For a year, we have been discussing vaccines against SARS-CoV2 (the virus that causes COVID-19, which people from many walks of life have poo pooed whenever reports have come out putting the efficacy of one vaccine or another below let’s say 90 percent. Throughout the pandemic, we have discussed why such a perspective is wrong. As the expression goes, don’t let the perfect be the enemy of the good. The approved COVID-19 vaccines vary in terms of the efficacy against developing any symptoms at all, including mild disease, and against whether or not you may, if exposed to the virus, test positive, despite being fully vaccinated several months before the exposure. But over all, for those who are not immunocompromised (such as organ transplant recipients, certain cancer patients), even many months after full vaccination efficacy remains close to 100 percent when it comes to the main purpose for which the vaccines were created, namely protection against severe COVID-19, disability, and death. This means that whether you received the Janssen (Johnson and Johnson), the AstraZeneca/Oxford, the Pfizer/BioNTech or the current media favorite, Moderna, you are extremely well protected, including if you are pregnant, when being unvaccinated puts you at particularly elevated risk of having a severe case of COVID-19 and requiring hospitalization, ICU admission, invasive ventilation, or of dying. In very real sense, society has held COVID-19 vaccination to a much higher standard than it has held vaccination against any other disease, complaining, not only about less-than-perfect efficacy, rare adverse effects, but also about possible emerging needs for a booster dose, meaning a third dose of one of the mRNA vaccines or of the AstraZeneca vaccine, or a second dose of Janssen. It’s as if people have forgotten that immunization regimens for most of the infectious diseases for which we vaccinate require multiple initiating doses and/or booster shots, because of the nature of how immunity works.
So how then might you react to news about a newly approved vaccine that requires 4 shots that if administered on the proper schedule give an efficacy of about 40 percent? What with the criticism that we have been hearing about the COVID-19 vaccines or for that matter vaccines against seasonal influenza, we might expect harsh remarks from the average person on the street, and, sadly, various politicians and media personalities. But that’s the efficacy range of the vaccine called RTS,S (trade name Mosquirix) that the World Health Organization (WHO) approved recently to confront malaria. And WHO approved it, because it is expected to make an enormous impact in malaria endemic countries, potentially saving hundreds of thousands of lives annually, mostly children. Children, you see, are particularly vulnerable to the causative agents malaria, a group of parasites within the biological genus called Plasmodium, but pregnant women constitute another group that is particularly vulnerable to developing severe malarial disease and dying from it.
Up until now, all vaccines approved for clinical use have been for protection against either viruses or bacteria, or, in the special setting of immunotherapy, human cancer cells. We’ll leave the cancer immunotherapy for another day, and consider malaria vaccination in comparison with vaccination against viral and bacterial agents. Although malaria kills hundreds of thousands of people each year, scientists have been working on malaria vaccines for decades, but only now have reached the point at which several vaccine candidates are nearly ready for clinical use, RTS, S being the first one to win WHO approval.
Currently, the most common species of Plasmodium causing malaria in pregnant women is one called Plasmodium falciparum, which resists many of the drugs used to treat malaria, including the anti-malaria drugs that can be given safely during pregnancy. Another species that is fairly common in malaria in pregnancy is Plasmodium vivax. People become infected with Plasmodium parasites when they are bitten by a female Anopheles mosquito, which lives in hot, humid climates, making sub-Saharan Africa the epicenter of malaria, but the disease is also endemic on other tropical places. Malaria presents itself with severe fever —so high that the fever itself is life threatening— and chills, along with sweating, fatigue, headache, muscle pains, and nausea and vomiting. It also causes anemia –low numbers of red blood cells– which if severe can lead to heart failure. The fact that pregnancy also causes anemia is one reason why malaria hits pregnant women worse than it hits their non-pregnant counterparts, but pregnancy also makes women more vulnerable because of issues involving the immune system. On top of this, malaria puts the fetus at risk of low birth weight and spontaneous abortion (miscarriage).
