Research Article: Age Interactions in the Development of Naturally Acquired Immunity to Plasmodiumfalciparum and Its Clinical Presentation

Date Published: July 31, 2007

Publisher: Public Library of Science

Author(s): John J Aponte, Clara Menendez, David Schellenberg, Elizeus Kahigwa, Hassan Mshinda, Penelope Vountasou, Marcel Tanner, Pedro L Alonso, Lars Hviid

Abstract: BackgroundNaturally acquired malaria immunity has many determinants and, in the absence of immunological markers of protection, studies assessing malaria incidence through clinical endpoints remain an approach to defining immunity acquisition. We investigated the role of age in disease incidence and the effects of chemoprophylaxis on clinical immunity development to Plasmodium falciparum during a randomised controlled trial.Methods and FindingsA total of 415 Tanzanian infants were randomly assigned to receive weekly malaria prophylaxis with Deltaprim (3.125 mg of pyrimethamine plus 25 mg of dapsone) or placebo between the ages of 2 and 12 mo. Children were followed up until 4 y of age. Uncomplicated febrile malaria, severe malaria, and anaemia morbidity were assessed through hospital-based passive surveillance. Compared with the group of control participants, there was a marked reduction in the incidence of clinical malaria, severe malaria, and anaemia in the group of children who had received chemoprophylaxis during the first year of life. After discontinuing the intervention, there was a significant increase in the incidence of clinical malaria for 2 y. The cumulative rates of clinical malaria, by age 4 y, were slightly higher in the group of children who had previously received chemoprophylaxis: 3.22 episodes versus 3.02 episodes in the group of control participants; rate difference 0.20 (95% confidence interval [CI]: −0.21 to 0.59). By age 4 y, the cumulative rates of severe malaria, however, were slightly lower in chemosuppressed children (0.47 versus 0.59) (rate difference −0.12 [95% CI: −0.27 to 0.03]). The number of episodes of anaemia was also slightly lower in chemosuppressed children by age 4y: 0.93 episodes (95% CI: 0.79 to 0.97) versus 1.12 episodes in the group of control participants (95% CI: 0.97 to 1.28) (rate difference −0.19 [95% CI: −0.40 to 0.01]), respectively.ConclusionsReducing exposure to P. falciparum antigens through chemoprophylaxis early in life can delay immunity acquisition. Infants appear to acquire immunity faster than older children, but have a higher risk of developing severe forms of malaria and anaemia. These findings provide insight on the interplay between immunity and exposure-reduction interventions.

Partial Text: More than 100 y ago on the island of Java, Koch described how the clinical and parasitological manifestations of malaria decreased with age. He interpreted this as a function of acquired resistance through exposure to the parasite [1]. However, despite a plethora of immunological investigations, no surrogate marker of protective immunity has been identified. A number of humoral and cellular immune responses are known to be associated with reduced risk from Plasmodium falciparum infection and disease [2], but none has been shown to be causally related. Hence, studies assessing malaria incidence through its different clinical endpoints remain the best approach to determine the rate of acquiring immunity.

The trial profile for the intervention and corresponding cohort of control participants is shown in Figure 1. Of the original 415 children, 256 (61.7%) completed the 4 y of follow-up. Thirty-two children (7.7%) died, 121 (29.2%) migrated or were lost to follow-up, and six (1.4%) refused to continue in the study.

This study investigated the development of clinical immunity against malaria during the first 4 y of life in two contemporaneous cohorts of children experiencing P. falciparum infections at different ages. A major strength of this study was that, although transmission intensity varied over the course of follow-up, both cohorts were similarly exposed to malaria. The incidence of clinical malaria in children receiving placebo fell gradually during the first 4 y of life, reflecting the natural development of immunity to uncomplicated clinical disease. However, the documented rate of immunity acquisition was slower than expected given the moderate-to-high transmission rate that had been estimated in the area. This may be partly explained by the fact that the study population had prompt access to diagnosis and treatment, which may delay the development of immunity [18,19]. Nonetheless, immunity development against severe malaria and severe anaemia in the group of control participants was faster, and was consistent with the long-standing view that a relatively small number of infections are sufficient to develop reasonably solid protection against the more severe consequences of P. falciparum infection [20].



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