Acquired immunity to malaria

Abstract

Naturally acquired immunity to falciparum malaria protects millions of people routinely exposed to Plasmodium falciparum infection from severe disease and death. There is no clear concept about how this protection works. There is no general agreement about the rate of onset of acquired immunity or what constitutes the key determinants of protection; much less is there a consensus regarding the mechanism(s) of protection. This review summarizes what is understood about naturally acquired and experimentally induced immunity against malaria with the help of evolving insights provided by biotechnology and places these insights in the context of historical, clinical, and epidemiological observations. We advocate that naturally acquired immunity should be appreciated as being virtually 100% effective against severe disease and death among heavily exposed adults. Even the immunity that occurs in exposed infants may exceed 90% effectiveness. The induction of an adult-like immune status among high-risk infants in sub-Saharan Africa would greatly diminish disease and death caused by P. falciparum. The mechanism of naturally acquired immunity that occurs among adults living in areas of hyper- to holoendemicity should be understood with a view toward duplicating such protection in infants and young children in areas of endemicity.

FIG. 1.

Hypothetical immunity-exposure curve, showing the hypothesized rise and fall of host susceptibility to severe disease with falciparum malaria. Segment A shows an increasing risk of death, principally from hyperparasitemia and cerebral malaria (and perhaps from respiratory and renal failure), rising with an increasing risk of exposure to infection. Segment B shows a declining risk of death with the onset of sufficient exposure to induce NAI. Segment C represents the threshold of exposure that maintains maximum NAI. Segment D shows an intensity of exposure that overwhelms NAI and where the risk of disease states such as severe anemia becomes predominant. (Reproduced from reference with permission of the publisher.)

FIG. 2.

Onset of age-dependent NAI. The graph illustrates the prevalence of parasitemia (percent) across age groups (years) among malaria-naive newcomers to Indonesian New Guinea. After 8 months of exposure, all ages appear to be equally susceptible to parasitemia detectable by microscopic diagnosis. One year later (20 months), a distinct age-dependent pattern of susceptibility to parasitemia has appeared. These data revealed the onset of NAI to be dependent upon intrinsic age-related factors independent of lifelong, chronic exposure. (Reproduced from reference with permission of the Liverpool School of Tropical Medicine.)

FIG. 3.

Age- and exposure-dependent inversion of susceptibility to disease. These graphs illustrate the apparent age-dependent inversion of susceptibility to death caused by P. falciparum with acute (a) versus chronic (b) exposure. Malaria-naive travelers experiencing acute exposure to infection show a sharp increase in the risk of death (odds ratio) with increasing age, whereas the mortality rate for malaria among people living in an area of holoendemic transmission shows the opposite trend. (Reproduced from reference with permission of the Liverpool School of Tropical Medicine.)

FIG. 4.

Hypothetical basis of age-dependent inversion of susceptibility to disease with acute versus chronic exposure in children and adults. Consider Th1- and Th2-type immune responses as surrogates for any immune response that changes with age independent of exposure and plays a critical role in infection outcomes. Th1-driven effectors may dominate the immune response of children (hollow arrows), whereas Th2-driven effectors may dominate the adult immune response (solid arrows). These distinct, age- and exposure-dependent responses cause harm or benefit to the host. (Reproduced from reference with permission of the Liverpool School of Tropical Medicine.)

FIG. 5.

Onset of clinical immunity to falciparum malaria in a second experimental challenge with homologous versus heterologous strains. Solid bars show the percent reduction in number of days with greater than 1,000 parasites per μl after challenge with a homologous (left, data from 14 human subjects) or heterologous (right, data from 5 human subjects) strain. Gray bars show the percent reduction in mean number of days with a fever higher than 100°F. Light bars show the same for a fever higher than 102°F. (Based on data from reference .)