Dace V. Madore

A randomized comparison of three bivalent Streptococcus pneumoniae glycoprotein conjugate vaccines in young children: effect of polysaccharide size and linkage characteristics.

Because most childhood invasive pneumococcal disease occurs before the age of 2 years, the development of a pneumococcal vaccine that is immunogenic in infants is a priority. We assessed the safety and serum antibody responses to two dose levels of three bivalent pneumococcal capsular polysaccharide (CPS)-protein conjugate vaccines incorporating the poorly immunogenic serotypes 6A and 23F. The conjugate vaccines differed in CPS size and chemical linkage, but all used a nontoxic cross-reactive mutant diphtheria toxin (CRM197) as the protein carrier. 118 young children 18 to 30 months of age received a single immunization with one of the three glycoconjugates or with licensed pneumococcal vaccine. Sera were obtained before and 1 month after immunization and analyzed by enzyme-linked immunosorbent assay for serotype-specific antibody titers. The 23F CPS was more immunogenic than the 6A CPS in all vaccine formats. The most immunogenic 23F conjugate vaccine consisted of native CPS directly linked to the carrier protein; smaller CPS or the use of a six-carbon linker did not appear to enhance immunogenicity in these young children. Conjugation of two pneumococcal CPSs is associated with an increase in immunogenicity, and the characteristics of the CPS and of the CPS-protein linkage appear to influence the antibody response.

Immunologic priming of young children by pneumococcal glycoprotein conjugate, but not polysaccharide, vaccines

BACKGROUND Streptococcus pneumoniae is the most common cause of invasive bacterial disease and otitis media in infants and young children. Licensed pneumococcal polysaccharide vaccines are not reliably immunogenic in children younger than 2 years of age; therefore pneumococcal glycoprotein conjugate vaccines are currently being evaluated for safety, immunogenicity and efficacy in various age groups. METHODS During a 12-month period we determined the kinetics of pneumococcal IgG antibody in 60 children who received primary immunization with one dose of bivalent (serotypes 6A and 23F) pneumococcal polysaccharide-CRM197 vaccines at 18 to 30 months of age. To assess immunologic priming a subgroup of 20 subjects received secondary immunization with pneumococcal polysaccharide vaccine, including serotypes 6B and 23F, at 11 to 20 months after primary immunization. Pneumococcal-specific IgG subclass distributions were also evaluated in the subgroup. RESULTS In the 12 months after primary immunization with glycoprotein conjugate vaccine, geometric mean pneumococcal IgG antibody concentrations to 6B and 23F serotypes remained stable. Pneumococcal polysaccharide vaccine induced a greater anamnestic response in children primed with glycoprotein conjugate vaccines (13- to 40-fold increases to geometric mean concentrations of 6 to 30 micrograms/ml for type 23F), than in those primed with polysaccharide (2- to 4-fold increases). A greater IgG response to pneumococcal serotype 23F than to 6B was observed with both primary and secondary immunization. The serotype-specific pneumococcal IgG antibody response was virtually restricted to the IgG1 subclass after primary immunization, but secondary immunization elicited antibodies of IgG1 and IgG2 subclasses. CONCLUSIONS These glycoprotein conjugate vaccines appear to prime for anamnestic IgG antibody responses to subsequent immunization with polysaccharide vaccine, suggesting that the polysaccharide-CRM197 vaccine effectively induces a predominantly T cell-dependent immune response. The greater IgG response to 23F than to 6B indicates that pneumococcal serotype is a major determinant of immunogenicity of pneumococcal glycoprotein conjugate vaccines.

Safety of combined oligosaccharide conjugate Haemophilus influenzae type b (hboc) and whole cell diphtheria-tetanus toxoids-pertussis vaccine in infancy

The safety of the combined oligosaccharide conjugate Haemophilus influenzae (Hib) type b (HbOC) and whole cell diphtheria-tetanus toxoids-pertussis (DTP) vaccine (Tetramune

Response to a Haemophilus influenzae type b diphtheria CRM197 conjugate vaccine in children with a defect of antibody production to Haemophilus influenzae type b polysaccharide

, HbOC-DTP; Lederle) in infancy was evaluated in 6644 recipients of this vaccine and compared with 3914 recipients of separate injections of whole cell DTP and HbOC vaccines when given as a three dose regimen to infants at 2, 4 and 6 months of age in each group. Of the total number of infants in the study, a subset of 1435 were enrolled into the study and then randomly assigned to recieve either the Hib-DPT combined vaccine or the separate components. This subset was used to assess local and systemic side effects which were evaluated utilizing telephone interviews 48 to 72 hours after vaccine. The remaining children in the study population were enrolled in a nonrandomized manner. For these children parents were offered the experimental Hib-DPT vaccine and refusers were given HbOC and DTP. Both of these groups of children as well as the randomized subset described above were used to assess rates of episodes of hospitalization, emergency room utilization and sudden infant death syndrome in HbOC-DTP recipients and children who received HbOC and DTP separately. Immunogenicity was evaluated in 123 children by collection of a single serum sample 30 days after the third dose of HbOC-DTP. The observed immunogenicity was comparable to that observed in other recent studies for HbOC and DTP component antigens. The profile of local and systemic side effects observed was virtually identical to that observed after DTP plus HbOC given separately. In initial analyses the Hib-DPT children appeared to have a higher rate of hospitalization for pneumonia than the children with separate shots. After further analyses including chart review, review of chest radiographs, and adjustment for age and season, this initial association was believed most probably to be a result of chance alone. The HbOC-DTP vaccine offers the convenience of a single combined vaccine offering protection against diphtheria, pertussis, Hib and tetanus without any substantial or significant change in safety or immunogenicity profile.

