The end of a massive killer - The Malaria vaccine story

 

A program on BBC iPlayer tells the story of the search for the first Malaria vaccine. This is an exciting story. It has everything, from an exciting detective story to romance, horror, thriller, and finance. The individuals involved go from country to country, from London, Oxford, and New York to Villages in Africa and India. It involves multi-million organisations and sole individuals working against the system. It is recorded that one child dies every minute from Malaria, and it is a significant killer in a large number of countries. This program tells the story of how the Oxford University Team, the same team that developed the COVID-19 vaccine AstraZencetra as part of the Academic Vaccine Development Program. They had produced about 3 billion doses and had been used in 170 countries. This was also helped by a grant from the EU.

Malaria was endemic throughout the Western world. It got its name from Rome. The "bad air" (Medival Latin' mala aria') surrounding Rome due to the swamps was thought to be the cause. This protected Rome initially because any invading army had to go through the swamps surrounding Rome, resulting in the unprotected dying in hundreds. As Rome developed and expanded, these swamps and marshes were eventually drained. After WW2, the US military and others decide to fight a war against Malaria. Extensive swamps were event drained; those that could not be drained had either a thin layer of oil placed in them or insecticides were extensively used, including DDT, and all cases of Malaria were identified and treated. In less than 10 years, Malaria was eradicated from specific areas, remaining only in the lower socioeconomic countries.  

The mosquito females are bloodsuckers because they need a high-protein meal to produce eggs, spreading the disease. The organism that actually causes the most common form of Malaria is Plasmodium falciparum, a unicellular protozoan parasite of humans and the deadliest species of Plasmodium that causes Malaria in humans. The Malaria Plasmodium falciparum larvae (sporozoites) are found in an infected Mosquito's salivary gland. The saliva from the glands is injected into the blood as it contains an anticoagulant, which prevents the blood from clotting and blocking the Mosquito's mouth-like tube. The male Mosquitoes are vegetarians. Once in the blood, the sporozoites go straight to the liver, where they reproduce after a period of dormancy. The initial transient blood sporozoite stage before it goes into the liver cells is what the scientists have identified as being the most vulnerable point. If you are to attack the protozoa in the human body, do it at the point before it reproduces. It is weak, and they are few in number. Giving a short window for attack, i.e. 30 minutes to 2 hours. Once it enters the Liver cells, it is known as the Hepatic Stage. The sporozoites mature in the liver into Schizonts. The initial transient blood sporozoite has a weakness that can be exploited, as it needs an enzyme (protein) to attach and penetrate the Liver cells. This enzyme can have antibodies attached to it, lighting the whole sporozoite like a Christmas tree and marking it for destruction by the White Blood Cells. These Schizonts divide into multiple Merozoites and burst out of the Liver Cells. Merozites then invade Red Blood Cells (Erythrocytic Stage) and can go into either of 2 stages. Some of them recycle themselves, infecting and reinfecting Red Blood Cells. Others mature into Gametocytes in the Red Blood Cell to be picked up by another female Mosquito, infect the Mosquito, and make their way to its Saliva Glands. For the cycle to repeat itself again. Hence, unwittingly, the Mosquito becomes the carrier of this disease.

The organism that causes Malaria is not a virus or bacteria but a protozoa. Malaria has an Achilles heel, especially at the Sporozite, when the larvae enter the Liver Cells. It needs a protein enzyme called Circumsporozite Protein (CSP) to enter the Liver Cells. This is its place of vulnerability as the sporozoite is only in the bloodstream for 30 minutes to two hours. The Sporozoites multiply asexually in the liver cells over the next 7 to 10 days, causing no symptoms. If there are antibodies to the CSP, it then marks the Sporozoites for destruction and their subsequent removal by the White Blood Cells, then we have a winner. This journey had been long in the making. RTS, S/AS01 (trade name Mosquirix) is a recombinant protein-based malaria vaccine. It was made in 1987 with 40% efficacy and was expensive, so most African countries could not justify its usage. 

Hence, after COVID-19 hit the world, AstraZeneca and Oxford's Jenner Institute developed the Messenger RNA (mRNA) vaccine. They have distributed about 3 billion doses to about 170 countries and are estimated to have saved more than six million lives. They used the technology and methodology to develop a Malaria vaccine. They have been working on a vaccine for Malaria for the past 15 years. 142 vaccines were accepted into Clinical trials, and a few worked. This is a highly complex process, and if it were to be done by a commercial entity, it would have since stopped. Still, being an Academic Vaccine Development Program, the funds came from the government, charity organisations, the public, etc. They produced a vaccine 2012 and started testing it in mice, which needed further tweaking and minor alternating. Human trials of the R21/Matrix-M vaccine started in 2015 at Oxford, and the next step was field testing.

Then, after receiving positive feedback from the human trials, they decided that unlike the COVID-19 - vaccine, which was sponsored by big governments, that had numerous people working on it all around the world intensively. In this case, only the Oxford Team was the major contributor, and they did not have the luxury of having the major pharmaceutical giants working on it simultaneously. Most of the time, 6 scientists in the Jenner Institute, compared to hundreds out of thousands in other centres for COVID. Hence, they must scale down and need a cheaper alternative whose price will be scaled down. Then, their partners in India, Serum Insitutitue of India. Serum Institute of India was founded in 1966 by Dr Cyrus Poonawalla to manufacture life-saving immuno-biologicals, which were in shortage and imported at high prices. After that, several life-saving biologicals were manufactured at prices affordable to the common man and in abundance, with the result that the country was made self-sufficient for Tetanus Anti-toxin and Anti-snake Venom serum, followed by DTP (Diphtheria, Tetanus and Pertussis) group of Vaccines and then later on MMR (Measles, Mumps and Rubella) group of vaccines. Serum Insitute is now the world's largest vaccine manufacturer, producing and selling more than 1.5 billion doses globally. The company raised the $10 million needed and started the field tests Phase 1 - 3.  

Mr Adar Poonawalla - CEO of Serum Institute

Phase 1 of the efficacy and immunogenicity of the R21/Matrix-M vaccine against clinical Malaria was done in Burkina Faso, which consists of about 521 individuals; soon after Phase 2 in 2019, 450 showed about 77% efficacy. For Phase 3,  a more significant number started in April 2021 across Mali, Burkina Faso, Kenya and Tanzania. About 800 children were tested. Because of a double-blind study, nobody knew what they were getting, and the control was the Rabies Vaccine. Blood Sa plus was analysed, and a positive response was obtained. Although the Serum Insititute of India made a lot of money from it, they could produce it at a reasonably low price compared to the African country's family record. Having a family-run business that does not depend on share price, elders, or its share price, and investing in the long-term goal and benefit of eradicating Malaria. 

This has been a long story, and following the journey is similar to the incredible journeys and tales we learnt as children. It is so long and complex, and the effects are significant and life-changing that it appears magical and mythological. This is a remarkable feat to achieve or a dangerous monster to be slained (Malaria). We have heroes at the Jenner Institute, Oxford and Serum Institute of India, doctors and nurses on the front line and the various African health teams. Then, there are villains, individuals spreading false information about the vaccine, drawing all of us back into the dark ages. 

These are part of the Oxford Team at Jenner Institute and the field operatives.