Young lives lost as B cells falter: what we are learning about antibody responses in malaria

Abstract

Plasmodium falciparum malaria remains a major public health threat for which there is no licensed vaccine. Abs play a key role in malaria immunity, but Ab-mediated protection is only acquired after years of repeated infections, leaving children in endemic areas vulnerable to severe malaria and death. Many P. falciparum Ags are extraordinarily diverse and clonally variant, which likely contribute to the inefficient acquisition of protective Abs. However, mounting evidence suggests that there is more to the story and that infection-induced dysregulation of B cell function also plays a role. We herein review progress toward understanding the B cell biology of P. falciparum infection, focusing on what has been learned from population-based studies in malaria-endemic areas. We suggest ways in which advances in immunology and genomics-based technology can further improve our understanding of the B cell response in malaria and perhaps illuminate new pathways to the development of effective vaccines.

Figure 1. The P. falciparum life cycle: no shortage of Ab targets

The P. falciparum life cycle in humans includes the asymptomatic liver stage; the blood stage which causes disease; and the sexual gametocyte blood stage which infects mosquitoes that transmit the parasite. Infection begins when Anopheles mosquitos inject sporozoites into the skin and blood (a) which migrate to the liver and invade a small number of hepatocytes (b). Each sporozoite gives rise to thousands of asexual parasites called merozoites (c). ~1 week after hepatocyte invasion merozoites exit the liver into the bloodstream and begin a 48 hr cycle (d) of RBC invasion, replication, RBC rupture, and merozoite release (e). Once inside RBCs the parasite exports variant surface antigens (VSAs) such as PfEMP1 to the RBC surface. VSAs mediate binding of iRBCs to the microvascular endothelium of various organs (f) and placental tissue (g) allowing parasites to avoid splenic clearance and promoting the inflammation and circulatory obstruction associated with clinical syndromes such as cerebral malaria (coma) and pregnancy-associated malaria. VSA-mediated rosetting (binding of iRBCs to RBCs) may also contribute to disease (h). A small number of blood-stage parasites differentiate into sexual gametocytes (i) which are taken up by mosquitos (j) where they differentiate into gametes that fuse to form a motile zygote, the ookinete (k), where meiosis occurs. The ookinete crosses the midgut wall and forms an oocyst (l) that develops into sporozoites that enter the mosquito salivary gland to complete the life cycle (a). Abs that sterilely protect by neutralizing sporozoites (a) and/or blocking hepatocyte invasion (b) are rarely if ever acquired through natural infection (4). Abs induced by the RTS,S vaccine target the circumsporozoite (CS) protein on the sporozoite surface (98) and correlate with sterile protection in malaria-naïve adults (99); but in African children RTS,S generally protects against disease not infection and the correlation between Abs and protection is less clear (100, 101). Abs are a key component of naturally-acquired blood stage immunity (7) but the Ag targets and mechanisms of protection are incompletely understood and likely multifaceted. Abs may contribute to protection by clearing merozoites (102) and iRBCs (e) through opsonization (103) or complement-mediated lysis (104); inhibiting merozoite invasion of RBCs (d) (105); and/or blocking adhesion of iRBCs to vascular endothelium (f) (106). Non-neutralizing Abs may contribute to protection through Ab-dependent monocyte-(107) or NK cell-mediated cytotoxicity. Blood stage vaccines have focused primarily on generating Abs to merozoite proteins but with limited success (54, 108), probably due to Ag polymorphism (14, 108) and redundant RBC invasion pathways (109). Of note, the conserved merozoite protein PfRh5 appears to be essential for RBC invasion (80) and may be susceptible to vaccine-inducible cross-strain neutralizing Ab (110). Protection from pregnancy-associated malaria correlates with IgG specific for VAR2CSA, a conserved protein which mediates adherence to placental tissue (g) (111). Vaccine-induced Abs targeting Ags on gametocytes and gametes that are ingested with the blood meal (i–l) could prevent parasite development in the mosquito and block or reduce transmission (112).

Figure 2. The P. falciparum-specific IgG response is broad but short-lived in children

Shown is IgG reactivity (red) specific for 491 P. falciparum proteins (columns) in plasma collected from children (n=157) and adults (n=37) before and after an intense 6 month malaria season [(55) for detailed Methods and Results]. The average IgG level for each protein is stratified by 1-yr age groups from 2–21 yrs, and within each age group from before to after the malaria season (rows). A broad P. falciparum-specific IgG response is present after the 6-month malaria season in children as young as 2 yrs, however, the IgG response in young children is short-lived based on IgG levels at the end of the 6 month dry season, a period of little to no P. falciparum transmission. With increasing age, IgG levels at the end of the dry season gradually increase until plateauing in adulthood.