Tuesday, October 18, 2011

Malaria vaccine

We've been talking in class about overdominance, or heterozygote advantage. One of the classic examples of overdominance is the case of sickle-cell anemia. A brief synopsis is given here. Basically, the sickle-cell mutation results in clumped hemoglobin. If you are homozygous for this mutation, you have the disease and have a low probability of survival. However, heterozygotes do not show the disease, and are more resistant to malaria than homozygotes without the sickle-cell allele. Therefore, in malaria-ridden areas, the fittest genotype will be the heterozygote. Because of this fact, we see an equilibrium that maximizes the fitness of the population by balancing the number of heterozygotes with high fitness against the number of homozygous individuals with sickle-cell anemia, resulting in an intermediate frequency of the sickle-cell allele. This is natural selection's solution to the problem, and it isn't an ideal one. Again, natural selection doesn't lead to perfection.

Perhaps we won't have to rely on this cheesy evolutionary fix much longer though, as there is great news on the fight against malaria. A new study of an experimental vaccine has shown that it reduces incidence of malaria in children by about 55% [STORY]. This is the first vaccine to be used against a eukaryotic parasite. In general, fighting eukaryotic diseases can be tricky. For example, it is often easier to clear a bacterial infection than a fungal infection. Why? Evolutionary principles! Eukaryotes are more closely related to us, so they share more of our molecular machinery. Consequently, it's easy to kill a fungus, but it may be hard to kill a fungus without killing us in the process.

The way the vaccine was made also seems pretty slick, a quote from the science article:
It contains an engineered protein that combines a protein fragment from the malaria parasite, Plasmodium falciparum, and a protein from the Hepatitis B virus that helps trigger a strong immune response.
Even though 55% reduction isn't great by vaccine standards against bacteria and viruses, this is a spectacular development which could save many, many lives around the world.

Could the parasite evolve resistance to the vaccine? It's certainly seems possible. I don't know what the protein they used does in a normal parasite, or how conserved or variable it is in natural populations. Normally, vaccines that are highly effective knock down the population so low so that there is little to no genetic variation for the disease-causing agent, and no possibility for evolution of resistance. But this works mostly for diseases that are restricted to humans. For example, vaccines against polio are effective for this reason. However, since this vaccine only protects part of the population, and the fact that malaria infects many, many species of vertebrates, means that such an effort is unlikely to happen, and we will probably never get rid of malaria completely. However, there is a silver lining to this. I would venture to guess that humans make up only a very small portion of the hosts used by most of the world's malaria parasites. Because of this, losing us as a host probably doesn't affect fitness that much, and wouldn't be that much of a selection pressure to the parasite itself. Consequently, it might be possible that resistance wouldn't evolve so easily. I suppose even if the disease did mutate and develop resistance, we could do something like what we do for the flu virus and produce a new vaccine every year for the most common strain. This is all speculation on my part based on some pretty cursory examination of the latest news. I'm sure my friends who know more about disease ecology could talk more cogently on this!


  1. I am really interested in this topic and did some further reading. On the malariavaccine.org website, they say about resistance to vaccines, “It is theoretically possible for any microbe to develop resistance to vaccines. The global experience with vaccines licensed for childhood diseases indicates that this is not a huge problem. The malaria vaccines that are being developed are using various strategies to minimize the possibility of resistance”. I think this is where they are referring to combining a protein from the parasite with a Hepatitis B protein. But they could also be referring to the various types of vaccines they are investigating. I was really interested in the three main ways they are approaching vaccines: pre-erythrocytic, blood-stage, and transmission blocking. The pre-erythrocytic vaccine would somehow prevent the infection from starting or it would specifically attack the infected cells only if infection did occur. The blood-stage vaccine would help to decrease the effectiveness of the infection once in the host blood, most likely by just decreasing the number of infected cells. But I am most interested in the transmission blocking vaccine, which interrupts the parasite’s life cycle while in the mosquito making it ineffective when the mosquito goes to bite a new host. This would not be very effective if only a few people received the vaccine, but in largely exposed malaria areas, if everyone or most everyone received a vaccine that did this, malaria would not spread nearly as easily.
    Reading these articles about malaria reminded me of when I read the (basically non-fiction) book The Hot Zone, by Richard Preston. The Hot Zone is about the Ebola and Marburg viruses and how they work. One part of the book I specifically remember. There was a virus found in Reston, Virginia (later named Reston virus), that is very similar to Ebola and found in monkeys. That was scary because Reston is only about 15 miles from Washington, D.C. And there was a strain of the virus that spread through the air. This whole thing doesn’t exactly relate to the malaria topic, but it made me think about how easily diseases spread. A mosquito can become infected with malaria by feeding on an infected host. But I was interested in knowing if there are other ways they could become infected, such as by vertical transmission. I did a bit more reading and found this article about spermless mosquitos. http://www.reuters.com/article/2011/08/08/us-malaria-mosquitoes-sperm-idUSTRE77758A20110808 If the males were spermless, and the females only mate once before laying eggs, then hypothetically this could eventually reduce the spread of malaria. Also on the topic of malaria spreading, the disease isn’t very common in the United States; most people from the US only get infected while traveling abroad. But what if someone brought a box of infected mosquitos to the US and released them in a highly populated area? That would be pretty scary too.

