Abstract
Antibodies that neutralize infectivity of malaria sporozoites target the central repeat region of the circumsporozoite (CS) protein, which in Plasmodium falciparum is comprised primarily of 30–40 tandem NANP tetramer repeats. We evaluated immunogenicity of an alum-adsorbed (NANP)6 peptide conjugated to an outer membrane protein complex (OMPC) derived from Neisseria meningitidis, a carrier protein used in a licensed Haemophilus influenzae pediatric vaccine. Mice immunized with (NANP)6-OMPC adsorbed to Merck's alum adjuvant (MAA), with or without Iscomatrix® as co-adjuvant, developed high levels of anti-repeat peptide antibody that inhibited in vitro invasion of human hepatoma cells by transgenic P. berghei sporozoites that express P. falciparum CS repeats (PfPb). Inhibition of sporozoite invasion in vitro correlated with in vivo resistance to challenge by the bites of PfPb-infected mosquitoes. Challenged mice had >90% reduction of hepatic stage parasites as measured by real-time PCR, and either sterile immunity, i.e., no detectable blood stage parasites, or delayed prepatent periods which indicate neutralization of a majority, but not all, sporozoites. Rhesus macaques immunized with two doses of (NANP)6-OMPC/MAA formulated with Iscomatrix® developed anti-repeat antibodies that persisted for ~2 years. A third dose of (NANP)6-OMPC/MAA+ Iscomatrix® at that time elicited strong anamnestic antibody responses. Rhesus macaque immune sera obtained post second and third dose of vaccine displayed high levels of sporozoite neutralizing activity in vitro that correlated with presence of high anti-repeat antibody titers. These preclinical studies in mice of different MHC haplotypes and a non-human primate support use of CS peptide-OMPC conjugates as a highly immunogenic platform to evaluate CS protective epitopes. Potential pre-erythrocytic vaccines can be combined with sexual blood stage vaccines as a multi-antigen malaria vaccine to block invasion and transmission of Plasmodium parasites.
Highlights
Malaria caused by the parasite Plasmodium falciparum is considered one of the most prevalent and deadliest of diseases
We evaluated immunogenicity of an alum-adsorbed (NANP)6 peptide conjugated to an outer membrane protein complex (OMPC) derived from Neisseria meningitidis, a carrier protein used in a licensed Haemophilus influenzae pediatric vaccine
IMMUNOGENICITY OF (NANP)6-OMPC CONJUGATE IN INBRED STRAINS OF MICE Initial studies carried out in BALB/c mice established the number of repeats and peptide orientation required for optimal immunogenicity of the peptide-OMPC conjugates
Summary
Malaria caused by the parasite Plasmodium falciparum is considered one of the most prevalent and deadliest of diseases. One of the lead vaccine candidates in clinical trials is the circumsporozoite (CS) protein which is a major surface protein of the infective sporozoite. A Phase III trial is in progress of a CS-based pediatric malaria vaccine RTS,S which can protect 35–40% of African infants against clinical disease (Agnandji et al, 2011). Immunization with RTS,S in a potent adjuvant formulation elicited sterile immunity in 30–40% of malaria-naïve volunteers, only transient protection against infection was obtained in African adults (Bojang et al, 2001; Kester et al, 2009). Protection correlated with high levels of anti-repeat antibodies and CS-specific CD4+ T cells
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