Diphtheria-tetanus-acellular pertussis vaccines (DTaP) combined with Haemophilus influenzae type b (Hib) tetanus conjugate (PRP-T) vaccines are already licensed in Canada, several European countries and elsewhere for use in infants beginning at 2 months of age. Licensure was granted despite lower quantitative anti-Hib polyribosylribitol phosphate (PRP) polysaccharide (PS) antibody responses compared with those after separate vaccinations. The absence of licensure for these products in the US is in large part the result of a difference of opinion between US and other regulatory authorities about the role of immunologic memory in protection against Hib disease in vaccinated children. Even in those with low (<1.0 μg/ml) or undetectable (<0.10 μg/ml) post primary anti-Hib-PS antibody titers after DTaP-Hib-PS conjugate vaccination, we1 and others2 found evidence for the induction of immunologic memory based on observing high titered, IgG-predominant responses after PRP or PRP conjugate boosters (CRM197-OS). However, uncertainty remains about the kinetics of this memory response. If Hib exposure were to occur in nature would disease occur before immune memory activation? In this study we examined the kinetics of the anti-Hib-PS antibody response after a PRP-T booster in a cohort of 13- to 17-month-old children after a three-dose primary series of DTaP-PRP-T combination vaccine (manufactured by Pasteur Mérieux Connaught, Swiftwater, PA). Materials and methods.Study design. A multicenter National Institute of Allergy and Infectious Diseases-sponsored prospective, randomized trial evaluating the safety and immunogenicity of three different primary polio vaccine schedules was conducted (M Rennels et al., submitted for publication). Infants at 2, 4 and 6 months of age were given all oral polio (OPV), inactivated polio (IPV) or sequential IPV-OPV dosing, concurrently with DTaP and PRP-T as separate vaccines given simultaneously or as a single combined vaccine DTaP-PRP-T (Pasteur Mérieux Connaught). Infants from that trial enrolled in Rochester, NY, were identified. The immune response of these infants to a Hib vaccine booster was of interest to assess whether priming had occurred. Eligibility criteria were that the child had not yet received a Hib-PS conjugate booster and that their anti-PRP antibody titer after the primary series of vaccination was >0.15 μg/ml. Written informed consent was obtained from parents of 21 of the 30 eligible children; refusers all objected to the phlebotomy requirement. The primary vaccine products and number of children from each vaccine group enrolled in our study was as follows: Group 1, all OPV + DTaP-PRP-T (n = 6); Group 2, IPV, IPV, OPV + DTaP-PRP-T (n = 5); Group 3, all IPV + DTaP-PRP-T (n = 4); Group 4, all OPV + DTaP + PRP-T (n = 6). The Hib-PS conjugate booster used was a licensed PRP-T vaccine (Pasteur Mérieux Connaught) and was administered when the children were 13 to 17 months of age. Pre- and 1 month post-PRP-T booster sera were obtained from all children and one additional sera sample was obtained from 20 children at Day 3, 4, 5, 7, 10 or 14 postbooster to study the kinetics of the antibody response. Assays: H. influenzae type b enzyme-linked immunosorbent assay (ELISA). Anti-capsular (anti-polyribosylribitol phosphate; Hib-PS) antibody was quantitated by ELISA as described by Phipps et al.3 using Tyraminated-PS as a coating antigen (lower limit of detection, 0.10 μg antibody per ml). The Hib reference serum was the Center for Biologics Evaluation and Research standard Lot 1983 containing 70 μg/ml total anti-Hib-PS antibody. The coefficient of variation for the assay was 12% (420 determinations). A change in anti-PRP antibody level of 30% is significant in our laboratory. Statistical analysis. An unpaired Student t test was performed to compare anti-Hib-PS antibody titers between pre- and 1 month postvaccination time points. Results. Anti-Hib-PS IgG antibody titers for the studied infants pre- and postboost are shown in Figure 1. A rise in anti-Hib-PS antibody was measured in 0 of 4 infants on Day 3, 1 of 1 on Day 4, 3 of 3 on Day 5, 9 of 9 on Day 7, 1 of 1 on Day 10 and 2 of 2 on Day 14. All 21 children showed significant antibody rises on Day 30 after the PRP-T booster (P < 0.001). Kinetics for the anti-Hib PS booster antibody response in the four vaccinees with <1.0 μg/ml anti-Hib-PS IgG antibody was similar to the 17 vaccinees who had ≥1.0 μg/ml when measured after the primary series of DTaP vaccinations.Fig. 1: Geometric mean anti-Hib-PS IgG titers (micrograms/ml) are shown for 21 subjects. Infants had sera drawn at three time points: preboost; between Days 3 and 14 postboost; and 1 month postboost. Results were grouped for infants whose second sera draw occurred on Day 3 (n = 4), Days 4 and 5 (n = 4), Day 7 (n = 9) and Days 10 to 14 (n = 4) postboost.Discussion. We characterized the kinetics of the anti-Hib-PS antibody response after a booster with a Hib conjugate vaccine in DTaP-Hib-primed children. An increase in antibody titer was detected by 4 to 5 days after the booster. This rapid rise in antibody is a major feature of immunologic memory. Only children with >0.15 μg/ml anti-Hib-PS antibody after the primary series received the PRP-T booster in this study. All responded with a significant rise in IgG anti-Hib-PS antibody. The study design did not permit an analysis of antibody responses in children with <0.15 μg/ml anti-Hib-PS antibody after a primary series of vaccinations. Although we did not concurrently study a toddler control group who received an Hib conjugate vaccine without prior Hib-PS immunization (an unethical design in the US), prior studies during the development of Hib vaccine suggest that our observed responses would be unexpected in unprimed children.4 A lower total anti-Hib-PS antibody titer occurs in some children when Hib vaccines are combined with DTaP vaccines compared with titers after DTaP and Hib-PS conjugate vaccines are administered separately.1, 2, 5, 6 The clinical relevance of these differences is debated.2, 7-10 Seroresponses have been observed in all vaccinees when a Hib booster vaccination is given, suggesting that immunologic memory is induced even in infants with lower (<1.0 μg/ml) and even undetectable (<0.10 μg/ml) post-primary anti-Hib-PS antibody titers.1, 2 Our study suggests that the kinetics of the antibody response to a PRP-T booster is similar for those with lower post-primary anti-Hib-PS titers. The question remains, "If a child were to experience exposure to wild Hib in nature and attachment to the nasopharynx occurred, would immunologic memory proceed at a pace sufficient to allow expansion of memory B and T cell clones with production of protective antibody before bacterial invasion occurred?" Whereas the kinetics of bacterial invasion after intranasal inoculation with nonphysiologic quantities of Hib has been well-studied in rodents,11 similar data are lacking in the human situation. Memory to Hib-PS must play an important role, as Hib disease is not seen throughout childhood or in adults. Epidemiologic surveillance for Hib disease in countries that have licensed DTaP-Hib conjugate combination vaccines for infant use should be helpful. Acknowledgments. Supported by National Institutes of Health Grant AI45248. We thank Drs. S. Stanley Plotkin, Richard Insel, Pamela McInnes, David Klein, Regina Rabinovich and Margaret Rennels for encouragement and support. Michael E. Pichichero, M.D. Timothy Voloshen, B.S. Sherry Passador, M.S.
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