Evidence That Invasion-Inhibitory Antibodies Specific for the 19-kDa Fragment of Merozoite Surface Protein-1 (MSP-119) Can Play a Protective Role against Blood-Stage Plasmodium falciparum Infection in Individuals in a Malaria Endemic Area of Africa

Abstract

The C-terminal 19-kDa fragment of Plasmodium falciparum merozoite surface protein-1 (MSP-119) is a target of protective Abs against blood-stage infection and a leading candidate for inclusion in a human malaria vaccine. However, the precise role, relative importance, and mechanism of action of Abs that target this protein remain unclear. To examine the potential protective role of Abs to MSP-119 in individuals naturally exposed to malaria, we conducted a treatment time to infection study over a 10-wk period in 76 residents of a highland area of western Kenya during a malaria epidemic. These semi-immune individuals were not all equally susceptible to reinfection with P. falciparum following drug cure. Using a new neutralization assay based on transgenic P. falciparum expressing the P. chabaudi MSP-119 orthologue, individuals with high-level MSP-119-specific invasion-inhibitory Abs (>75th percentile) had a 66% reduction in the risk of blood-stage infection relative to others in the population (95% confidence interval, 3–88%). In contrast, high levels of MSP-119 IgG or IgG subclass Abs measured by enzyme immunoassay with six different recombinant MSP-119 Ags did not correlate with protection from infection. IgG Abs measured by serology and functional invasion-inhibitory activity did not correlate with each other. These findings implicate an important protective role for MSP-119-specific invasion inhibitory Abs in immunity to blood-stage P. falciparum infection, and suggest that the measurement of MSP-119 specific inhibitory Abs may serve as an accurate correlate of protection in clinical trials of MSP-1-based vaccines.

Variation in use of erythrocyte invasion pathways by Plasmodium falciparum mediates evasion of human inhibitory antibodies

“…However, antibodies measured by ELISA cannot be relied on as a direct measure of functional immunity, as we found no clear or consistent association between antibodies by ELISA and differences in inhibitory activity between comparison lines. Consistent with this, prior studies reported no correlation between antibodies against MSP1 19 by ELISA and MSP1 19 -specific inhibitory antibodies (46). In other studies we have found antibodies against other merozoite antigens measured by ELISA to be poor predictors of inhibitory activity (F. McCallum, K. Persson, D. Wilson, and J. Beeson, unpublished observations).…”

Naturally acquired antibodies to merozoite surface protein (MSP)-1(19) and cumulative exposure to Plasmodium falciparum and Plasmodium vivax in remote populations of the Amazon Basin of Brazil

“…However, it remains unknown whether all antibodies to PfMSP-1 19 detected by ELISA are functionally relevant. A recent cohort study in Western Kenya suggested that the ability of naturally acquired antiPfMSP-1 19 antibodies to inhibit merozoite invasion in vitro may be a better correlate of clinical immunity to malaria than the mere presence of antibodies measured by conventional ELISA (John et al 2004). Contrasting with the extensive investigation of the role of Pf MSP-1 19 in naturally acquired immunity, little is known about the immune recognition of the ortholog protein of P. vivax (Pv).…”

The Impact of Immune Responses on the Asexual Erythrocytic Stages of Plasmodium and the Implication for Vaccine Development

“…The results demonstrated that the invasion inhibitory antibodies were specific for the C-terminal MSP-1p19 (John et al, 2004). Overall, there was a lack of association of total IgG or IgG subclass Abs to MSP-1p19 measured by ELISA with either invasion-inhibitory activity or protection against infection.…”

“…Serological studies have provided significant evidence suggesting that immune responses directed against the C-terminus of MSP-1 (MSP-1p19 and MSP-1p42) are associated with immunity in preclinical models (Long et al, 1994;Egan et al, 1999;Darko et al, 2005;Parkkinen et al, 2006). Moreover, protective immunity as defined by lower mortality and morbidity of individuals residing in endemic areas was also associated with MSP-1p19 (Egan et al, 1999;John et al, 2004).…”