Vaccines have been prominent during the course of the Covid pandemic, with the development of several highly efficacious ones (over 90% protection) in less than a year. Even though much preparatory work had already been done, this was an outstanding achievement.
Contrast this with the case of malaria, a scourge for thousands of years. After 200 years of vaccination techniques (one of the first examples of doctors actually preventing illness), and 50 years of research into a malaria vaccine, only in the last few weeks have we heard of one, R21, which is 75% effective against malaria (the WHO target), an improvement on its predecessor, RTS,S, at about 55%.
Malaria, despite its name (Italian: mal’aria = bad air), is caused by the protozoon* Plasmodium, a parasite of insects and vertebrates. Infection is transmitted in the bite of the mosquito, the females of which require blood meals to provide protein for egg production: those infected with Plasmodium parasites in their salivary glands inject them into their victims; mosquitoes are themselves infected when they take blood from a malaria sufferer.
The extent of malaria
Malaria features in recorded history from the earliest times, probably becoming a major problem when agriculture first developed and population densities became great enough to support endemic illnesses. Plasmodium parasites have been found in a mosquito preserved in amber from 30 million years ago. Mosquitoes date from the Jurassic period,Plasmodium probably from a similar time, so it is quite plausible that dinosaurs could have caught malaria.
At its greatest extent, malaria affected every continent except Antarctica (being imported to the Americas by Europeans). In England, as “ague”, it was common in coastal marshlands, including London, causing significant mortality. Mentioned in eight Shakespeare plays, malaria may have caused the death of Oliver Cromwell. It was eliminated by the draining of marshes, the last natural UK cases being in the early 20th century. Nowadays, it is largely confined to the tropics, with over 90% of cases being in sub-Saharan Africa. Through debility and deaths, malaria imposes a substantial economic burden in health costs and loss of productivity, hindering the growth of affected countries. The WHO estimates 230 million cases in 2019 worldwide, with 400,000 deaths, two thirds being of children under five.
Malaria and human evolution
In earlier times, when the cause of malaria was not known, it exerted a significant selection pressure on human populations. Genes providing a measure of protection spread in susceptible populations since their possessors had a better chance of surviving to adulthood. These genes coded for the production of mutant forms of haemoglobin which somehow interfered with the infection: resistance to malaria was greatest in individuals carrying one normal haemoglobin gene (inherited from one parent) and one mutant gene (inherited from the other).
However, those children inheriting two mutant genes suffered from severe life-shortening anaemias, the most common of which are sickle cell anaemia (among people of African ancestry) andthalassaemia (among those of Mediterranean ancestry). Back in the 1940s, the socialist geneticist, JBS Haldane calculated that heterozygotes (i.e. one normal and one mutant gene) for thalassaemia had a more than 2% survival advantage over those with only normal genes in areas of high malaria incidence, even though the double mutant caused very painful and debilitating symptoms, before an early death. The latter is a serious problem among descendants, who are no longer at risk of malaria, though life expectancy has been greatly increased by modern medicine.
Defences against malaria
Simple physical barriers to biting mosquitoes, such as insecticide-treated bed nets, prevent infection while sleeping. Spraying insecticides (such as DDT) in mosquito breeding grounds or in homes helped reduce numbers of mosquitoes but the insects started evolving resistance; there were also adverse effects on other wildlife. Drugs, such as quinine and artemisinin (both from folk remedies), which interfered with Plasmodium’s life within red blood cells, were and are effective, but resistance has quickly evolved. Other drugs, such as chloroquine and Lariam, can get round resistance to earlier drugs but resistance to these is now known, too.
Vaccines against malaria: the problem
As with smallpox, polio, and several major killers of children in the past, a vaccine against malaria would seem the ideal solution. If used widely in the most affected regions, the disease would eventually die out, since Plasmodium requires both parts of its lifecycle to take place. One major problem with a malarial vaccine is the lack of investment by states and drug companies in the developed world, now that malaria is no longer seen as a threat.** But the crucial problem is the complexity of the Plasmodium lifecycle.
The malarial parasite’s lifecycle
When injected (as the sporozoite form) into the blood by the bite of an infected mosquito, Plasmodium parasites rapidly enter liver cells (hepatocytes), where they are hidden from the immune system. There, they change into the merozoite form and multiply into some 30,000 descendants. The hepatocytes burst, releasing the merozoites into the blood, where they enter red blood cells (RBCs). Here, the merozoites consume haemoglobin as their food and multiply about 20-fold; they are released in waves to infect more RBCs.
As they are released, the victim feels fever, chills, body aches, headaches and nausea, with each subsequent wave worse, as the number of infected RBCs increases up to 20-fold each time. The victim becomes anaemic and organ damage occurs as infected RBCs clog up small blood vessels; excessive inflammatory responses also harm the victim. Complications include organ failure, cerebral malaria (causing coma, brain damage or death), hypoglycaemia, and breathing difficulties.
In time, the merozoites form male and female sex cells (gametocytes). If taken up in the blood meal of another mosquito, these fertilise each other and new sporozoites are formed in the mosquito’s salivary glands, ready to infect another victim and complete the cycle.
The body does mount an immune defence to the Plasmodium parasite but this is of limited effectiveness, hampered by the fact that, for the vast majority of the time, the parasite is “hiding” inside hepatocytes or RBCs, where antibodies and white blood cells cannot go. The youngest children are particularly vulnerable to malaria as they have not yet developed a specific immunity to infection. Adults may be able to develop some immunity which may reduce the intensity of recurrent infections.
The new vaccine, R21
Plasmodium produces many proteins on its surface (antigens) that might produce an immune response but these are only visible to the immune system for short periods of time, when it is free in the blood prior to infecting a hepatocyte or RBC. Furthermore, its rapid reproduction rate allows evolution in these surface proteins so they can evade specific antibodies. The vaccine candidate R21, and its less effective predecessor, RTS,S, are targeted at the circumsporozoite protein (CSP). This is used to attach to hepatocytes before invading them and is highly conserved, meaning that it cannot evolve without losing its efficacy and disruptingPlasmodium’s lifecycle. The recently reported R21 trial claims about 75% effectiveness in preventing infection in children. Larger trials, just starting, are needed. Other vaccines targeting the merozoite surface proteins similar to CSP are also planned. This could be the beginning of the end of one of humanity’s worst natural enemies.
* a single-celled organism related to us, not to bacteria, similar to Amoeba. Protozoal infections include amoebic dysentery, Chagas disease, African sleeping sickness, and toxoplasmosis. There are no vaccines against protozoal infections apart from the newly developed anti-malarial ones.
** Readers might like to ponder the role of the Bill and Melinda Gates Foundation in funding much of this research.