Heterologous prime-boost immunization in rhesus macaques by two, optimally spaced particle-mediated epidermal deliveries ofPlasmodium falciparumcircumsporozoite protein-encoding DNA, followed by intramuscular RTS,S/AS02A

• Published in: Vaccine Vol. 24; no. 19; p. 4167
• Main Authors: Walsh, Douglas S, Gettayacamin, Montip, Leitner, Wolfgang W, Lyon, Jeffrey A, Stewart, V Ann, Marit, Gary, Pichyangkul, Sathit, Gosi, Panita, Tongtawe, Pongsri, Kester, Kent E, Holland, Carolyn A, Kolodny, Nelly, Cohen, Joe, Voss, Gerald, Ballou, W Ripley, Heppner, D Gray
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Limited 08-05-2006
• Subjects: Deoxyribonucleic acid; DNA; Hypersensitivity; Immune system; Immunization; Immunogenicity; Laboratory animals; Malaria; Peptides; Plasmids; Proteins; Vaccines; Vector-borne diseases
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2006.02.041

Background RTS,S/AS02A, a recombinantPlasmodium falciparumvaccine based on the circumsporozoite protein (CSP) repeat and C-terminus regions, elicits strong humoral and Th1 cell-mediated immunity. In field studies, RTS,S/AS02A reduced malaria infection, clinical episodes, and disease severity. Heterologous prime-boost immunization regimens, optimally spaced, might improve the protective immunity of RTS,S/AS02A. Methods DNA plasmid encodingP. falciparumCSP (3D7) was administered to six experimental groups of rhesus monkeys (N=5) by gene gun (coded as D), followed by a 1/5th human dose of RTS,S/AS02A (coded as R). Immunization regimens, including a numeral to denote weeks between immunizations, were D-4-R, D-16-R, D-4-D-4-R, D-4-D-16-R, D-16-D-4-R and D-16-D-16-R. A control group (N=5) received a single 1/5th dose of RTS,S/AS02A. Endpoints were antibody (Ab) to homologous CSP repeat and C-terminus regions and delayed-type hypersensitivity (DTH) to CSP peptides. Findings Monkeys immunized twice with DNA, 16 weeks apart (D-16-D-4-R and D-16-D-16-R), developed higher levels of anti-C-terminus Abs than control monkeys (p<0.02). No CSP DNA priming regimen increased RTS,S/AS02A-induced Ab to CSP repeats. At 16 months after first immunization, D-R and D-D-R, but not control, monkeys had histologically confirmed DTH reactions against CSP C-terminus, which persisted at repeat testing 12 months later. Interpretation Two optimally spaced, particle-mediated epidermal deliveries of CSP DNA improved the humoral immunogenicity of a single dose of RTS,S/AS02A. Further, CSP DNA prime followed by one dose of RTS,S/AS02A gave biopsy proven DTH reactions against CSP C-terminus of up to 2 years duration, implying the induction of CD4+ memory T cells. Heterologous prime-boost strategies for malaria involving gene gun delivered DNA or more potent vectors, administered at optimal intervals, warrant further investigation.