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.

HIV and Malaria Co-Infection: A Game of Immunological Russian Roulette

Around the world, there are approximately 300 million cases of malaria, from which 1 million deaths occur (1). In 2010 alone, the number of people infected with HIV increased by 2.7 million, altogether amounting to 36.7 million HIV-infected individuals globally (2). Both “diseases of poverty”, malaria and HIV have similar geographical distributions, prevalent particularly in third-world sub-Saharan Africa, the Indian subcontinent, and Southeast Asia. Studies have shown that due to this geographical overlap, co-infection of the two diseases is a common phenomenon in these regions (3,4).

HIV/AIDS is brought about by a virus whereas malaria is caused by a plasmodium. Co-infection of the two diseases, therefore, has great potential towards the investigation of dynamics between the mechanisms of immune response to both infections. Ryan-Payseur, et al., in this paper, are looking to elucidate just that; that is, what exactly happens to the immune system when it is infected by a virus and a parasite? This is an interesting paper because in research, it is difficult to examine the effects of co-infection in naturally occurring infections because naïve individuals do not exist—humans co-infected with HIV and malaria often have been previously exposed to malaria, which can complicate results (5). Nevertheless, the researchers for this paper were able to circumvent this problem, as well as the additional problem of an accurate animal model (Fig. 1), through a series of imaginative tweaks to the primate model of Simian Immunodeficiency Virus (SIV)-plasmodium infection.

[ Fig. 1 ]

Don't forget the bug spray! Establishing T-cell and memory T-cell responses to malaria

Malaria, and its causative agent, the parasite Plasmodium falciparum, is transmitted person-to-person through a bite from an Anopheles mosquito.  After being bitten by an infected mosquito, P. falciparum parasites in the sporozoite stage (PfSpz) enter the body and travel to the liver where they infect liver cells—this stage of the disease is asymptomatic.  In liver cells the sporozoites divide into merozoites (PfRBC) that then exit the liver cell and infect red blood cells.  This infection of red blood cells causes the symptomatic stage of malaria.

In the field of public health, it is generally accepted that immunity from malaria infections is usually short-lived and weak at best.  A study by Teirlinck et al published December 1 in PLoS Pathogens set out to test whether or not lasting immunity is actually induced by infection with P. falciparum.  In order to direct their experiment, the researchers chose to investigate recent findings that cytokines, small signaling proteins, play a role in the cellular immune response to P. falciparum.  To do this, the researchers infected two groups via mosquito bites; group A was treated with the prophylactic anti-malaria drug chloroquine while group B received no prophylaxis.

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.