Safety and Immunogenicity of Vi Conjugate Vaccines for Typhoid Fever in Adults, Teenagers, and 2- to 4-Year-Old Children in Vietnam

Abstract

ABSTRACT The capsular polysaccharide of Salmonella typhi, Vi, is an essential virulence factor and a protective vaccine for people older than 5 years. The safety and immunogenicity of two investigational Vi conjugate vaccines were evaluated in adults, 5- to 14-year-old children, and 2- to 4-year-old children in Vietnam. The conjugates were prepared with Pseudomonas aeruginosa recombinant exoprotein A ( r EPA) as the carrier, using either N -succinimidyl-3-(2-pyridyldithio)-propionate (SPDP; Vi- r EPA 1 ) or adipic acid dihydrazide (ADH; Vi- r EPA 2 ) as linkers. None of the recipients experienced a temperature of >38.5°C or significant local reactions. One injection of Vi- r EPA 2 into adults elicited a geometric mean (GM) increase in anti-Vi immunoglobulin G (IgG) from 9.62 enzyme-linked immunosorbent assay units/ml (EU) to 465 EU at 6 weeks; this level fell to 119 EU after 26 weeks. In the 5- to 14-year-old children, anti-Vi IgG levels at 6 weeks elicited by Vi- r EPA 2 , Vi- r EPA 1 , and Vi were 169, 22.8, and 18.9 EU, respectively ( P = 0.0001 for Vi- r EPA 1 and Vi with respect to Vi- r EPA 2 ). At 26 weeks, the anti-Vi IgG levels for recipients of Vi- r EPA 2 , Vi- r EPA 1 , and Vi were 30.0, 10.8, and 13.4 EU, respectively ( P < 0.001 for Vi- r EPA 1 and Vi with respect to Vi- r EPA 2 ); all were higher than the preinjection levels ( P = 0.0001). Vi- r EPA 2 also elicited the highest anti-Vi IgM and IgA levels of the three vaccines. In the 2- to 4-year-old children at 6 weeks following the first injection, Vi- r EPA 2 elicited an anti-Vi IgG level of 69.9 EU compared to 28.9 EU for Vi- r EPA 1 ( P = 0.0001). Reinjection increased Vi antibody levels from 69.9 to 95.4 EU for Vi- r EPA 2 and from 28.9 to 83.0 EU for Vi- r EPA 1 . At 26 weeks, anti-Vi IgG levels remained higher than those at preinjection (30.6 versus 0.18 for Vi- r EPA 2 and 12.8 versus 0.33 for Vi- r EPA 1 ; P = 0.0001 for both). Vi vaccine is recommended for individuals of 5 years of age or older. In the present study, the GM level of anti-Vi IgG elicited by two injections of Vi- r EPA 2 in the 2- to 4-year-old children was higher than that elicited by Vi in the 5- to 14-year-old children (30.6 versus 13.4; P = 0.0001). The safety and immunogenicity of the Vi- r EPA 2 conjugate warrant further investigation.