Immunogenicity and safety following primary and booster vaccination with a hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus and Haemophilus influenzae type b vaccine: a randomized trial in the United States

Abstract

Combined hexavalent diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis and Haemophilus influenzae type b vaccine (DTaP-HBV-IPV/Hib) can further reduce the number of injections in pediatric immunization schedules of countries currently using pentavalent DTaP combination vaccines. This open-label, randomized, multicenter study (NCT02096263) conducted in the United States evaluated the immunogenicity and safety of DTaP-HBV-IPV/Hib vaccine compared with concomitant administration of DTaP-HBV-IPV and HibA or DTaP-IPV/Hib and HBV vaccines. We randomized (1:1:1) infants to receive 3-dose priming with DTaP-HBV-IPV/Hib boosted with DTaP+ HibB, DTaP-HBV-IPV+ HibA boosted with DTaP+ HibA, or DTaP-IPV/Hib+ HBV boosted with DTaP-IPV/Hib, at 2, 4, 6, and 15-18 months of age. We enrolled and vaccinated 585 participants, 486 received a booster, and 476 completed the study. Of these, 466 participants were included in the primary and 408 in the booster according-to-protocol cohorts for immunogenicity. We demonstrated non-inferiority of DTaP-HBV-IPV/Hib vaccine to DTaP-HBV-IPV+ HibA co-administered vaccines in terms of geometric mean concentrations for pertussis antibodies post-primary vaccination. Post-primary vaccination, seroprotection/seropositivity rates for all vaccine antigens were similarly high between DTaP-HBV-IPV/Hib (≥ 94.8%), DTaP-HBV-IPV+ HibA (≥ 98.1%) or DTaP-IPV/Hib+ HBV (≥ 97.8%) groups. We observed robust immune responses post-booster, indicating effective priming by the 3 regimens. Reactogenicity was similar in the 3 groups. Twenty-eight serious adverse events were reported during the study; 3 were considered related to vaccination and resolved by the end of the study. These results confirm that DTaP-HBV-IPV/Hib could be a valuable additional source of pediatric DTaP, IPV, HBV, and Hib-containing vaccine in countries that currently use multivalent vaccines.

Keywords: type b; acellular pertussis; diphtheria; hepatitis B; immunogenicity; infants; non-inferiority; poliovirus; safety; tetanus.

Figures

Figure 1.

Study design. , vaccination; , blood sampling; DTaP-HBV-IPV/Hib, diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b (Hib) vaccine; DTaP-HBV-IPV, diphtheria, tetanus, acellular pertussis, hepatitis B, and inactivated poliovirus vaccine; DTaP-IPV/Hib, diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Hib vaccine; DTaP, diphtheria, tetanus, acellular pertussis vaccine; PCV13, 13-valent pneumococcal conjugate vaccine; HRV, human rotavirus vaccine, administered at 2 and 4 months of age only; HBV, hepatitis B vaccine (not given at 4 months of age if a dose was administered at birth or 30 days prior to enrollment); HibA, HibB, monovalent Hib conjugate vaccines; AE, adverse event; SAE, serious adverse event; NOCIs, new onset of chronic illnesses; ESFU, extended safety follow-up.Infants in Group 1 received one of three lots of DTaP-HBV-IPV/Hib, but these three groups were pooled for all analyses presented here. The final randomization scheme was (1:1:1):3:3.

Figure 2.

Flow of participants. N, number of participants in each group; SAE, serious adverse event; TVC, total vaccinated cohort; ATP, according-to-protocol. Group 1 received DTaP-HBV-IPV/Hib at primary vaccination and DTaP and HibB at booster vaccination. Group 2 received DTaP-HBV-IPV and HibA at primary vaccination and DTaP and HibA at booster vaccination. Group 3 received DTaP-IPV/Hib and HBV at primary vaccination and DTaP-IPV/Hib at booster vaccination.

Figure 3.

Incidence of local (A) and general (B) solicited symptoms post-primary vaccination (primary total vaccinated cohort, Days 0–3). Footnote: N, maximum number of participants with ≥ 1 documented dose. Infants received 3 doses of study vaccines at 2, 4 and 6 months of age. Infants also received PCV13 (3 doses at 2, 4 and 6 months of age) and oral HRV (2 doses at 2 and 4 months of age). Local symptoms are those reported at the DTaP combination vaccine and Hib or HBV injection sites. Local symptoms at the PCV13 injection site were not recorded.Note: Fever was defined as a temperature ≥ 38.0°C. Grade 3 symptoms are as defined in the Patients and Methods section.

Figure 4.

Incidence of local and general solicited symptoms post-booster vaccination (booster total vaccinated cohort, Days 0–3). Footnote: N, maximum number of participants with ≥ 1 documented dose. Children received the booster dose a 15–18 months of age. Grade 3 symptoms are as defined in the Patients and Methods section.

Figure 5.

Focus on the Patient.