  2. I'll chime in as the class's lonesome microbiology major:

    This isn't actually a new idea; in fact this is the same strategy that we use for just about all vaccines. Add one part pathogen specific antigen and one part adjuvant (in this case the HepB adjuvant)

    A little immunology background first though: Almost all cells in the body express MHC (we call it HLA in humans); their job is to express foreign antigens on their surface in the hope that the right lymphocyte will see it. The exceptions here are that certain areas of the body are immunologically privileged (eyes, testes, most of the CNS etc). Other cells are more or less hidden, as they do not express large amounts of MHC upon their surface like RBC’s.

    While RBCs are generally privileged, they have limited MHCI expression; thus if you had a trophozoite stage in the RBC, it is likely to at least minimally express Plasmodium antigens on MHCI, but without much costimulation. So a CD8+ T cell comes along and sees the MHCI and activates and expands a little but never really gets to do much mostly because you require B7 ligand costimulation.

    This sounds like a bad thing until you realize that CD8+ thymocytes are cytotoxic and will lyse the offending RBC and any others they find that also express this antigen on MHC. If you ever had widespread CD8+ activation against RBCs you would see such dramatic hemolysis that the host would probably die sooner than they would have with out immunological involvement.

    Stepping back to the idea of a vaccine, using the ideas above:

    1) RBC’s generally don’t show widespread MHCI expression, thus even if you managed to expand T cells the chance that the one antigen the T cell is primed for happens to be expressed on the already limitedly expressed RBC MHCI is fairly low, likely too low for it to be of use.
    2) Even if it did, it would likely lead to worse anemia than you would see without the vaccine.

    So the next step is obviously to try to target other stages of the lifecycle. You can try to target the merozoite stage, but that’s actually not very helpful in the long run because A) by that point hemolysis has already occurred with is responsible for most of the anemia and B) your innate immune system already handles merozoites fairly competently with complement and apparently targeting this stage doesn’t help much with the overall course of the disease.

    You can try to target the hepatic stages, but you actually have the same problem as with RBC’s, only to a worse degree. Hepatocytes express MHCI normally and activation of a CD8+ against hepatocytes displaying MHCI with plasmodium antigen would lead to hepatic lysis…also not good for the host.

    On top of all of this, you have an additional problem that a few parasites, including P. falciparum, can switch between surface antigens, complicating any attempt at an adaptive immune response. (We can also add the issue that there is not only one species that causes malaria, falciuparum is easily the most pathological, but vivax and ovale are also common)

    The only real viable vaccine approach would be to target sporozoites as they enter the bloodstream after an Anophiles blood meal. This is difficult though as they have a very short lifespan in the blood before they enter hepatocytes or erythrocytes and begin merogany. If the lympochyte can’t see the antigen, it would respond.

    In fact the vaccine in the article turns out to be a sporozoite surface antigen. 55% is actually very impressive given the fact that this is probably subject to antigen switching and has to combat the swift sporozoite stage. I’m not convinced though that this is going to be the answer. For one, the study was conducted on children and only shows immunity through the first few years of life. I’d be curious to see if the issues with sporozoite vaccines start to show up later on. We also don’t know anything about the lifelong immunity and quite frankly, if the vaccine is going to require boosters, it won’t work economically.