Group-specific antibody levels surrounding invasive pneumococcal illness in children infected with human immunodeficiency virus.

A defect in antibody response to immunization with Haemophilus influenzae type b (Hib) capsular polysaccharide vaccine has been reported in children with recurrent infections and normal immunoglobin levels. We identified 15 children, aged 2 to 6 years, with this defect, and we evaluated their response to immunization with an Hib capsular oligosaccharide diphtheria CRM197 protein-conjugate vaccine (HbOC). The children received a series of three vaccines: HbOC at 0 and 8 weeks, and the Hib polysaccharide vaccine at 16 weeks. Levels of antibody to the Hib capsular polysaccharide (polyribosyl ribitol phosphate, PRP) and to diphtheria toxoid were obtained before and 4 weeks after each vaccination. The geometric mean serum anti-PRP concentration was 0.17 microgram/ml before immunization and 29.3 micrograms/ml after the second HbOC immunization (week 12). All 15 children had postvaccination anti-PRP antibody levels greater than 1.0 microgram/ml after receiving the second HbOC (week 12). In addition, booster responses were observed after the second Hib conjugate in 13 of the patients and after the Hib polysaccharide in four of the patients. All patients with low preimmunization diphtheria titers had a response to the diphtheria toxoid. These results suggest that conjugation of Hib polysaccharide with diphtheria CRM197 overcomes the defective antibody response to Hib oligosaccharide in children who are initially observed with recurrent infections and inability to respond to the Hib polysaccharide vaccine.

Comparison of antigenuria after immunization with three Haemophilus influenzae type b conjugate vaccines.

Pneumococcal antibody levels surrounding systemic pneumococcal illness (SPI) were measured in children infected with human immunodeficiency virus (HIV). Archived serum samples were collected from 28 HIV-infected children who had 34 cases of SPI, caused by pneumococcal groups 4, 6, 9, 14, 19, and 23. Serum samples collected within 23 weeks before and 13 weeks after the SPI were assayed by ELISA for antipneumococcal polysaccharide (PnPs) IgG antibody to 6 representative pneumococcal serotypes. There was a wide range (0. 16-30.80 microg/mL) of pre-SPI anti-PnPs antibody levels to the presumed infecting serotypes, with a geometric mean level of 0.83 microg/mL (n=34). Seventy-six percent of the antibody values were <2.0 microg/mL, and 95% were <5.0 microg/mL. Homologous seroresponses (>/=4-fold rise in anti-PnPs antibody) were detected in only 4 (27%) of 15 paired serum samples. Heterologous, noninfecting group seroresponses were detected frequently (72%) in the paired serum samples from these 4 homologous group seroresponders.

Haemophilus b Oligosaccharide-CRM197 and Other Haemophilus b Conjugate Vaccines: A Status Report

The incidence of antigenuria was documented after vaccination of 75 children 15 to 60 months of age with one of three Haemophilus influenzae type b conjugate vaccines, PRP-D (ProHIBiT“), PRP-T and HbOC (HibTITER). Unconcen-trated and concentrated urine was tested on the first, third, fifth and seventh days after vaccination. Antigenuria occurred on Day 1 in 100% of PRP-D, 43% of PRP-T and 12% of HbOC recipients. The percentages of children excreting antigen on Day 3 were 95, 17 and 8%; on Day 5 they were 36, 4 and 12%; and on Day 7 they were 14, 0 and 18% for PRP-D, PRP-T and HbOC, respectively. The difference in the occurrence of antigenuria resulting from each vaccine was statistically significant on Day 1 and for PRP-D compared with PRP-T or HbOC on Day 3. It is important for clinicians to be aware of the frequency with which antigenuria occurs after these vaccines so that appropriate therapeutic decisions can be made.

Safety and Immunogenicity of a Combined Diphtheria, Tetanus, Pertussis and Haemophilus influenzae Type b Vaccine in Young Infants

Haemophilus influenzae type b (Haemophilus b) is a major cause of life-threatening and debilitating diseases in infants and young children. In the United States, it is the most common cause of bacterial meningitis, and also causes other invasive diseases, such as epiglottitis, septic arthritis, cellulitis, pneumonia and bacteremia. In 1985, United States Public Health officials estimated that, despite the availability of potentially effective antibiotics and medical care, up to 1 in every 200 children in the USA develops an invasive Haemophilus b disease before the age of five years (Cochi et al., 1985). The 1985 report by the U.S. National Academy of Science on establishing vaccine priorities in the United States (NRC, 1985) estimated the annual vaccine preventable costs of Haemophilus b disease to be approximately 425 million dollars, and ranked Haemophilus b vaccine among the highest priorities for needed new vaccines.