Malaria causes anemia, because special proteins on the outside of the Plasmodium parasite —which is a single cell, but a complex cell, like our cells— attach to particular particular molecules on the surface of red blood cells, causing the cells to break as the parasite transforms and multiples in the red blood cell. The surface molecules differ among the red blood cells of the human population, leading to varying vulnerabilities of different people to malaria, plus there is another thing that makes red blood cells particularly resistant to the parasite and that is the sickle cell gene. Children who have one sickle cell gene from each parent generally do not do well and without modern medical care do not survive. But people with a sickle cell gene from just one parent —we say that they have not sickle cell disease, but sickle cell trait— make some of what is called hemoglobin S, which messes up the shape of red blood cells, but also makes it harder for the Plasmodium to infect those cells. Similar protection results from other conditions that involve abnormal red blood cell shape. While the presence of the sickle cell gene causes some babies to be born with sickle cell disease and to die, many more babies are born with sickle cell trait and they benefit in places where malaria is endemic. Like doctors balancing the benefits and drawbacks of various treatments, evolution also makes such tradeoffs.
The notorious high fever of malaria also develops at the time that the parasite infects red blood cells, but the interaction with red blood cells does not happen right after the mosquito bite. Rather, the mosquito injects. As noted above, Plasmodium is a complex organism. As such, it has a complicated lifestyle, transitioning into different forms as it goes through its life cycle. Just as a human begins as an embryo, then a fetus, then an infant, a child, and so on, the Plasmodium goes through various phases. What enters the blood from a mosquito bite is a sporozoite, a form of Plasmodium parasite that likes to infect liver cells, where it thrives, and matures over about seven days, into thousands of merozoites, which leave the liver and travel in the blood to encounter red blood cells. During those days after the mosquito bite, while the parasite is only in the liver, the victim does not feel sick and the merozoites and sporozoites are different, as far as what the immune system sees. They have different proteins on their exteriors, as does yet another form of the parasite that leaves the victim in blood when yet another female Anopheles mosquito bites, thereby infecting her. For vaccine developers considering the issue since the middle of the last century, this has raised the question of which form of the parasite would make the best target for a vaccine to teach the immune system to recognize?
In some experimental vaccines, including the RTS,S that was just approved, the goal has been to immunize against the sporozoites that the victim receives from the mosquito, that go to the liver. Specifically, the vaccine utilizes a protein on the sporozoite surface called circumsporozoite protein, but this protein alone would not create good immunity and certainly not lasting immunity. One phenomenon that makes malaria a challenge to vaccine designers is that the parasite itself does not generate good immunity, which is why people can get malaria multiple time. To counter this problem, scientists used genetic engineering to create a combined protein that includes a region of the circumsporozoite protein that the immune system sees and also includes the protein that is used in the hepatitis B vaccine. The fact that the business end of the RTS,S vaccine is a protein, or a fusion of a few proteins, means that we can classify the vaccine into the same category as the Novavax vaccine for COVID-19 that may soon receive emergency use authorization, and for that matter the same category as the hepatitis vaccine. This means that there will be no reason for pregnant women to avoid the RTS,S vaccine for malaria, in contrast with another malaria vaccine that is in the works that requires more caution as it is made by irradiating Plasmodium parasites to make them into a live attenuated vaccine. Such live vaccines are avoided in pregnancy, because of a hypothetical risk to infect the fetus, although one cannot really know that any particular live vaccine will do this.
The RTS,S vaccine is most effective in young children, so we don’t know yet if this will be the vaccine for pregnant women in malaria endemic areas to get. Importantly, this vaccine, and the others that will follow, must be used in combination with other preventive measures, such as insecticide-treated netting (ITN), drainage or elimination of standing water sources, and insect repellent. One additional measure under development involves genetically modified male Anopheles mosquitos that can be introduced in to malaria-infested regions of the world. Only female mosquitos bite humans, but the modified male mosquitos mate with the females to produce either sterile baby mosquitos, or mosquitos that never hatch. The most advanced genetic modification project involves what is called a gene drive. In this method, experimental male mosquitos carry a gene that makes mosquitos immune to Plasmodium parasites, and that gene is transmitted through succeeding generations of mosquitos until the entire population of the insects is immune to the parasite.