Malaria Vaccine: A Long Haul

During a meal, a mosquito infected with Plasmodium falciparum will inject between 5 and 20 sporozoites into the host. The ID50 for malaria is 10, so there is a possibility of developing clinical malaria in nonimmune hosts after just one bite from an infected mosquito. The passage of the sporozoites through the blood stream to the liver is rapid. After 45 minutes most sporozoites would have left the blood. Sporozoites migrate through several hepatocytes before entering one, which marks the start of the liver stage. Over 6 days or so sporozoites develop within the liver cells which eventually rupture releasing 20 000 to 30 000 merozoites per original sporozoite into the hepatic circulation from where they disseminate into the host’s bloodstream. Merozoites next invade erythrocytes and commence a 48-hour cycle of replication forming a schizont. When the schizont ruptures, a large number of merozoites are released which invade more erythrocytes and the blood stage of malaria commences. As the malaria parasite progresses through the above stages viz. sporozoite, schizont, merozoites, different antigens are expressed at each stage of the life cycle. This means that different immune recognition patterns are required at each stage, and different immune effector mechanisms must be called upon at each stage. Some merozoites differentiate into male or female gametocytes. When ingested by the anopheles mosquito, fertilization occurs within the mosquito’s mid-gut leading to completion of the life cycle. In endemic areas, people exposed to repeated malarial infection gradually acquire immunity, first to severe disease and then to mild disease. Repeated infections are required to maintain immunity. The immunity is species-specific and largely strainspecific. A rise in serum immunoglobulins accompanies the acquisition of immunity. Levels of IgM, IgG, and IgA all increase, sometimes several-fold. It has been shown that IgG from West African adults can reduce the P. falciparum levels when transfused into parasitaemic children from the same locality. Infants born to immune mothers are partially protected against severe malaria attacks by transplacental antibodies and those acquired from breast milk for a few months, after which they suffer from severe malaria attacks with gradual acquisition of resistance. The basis of clinical immunity, which is both antibody and T-cell dependent is still to be delineated. There is a diversity of antigenic stimulus as the parasite goes through its various stages of development. An estimated 5300 antigens are encoded by P. falciparum, and immunity to one stage of the parasite is largely restricted to that part of the life cycle. Antibodies can recognise the sporozoite as it passes through the blood to the liver cells. Although the duration of the stage is short, the numbers are not so many. Later on, different antibodies are called upon to act against the merozoites as they move between red blood cells. With regard to cell-mediated immunity, lymphocytes recognise infected liver cells, but the absence of class II major histocompatibility antigens on infected red cells makes T-cell recognition of parasitized cells difficult. Intracellular localization of the parasite for the major part of its life-cycle shields the plasmodium from most defences. Also the parasite can evade antibody response by releasing a decoy protein. These are molecules released from the pathogen surface or from the surface of an infected cell that can bind and mop up free antibody. Immune complexes form away from the surface of the pathogen with the result that macrophages, complement and natural killer (NK) cells are less likely to be able to bind to the cell surface antigens. The circumsporozoite antigen of the plasmodium acts as a decoy protein. In 1967, using a mouse model, it was shown that protective immunity can be induced by administering Plasmodium berghei sporozoites that had been attenuated by gamma irradiation when given to mice in a prime-boost combination. The procedure generated long lasting immunity to subsequent challenge by wild type parasites. Immunity results from multiple responses including sporozoitespecific antibodies, effector CD8þ and CD4þ T cells and memory CD8þ T cells that recognise the infected hepatocytes. These studies provided the impetus for human studies. Clyde et al. demonstrated that immunity is induced in human volunteers by bites from irradiated mosquitoes in a number of groundbreaking studies in the 1970’s. These studies established that immunizing human volunteers with the bites of irradiated mosquitoes carrying P. falciparum or P. vivax sporozoites in their salivary glands could protect the human host against challenge with fully infectious sporozoites. Further studies in 1989 showed that protection lasted