Phase 2 clinical trial of attenuated Salmonella enterica serovar typhi oral live vector vaccine CVD 908-htrA in U.S. volunteers.
Salmonella enterica serovar Typhi strain CVD 908-htrA is a live attenuated strain which may be useful as an improved oral typhoid vaccine and as a vector for cloned genes of other pathogens. We conducted a phase 2 trial in which 80 healthy adults received one of two dosage levels of CVD 908-htrA in a double-blind, placebo-controlled, crossover study. There were no differences in the rates of side effects among volunteers who received high-dose vaccine (4.5 x 10(8) CFU), lower-dose vaccine (5 x 10(7) CFU), or placebo in the 21 days after vaccination, although recipients of high-dose vaccine (8%) had more frequent diarrhea than placebo recipients (0%) in the first 7 days. Seventy-seven percent and 46% of recipients of high- and lower-dose vaccines, respectively, briefly excreted vaccine organisms in their stools. All blood cultures were negative. Antibody-secreting cells producing antilipopolysaccharide (LPS) immunoglobulin A (IgA) were detected in 100 and 92% of recipients of high- and lower-dose vaccines, respectively. Almost half the volunteers developed serum anti-LPS IgG. Lymphocyte proliferation and gamma interferon production against serovar Typhi antigens occurred in a significant proportion of vaccinees. This phase 2 study supports the further development of CVD 908-htrA as a single-dose vaccine against typhoid fever and as a possible live vector for oral delivery of other vaccine antigens.
Tacket
C O
CO
Center for Vaccine Development, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA. ctacket@medicine.umaryland.edu
Sztein
M B
MB
Wasserman
S S
SS
Losonsky
G
G
Kotloff
K L
KL
Wyant
T L
TL
Nataro
J P
JP
Edelman
R
R
Perry
J
J
Bedford
P
P
Brown
D
D
Chatfield
S
S
Dougan
G
G
Levine
M M
MM
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000907:Antibodies, Bacterial / Q000097:blood; D001428:Bacterial Vaccines / Q000009:adverse effects / Q000276:immunology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005822:Genetic Vectors; D006360:Heat-Shock Proteins; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D033903:Periplasmic Proteins; D012485:Salmonella typhi / Q000276:immunology*; D012697:Serine Endopeptidases / Q000235:genetics*; D015164:Vaccines, Inactivated / Q000276:immunology
D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D006360:Heat-Shock Proteins; D033903:Periplasmic Proteins; D015164:Vaccines, Inactivated; D007371:Interferon-gamma; C061682:DegP protease; D012697:Serine Endopeptidases