Cutaneous delayed-type hypersensitivity (DTH) in a multi-formulation comparator trial of the anti-falciparum malaria vaccine candidate RTS,S in rhesus macaques.
BACKGROUND
Studies are underway to identify more immunogenic formulations of the existing anti-falciparum malaria vaccine RTS,S/AS02A. To supplement in vitro immunogenicity assays, cutaneous delayed-type hypersensitivity (DTH) may be a useful indicator of functional, cell-mediated immunogenicity.


METHODS
Adult rhesus monkeys were immunized with saline or one of four RTS,S/adjuvant formulations: RTS,S/AS01B, RTS,S/AS02A-standard (current formulation), RTS,S/AS05 or RTS,S/AS06 at 0, 4, and 12 weeks. An additional cohort received RTS,S/AS02A-accelerated, at 0, 1, and 4 weeks. Six months after completing immunizations, five vaccine-relevant antigens (high and low doses) and two controls were administered intradermally. DTH reactivity (induration) was measured at 48 and 72h, and selected sites were biopsied for histological confirmation.


RESULTS
In comparison with RTS,S/AS02A-standard, RTS,S/AS01B and RTS,S/AS05 each had larger mean reactions (induration) at 5 of 10 (p<0.01, at each site) and 1 of 10 (p<0.05, at the single site) vaccine relevant test sites, respectively. Histologically, perivascular mononuclear cell infiltrates, a cardinal feature of DTH, were largest in the RTS,S/AS01B monkeys.


CONCLUSIONS
In DTH testing, with histological confirmation, RTS,S/AS01B was immunogenically superior to RTS,S/AS02A-standard and two other novel RTS,S formulations. The DTH outcomes paralleled conventional in vitro cellular immunogenicity assessments in distinguishing among similar RTS,S formulations, even at 6 months after final vaccination.
Stewart
V Ann
VA
Department of Immunology, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA. ann.stewart@na.amedd.army.mil
Walsh
Douglas S
DS
McGrath
Shannon M
SM
Kester
Kent E
KE
Cummings
James F
JF
Voss
Gerald
G
Delchambre
Martine
M
Garçon
Nathalie
N
Cohen
Joe D
JD
Heppner
D Gray
DG
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D002626:Chemistry, Pharmaceutical; D015331:Cohort Studies; D004890:Erythema / Q000276:immunology / Q000473:pathology; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology* / Q000473:pathology; D007111:Immunity, Cellular / Q000276:immunology; D007117:Immunization, Secondary; D008253:Macaca mulatta; D017780:Malaria Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016778:Malaria, Falciparum / Q000276:immunology*; D020556:Neutrophil Infiltration; D010963:Plasmodium falciparum / Q000276:immunology*; D012867:Skin / Q000473:pathology; D012882:Skin Tests
D000276:Adjuvants, Immunologic; D017780:Malaria Vaccines