Malaria vaccines trials and tribulations

Very high antibody levels are needed to stall P. Following a promising Phase 2 trial , a Phase 3 study in enrolled nearly 15, children aged between 6 and 12 weeks or between 5 and 17 months in seven sub-Saharan African countries. Participants were selected at random to receive three doses of the RTS,S vaccine or a control vaccine, each a month apart—with some receiving a fourth dose 20 months after the first.

Importantly, vaccine efficacy waned over time the 36 percent efficacy over several years in children was a decrease from more than 50 percent efficacy at one-year post-vaccination. And in an extended analysis of the Phase 2 study, which tracked three-dose recipients for seven years, Bejon and his colleagues observed that in certain areas, RTS,S-vaccinated children actually had a slightly higher risk of clinical malaria episodes than unvaccinated kids.

In a positive sign, a longer follow-up of the Phase 3 study —in which some participants received a fourth dose—found no evidence for a rebound effect, except for at one high-transmission site in Burkina Faso. But overall, there clearly is a reduction in terms of numbers of malaria episodes. In addition to the modest and waning efficacy offered by RTS,S, data from the Phase 3 study hinted at possible safety risks of the vaccine: a tenfold increase in meningitis cases and a doubling in rare but severe cerebral malaria in RTS,S recipients compared to controls.

In an independent analysis of trial data, epidemiologist Christine Stabell Benn of the University of Southern Denmark calculated a 24 percent increase in overall mortality among vaccine recipients—though not statistically significant, a worrying observation, she says.

Barriers to Developing a Malaria Vaccine The development of a malaria vaccine has faced several obstacles: the lack of a traditional market, few developers, and the technical complexity of developing any vaccine against a parasite. Whole Sporozoite Vaccines Another promising malaria vaccine candidate includes whole sporozoites, the sexual form of the parasite extracted from mosquito salivary glands, which have either been made non-infectious through irradiation or are administered along with chemoprophylaxis.

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Scientists then found that only the female Anopheles mosquito transmits the parasite males do not feed on blood. The females of 60 different species of Anopheles mosquitoes can serve as malaria vectors.

The parasite infects around million people each year. Quinine, a substance derived from the bark of the cinchona tree, has been known to be effective against malaria since the s. They hypothesized that that by killing the vector, they could halt the cycle of infection. Consequently, DDT and other insecticides came into vogue in the mids and have been used ever since. Bed nets to protect sleeping people from mosquito bites are another form of vector control that is not only effective, but also extremely cost effective.

With all of these developments, why does malaria remain a problem? The emergence of resistance to drugs and insecticides is a major concern. The malaria parasite has survived for more than 50, years, and natural selection favors strains of the organism with mutations that help them evade threats. Today we are seeing more and more drug-resistant parasites and insecticide-resistant mosquitoes. Global efforts are underway in the next era of malaria prevention: the development of malaria vaccines that have the potential to save countless lives and that could ultimately help eradicate this historic plight.

Malaria is unlike any infectious disease for which we have already created a successful vaccine. Most notable of these differences is that malaria is transmitted via a parasite that passes through multiple life stages, each of which presents a unique challenge to vaccine developers. Because the parasite can reproduce both asexually and sexually, it has many advantages over the viruses and bacteria that we currently vaccinate against.

The three stages of the Plasmodium life cycle are 1 the pre-erythrocytic stage, better known as the liver stage, or the stage before the parasite infects human red blood cells, 2 the erythrocytic stage, or the blood stage when the parasite is infecting the red blood cells, and 3 the sexual stage, the stage when the parasite has been taken up by a mosquito and is sexually reproducing in the mosquito gut.

First, when a mosquito infected with Plasmodium bites a human host, the parasite goes directly to the liver. Second, once the parasite has matured in the liver it will enter the bloodstream and invade blood cells.

The first form is known as the sporozoite pronounced spore-o-zo-ite. Once the sporozoite gets to the liver, it quickly infects the liver cells and goes through multiple rounds of asexual reproduction to produce merozoites pronounced mer-o-zo-ites.

One sporozoite can asexually reproduce to form up to 40, merozoites, a large enough number to seriously challenge the ability of the immune system to control the parasite. The erythrocytic stage is the next stage, which occurs once the merozoites leave the liver cells and enter the bloodstream. Here, a merozoite infects a red blood cell and begins asexually reproducing and releasing hundreds of new merozoites.

This is the stage when an individual would start to experience symptoms such as malaria-associated periodic fever. The symptoms are the result of the bursting of red blood cells, which is why symptoms often occur periodically — when the parasite is inside the red blood cell reproducing, the fever will decrease and the patient will appear to be improving, but will start up again when the merozoites are released. In the third stage, or the sexual stage, a few merozoite-infected blood cells will stop asexually reproducing and instead mature into sexual forms of the parasites — known as male and female gametocytes pronounced gam-eat-o-cytes.

Under a microscope, P. When an Anopheles mosquito bites a human who has malaria, it will take up the gametocytes along with the blood. These gametocytes are then able to further sexually reproduce in the mosquito gut, developing into mature sex cells or gametes, and finally fusing as they move up the mosquito gut wall to become an oocyst. If you will recall the sporozoite is the form of the parasite that infects the liver.

The complicated life cycle of Plasmodium presents a challenge to malaria vaccine development. Researchers must determine which life stage of the parasite to target, or whether the vaccine needs to combine elements that target more than one life stage.

However, recent findings allow us to be optimistic about the possibility of an effective malaria vaccine. Malaria is a bit different from many of the diseases we currently vaccinate for because it does not confer so-called sterile immunity. This means that if you become ill from malaria and recover, you can be infected over and over again. The fact that your immune system responded to malaria in the past will not prevent future infection. This is very different from a disease such as measles: most people who contract measles will be immune to future measles infection for life.

With malaria, there is some evidence of a degree of naturally acquired immunity — someone who has had malaria in the past can still get it again, but she will probably get a less severe case. In many African countries where malaria is common, most people who are re-infected with malaria experience only mild symptoms due to this partial acquired immunity.

This is also the reason that malaria is so deadly for children under five. These children have not yet acquired any level of immunity to the parasite, and they are much more likely to experience a severe case that may lead to fatal complications. Moreover, this is also the reason that foreigners who have never experienced malaria must be very careful — they may develop a very serious case when they first are infected.

Finally, naturally acquired partial immunity does not last long. It is made chemically, by synthesising segments of protein from different regions of the malaria parasite. The relatively low degree of protection found in the Colombian trials might be partly explained, says Patarroyo, by problems with the formulation of the vaccine at the time it was made, more than two years ago. These problems have since been resolved, he says. The pH of the vaccine used in the trials was found to be lower than usual, and subsequent studies have shown that the lower-pH formulation provokes a weaker immune response.

Later trials elsewhere have used a higher-pH formulation. No one understands how the vaccine works, because there is no correlation between the concentration of antimalarial antibodies it provokes in individuals and their degree of protection from disease.