Malaria vaccines

I just returned from the annual meeting of the American Society of Tropical Medicine and Hygiene (ASTMH) where I attended symposia and scientific sessions on a number of topics including multidrug resistant tuberculosis, rabies, polio eradication, and child health. I also attended several presentations on malaria and dengue vaccines.

You may have heard about malaria vaccines in the news. The Bill and Melinda Gates Foundation has been funding malaria vaccine research and there have been some successes and some disappointing results reported in the news.

Although it's the American Society of Tropical Medicine and Hygiene, scientists from around the world come to ASTMH meetings to present their research. There are a number of malaria vaccines in various stages of development; some of them are in preclinical (animal) trials and some in clinical (human) trials. There are no malaria vaccines licensed or approved for use and none are available to the public.

Niger River, Mali 1988

Malaria is a disease with which I am fascinated and for which I have tremendous respect – it nearly killed me the second time I had it. I could spend several pages discussing malaria, but it's a complex disease with complex interactions between humans, mosquitoes, and the environment and, as much as I enjoy talking about malaria, I won't go into that level of detail here. I have included some links to webpages on malaria at the end of this post.

About half of the world's population lives in areas where malaria is transmitted. The World Health Organization estimates that there were about 216 million cases of malaria worldwide in 2011 and that around 655,000 malaria deaths in 2010, most of them children under five years of age in sub-Saharan Africa. Although that's down from over a million malaria deaths every year, some researchers believe that the annual number of malaria deaths is underestimated. That's not surprising considering that many of those deaths occur in rural areas of developing countries and are not reported to health authorities.

In addition to being one of the leading causes of death of children under 5 years of age, malaria also affects children's ability to learn in school and is a major contributor to poor economic development in endemic countries.

When I've mentioned that I've had malaria, people have said to me, "You must have drunk the water," "You must not have gotten the vaccine," or, "I heard that once you have it you have it for life," so it seems to me that there is some confusion about malaria – which doesn't surprise me.

Malaria is caused by a protozoan parasite which is transmitted through mosquito bites. Different species of Plasmodium infect humans, other mammals, birds, and reptiles. There a four species of human malaria: P. falciparum, P. malariae, P. ovale, and P. vivax. Humans can also be infected with P. knowlesi, a monkey malaria. P. ovale and P. vivax can cause relapses months to years after the first infection and people can have subclinical P. malariae infections for decades, but all of the species are curable, so "once infected, always infected" is not necessarily true.

Most malaria deaths and severe malaria infections are caused by P. falciparum. In addition to its severity and lethality, P. falciparum has developed resistance to almost every drug used to prevent and treat infection. For these reasons, most of the malaria vaccines that are in development are against P. falciparum.

The malaria parasite has several mechanisms by which it evades the human immune system. These create challenges for malaria vaccine developers. I will briefly discuss two of them:

Malaria lifecycle

The malaria parasite lifecycle includes several stages in both vertebrate and mosquito hosts. The parasite expresses different antigens at each stage of its lifecycle so that an immune response against one stage of the parasite will not "recognize" the parasite at a different stage.

 

 

Most cells in the body are able to signal cytotoxic lymphocytes that they are infected. These white blood cells can then kill the infected cell and the infecting agent along with it. The malaria parasite spends most of its time in the human body inside hepatocytes (liver cells) and erythrocytes (red blood cells), two types of cells that lack the ability to notify the immune system that they are infected with the parasite. The two extracellular (outside of cells) stages, sporozoites and merozoites, are present in the blood for a very short time, which limits their exposure to antibodies against them.

Immunity to malaria

Humans do not develop sterilizing immunity to malaria, that is, people who have been infected with malaria can have it again. The most effective immune responses are against proteins that are made by the parasite and expressed on the surface of infected red blood cells. The problem is, the parasite has genes that allow it to change those surface antigens and make infected cells unrecognizable to the immune system.

People who live in areas where malaria is transmitted develop a repertoire of antibodies against P. falciparum erythrocyte membrane protein 1 (PfEMP1). This keeps the number of infected blood cells low so that the person can be infected with the parasite but have relatively minor symptoms or no symptoms at all ("partial immunity").

