Developing a malaria vaccine: via IV or not via IV, that is the question

Malaria, the veritable scourge of Africa, causes almost 1 million deaths and 300 million sicknesses yearly, and is caused by a parasite that infects liver cells, or hepatocytes, and red blood cells.  This kind of parasite is known as an intracellular parasite—in the case of malaria, the most fatal causative agent is Plasmodium falciparum.  P. falciparum is transmitted by a mosquito bite, usually from an Anopheles mosquito. P. falciparum has development cycles that occur in the gut of the mosquito, and the liver and red blood cells of humans: because of this incredibly complex lifecycle, P. falciparum is very difficult to develop a vaccine.  In the past, vaccines that contain proteins from the surface of the parasite, but not the parasite itself—known as subunit vaccines—have been developed, but did not give high-level immunity (Draper et al 2010).  As a result, the development of a vaccine that contains the entire live parasite in a non-infectious form has been explored.  This type of vaccine, known as a live attenuated vaccine, has been manufactured—the results of the first human clinical trials are explained in a paper by Epstein et al published in Science Magazine.

The researchers developed a vaccine that contained live attenuated, non-reproductive sporozoites, the infective stage (but not the symptomatic stage) of P. falciparum.  The researchers wanted to test the effectiveness of the vaccine based on different transmission routes.  The transmission routes tested were: intra-dermal (ID)—in the skin—and sub-cutaneous (SC), or just below the skin.  These two routes were tested because of their similarity to the natural mode of transmission of the parasite.  A mosquito bite does not penetrate down to the muscle; instead the proboscis (the part that the mosquito sucks blood with) is inserted ID, and the researchers attempted to mimic this transmission.

 Differing concentrations of the live attenuated parasite were administered to three different groups once a month for four months.  Another group received the same treatment, but also received two boosters three and four months after the initial treatment.  After administering the vaccine, Epstein et al tested blood smears from patients every two weeks in order to ensure that the vaccine was properly attenuated and would not develop into the symptomatic stage of malaria, known as merozoites.  While none of the vaccines developed into merozoites, half the patients suffered from an “adverse event:” headache, malaise, fever, or aches.  While these data suggest that the vaccine may be bad because half of the patients had adverse reactions, something to keep in mind is that flu vaccines, tetanus boosters, and myriad of other vaccines cause similar “adverse events” in similar numbers of patients.

After establishing safety and tolerance of the vaccine, Epstein et al investigated the heart of the issue: whether or not the vaccine conferred immunity.  The researchers tested for interferonγ (IFNγ), a protein that is indicative of a cellular immune response, and were able to estimate the magnitude of the immune response by CD8 T-cells.  CD8 T-cells, also called CTLs, are responsible for recognizing cells that are being infected from the inside, as is the case in viruses and intracellular parasites, and mediating their destruction.  The researchers found that patients who received the vaccine SC had significantly greater magnitude of reactive CD8 T-cells with increasing concentrations of vaccine; the ID group however did not see this significant trend.  These data, while initially appear to be paradoxical, are not.  We must keep in mind that the route of natural infection is ID, and when humans are infected with P. falciparum they are unable to develop lasting immunity.  It should follow then that when a more direct route of transmission, in this case SC, should stimulate a stronger and longer-lasting response. 

Three weeks after administering the final dose, Epstein et al exposed the patients to Anopheles mosquitos infected with P. falciparum. Of the 18 controls, all 18 developed malaria, and of the vaccinated patients only two were protected and did not develop malaria.  As a result of these findings, the researchers conducted experiments on rhesus macaques (non-human primates NHPs), rabbits, and mice to test whether efficacy is affected by vaccine transmission route.  The two transmission routes tested were SC and intravenous (IV).  Two groups of NHPs were given the vaccine either by SC or IV routes, and tested for CD8 T-cells and IFNγ.  Of NHPs that were given the vaccine SC, only one developed CD8 T-cells reactive to sporozoites at an acceptable level (.08%).  When the NHPs were given the vaccine IV, three of five developed CD8 T-cells reactive to sporozoites.  After four months, the researchers tested the CD8 T-cell responses again and found that none of the NHPs vaccinated via SC had reactive T-cells, while all those vaccinated IV had some reactive T-cells.  The researchers were not able to test efficacy of the vaccine however, because rhesus macaques cannot be infected with malaria.

To test the efficacy of the vaccine, Epstein et al used the malarial mouse model to test the vaccine.  Mice were vaccinated via IV in three doses, and the researchers achieved 71-100% immunity in the mice.  In the mouse model, SC and ID routes were also tested: these routes were found to require up to ten times as much live attenuated parasite than IV to achieve the same results.  These data align very well with what was discussed earlier: more direct routes of transmission result in stronger, longer-lasting immunity. 

While we are still far from developing a working, tolerable, safe malaria vaccine, this study evidences that it is in fact possible.  There are several problems with this vaccine.  The biggest issues stem from the vaccine’s greatest strength: live attenuation.  The most obvious of these issues is that a live attenuated vaccine needs to be kept cold.  This may not be an issue in developed nations, but in places where malaria is rampant, keeping the vaccine cold poses a challenge.  As well, because the parasite is alive, it is possible for it do revert back to its wild type, and become infectious, thereby giving patients malaria instead of vaccinating them.  Finally, people who are immunocompromised (people with HIV/AIDS) cannot receive live attenuated vaccines—this poses an issue in sub-Saharan Africa where the HIV/AIDS rate is nearly 5%.  This research holds great promise for the future of vaccinations against P. falciparum and could eventually aid agencies such as the WHO and PAHO in fighting the scourge of the tropics. 

More likely than not, future clinical research will investigate the effectiveness of the vaccine in humans when administered via IV.  On a final note, this also poses an issue: whereas administration of vaccines via ID or SC requires minimal training, placing an IV requires a trained professional.

Primary Source

Epstein, J. E., Tewari, K., Lyke, K. E., Sim, B. K. L., Billingsley, P. F., Laurens, M. B., et al. (2011). Live attenuated malaria vaccine designed to protect through hepatic CD8+ T cell immunity. Science, 334(6055), 475-480. 

Additional Scources

Draper, S. J., Biswas, S., Spencer, A. J., Remarque, E. J., Capone, S., Naddeo, M., Dicks, M. D. J., et al. (2010). Enhancing blood-stage malaria subunit vaccine immunogenicity in rhesus macaques by combining adenovirus, poxvirus, and protein-in-adjuvant vaccines. The Journal of Immunology, 185(12), 7583-7595.

"WHO | Global Health Observatory Data Repository- HIV/AIDS." Web. 01 Dec. 2011. <http://apps.who.int/ghodata/?vid=360>.

"WHO | Global Health Observatory Data Repository- Malaria." Web. 01 Dec. 2011. <http://apps.who.int/ghodata/?vid=440>.