Inhibition of entry of Plasmodium falciparum and P. vivax sporozoites into cultured cells; an in vitro assay of protective antibodies.

Abstract

Plasmodium falciparum and P. vivax sporozoites were observed to invade cultured human hepatoma cells in vitro. Monoclonal antibodies to the circumsporozoite (CS) protein of each of these malarial species blocked invasion. Inhibition was species-specific, but was independent of the geographic origin of each strain. Because these monoclonal antibodies have been shown to diminish or abolish sporozoite infectivity to susceptible primate hosts, it is suggested that inhibition of invasion of sporozoites (ISI) into cultured cells may represent in in vitro assay for protective antibodies. This was confirmed by the finding that serum taken from volunteers immune to sporozoite challenge also totally blocked sporozoite invasion. The ISI assay also detected naturally acquired invasive-neutralizing antibodies in areas endemic for malaria. This ISI assay may therefore be useful in determining the incidence of inhibitory anti-sporozoite antibodies in general populations, and allow the monitoring of the effect of an anti-malarial vaccine using sporozoite-derived antigens.

Cytotoxic anti-circumsporozoite antibodies target malaria sporozoites in the host skin

“…The central repetitive domain and the CT region constitute the basis for the most advanced malaria vaccine candidate, RTS,S/AS01, which partially protects humans against malaria 16 , presumably via high levels of anti-PfCSP repeats antibodies 17 . Indeed, mAbs targeting the CSP central repeats are known to immobilize SPZs and inhibit their infectivity both in vitro [18][19][20] and in vivo [1][2][3][4][5]7 . Accordingly, human, monkey and rodent-infecting SPZs lose their in vivo infectivity following pre-incubation with anti-CSP mAbs [1][2][3] or when intravenously (iv) inoculated into passively immunized hosts 4,5,21 .…”

Immunogenicity, Efficacy, and Safety of a Novel Synthetic Microparticle Pre-Erythrocytic Malaria Vaccine in Multiple Host Species

“…These efforts have been extended to include additional preclinical species (NHPs and rabbits), modifications to the LbL-MP design, including incorporation of an innate immune agonist, and a demonstration of safety and immunogenicity in a GLP-compliant rabbit toxicology study in preparation for clinical evaluation. The first immune effector mechanism identified in sporozoite-immunized hosts was sporozoite-neutralizing antibodies that target the NANP tetramer repeats in the CS central region [ 40 , 41 , 42 , 43 ], immobilizing sporozoites in the skin at the site of the mosquito bite and delaying their egress into the circulation [ 44 ], thus providing a longer window for an antibody-mediated attack [ 45 , 46 , 47 ] and blocking invasion of the host hepatocytes [ 21 , 48 , 49 , 50 ]. Induction of high levels of sporozoite-neutralizing antibodies is T-cell-dependent, requiring CD4+ T-cell help for B-cell differentiation and for the development of CD8+ memory T-cells [ 15 , 16 ].…”

Humoral Immune Responses to P. falciparum Circumsporozoite Protein (Pfcsp) Induced by the RTS, S Vaccine – Current Update

“…55 The central repeat region is also thought to be immunodominant since it is a primary target of antibodies produced by whole, irradiation, attenuated sporozoite vaccines, and naturally occurring malaria exposure, and repeat-specific antibodies can inhibit sporozoite infectivity in vitro. 66 However, non-repeat area antibodies can also be developed spontaneously and have been shown to have inhibitory action in vitro. [66][67][68][69] When considered as a whole, the evidence points to the significance of antibodies to the central repeat region of CSP but also encourages further research into antibody responses to the C-terminal region, especially given that antibodies specific to the repeats alone are a poor correlate of protection.…”

“…66 However, non-repeat area antibodies can also be developed spontaneously and have been shown to have inhibitory action in vitro. [66][67][68][69] When considered as a whole, the evidence points to the significance of antibodies to the central repeat region of CSP but also encourages further research into antibody responses to the C-terminal region, especially given that antibodies specific to the repeats alone are a poor correlate of protection.…”