Commentary

Conjugate Hib vaccines

While combination vaccines have contributed to improved vaccine uptake rates in children, studies have documented varied immunogenicity to specific vaccine components. We studied whether varying the amount of tetanus toxoid (TT) in a DTaP and Hib combination vaccine would result in immunogenicity comparable with separate, concurrent administration.

We evaluated the immunogenicity of Massachusetts Biologic Laboratories (MBL) diphtheria, tetanus, and acellular pertussis (mDTaP) vaccine combined with tetanus-conjugated MBL Haemophilus influenzae type b vaccine (mHib) in a single injection (DTaPH). We compared four DTaPH vaccines containing varying concentrations of TT. We also evaluated the immune response to the DTaP vaccine manufactured by Connaught Laboratories (now known as Sanofi Pasteur) given with mHib and with Wyeth Hib-CRM₁₉₇ (HbOC) as separate injections. Vaccines were administered to 240 healthy infants at 2, 4, and 6 months of age, and blood specimens for antibody determination were obtained before each immunization and one month after the third immunization.

We found no significant differences in immune response to the vaccines between the four DTaPH groups. Hib antibody responses were similar in the mHib and the HbOC groups but significantly lower in the DTaPH groups, as measured by Chinese Hamster Ovary (CHO) cell neutralization titers and filamentous hemagglutinin antigen (FHA) geometric mean concentrations (GMC) of anti-Hib antibodies. There were no significant differences between the groups in pertussis or tetanus toxoid antibody levels.

Reducing tetanus toxoid amounts did not produce comparable immunogenicity for Hib. The nature of the interaction between immune responses to DTaPH components should be explored further to enable the development of better Hib-containing combination vaccines.

The immunogenicity and reactogenicity of a meningococcal serogroup C (MenC) conjugate vaccine given concomitantly with DTaP-IPV-HBV/Hib vaccine according to a two- or three-dose schedule in healthy infants was evaluated. At 1 month post-vaccination, 98% (two doses) and 100% (three doses) of subjects had serum bactericidal antibody using human complement assay (hSBA) titres ≥1:8; at 12 months of age ≥89% of subjects in each group remained seroprotected. Induction of immunological memory, as evaluated by administration of a meningococcal serogroup A/C polysaccharide vaccine challenge dose, was similar for both regimens and no interference was observed in the immune response to MenC or hepatitis B virus antigens. Reactogenicity was similar in each group. MenC conjugate vaccine given concomitantly with DTaP-IPV-HBV/Hib to healthy infants in the first year of life using a two-dose schedule is as safe and immunogenic as a three-dose regimen.

Immunogenicity and safety of a novel combined Haemophilus influenzae type b-Neisseria meningitidis serogroups C and Y-tetanus-toxoid conjugate vaccine (Hib-MenCY-TT) candidate was evaluated when co-administered with DTPa-HBV-IPV(Pediarix™³) + PCV7(Prevnar™⁴) at 2–4–6 months of age. Anti-PRP concentrations ≥1.0 μg/mL were observed in 92.9–98.7%, rSBA-MenC/Y titres ≥1:8 in >98%, rSBA-MenC/Y titres ≥1:128 in >95.8 and >89.9% subjects. PRP and MenC responses were similar to respective controls (ActHIB™⁵ and Menjugate™⁶) including for antibody persistence. Response to co-administered vaccines was not impaired. Polysaccharide challenge (PRP, PSC, PSY at 11–14 months of age) evidenced immune memory was induced for Hib, MenC/Y conjugate components. The safety profile of Hib-MenCY-TT was similar to controls. Hib-MenCY-TT administered according to the current US Hib vaccine schedule has the potential to induce protective antibodies against Hib and meningococcal-CY disease in infants and toddlers.

