Immunity to the liver stage of malaria

The search for subunit vaccines against malaria has concentrated on asexual and sexual blood stage and sporozoite antigens. In recent years the search for the basis of the protection against sporozoite challenge obtained in mice immunized with irradiated sporozoites has focused attention on the liver or exoerythrocytic (EE) stage of the malaria life cycle. Here, Andreas Suhrbier looks at the various immune responses that appear to be active against this stage, which was once thought to be immunologically insignificant. The liver stage of malaria has thus emerged as a legitimate target for vaccine development.     

Immunity to exoerythrocytic forms of malaria. II. Passive transfer of immunity to exoerythrocytic forms

The passive transfer of heat-inactivated or nonheat-inactivated convalescent serum, from turkeys inoculated with Plasmodium fallax exoerythrocytic forms and treated with chloroquine to suppress the development of erythrocytic forms and the development of immunity to them, delayed the exoerythrocytic-form infection in turkeys inoculated intravenously with exoerythrocytic forms. The degree of exoerythrocyticform parasitization in cerebral tissue was significantly less in the experimental groups than the degree of parasitization in control groups, and the experimental birds continued gaining weight for a longer period than the control birds. The passive transfer of immune serum had an effect on the course of the exoerythrocytic-form infection equivalent to killing 90% of the exoerythrocytic-form inoculum. The immunity to exoerythrocytic forms is form-specific, since the infected, chloroquine-treated, serum donors were just as susceptible to an erythrocytic-form challenge infection as normal turkeys.In vitro studies demonstrated that heat-inactivated serum from turkeys immune to exoerythrocytic-form infections caused a precipitate to form at the small end of exoerythrocytic merozoites. This precipitate was not observed on merozoites mixed with control serum.     

Immunity to asexual blood stage malaria and vaccine approaches

The development of a malaria vaccine seems to be a definite possibility despite the fact that even individuals with a life time of endemic exposure do not develop sterile immunity. An effective malaria vaccine would be invaluable in preventing malaria-associated deaths in endemic areas, especially amongst children less than 5 years of age and pregnant women. This review discusses our current understanding of immunity against the asexual blood stage of malaria - the stage that is responsible for the symptoms of the disease - and approaches to the design of an asexual blood stage vaccine.     

Immunity to exoerythrocytic forms of malaria. I. Course of infection of Plasmodium fallax in turkeys

Turkeys inoculated intravenously with Plasmodium fallax parasitized erythrocytes developed an initial parasitemia. After the parasitemia crisis, the number of exoerythrocytic forms increased and caused the death of the bird about a week later. When the size of the erythrocytic-form inoculum was decreased tenfold, the day of maximum parasitemia and the day of death due to a high level of exoerythrocytic-form parasitism was delayed approximately 1 day.Turkeys inoculated intravenously with exoerythrocytic forms obtained from erythrocyte-free tissue cultures of parasitized turkey embryo brain cells developed an initial exoerythrocytic-form infection. The growth of exoerythrocytic forms in the poults was not affected by daily drug treatment with chloroquine; the number of exoerythrocytic forms/1000 cerebral cell nuclei was not significantly different in chloroquinetreated or untreated poults. Following the exoerythrocytic-form crisis, the parasitemia increased for several days in nondrug-treated birds. In chloroquine-treated birds, the erythrocytic forms were only detected during the period when exoerythrocytic forms were prevalent. Erythrocytic-form schizonts were not observed in chloroquinentreated birds. The poults stopped gaining body weight when either the exoerythrocytic forms or the erythocytic forms were prevalent. A tenfold decrease in the exoerythrocytic-form inoculum size delayed the exoerythrocytic-form infection 1 day. The development of exoerythrocytic forms was not synchronous in turkeys inoculated with exoerythrocytic forms and examined prior to the exoerythrocytic-form crisis.     

