© 1998 Nature Publishing Group http://www.nature.com/naturemedicine REVIEW Louis Miller (National Institute of Allergy and Infectious Diseases) and Stephen Hoffman (Naval Medical Research Institute) review progress toward developing malaria vaccines. They argue that multiple antigens from different stages may be needed to protect the diverse populations at risk, and that an optimal vaccine would Induce Immunity against all stages. Vaccines for African children, In whom the major mortality occurs, must induce immunity against ase,cual blood stages. Research toward vaccines against malaria Malaria is one of the major causes of the only stage of the life cycle that causes disease and death between the Tropic LOUIS H. MILLER1 disease. The stages before the asexual of Cancer and Tropic of Capricorn. & STEPHEN L. HOFFMAN2 blood stage are lumped together and Plasmodium falciparum has an especially called pre-erythrocytic. A small propor­ profound impact on infants and children in sub-Saharan Africa, tion of the asexual blood stages differentiate into sexual stages, where its effect on health is increasing as chloroquine resistance the gametocytes in red cells that infect mosquitoes; vaccines to spreads across the continent. We believe that vaccination the mosquito stages are called transmission-blocking vaccines. against P. falciparum is the intervention with the greatest poten­ The parasites' multistage life cycle and the fact that immune re­ tial to reduce malaria-associated severe morbidity and mortality sponses that recognize one stage often do not affect the next in areas with the most intense transmission and that it may do stage have made vaccine development for malaria more diffi­ so without necessarily preventing blood stage infection. Malaria cult than for antiviral and antibacterial vaccines. vaccines also would be the optimal method for preventing The pre-erythrocytic stages include sporozoites and para­ malaria in travelers to countries where malaria is transmitted. sites that develop in hepatic parenchymal cells. Sporozoites, Such vaccines will have to entirely prevent the development of after inoculation by the mosquito, spend only a few minutes any clinical manifestations of infection with P. falciparum and in the blood stream before they invade hepatocytes, in which of the second most common human malaria parasite, P. vivax. development takes a minimum of five and a half days in P. This will require preventing blood stage infection. falciparum. Antibodies to sporozoites block their infection of Infants and young children at risk from P. falciparum in Africa hepatocytes. The liver stage in rodent malarias, and probably and nonimmune travelers to areas endemic for P. falciparum and in human malarias, is attacked primarily by CDS· T cells, but P. vivax represent the extremes of target groups in whom malaria also by co4• T cells. These cells can directly eliminate the in- vaccines would be useful. Even fected cells or secrete inter­ in countries where the overall Slngea Goals Ta,vel Populallon feron (IFN)-y that induces numbers of afflicted individuals A Prevent dlJHH A Nonrnmune nitric oxide-dependent killing by blockmg "1111C · lravelen: and are not as great as in Africa, lion belofe re-nllfrom within hepatocytes. Killing all emargence ar•u of low parasites during the sporo­ malaria wreaks its havoc in from IMtr t,ansmtSSIOf\ many epidemiologic settings (o.g., lndta) zoite stage or during the he­ and population groups, dramati­ B. Reduu disease B. Ch,khn and patic infection prevents all by a "8CC11lt p,ognan1 women cally undermines the productiv­ lhal combtnes Ill.,... of high disease. Thus, stand-alone par 11ally •H• transrn.ssion ity of workers, and drains pr1t•orythrocyuc (o.g., Afnca) vaccines against pre-erythro­ national budgets. From the tnd blood suoge cytic stages are being devel- components Amazon basin to the Indian sub­ oped for protection of continent, Southeast Asia, and Reduce disuse by Chddlen and travelers. They may also have raduang blood pregnanl women a role in the general popula­ Oceania, malaria is often a major stage asuuaf ,n r&as ol high national public health problem. ~,tebu,oon transm1SSt0n tion in countries with low en- (eg., Afnca) In these settings, vaccines offer demicity such as India. Their the greatest potential for reduc­ application on their own in ing malaria's debilitating effects. areas with intense transmis­ The spread of drug-resistant P. sion is considered by some to falciparum and the recent emer­ PreYonUon or be inadvisable. There is a con­ 1rat111mls1lon cern that if the vaccines were gence and spread of chloro­ A Eradlcabon A. Vacanate enllr• quine-resistant P. vivax have community 1n too good, they would prevent IS<lltlad arou of created an increasing urgency