Acquisition, maintenance and adaptation of invasion inhibitory antibodies against Plasmodium falciparum invasion ligands involved in immune evasion

Abstract

Erythrocyte-binding antigens (EBAs) and P. falciparum reticulocyte-binding homologue proteins (PfRhs) are two important protein families that can vary in expression and utilization by P. falciparum to evade inhibitory antibodies. We evaluated antibodies at repeated time-points among individuals living in an endemic region in Nigeria over almost one year against these vaccine candidates. Antibody levels against EBA140, EBA175, EBA181, PfRh2, PfRh4, and MSP2, were measured by ELISA. We also used parasites with disrupted EBA140, EBA175 and EBA181 genes to show that all these were targets of invasion inhibitory antibodies. However, antigenic targets of inhibitory antibodies were not stable and changed substantially over time in most individuals, independent of age. Antibodies levels measured by ELISA also varied within and between individuals over time and the antibodies against EBA181, PfRh2 and MSP2 declined more rapidly in younger individuals (≤15 years) compared with older (>15). The breadth of high antibody responses over time was more influenced by age than by the frequency of infection. High antibody levels were associated with a more stable invasion inhibitory response, which could indicate that during the long process of formation of immunity, many changes not only in levels but also in functional responses are needed. This is an important finding in understanding natural immunity against malaria, which is essential for making an efficacious vaccine.

Impact of a Rapid Decline in Malaria Transmission on Antimalarial IgG Subclasses and Avidity

“…Therefore, the increase in avidity index we observed may indicate affinity maturation per se and/or the relative contributions of SLPCs and LLPCs following infection. A study conducted in the setting of ongoing malaria transmission and infection in Nigeria found that antibody avidity was stable among most individuals over time (77); this finding is largely consistent with our proposed model. In future studies, the direct quantification of high avidity antibodies-not performed heremay be a better indicator of affinity maturation compared to the avidity index.…”

Impact of a rapid decline in malaria transmission on antimalarial IgG subclasses and avidity

“…Therefore, the increase in avidity index we observed may indicate affinity maturation per se and/or the relative contributions of SLPCs and LLPCs following infection. A study conducted in the setting of ongoing malaria transmission and infection in Nigeria found that antibody avidity was stable among most individuals over time (56) ; this finding is largely consistent with our proposed model. In future studies, the direct quantification of high avidity antibodies -not performed here -may be a better indicator of affinity maturation compared to the avidity index.…”

Osteopontin and malaria: no direct effect on parasite growth, but correlation with P. falciparum-specific B cells and BAFF in a malaria endemic area

“…Details of the invasion inhibition method have been described elsewhere [ 43 , 84 ]. Briefly, in vitro culture of P. falciparum FCR3S1.2 was maintained using O + RBC at 4 % hematocrit in RPMI 1640-HEPES supplemented with 1 % Albumax II, 25 µg/mL gentamicin, 5 mM L-glutamine and 25 mM NaHCO 3 .…”