Anti-Apical-Membrane-Antigen-1 Antibody Is More Effective than Anti-42-Kilodalton-Merozoite-Surface-Protein-1 Antibody in Inhibiting Plasmodium falciparum Growth, as Determined by the In Vitro Growth Inhibition Assay

Abstract

Apical membrane antigen 1 (AMA1) and the 42-kDa merozoite surface protein 1 (MSP1 42 ) are leading malaria vaccine candidates. Several preclinical and clinical trials have been conducted, and an in vitro parasite growth inhibition assay has been used to evaluate the biological activities of the resulting antibodies. In a U.S. phase 1 trial with AMA1-C1/Alhydrogel plus CPG 7909, the vaccination elicited anti-AMA1 immunoglobulin G (IgG) which showed up to 96% inhibition. However, antibodies induced by MSP1 42 -C1/Alhydrogel plus CPG 7909 vaccine showed less than 32% inhibition in vitro. To determine whether anti-MSP1 42 IgG had less growth-inhibitory activity than anti-AMA1 IgG in vitro, the amounts of IgG that produced 50% inhibition of parasite growth (Ab 50 ) were compared for rabbit and human antibodies. The Ab 50 s of rabbit and human anti-MSP1 42 IgGs were significantly higher (0.21 and 0.62 mg/ml, respectively) than those of anti-AMA1 IgGs (0.07 and 0.10 mg/ml, respectively) against 3D7 parasites. Ab 50 data against FVO parasites also demonstrated significant differences. We further investigated the Ab 50 s of mouse and monkey anti-AMA1 IgGs and showed that there were significant differences between the species (mouse, 0.28 mg/ml, and monkey, 0.14 mg/ml, against 3D7 parasites). Although it is unknown whether growth-inhibitory activity in vitro reflects protective immunity in vivo, this study showed that the Ab 50 varies with both antigen and species. Our data provide a benchmark for antibody levels for future AMA1-or MSP1 42 -based vaccine development efforts in preclinical and clinical trials.

Enhancing Blood-Stage Malaria Subunit Vaccine Immunogenicity in Rhesus Macaques by Combining Adenovirus, Poxvirus, and Protein-in-Adjuvant Vaccines

“…IgG end point titers against both alleles of AMA1 correlated with GIA measured at 5 mg/ml (data not shown) and 10 mg/ml, showing a sigmoidal relationship as seen before in such studies (Fig. 4C, 4D) (50). Overall, in vitro GIA was lower in all samples when purified IgG was assayed at 5 mg/ml, in agreement with other studies (41,51), and confirming that the growth inhibitory effect can be titrated out.…”

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

“…Hodder et al , 2001; Miura et al , 2009; Reiling et al , 2012; Schwartz et al , 2012). In a new study, however, Boyle et al (2015) demonstrated that acquired invasion‐inhibitory antibodies act through binding of C1q and activation of the classical complement pathway rather than by functionally inhibiting invasion.…”

Identification and Prioritization of Merozoite Antigens as Targets of Protective Human Immunity to Plasmodium falciparum Malaria for Vaccine and Biomarker Development

“…Many of the key Ags of P. falciparum are either not present in rodent malaria species or have major differences in structure and sequence, limiting their ability to be studied in animal models of human malaria. Additionally, Abs induced by immunization of animals can have important differences in affinity, specificity, and function from that seen in humans (69). Therefore, human studies are a crucial part of establishing evidence for a protective role of responses to specific Ags.…”