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Malaria is a disease caused by repeated cycles of growth of the parasite Plasmodium in the erythrocyte. Various cellular and molecular strategies allow the parasite to evade the human immune response for many cycles of parasite multiplication. Under certain circumstances Plasmodium infection causes severe anemia or cerebral malaria; the expression of disease is influenced by both parasite and host factors, as exemplified by the exacerbation of disease during pregnancy. This article provides an overview of malaria pathogenesis, synthesizing the recent field, laboratory, and epidemiological data that will lead to the development of strategies to reduce mortality and morbidity.

In recent malaria sporozoite vaccine trials in humans and mice, antibodies to the sporozoite coat protein have given only modest protection against sporozoite challenge. In contrast, irradiated sporozoites can protect mice against massive sporozoite infections. Evidence suggests that immunity in these mice is mediated by T cells. To identify the mechanism of immunity, we used monoclonal antibodies specific for either the CD4 or CD8 molecule to selectively deplete sporozoite-immunized mice of T-cell subsets. Though in vivo depletion of CD4+ T cells did not reduce immunity, depletion of CD8+ T cells abolished protection. Monoclonal antibody treatment did not affect anti-sporozoite antibody levels. Our data indicate that cytotoxic T cells are critical for immunity to large numbers of sporozoites and suggest that vaccine development should be reoriented toward stimulating cellular as well as humoral immunity.In the life cycle of the malaria parasite, sporozoites pass from the mosquito through the blood of the host and invade liver cells where they develop into hepatic-stage parasites. Later, mature parasites are released from the liver to invade erythrocytes. When sporozoites are experimentally irradiated, they still invade liver cells but they are unable to mature to the stage that infects erythrocytes (1). Immunization with irradiated sporozoites can protect mice against infection with several thousand sporozoites (2). Humans can also be successfully immunized with irradiated sporozoites (3,4), but use of attenuated parasites as a vaccine is impractical. A current sporozoite vaccine strategy is to induce antibodies against the central repetitive sequence of the circumsporozoite (CS) protein, which covers the sporozoite surface (5-7). Several recent trials of such vaccines in humans (8, 9) and mice (10, 11) have had limited success. This suggests that humoral immunity may be less important than previously thought and that cellular immunity may be critical for a highly effective vaccine (10,12,13 (20). Thirty to 60 mosquitoes were anesthetized with chloroform and placed on a glass slide in a drop of medium 199 with 3% mouse serum. The abdomen was held with fine forceps, and the thorax of each mosquito was cut just anterior to the wing. The collection of upper bodies without further preparation was then spun through glass wool according to the published method. After counting in a hemacytometer, sporozoites were diluted to final concentration in medium 199 with 3% mouse serum.Antibodies. Monoclonal antibodies were produced in ascites fluid of athymic mice and of BALB/c mice treated with cortisone and irradiation (21). Anti-CD8 antibody came from the anti-Lyt2.2 hybridoma 19/178 (mouse IgG2a) (22). Anti-CD4 antibody came from the anti-L3T4 clone GK1.5 (rat IgG2b) (23). A control antibody came from the antiPlasmodium falciparum gamete clone 1B3 (mouse IgG2a) (45). Control rat immunoglobulin was from normal rat serum purchased from Accurate Chemical and Scientific (Westbury, NY). All immunoglobulins were purifie...

A conformationally constrained, minimally conserved peptide from the M protein of group A streptococcus (GAS) has been defined. It consists of 12 amino acids from the C-repeat region within a non-M protein helix-forming sequence and is referred to as "J8." Here, we investigate the immunogenicity of a J8-diphtheria toxoid (DT) conjugate adjuvanted with the human-compatible adjuvants, SBAS2 and alum, and demonstrate that it is capable of inducing opsonic antibodies and can protect outbred mice from virulent challenge. In a range of experiments, protection correlated with the titer of J8-specific antibodies and not with the induction of J8-specific T cells. However, DT-specific antibodies (as well as J8-specific antibodies) were shown to stain the surface of fixed GAS and to be capable of opsonizing live organisms. DT may be an ideal carrier protein for J8 and other GAS peptides for GAS vaccines.

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