The quantitative (anti-Hib capsular polysaccharide antibody concentrations; anti-HibPS) and qualitative (bactericidal activity and avidity) aspects in immune responses to Haemophilus influenzae type b polyribosyl ribitol phospshate-CRM₁₉₇ conjugate vaccine (HibCV; HibTiter^®) were evaluated in 66 HIV infected children not receiving anti-retroviral therapy and 127 HIV uninfected children. Surveillance was conducted for invasive Hib disease in a cohort of 39 865 (approximately 6.4% of whom were HIV infected) children from March 1998 to June 2004. HIV infected children had lower anti-HibPS geometric mean antibody concentrations 1 month post-immunisation than HIV uninfected children (P < 0.00001) and were less likely to have anti-HibPS antibody concentrations of ≥1.0 μg/ml (RR 0.54; 95% CI 0.43–0.69). A lower proportion of HIV infected children than HIV uninfected children (RR 0.78; 95% CI 0.66–0.93) had measurable anti-Hib serum bactericidal activity (SBA) and the HibPS antibody concentration required for 50% killing of Hib bacteria was greater among HIV infected than HIV uninfected children (P = 0.001). The estimated risk of HibCV failure was 35.1-fold greater (95% CI 14.6–84.6) amongst HIV infected than HIV uninfected children.

Objective and method. – Five hundred and seventy-eight strains of type b Haemophilus influenzae (521 isolated in children, and 57 in adults) were compared using pulsed-field gel electrophoresis (PFGE) to assess strain evolution and to study the impact of the generalization of anti-Haemophilus b (anti-Hib) vaccination in France. Among these strains, 398 (including 342 from meningitis) were isolated in 1985–1992 (pre-vaccination era), 39 (including 31 from meningitis) in 1993 (year of the generalization of anti-Hib vaccination), and 141 (including 50 from CSF) in 1994–2001 (vaccination era).

Results. – A total of 102 PFGE patterns (patterns for 1–101 isolates) were obtained after SmaI restriction of the 578 strains. The strains isolated in children were distributed in 96 patterns, and those isolated in the adult in 34 patterns. The strains isolated during the pre-vaccination era presented 94 patterns. During the vaccination era, 50% of the patterns disappeared and 12 new patterns (11.7%) including 15 strains were observed. The strains belonging to the new patterns (including the two observed in 1993) were isolated in adults (n = 7) from blood culture and bronchial secretions, and children (n = 9) from CSF, blood culture, and bronchial secretions. In children, among the strains associated to vaccination failure, two presented with a new pulsotype.

Conclusion. – There is no evidence that the vaccination program brought about any drastic modifications in the type b strains causing meningitis or in the other type b strains in circulation whether in adults or children.

Objectifs et méthodes. – Afin d'apprécier l'évolution des souches d'Haemophilus influenzae de type b et d'étudier l'impact de la généralisation de la vaccination anti Hib en France, 578 souches de type b (52 chez des enfants et 57 chez des adultes) ont été étudiées avec la technique d'électrophorèse en champ pulsé après digestion enzymatique du génome. Parmi elles, 398 (dont 342 responsables de méningites) ont été isolées pendant la période 1985–1992 (avant la vaccination), 39 (31 lors de méningite) en 1993 (généralisation de la vaccination anti Hib) et 141 (50 lors de méningite) pendant l'ère vaccinale 1994–2001.

Résultats. – À partir des 578 souches, 102 pulsotypes ont été obtenus après digestion par Sma I. Les souches isolées chez les enfants étaient distribuées dans 96 pulsotypes, celles des adultes dans 34 pulsotypes. Les souches isolées pendant la période 1985–1992 sont dans 94 pulsotypes. Pendant l'ère vaccinale il est observé la disparition de 50 % des pulsotypes et l'apparition de 12 nouveaux pulsotypes (11,7 % des pulsotypes concernant 15 souches). Les souches appartenant à ces nouveaux pulsotypes (y compris celles isolées en 1993) ont été isolées chez des adultes (n = 7) d'hémoculture et de secrétions bronchiques et chez l'enfant (n = 9) de liquide céphalo-rachidien, hémoculture et sécrétions bronchiques. Chez l'enfant parmi les souches associées à un échec de vaccination, deux appartiennent à de nouveaux pulsotypes.

Conclusion. – Le programme de vaccination n'a pas entraîné de modifications importantes au sein des souches responsables de méningites ou parmi les autres souches de type b.