low ltanaml&lion the development of naturally for effective malaria vaccines. B umll spread of B. Vacc,nata aa acquired anti-blood stage im­ para51tu reslSlanl combmallon with tovacc,nu blood •uoge "' munity, and if the anti-pre - p,a-e,ythrocyuc Life cycle and targets of vaccine erythrocytic immunity waned immunity ~ C. Pr..,.nl epdem• C. Vacc,nata Iha with time, the immunized ~ ,cs.,., .. of 1nbr• populalJon Understanding the life cycle I un&table malana belora lhe rains population would be left with­ (Fig. 1) of the parasite is funda­ transmlSSIOll out any immunity and could suffer an increased incidence mental to all efforts to develop Fig. 1 Multiple vaccines may need to be developed, each for a differ­ vaccines-efforts that in the ent population. Each may contain multiple antigens from one stage or of severe disease and death. end focus on reducing the ef­ combine antigens from different stages. Different formulations and This problem would be miti­ fects of the asexual blood stage, presentations may be needed for antibody or cellular immunity. gated if a pre-erythrocytic 520 NATURE MEDICINE VACCINE SUPPLEMENT • VOLUME 4 • NUMBER 5 • MAY 1998 © 1998 Nature Publishing Group http://www.nature.com/naturemedicine ·········REVIEW stage vaccine were com­ invades midgut epithelial cells. Parasites on the midgut ep­ bined with a blood stage ithelium develop into thousands of sporozoites that invade vaccine, a strategy some the salivary glands to transmit the infection while feeding on consider to be optimal. people. Transmission-blocking vaccines under development The blood stage begins contain gamete, zygote and ookinete surface proteins and se­ when parasites leave liver creted proteins from ookinetes. They induce antibodies that, cells and invade red cells. when ingested with the blood meal, block fertilization, de­ The parasite develops and velopment, penetration of the peritrophic membrane or in­ j multiplies within the red vasion of midgut epithelium. Such vaccines would block ! cell; 16 or more merozoites transmission of mutant parasites resistant to drugs or to vac­ j appear 48 hours after inva­ cines against other stages. Furthermore, they could be used " sion (in P. falciparum and P. for epidemic control in areas of unstable transmission. The f vivax). The infected red cell third use, in combination with other interventions such as .u lyses, releasing merozoites, insecticides, would be for malaria eradication in island com­ Human red cells infected with each capable of invading munities (such as Sri Lanka) where transmission is low. Plasmodium falciparum. other red cells. The para­ Several constructs that contain a surface protein on sitemia can increase ten-fold ookinetes, Pfs25, are under development and are being tested each 48 hours. No disease occurs until the parasitemia in normal volunteers. reaches a level critical for induction of fever and shaking Unlike most viral vaccines, malaria vaccines will be pro­ chills. The serious complications of anemia and coma ap­ duced as subunits that will contain only a few of the esti­ pear later in the infection as the parasitemia rises. The cur­ mated 5,000-7,000 proteins in the parasite or parts of these rent vaccine approach is to design blood stage vaccines that proteins. Below, we identify obstacles to successful subunit will prime the individual for boosting of immunity by the vaccine development for pre-erythrocytic and blood stage parasite during each infection, thereby controlling para­ vaccines and present our perspective on how to overcome sitemia before serious complications occur. There are data them. For those interested in the details of antigens and indicating that disease in young children in Africa is influ­ strategies for vaccine development, see refs. 4 & 5. enced by the intensity of transmission (number of infectious bites per year), the child's genetics, and perhaps virulence Pre-erythrocytic stage vaccines factors in P. falciparum 1• For example, in many areas, cere­ Immunization of mice and humans with radiation-attenu­ bral malaria (coma and seizures with high mortality) is un­ ated sporozoites of rodent and human malaria parasites, re­ common before two years of age2• In low-transmission areas spectively, induces complete protection against the (< 15 bites/individual by infected mosquitoes per year), se­ pathologic and clinical manifestations of the infection. The vere anemia occurs early in life and cerebral malaria later, protective immunity prevents the parasites from emerging suggesting a developmental susceptibility to cerebral from the liver into the bloodstream, is not strain specific, malaria in children2 • In high-transmission areas (> 100 and lasts in humans for at least nine months (ref. 6 for re­ bites/individual by infected