Safety, Immunogenicity, and Efficacy of a Recombinantly Produced Plasmodium falciparum Circumsporozoite Protein-Hepatitis B Surface Antigen Subunit Vaccine

Abstract

Twenty malaria-naive volunteers received a recombinant Plasmodium falciparum malaria vaccine (RTS,S) containing 19 NANP repeats and the carboxy terminus (amino acids 210-398) of the circumsporozoite (CS) antigen coexpressed in yeast with hepatitis B surface antigen. Ten received vaccine adjuvanted with alum, and 10 received vaccine adjuvanted with alum plus 3-deacylated monophosphoryl lipid A (MPL). Both formulations were well tolerated and immunogenic. MPL enhanced CS antibody levels (measured by ELISA, immunofluorescence, and inhibition of sporozoite invasion assays). After sporozoite challenge, 6 of 6 in the alum group and 6 of 8 in the alum-MPL group developed patent malaria. Protected subjects had higher levels of CS antibody titers on day of challenge than did nonprotected subjects. After immunization, 1 protected subject had increased cytotoxic T lymphocyte activity against CS and recall of memory T cell responses to RTS,S and selected CS.

Cellular responses to Plasmodium falciparum major surface antigens and their relationship to human activities associated with malaria transmission.

“…Such studies should provide baseline information that will be crucial for understanding the effects of vaccines now in development. [7][8][9][10][11] …”

“…Recombinant P. falciparum proteins from the sporozoite (CS) and the bloodstage (MSP-1) were used for the in vitro lymphoproliferative assays; they represent two of the major candidates for inclusion in a subunit vaccine. [7][8][9][10][11] …”

“…Recombinant P. falciparum proteins from the sporozoite (CS) and the bloodstage (MSP-1) were used for the in vitro lymphoproliferative assays; they represent two of the major candidates for inclusion in a subunit vaccine. [7][8][9][10][11] MATERIALS AND METHODS Area and individuals studied. The study was carried out in Pontes-Lacerda, Mato Grosso State, Brazil (Figure 1), which has one of the highest incidences of malaria in the Brazilian Amazon.…”

Protective Immunity Induced with Malaria Vaccine, RTS,S, Is Linked to Plasmodium falciparum Circumsporozoite Protein-Specific CD4+ and CD8+ T Cells Producing IFN-γ

“…RTS,S represents a particulate form of an Ag, and the portion of the CS protein included in the RTS,S vaccine contains both CD4 and CD8 T cell epitopes (7). In an earlier study we observed that RTS,S/MPL/Alum or RTS,S/ AS04 could induce a CS protein peptide-specific CD8 ϩ CTL response (29). Moreover, we previously demonstrated that inclusion of CS protein in liposomes allows MHC class I presentation of CS to CD8 ϩ T cells in mice (30) and to a less detectable degree in humans (31).…”

Alternative approaches to vaccine delivery

“…3,4 In RTS, S, a portion of CSP is fused to hepatitis B surface antigen (HBsAg), co-expressed in yeast with unfused HBsAg, and the resulting particulate antigen is formulated with the adjuvants AS01 or AS02. 5,6 RTS, S has demonstrated significant protection against clinical malaria in both adults and children in several clinical trials 3,4,7,8 and is currently the most advanced malaria vaccine candidate in development. There has been less success with asexual blood stage vaccines; the two leading vaccine candidates, merozoite surface protein 1 (MSP1) and apical membrane antigen 1 (AMA1), have both showed disappointing results in the recent Phase 1/2 trials.…”