What is Malaria?Like dengue, which I wrote about in my last blog post, malaria is spread by the bite of an infected mosquito. However, unlike dengue, malaria is caused by parasites of the genus Plasmodium, not a virus. In fact, there are four distinct Plasmodium species that cause malaria in humans: P. falciparum, P. vivax, P. malariae, and P. ovale. Additionally, possible sub-species are associated with malaria infections. These parasites are primarily found in tropical and sub-tropical regions and endanger about half the world’s population in about 109 countries and territories. Malaria parasites infect specific cells and tissues within the human body and use them to mature and multiply, ultimately causing illness. It is particularly troubling for children and pregnant women because the parasite can be transmitted congenitally from mother to child. When an individual has been injected with the parasite-ridden saliva of a mosquito, the sporozoites (the first stage in the parasites life cycle) travel to the liver through the bloodstream. Once there, the parasites mature and release merozoites, the next stage of the parasite. The merozoites re-enter the bloodstream and infect the body’s red blood cells. (For an animated video depicting the spread of the parasite from initial infection through maturation and multiplication, click here.) Symptoms of malaria appear anywhere between 7 days to 10 months after the initial infection, depending upon which Plasmodium parasite is responsible. Other factors that affect the incubation period include whether or not an individual has taken any medicine to prevent infection, the individual’s general health, and whether or not the individual has built up some immunity due to previous infections. Common symptoms of malaria include fever, chills, headache, sweats, fatigue, and nausea and vomiting. In severe cases, individuals may even experience impaired function of the brain or spinal cord, seizures, or loss of consciousness. P. falciparum infection is typically more serious than the other species and can sometimes become life-threatening. Due to the lifecycle of the malaria parasites, the symptoms may come and go in a cyclical pattern, which actually serves as a key indicator of malarial infection.
What Challenges do Vaccine Developers Face?Recent attempts using traditional vaccine approaches have been unsuccessful – they have been unable to prevent the parasite from causing infection. However, because DNA vaccines have the ability to stimulate both humoral and cellular immune responses, they possess a greater potential to stop malaria. The major contributing factor to the difficulty of malaria vaccine development is due to the complexity and genetic diversity of the antigens expressed by the malaria parasites. In addition, many malaria parasites have begun to show resistance to several of the commonly used preventive treatments due to the rapid mutation rates that have been observed within the Plasmodium genus. Additional challenges faced by those undertaking the development of a malaria vaccine are the same faced by developers of many vaccines for diseases that primarily affect poorer countries lacking infrastructure. . Approximately 2 billion people live in regions where malaria is present, which makes production and delivery costs for this potential vaccine a quite formidable opponent. The ideal vaccine should be produced as inexpensively as possible, while remaining stable at room temperature to reduce delivery and storage costs. Those are two advantages DNA Vaccines have over traditional viral-based vaccines. Fortunately for malaria vaccine researchers, the genomes of humans, A. gambiae (the mosquito primarily responsible for the spread of malaria), and P. falciparum have been sequenced. These significant advances will undoubtedly be invaluable as research and development on malaria vaccines continues.
Who, what, when, and how?The Malaria Vaccine Initiative (MVI) has set an expectation for the timeline for development and licensure of the first malaria vaccines. Their goal is to have a licensed vaccine by 2015 with at least 50 percent protective efficacy against severe disease and death that would last longer than one year. By 2025 they plan to have a vaccine that would have a protective efficacy of more than 80 percent against clinical disease in general that would provide protection for longer than four years. Seem like lofty goals? Here’s a table of who’s working on what vaccine for malaria and the status of their project to date. If you know of any other studies that are not mentioned below, please add them in the comments section.
Malaria Vaccine Development Pipeline
|RTS,S/AS01 antigen produced in S. cerevisiae
|In October of 2011, GSK announced results from a Phase III clinical trial wherein 15,460 children in two age groups, 6 to 12 weeks old and from 5 to 17 months old, were given three doses. In the 5 to 17 month old age group, the vaccine was found to be 50% effective. However, it was only 30% effective in the infant group. The vaccine is still undergoing late stage testing in Africa and may be available as early as 2015 in Africa.
|Texas A&M University’s Reproductive Science Lab in conjunction with GTC Biotherapeutics
|Transgenic malaria vaccine using goat’s milk as a delivery method
|Admittedly the most unique approach to the malaria vaccine race, this vaccine has been proven effective in mice. Using a transgenic goat to produce the vaccine in her milk, the vaccine must then be isolated, purified, and injected. Further research is required by GTC’s labs. In March of 2012, researchers were seeking funding for further development of this potential vaccine.
|UC San Diego
|Pfs25 subunit vaccine produced in algae
|UC San Diego released a paper in May of 2012 stating that the antibodies to their algae-produced protein recognize the native proteins in malaria and, inside the mosquito, block the development of the malaria parasite so that the mosquito cannot transmit the disease. Next steps will include early trials to determine if the algae proteins work to protect humans from malaria.
|Oxford University’s Jenner Institute
|RH5 subunit vaccine
|Oxford published their findings from preclinical trials in December of 2011 stating that their vaccine induces an antibody response in animal models that is capable of neutralizing all the strains they tested. Currently, safety trials are being conducted with the goal of beginning human clinical trials in two to three years.
|University of Maryland School of Medicine’s Center for Vaccine Development (CVD) and the Malaria Research and Training Center at the University of Bamako in Mali, West Africa
|Findings from a clinical trial in children were released in 2010 showing that the vaccine stimulated strong and long-lasting immune responses. Following this trial, further study is being conducted with 400 Malian children to evaluate its effectiveness against malaria disease. They hope that this vaccine can be combined with other vaccines to create a multi-component immunization.
|Crucell and GlaxoSmithKline
|AdVac® recombinant vaccine
|Crucell evaluated their Ad35-CS malaria vaccine candidate in a Phase I trial in Africa in 2010 for safety and immunogenicity. Crucell and GlaxoSmithKline plan to combine Crucell’s Ad35-CS with GSK’s late-stage RTS,S/AS.
|National Institute of Allergies and Infectious Diseases (NIAID)
|DNA vaccine against P. falciparum malaria
|A Phase I clinical trial for this DNA vaccine candidate was initiated in August of 2010 to establish whether the vaccine is safe and well-tolerated. The estimated completion date is scheduled for the end of 2012.
|The U.S. Naval Medical Research Center (NMRC)
|PfSPZ live attenuated vaccine
|In early 2012, the NMRC announced that an agreement had been made with the Bill & Melinda Gates Foundation to further research on their vaccine. Clinical trials were scheduled to include immunization of 20 individuals via mosquito bite followed by immunoassays and antigen discovery. The NMRC is also working with GenVec to exlore a prime-boost approach using DNA vaccines and adenovirus.
|Avanti is currently undergoing preclinical assessments of their DNA vaccine.
|Currently undergoing development and preclinical trials.