People who live in endemic areas remain partially immune to malaria as long as they continue to be periodically infected with the parasite. Once a person is no longer exposed to malaria (e.g., moves someplace where malaria is not transmitted), she or he loses immunity and becomes susceptible to severe malaria again. A large proportion of cases of malaria in the U.S. are in people who came from malaria-endemic countries, lived in the U.S., and then returned to their country of origin to visit friends and relatives (VFR), thinking that they were still protected against malaria and did not need to take malaria prophylaxis.

Malaria vaccines



Mosquito injecting sporozoites
CDC

Researchers must choose a parasite antigen to which the human body will develop an adequate immune response. So far, the most successful vaccines have been against sporozoites, the infective stage of the parasite that is injected into the blood with mosquito saliva. Vaccines against other parasite stages have been developed, including transmission blocking vaccines which stimulate the immune system to produce antibodies that are ingested by the mosquito and prevent parasite development in the mosquito gut. These vaccines do not directly prevent human infection and disease but, theoretically, prevent transmission from an infected person to an uninfected person.

RTS,S is a sporozoite antigen vaccine in phase III trials which test how well the vaccine prevents disease in people who live in malaria endemic areas. Results of a study in African children 5 to 17 months of age and African infants 6 to 12 months of age (presented at the ASTMH meeting this year) demonstrated that RTS,S provides modest protection against malaria in children who received three doses of the vaccine.

While the press has called these results "disappointing" because the vaccine did not protect against malaria as well as had been hoped, these are positive results against an elusive pathogen. Even a modest reduction in malaria burden can save thousands of lives. I think it's also important to remember that current vaccines prevent bacterial and viral infections. This is the first vaccine against a protozoan pathogen.

Further RTS,S trials in different populations and using different dosing schedules are ongoing as are trials of other malaria vaccine candidates.

In the mean time, controlling malaria depends on preventing mosquito bites and treating people infected with malaria.

More information

• Centers for Disease Control and Prevention: http://www.cdc.gov/malaria
• Malaria Journal: http://www.malariajournal.com
• Malaria Vaccine Initiative: http://www.malariavaccine.org
• World Health Organization: http://www.who.int/topics/malaria/en

References

Fairhurst, R. M. & Wellems, T. E. (2009). In G. L. Mandell, J. E. Bennett, & R. Dolin (Eds.) Mandell, Douglas, and Bennett's principles and practice of infectious diseases (7th ed.). Elsevier [Electronic version].

Holding, P. A., Snow, R. W. (2001). Impact of Plasmodium falciparum malaria on performance and learning: review of the evidence. American Journal of Tropical Medicine and Hygiene, 64(Suppl. 1), 68-75. http://www.ajtmh.org/content/64/1_suppl/68.abstract.

Murray, C. J., Rodenfeld, L. C., Lim, S. S., Andrews, K. G., Foremen, K. J., Haring, D. et al. (2012). Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet, 379(9814), 413-431. http://www.ncbi.nlm.nih.gov/pubmed/22305225.

Plebanski, M., & Hill, A. V. S. (2000). The immunology of malaria infection. Current Opinion in Immunology, 12(4), 437-441. http://www.ncbi.nlm.nih.gov/pubmed/10899022.

The RTS,S Clinical Trials Partnership. (2011). First Results of Phase 3 Trial of RTS,S/AS01 Malaria Vaccine in African Children. New England Journal of Medicine, 365(20), 1863-1875. http://www.nejm.org/doi/full/10.1056/NEJMoa1102287.

The RTS,S Clinical Trial Partnership. (2012). A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. New England Journal of Medicine [Epub ahead of print]. http://www.nejm.org/doi/full/10.1056/NEJMoa1208394.

Sachs, J. & Malaney, P. (2002). The economic and social burden of malaria. Nature, 415(6872), 680-685. http://www.ncbi.nlm.nih.gov/pubmed/11832956.

Yazdani, S. S., Mukherjee, P., Chauhan, V. S., & Chitnis, C. E. (2006). Immune responses to asexual blood-stages of malaria parasites. Current Molecular Medicine, 6(2), 187-203. http://www.ncbi.nlm.nih.gov/pubmed/16515510.