New hope for malaria vaccine: the science, challenges, opportunity

After decades of slow progress, there seems to be light at the end of the long tunnel. WHO approval in October 2021 for RTS,S/AS01 (Mosquirix) developed by GlaxoSmithKline for immunising children was a major milestone. Although RTS,S/AS01 has modest efficacy and reduces severe malaria cases by only about 30 per cent after four doses given to children under age 5, it still provides significant public health benefits, and could save thousands of lives every year.

It took more than 30 years and approximately $700 million for this breakthrough, which underscores the scientific and logistic challenges in developing a vaccine against a parasitic disease like malaria. GSK has granted Bharat Biotech licence to manufacture Mosquirix, and by 2029, the Hyderabad-based company is expected to be the sole global manufacturer of this vaccine.

However, RTS,S/AS01 fails to meet the WHO’s own benchmark for malaria vaccine efficacy of 75 per cent set in 2015. In September 2021, another malaria vaccine, R21/Matrix M, developed by the University of Oxford in the UK, demonstrated an efficacy of 77 per cent in phase 1 and 2 trials among 450 children in Burkina Faso. In early September 2022, this vaccine once again made headlines after publication of results of a booster dose of R21/Matrix-M in the journal Lancet Infectious Diseases showed a high efficacy of 80 per cent was maintained after two years.

Ways the vaccines work

RTS,S and R21 are similar in that they both contain the same part of a major protein that is found on the surface of the liver stage parasite, called sporozoite. Both also contain hepatitis B virus surface antigen (HBsAg), a protein that has an ability to self-assemble and that helps as the formation of virus-like particles of the CSP antigen fused with it.

The important difference between the two vaccines is in the amount of the HBsAg. RTS,S has about 20 per cent of the fusion protein, with the remaining 80 per cent made up of HBsAg antigen, produced separately. R21, on the other hand, is made up entirely of the CSP fusion protein moieties, resulting in much higher proportion of CSP antigen displayed on the virus-like particle surface, which significantly raises its exposure to the immune system of the host.

To boost immune responses, all protein based recombinant vaccines rely heavily on a strong adjuvant. RTS,S is formulated with an adjuvant called AS01 developed at GSK; R21 employs an adjuvant called Matrix-M developed by Novavax (Sweden). Matrix M contains saponin-plant based material and stimulates both antibody and cellular immune responses to vaccines. Both adjuvants have shown high levels of efficacy and safety. Matrix-M has been used in a variety of vaccine formulations against influenza, and more recently in the Novovax Covid-19 vaccine.

Phase 3 results awaited

While the recent results of a booster dose of R21 have created well-deserved excitement, the results of a larger phase 3 trial of the vaccine will be keenly awaited. Phase 3 trials of R21 are already underway in children aged 5-36 months in four African countries, including two in which malaria is a year-round threat. In these trials, efficacy and safety of R21 will be tested in 4,800 children across five sites in Burkina Faso, Kenya, Mali, and Tanzania. The first results are expected by the end of 2023.

Large-scale, well-collected safety data will be required to build the risk-benefit assessment. The SARS-CoV-2 experience has served as a reminder that significant adverse events may not be detected until millions of immunisations have been recorded.

The road ahead is long, but R21, alone or in combination with an efficacious blood stage or transmission stage vaccine candidate, can continue to be developed to achieve the ultimate goal of malaria eradication. It is clear that Indian companies will play a central role in the development and/ or production of efficacious malaria vaccines at an affordable cost.

India: weakness and strength

Why has India not been more successful in developing vaccines against diseases including malaria — especially when basic malaria research in India has been robust and there are well established malaria research and control centres across the country?

A major gap is in the establishment of safe and scientifically robust control human infection models in India for diseases like malaria or influenza. All malaria vaccines under development need to be tested in the safe and scientific robust Controlled Human Malaria Infection (CHMI) model after completing phase 1 safety studies. This has been established in many countries of Europe, the UK, Colombia, and Thailand. Both RTS, S and R21 were tested in CHMI before further safety and efficacy field trials.

Scientists at the International Centre for Genetic Engineering and Biotechnology (ICGEB) Delhi have carried out phase 1 safety trials of two experimental blood stage malaria vaccines developed and produced in the country. But further development of these vaccines has been a challenge in the absence of the CHMI model in India. Scientific, long term continuous funding, regulatory and logistic processes need to be better coordinated to assist scientists in the development of novel vaccines against infectious diseases. With a highly successful and deeply committed vaccine-producing biopharma industry and a strong scientific base, India should be able to lead the world in developing and producing vaccines.

Dr Chauhan is Emeritus Senior Scientist at ICGEB, who has made significant contributions to the development of a recombinant vaccine for malaria.