Mature beyond their years: young children who escape detection of parasitemia despite living in settings of intense malaria transmission

Abstract

Despite having the highest risk of progressing to severe disease due to lack of acquired immunity, the youngest children living in areas of highly intense malaria transmission have long been observed to be infected at lower rates than older children. Whether this observation is due to reduced exposure to infectious mosquito bites from behavioral and biological factors, maternally transferred immunity, genetic factors, or enhanced innate immunity in the young child has intrigued malaria researchers for over half a century. Recent evidence suggests that maternally transferred immunity may be limited to early infancy and that the young child's own immune system may contribute to control of malarial symptoms early in life and prior to the development of more effective adaptive immunity. Prospective studies of active and passive detection of Plasmodium falciparum blood-stage infections have identified young children (<5 years old) who remain uninfected through a defined surveillance period despite living in settings of highly intense malaria transmission. Yet, little is known about the potential immunological basis for this 'aparasitemic' phenotype. In this review, we summarize the observational evidence for this phenotype in field studies and examine potential reasons why these children escape detection of parasitemia, covering factors that are either extrinsic or intrinsic to their developing immune system. We discuss the challenges of distinguishing malaria protection from lack of malaria exposure in field studies. We also identify gaps in our knowledge regarding cellular immunity in the youngest age group and propose directions that researchers may take to address these gaps.

Keywords: Plasmodium falciparum; cellular immunity; early adaptive immunity; early life immunity; innate immunity; malaria.

Figure 1.. Surveillance of malaria infections in prospective cohort studies.

(A) Design of a prototypical prospective cohort study with passive and active detection of malaria episodes and P. falciparum infections. Figure adapted from [11]. Participant blood samples are collected at the start of the study to allow biological assessments that can be linked to prospective risk of clinical malaria or P. falciparum infection. Plasma/serum collected at the end of the surveillance period can be used to evaluate seroconversion of P. falciparum stage-specific antibodies as a surrogate of malaria exposure. PBMCs, peripheral blood mononuclear cells. Hypothetical infection cumulative incidence plots showing the fraction of young children escaping parasite detection for (B) an observational cohort study of natural P. falciparum infections in children and (C) a pre-erythrocytic malaria vaccine trial in infants aged 5–12 months. These conceptual plots were modeled after unpublished and published data from the Kalifabougou cohort study [10] and the KSPZV1 malaria vaccine trial [12,13], respectively.