Non-epitope-specific suppression of the antibody response to Haemophilus influenzae type b conjugate vaccines by preimmunization with vaccine components

Abstract

Recently, conjugate vaccines containing Haemophilus influenzae type b capsular polysaccharide (HibCP) coupled to protein carriers were introduced for use in infants and certain adult risk groups. Similar conjugate vaccines against other capsulated bacteria are currently under development for both children and adults. Despite its potential importance, the possible influence of preexisting immunity to the components of such conjugates on the vaccination response in humans has been addressed by few studies. To study this issue, we randomized 82 healthy adult volunteers into six groups and vaccinated them twice, with a 4-week interval between immunizations. Four groups received tetanus toxoid (TT) or diphtheria toxoid (DT) and then HibCP coupled to TT (HibCP-TT) or DT (HibCP-DT). Two groups received HibCP-TT followed by HibCP-DT or vice versa. The total antibody levels to HibCP, TT, and DT and the anti-HibCP immunoglobulin G1 (IgG1) and IgG2 levels were measured before and 4 weeks after the immunizations. For some of the vaccinees, the number of circulating antibody-secreting cells was evaluated 7 days after immunization. Surprisingly, preimmunization with the relevant carrier protein reduced the subsequent increase in the total HibCP antibody levels (P < 0.05), affecting the IgG1 and the IgG2 subclasses equally. Also, the responses to the carrier portions of the conjugates were suppressed, as demonstrated by the lack of significant increases in the antibody levels (P > or = 0.29) and, for HibCP-TT, by reduced numbers of anticarrier antibody-secreting cells (P = 0.009). Similar non-epitope-specific suppression was seen in the groups receiving both conjugates. Thus, preimmunization with one conjugate reduced the subsequent response to the carrier portion of the other conjugate (HibCP-DT and then HibCP-TT, P = 0.00002; HibCP-TT and then HibCP-DT, P = 0.06) as well as to HibCP itself. Possible mechanisms behind this non-epitope-specific suppression and its relevance for vaccine development are discussed.