Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine.

CD8+ cytotoxic T lymphocytes (CTLs) are critical for protection against intracellular pathogens but often have been difficult to induce by subunit vaccines in animals. DNA vaccines elicit protective CD8+ T cell responses. Malaria-naïve volunteers who were vaccinated with plasmid DNA encoding a malaria protein developed antigen-specific, genetically restricted, CD8+ T cell-dependent CTLs. Responses were directed against all 10 peptides tested and were restricted by six human lymphocyte antigen (HLA) class I alleles. This first demonstration in healthy naïve humans of the induction of CD8+ CTLs by DNA vaccines, including CTLs that were restricted by multiple HLA alleles in the same individual, provides a foundation for further human testing of this potentially revolutionary vaccine technology.

In vitro susceptibility of recent North American group A streptococcal isolates to eleven oral antibiotics.

Because of the recent resurgence of Group A streptococcal infections and their sequelae and to concerns about Group A streptococcal antimicrobial resistance, 282 isolates from acute pharyngitis and 43 additional isolates from severe, invasive infections were examined for susceptibility to 11 oral antibiotics. M serotypes 1, 2, 3, 4 and 12 accounted for more than one-half of the pharyngeal isolates; M serotypes 1 and 3 accounted for most isolates from severe infections. All 325 isolates were exquisitely susceptible to penicillin (Concentration of antibiotic required to inhibit 90% of isolates, 0.012 micrograms/ml). Only approximately 4% of the tested strains demonstrated an erythromycin minimum inhibitory concentration of 0.5 microgram/ml or greater; the new macrolides, azithromycin and clarithromycin, were similar. The cephalosporins varied somewhat in their ability to inhibit Group A streptococci, but all were effective in vitro. No major differences in minimum inhibitory concentrate were observed between strains associated with severe infections and those from uncomplicated upper respiratory tract infections. On the basis of the 325 isolates examined, we conclude that antimicrobial resistance has not been a factor in the recent resurgence of Group A infections.

Safety, tolerability and humoral immune responses after intramuscular administration of a malaria DNA vaccine to healthy adult volunteers.

DNA-based vaccines are considered to be potentially revolutionary due to their ease of production, low cost, long shelf life, lack of requirement for a cold chain and ability to induce good T-cell responses. Twenty healthy adult volunteers were enrolled in a Phase I safety and tolerability clinical study of a DNA vaccine encoding a malaria antigen. Volunteers received 3 intramuscular injections of one of four different dosages (20, 100, 500 and 2500 microg) of the Plasmodium falciparum circumsporozoite protein (PfCSP) plasmid DNA at monthly intervals and were followed for up to twelve months. Local reactogenicity and systemic symptoms were few and mild. There were no severe or serious adverse events, clinically significant biochemical or hematologic changes, or detectable anti-dsDNA antibodies. Despite induction of excellent CTL responses, intramuscular DNA vaccination via needle injection failed to induce detectable antigen-specific antibodies in any of the volunteers.