A New Vaccine to Protect Against Malaria

Malaria mosquito (4)

Malaria protozoan (5)

A New Vaccine to Protect 

Against Malaria

Malaria cases by country (6)

Malaria is a serious mosquito-borne illness that is present in tropical and sub-tropical countries all over the world. Roughly 3.3 billion people, almost half of the world’s population, live in areas where malaria is endemic (1). Malaria is caused by a unicellular eukaryotic organism called a protozoan. The protozoan that causes malaria, Plasmodium falciparum (Pf), replicates in human liver and red blood cells causing these cells to die. Uninfected mosquitos can then pick up the sporozoite by biting an infected person, thus propagating infection. Malaria causes high fevers, chills, and other flu-like symptoms, and can sometimes result in death (1).

Life cycle of plasmodium falciparum (7)

The protozoan that causes malaria is transmitted by mosquito bite as a sporozoite, an infectious form of the protozoan that is produced by asexual reproduction. Plasmodium falciparum lives in a mosquito’s mouth in the saliva, and when a human gets bitten, the sporozoites are transmitted to the human where they first replicate asexually in the liver and then spread to the blood and cause serious disease (1). In recent years many control interventions have been developed to attempt to reduce the number of cases of malaria; these include using bednets sprayed with insecticide in areas where malaria is endemic, spraying insecticides, and administering antimalarial drugs. Despite these efforts, in 2010 alone there were 220 million reported malaria cases, causing somewhere between 0.66 and 220 million deaths, the majority of those infections occurring in young children. Thus the current preventative measures are not sufficient; a vaccine against malaria will be the best method to combat malaria infections (2).

The most effective vaccine will be one that targets the sporozoite while humans are still asymptomatic; this is when the sporozoite has not yet spread from the liver to the blood (3). The World Health Organization has set a goal of obtaining a vaccine that is 80% effective by 2025. However, despite years of research and development, no current vaccines reach this level of efficacy. Currently the only way to confer protective immunity against malaria is by injecting people with inactivated sporozoites from >1000 mosquitos (the inactivation of the sporozoite is done by irradiation). Clearly, breeding this many mosquitos and isolating sporozoites from each one is not an optimal means of vaccination. As a result, a research group developed a way to grow radiation-attenuated Pf sporozoites (PfSPZ). The researchers attempted to vaccinate people subcutaneously, under the skin, but this method only caused minimal immune response and very low protective immunity. Recently however, the same group of researchers found that injecting PfSPZ intravenously (IV) provides protective immunity against malaria.  

The recent study used a vaccine with various doses of PfSPZ and injected it intravenously multiple times over the course of several weeks. The study participants, termed vacinees, were infected with controlled human malarial infection (CHMI), which involves giving a low dose of sporozoites and intervening with anti-malarial medications as soon as patients become symptomatic.  There were three study groups, with control individuals in each group whom did not receive the vaccine but were infected with CHMI. The three groups of vacinees received three different doses of PfSPZ, and varied in the number of vaccines of each dose administered. While protection was low in the group receiving the lowest dose, there was significant protection against malaria infection in the group receiving the highest dose of PfSPZ. In the group that received the highest concentration of PfSPZ per dose, 1.35 X 10⁵, and were administered the vaccine four or five times provided 66% and 100% protection against CHMI respectively. These results were promising, so the researchers then looked to see what types of immune responses were being elicited that were providing protection against CHMI.

            One component of the immune system that the researchers examined was the antibody response. Antibodies are proteins specific for a pathogen that are secreted by a certain type of immune cell called a B cell, and bind to the target pathogen to inactivate them, usually by blocking the function of key pathogen proteins. The researchers drew blood from the vacinees, isolated the antibodies, and quantified the number of antibodies. The concentration of PfSPZs-specific antibodies increased with increasing dose of the PfSPZ vaccine. The researchers did not find any antibodies against malaria sporozoite that infects red blood cells, indicating that the vaccinated individual’s sporozoites did not develop past the liver stage.

            In addition to looking at the antibody response, the researchers looked at the immune cell-mediated response since it is understood that full protective immunity against malaria requires cellular immunity. Specifically CD8+ T cells, which kill infected cells, and interferon-Υ (IFN-Υ), a signaling molecule that enhances the CD8+ T cell response, are critical for protective immunity against malaria. The investigators looked at the percentage of immune cells that were CD8+ T cells and that were also secreting only IFN-Υ to see if there was a difference in the fraction of immune cells meeting this criteria between protected and infected individuals. Indeed, people who received the highest dose of PfSPZ and were protected against malaria had a much higher portion of their immune cells that were CD8+ and secreted IFN-Υ. This reinforces the understanding that the cell-mediated immune response is critical for fighting and protecting against malaria.

            This is the first time that a malaria vaccine has achieved such high protection since the discovery that protection can be elicited by >1000 mosquito bites. The group that received the highest dose of PfSPZ had full protection against malaria. While this study was successful, more clinical trials need to be carried out before vaccine development can start. In order to optimize the vaccine’s protective function, different numbers of doses, and time between doses needs to be investigated to determine how to provide the greatest protection. In addition, clinical trials need to include more people, as this trial only had 57 subjects. Regardless of the need for further research, these findings provide new hope that the production of a malaria vaccine is on the horizon.

For more information on Malaria visit:

http://www.cdc.gov/malaria/

http://www.who.int/topics/malaria/en/

Primary Article:

Seder, R.A., Chang, L., Enama, M.E., Zephir, K.L., Sarwar, U.N., Gordon, I.J., et al. (2013). Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine. Science, 341, 359-1365.

Works Cited

 1. http://www.cdc.gov/malaria/

2. World Health Organization, World Malaria Report: 2012; available at www.who.int/malaria/publications_world_malaria_report_2012/report/en/index.html.  

3. Plowe, C.V., Alonso, P., & Hoffman, L. (2009). The potential role of vaccines in the elimination of falciparum malaria and the eventual eradication of malaria. J. Infect. Dis., 200, 1646-1649. 

Picture Sources

4. http://www.mr4.org/

5. http://www.plosbiology.org/article/browseIssue.action?issue=info:doi/10.1371/issue.pbio.v03.i06

6. http://keepingkidssafenow.info/disease/malaria-map-cdc-2/

7. http://www.niaid.nih.gov/topics/malaria/pages/lifecycle.aspx