BackgroundModels of immunity to malaria indicate the importance of CD8+ T cell responses for targeting intrahepatic stages and antibodies for targeting sporozoite and blood stages. We designed a multistage adenovirus 5 (Ad5)-vectored Plasmodium falciparum malaria vaccine, aiming to induce both types of responses in humans, that was tested for safety and immunogenicity in a Phase 1 dose escalation trial in Ad5-seronegative volunteers.Methodology/Principal FindingsThe NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 1 (n = 6) healthy volunteers received one intramuscular injection of 2×10∧10 particle units (1×10∧10 each construct) and Group 2 (n = 6) a five-fold higher dose. Transient, mild to moderate adverse events were more pronounced with the higher dose. ELISpot responses to CSP and AMA1 peaked at 1 month, were higher in the low dose (geomean CSP = 422, AMA1 = 862 spot forming cells/million) than in the high dose (CSP = 154, p = 0.049, AMA1 = 423, p = 0.045) group and were still positive at 12 months in a number of volunteers. ELISpot depletion assays identified dependence on CD4+ or on both CD4+ and CD8+ T cells, with few responses dependent only on CD8+ T cells. Intracellular cytokine staining detected stronger CD8+ than CD4+ T cell IFN-γ responses (CSP p = 0.0001, AMA1 p = 0.003), but similar frequencies of multifunctional CD4+ and CD8+ T cells secreting two or more of IFN-γ, TNF-α or IL-2. Median fluorescence intensities were 7–10 fold higher in triple than single secreting cells. Antibody responses were low but trended higher in the high dose group and did not inhibit growth of cultured P. falciparum blood stage parasites.SignificanceAs found in other trials, adenovectored vaccines appeared safe and well-tolerated at doses up to 1×10∧11 particle units. This is the first demonstration in humans of a malaria vaccine eliciting strong CD8+ T cell IFN-γ responses.Trial Registration ClinicalTrials.gov NCT00392015

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Electron-withdrawing substituents in meta and para positions increase whereas electron-donating substituents decrease the dissociation constants and the second-order rate constants for neutralization of l-phenyl-lnitroethanes by hydroxide ion in 50% (vol) dioxane-water. The ionization constants (PKa) and the neutralization rate constants (log kz) correlate with u constants for aqueous and for 50% (vol) dioxane-water systems. There is linear correlation of the rate constants (log k2) for neutralization and the ionization constants (pK.) of the l-phenyl-1-nitroethanes with a Brpnsted coefficient of 1.17-1.20. The Brmsted coefficient of greater than unity stems from the fact that as the electron-withdrawing capacity of the substituent is increased, the relative effects on the rate constants of neutralization of substituted 1-phenyl-1-nitroethanes are greater than on the ionization constants. meta and para electron acceptor groups accelerate and electron donor groups retard reversal of l-phenyl-l-ethanenitronates to 1-phenyl-1-nitroethanes. The Brqnsted coefficient for correlation of the logarithms of the rate constants of hydrolysis of 1-phenyl-1-ethanenitronates and thepK,'s of their 1-phenyl-1-nitroethanes is -0.17 -(-0.20).Electron-withdrawing meta and para substituents in a 1-phenyl-1-ethanenitronate result in electronic absorption at longer wavelengths. The long wavelength ultraviolet maximum of a 1-phenyl-1-ethanenitronate is shifted bathochronically in poor hydrogen bonding and in aprotic polar solvents. The rate of reversal of a l-phenyl-l-ethanenitronate upon introduction of an electron donor meta or para substituent may be retarded because the carbonitronate behaves relatively electron deficiently at CY carbon as a result of increased hydrogen bonding at oxygens of enhanced nucleophilicity and because of the increased work involved in breaking the hydrogen bonds. For salts of simple nitroalkanes there is a shift in the infrared absorption for C-N to longer wavelength as the charge density of the cation is decreased. Replacement of methyl groups for hydrogen in nitronates results in maximum ultraviolet absorption at shorter wavelengths; solvents of diminished hydrogen-bonding ability or of increased polarity lead to absorption at longer wavelengths. The effects of structure and environment on the properties of alkanenitronates are analogous to those for 1-phenyl-1-ethanenitronates. eutralization of acidic mononitro compounds is N subject to general base catalysis and there is Brdnsted correlation between the rates of neutralization of such nitro compounds and the strengths of unhindered bases.2 Previous studies of the rates of neutralization (or ionization) and the dissociation constants of nitroalkanes have been limited. The results are of interest however in that nitro compounds which are weaker (or stronger) may neutralize (or ionize) faster (slower) than their stronger (or weaker) homologs.(1) (a) (d) initial studylb of the equilibrium properties, the rate constants, and Hammett correlation for neutrali...

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