Immunity to non-cerebral severe malaria is acquired after one or two infections

In areas of stable transmission, clinical immunity to mild malaria is acquired slowly, so it is not usually effective until early adolescence. Life-threatening disease is, however, restricted to a much younger age group, indicating that resistance to the severe clinical consequences of infection is acquired more quickly. Understanding how rapidly immunity develops to severe malaria is essential, as severe malaria should be the primary target of intervention strategies, and predicting the result of interventions that reduce host exposure will require consideration of these dynamics. Severe disease in childhood is less frequent in areas where transmission is the greatest. One explanation for this is that infants experience increased exposure to infection while they are protected from disease, possibly by maternal antibody. They therefore emerge from this period of clinical protection with considerably more immunity than those who experience lower transmission intensities. Here we use this data, assuming a period of clinical protection, to estimate the number of prior infections needed to reduce the risk of severe disease to negligible levels. Contrary to expectations, one or two successful infective bites seem to be all that is necessary across a broad range of transmission intensities.     

Immunity promotes virulence evolution in a malaria model

Evolutionary models predict that host immunity will shape the evolution of parasite virulence. While some assumptions of these models have been tested, the actual evolutionary outcome of immune selection on virulence has not. Using the mouse malaria model, Plasmodium chabaudi, we experimentally tested whether immune pressure promotes the evolution of more virulent pathogens by evolving parasite lines in immunized and nonimmunized (“naïve”) mice using serial passage. We found that parasite lines evolved in immunized mice became more virulent to both naïve and immune mice than lines evolved in naïve mice. When these evolved lines were transmitted through mosquitoes, there was a general reduction in virulence across all lines. However, the immune-selected lines remained more virulent to naïve mice than the naïve-selected lines, though not to immunized mice. Thus, immune selection accelerated the rate of virulence evolution, rendering parasites more dangerous to naïve hosts. These results argue for further consideration of the evolutionary consequences for pathogen virulence of vaccination.     

Immunity to sporozoite-induced malaria infeciton in mice. I. The effect of immunization of T and B cell-deficient mice.

The cellular basis of immunity to sporozoites was investigated by examing the effect of immunization of T and B cell-deficient C57BL/6N X BALB/c AnN F1 (BLCF1) mice compared to immunocompetent controls. Immunization of T cell-deficient (ATX-BM-ATS) BLCF1 mice with x-irradiated sporozoites did not result in the generation of protective immunity. The same immunization protocols protected all immunocompetent controls. In contrast, B cell-deficient (micron-suppressed) BLCF1 mice were protected by immunization in the majority of cases. The absence of detectable serum circumsporozoite precipitins or sporozoite neutralizing activity in the micron-suppressed mice that resisted a sporozoite challenge suggests a minor role for these humoral factors in protection. These data demonstrate a preeminent role for T cells in the induction of protective immunity in BLCF 1 mice against a P. berghei sporozoite infection.     

Immunity to Bordetella pertussis.

Bordetella pertussis exploits extracellular and intracellular niches in the respiratory tract and a variety of immune evasion strategies to prolong its survival in the host. This article reviews evidence of complementary roles for cellular and humoral immunity in protection. It discusses the effector mechanisms of bacterial elimination, the strategies employed by the bacteria to subvert protective immune responses and the immunological basis for systemic and neurological responses to infection and vaccination.     

Falciparum malaria semi-resistant to clindamycin.

Clindamycin, a semi-synthetic antibiotic of the lincomycin family, at a dose of 450 mg eight-hourly for three days in adults cured five out of 10 patients moderately ill with chloroquine-resistant falciparum malaria. Combination therapy with full-dose quinine and clindamycin for three days cured all four patients so treated who were followed up, and with half dosage three out of five patients were cured. Both combinations, however, caused upper gastrointestinal toxicity and appeared to potentiate both toxicity and possibly antimalarial efficacy. Colitis due to clindamycin was not observed. Sequential therapy was not toxic and could be useful in patients who have relapsed after more conventional treatment.     

Immunity to Onchocerca spp. in animal hosts

This review summarizes research using Onchocerca spp. in chimpanzees, cattle and mice to gain insight into the protective immune response to the filarial worm Onchocerca volvulus in humans. In addition, Acanthocheilonema viteae has been evaluated as a surrogate filarial worm for studying immunity to the infection. Immune mechanisms controlling these infections are described and initial success using recombinant antigen vaccines in these models is reviewed.