on the continent, as they are the ones most affected by malaria. He said: "We've taken the first step, and we're not stopping here."