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.
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.
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.
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.
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| 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.
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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
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| Mosquito injecting sporozoites CDC |
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.
