Human challenge trial points the way to more effective malaria vaccine | Imperial News

Infecting volunteers with malaria could explain why some get the disease and others don't, and suggest ways to induce stronger immunity through vaccination.

“Human challenge” studies, in which volunteers are intentionally infected with malaria, have revealed important insights into how to design new, more effective malaria vaccines. Malaria is transmitted by certain types of mosquitoes and is responsible for an estimated 608,000 deaths in 2022, mainly in sub-Saharan Africa.

The study found that only a small part of a malaria infection is generating antibodies that attach to the pathogen and block it from entering human cells — the basis of most vaccines — and that antibodies that effectively “recruit” other parts of the immune system are more protective against malaria infection.

These discoveries could lead to improved vaccines for malaria and other diseases, potentially saving many lives around the world. Professor Faith Oshie

An international team of researchers has already identified one potential pathway for producing these kinds of antibodies and is producing vaccines on multiple platforms to determine which one elicits the most effective response.

The study, led by scientists from Imperial College London, Heidelberg University Hospital and the Kenya Medical Research Institute, was published in the journal Neurology. Immunity and Life Sciences Alliance.

Principal Investigator Professor Faith OshieCo-director Institute of Infectious Diseases Professor of Malaria Immunology and Vaccinology Department of Life Sciences Director of Imperial College London, Vaccination Hub“Malaria remains a significant burden, claiming the lives of hundreds of thousands of people each year, most of them children under the age of five. While there are many tools available to fight the disease, progress has stalled and there is a desperate need for a highly effective, long-lasting malaria vaccine,” said Dr.

“Our study shows that previous thinking about vaccines was too limited in terms of how they work. These findings could improve vaccines for malaria and other diseases and save many lives around the world.”

Vaccine design

Designing a vaccine for malaria is more challenging than for infectious diseases such as COVID-19 due to the complexity of the malaria parasite: the virus that causes COVID-19 is made up of around 30 protein components, whereas malaria is caused by a parasite made up of more than 5,000 protein components.

The malaria parasite also changes into several different forms in both humans and mosquitoes as it completes its life cycle. For the immune system, this means keeping track of the ever-changing invader.

Clinical symptoms of malaria appear after the parasite invades human red blood cells, where it multiplies and continues to infect and destroy new red blood cells. Therefore, vaccine development has logically focused on blocking the parasite from entering human cells, a strategy known as invasion inhibition.

It works by interfering with a protein “lock and key” system – a protein on the parasite is the lock and a protein on the red blood cell is the lock. The vaccine works by producing antibodies that attach to the lock on the parasite and block the lock and key interaction.

Identifying the “key” to malaria has been difficult. The two currently licensed malaria vaccines target one key, a circumsporozoite protein found in the form of the parasite injected into the skin by mosquitoes. These vaccines have efficacy ranging from 30-75% and require multiple repeated doses. Administration can be difficult as they require refrigerated storage and are often required in remote areas.

Goldmine Data

To design a better malaria vaccine, the team went back to basics, based on their observations of malaria in Africa: Why do some infected people get sick while others don't? To find the answer, the team conducted human experiments: they intentionally infected volunteers with malaria and studied in detail how their immune systems responded.

Thanks to the wealth of data available from human challenge studies, [we] It is working on developing and testing several vaccines. Professor Faith Oshie

The Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA) study involved 142 adult volunteers living in Kenya who had previously been infected with malaria multiple times through mosquito bites.

All volunteers were given an intravenous injection of a strain of malaria parasite that can be cured with antimalarial drugs if they became ill, and their health was then closely monitored for three weeks in a secure facility.

This produced what Professor Oshie calls a “gold mine of information”. The main finding was that the production of “lock-blocking” antibodies did not distinguish between the group of volunteers who got sick and those who did not.

Instead, volunteers who produced antibodies that were better at “recruiting” other parts of the immune system, such as macrophages, neutrophils, and natural killer cells, were more likely to be protected from developing clinical symptoms of malaria.

New Directions

The team also discovered that the game isn't over once red blood cells are invaded: They found that the parasite leaves protein traces on the surface of infected as well as uninfected red blood cells, which are detected by the same antibodies that are good at recruiting other components of the immune system. This part of the study Nature Communications.

Professor Oshie said: “Antibodies are the 'conductors' of the orchestra: other parts of the immune system cannot function without their instructions. Antibodies can play a dual role, both fighting infection and mobilising other parts to complete the symphony.”

“A new direction in vaccine research is emerging – this time, finding the 'right' protein on the pathogen to which these 'conductor' antibodies can attach. Thanks to the wealth of data from human challenge studies, we have already found candidates and are working on creating and testing several vaccines.”

“This study convincingly demonstrates the power of human challenge studies, not only in providing detailed data but also in opening entirely new avenues of research that are urgently needed to design better vaccines.”

Local manufacturing

Professor Oshie also £6.5m vaccine manufacturing hubThe Changjo Hub is an African-led industry-academia collaboration that aims to foster the local “ecosystem” needed to establish vaccine manufacturing in Africa through pilot projects in Kenya and Ghana.

They are currently producing an malaria vaccine based on the protein identified in their study, and the team hopes that this program will serve as a prototype for developing and strengthening vaccine manufacturing capacity in low- and middle-income countries.

Histesh Vajiani, Managing Director of partner Tasa Pharma, said: “Tasa Pharma is pleased to work with Professor Faith Oshie and Chanjo Hub to advance and localize vaccine production in Africa. This partnership marks a pivotal step towards achieving vaccine self-sufficiency and propels the development of a groundbreaking malaria vaccine for the region. Together, we are poised to make a positive impact on public health in Africa and advance a new era of healthcare resilience.”

Dr LM Bryden, CEO of partner Avril Biopharma, said: “We are pleased to support this groundbreaking effort led by Professor Oshie and his team at Imperial College London with our recombinant production technology. The end-to-end development of a next-generation malaria vaccine in Africa, by African scientists, industrialists and regulators, is a key milestone for this project. The catalytic role of the Changjo Hub will be crucial to its success.”

Philip Probert, technical lead at partner CPI (Center for Process Innovation), said: “We are delighted to be working with Professor Oshie to develop a more effective malaria vaccine for low- and middle-income countries. This is a very exciting project for us and the impact it could have on saving hundreds of thousands of lives each year is incredible. By contributing our knowledge and expertise in the development and manufacturing of novel vaccine therapies, we aim to accelerate the development of this life-saving treatment and expand its reach around the world.”

Dr Ebenezer Ansah, Director, CSIR (Council for Scientific and Industrial Research), said, “It was truly inspiring to interact with Professor Oshie and her team during her visit to CSIR. Her passion for using cutting edge technology to build vaccine development capacity in Africa is a great source of inspiration for our team in Ghana. This initiative will undoubtedly increase vaccine acceptance and usage in the region.”

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'Breadth of Fc-mediated effector functions correlates with clinical immunity following human malaria infectionBy Eileen N. & Rodney Ogwang et al. Immunity.

'Full-length MSP1 is a major target of protective immunity following controlled human malaria infection” ” by Mika Rosenkranz et al. Life Sciences Alliance.

'Phagocytosis of Plasmodium falciparum ring-stage parasites predicts protection against malaria” ” by Fauzia Mousasisa et al. Nature Communications.