Dose response of CRM197 and tetanus toxoid-conjugated Haemophilus influenzae type b vaccines

High vaccine cost has limited use of conjugate vaccines in the developing world where the disease burden is greatest. Fixed fractional doses of Haemophilus influenzae type b (Hib) vaccines have been shown to be immunogenic, but dose responses of these vaccines in humans are needed to determine the lowest immunogenic dose as an option for lowering vaccine cost. We randomized children to receive one of five doses (0.625, 1.25, 2.5, 5.0 and 10 mug) of either a diphtheria CRM197 or tetanus toxoid-conjugated Hib vaccine. The children received a primary three-dose series at 6, 10, and 14 weeks of age and a booster dose at 9 months. Anti-PRP IgG antibodies were measured at each vaccination, at 18 weeks, and at one week following the booster dose. Concentrations of >1.25 mug of HibCRM(197) vaccine produced mean anti-PRP responses at 18 weeks of greater than or equal to5.72 mug/ml and greater than or equal to0.15 mug/ml was achieved in >98% of the children with at least 79% reaching anti-PRP concentrations of greater than or equal to1.0 mug/ml. Concentrations of greater than or equal to1.25 mug of Hib-tetanus vaccine produced mean anti-PRP responses at 18 weeks of greater than or equal to8.63 mug/ml and greater than or equal to0.15 mug/ml was achieved in 100% of the children with at least 88.9% reaching anti-PRP concentrations of greater than or equal to1.0 mug/ml. While mean antibody concentrations after either vaccine decreased over time, the proportion of children with antibody levels of greater than or equal to0.15 mug/ml had not changed significantly at the 9 month measurement. Immunologic memory was demonstrated by significant increases in mean antibody concentrations one week after the booster dose for doses greater than or equal to1.25 mug of HibCRM(197) and Hib-tetanus to mean concentrations greater than or equal to37.71 and 16.07 mug/ml, respectively. There were no differences in antibody responses for vaccine doses greater than or equal to1.25 mug of the same vaccine or between the same concentrations of the two different vaccines. Our data suggest that doses of these vaccines of greater than or equal to1.25 mug may be sufficient to stimulate an immune response that offers both short and longer term protection from invasive Hib disease. (C) 2004 Elsevier Ltd. All rights reserved.