Hexavalent vaccines: What can we learn from head-to-head studies?

BACKGROUND: Three hexavalent vaccines against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B virus (HBV), and Haemophilus influenzae type b (Hib) are licensed in Europe: Infanrix hexa (DT3aP-HBV-IPV/Hib), Hexyon (DT2aP-HBV-IPV-Hib) and Vaxelis (DT5aP-HBV-IPV-Hib). METHODS: A systematic literature search was performed in various electronic databases to identify published peer-reviewed head-to-head studies comparing any licensed hexavalent vaccine to another. RESULTS: Predefined inclusion criteria were met by 12 articles. Individual studies concluded that the 3 hexavalent vaccines have acceptable safety profiles although some significant differences were observed in their reactogenicity profiles. The immunogenicity of DT2aP-HBV-IPV-Hib and DT5aP-HBV-IPV-Hib was non-inferior versus DT3aP-HBV-IPV/Hib. Some differences in immune responses to common antigens were observed, but their clinical relevance was not established. Anti-filamentous hemagglutinin (FHA) from pertussis and anti-polyribosylribitol phosphate (PRP) from Hib antibody concentrations tended to be higher, and anti-HBV and anti-pertussis toxin (PT) from pertussis antibody concentrations lower in DT2aP-HBV-IPV-Hib versus DT3aP-HBV-IPV/Hib vaccinees. Anti-PT and post-primary anti-PRP antibody concentrations tended to be higher, and anti-HBV, anti-FHA, anti-pertactin from pertussis and post-booster anti-PRP antibody concentrations lower in DT5aP-HBV-IPV-Hib versus DT3aP-HBV-IPV/Hib recipients. Slightly lower immune responses towards most vaccine antigens were observed with 2 + 1 versus 3 + 1 schedules post-primary vaccination, suggesting that 2 + 1 schedules should only be considered in countries with very high vaccination coverage. CONCLUSION: Although the licensed hexavalent vaccines are generally considered similar, analyses of immunogenicity data from head-to-head trials highlighted differences that could be related to differences in composition and formulation. In addition, the demonstrated non-inferiority of the immunogenicity of the more recent vaccines versus DT3aP-HBV-IPV/Hib does not allow a full bridging to similar efficacy, effectiveness and safety. The availability of DT3aP-HBV-IPV/Hib over > 20 years allowed to collect a wealth of data on its long-term immunogenicity, safety and effectiveness in clinical and post-marketing studies, and makes it a key pillar of pediatric immunization.

Infant vaccine co-administration: review of 18 years of experience with GSK's hexavalent vaccine co-administered with routine childhood vaccines.

INTRODUCTION: The benefits of vaccine co-administration include improved vaccine acceptance and uptake resulting in an increased coverage and protection against multiple childhood diseases, with minimal medical visits. The diphtheria-tetanus-acellular pertussis-hepatitis B-poliomyelitis-Haemophilus influenzae type b vaccine (DTaP-HBV-IPV/Hib) has been available for more than 19 years and is recommended for co-administration with several other infant vaccines. AREAS COVERED: This is a comprehensive review (34 studies, 21,000 participants) describing the immunogenicity and safety of DTaP-HBV-IPV/Hib when co-administered with 12 different vaccines in infants including pneumococcal, meningococcal, rotavirus or measles-mumps-rubella-varicella. EXPERT OPINION: Interactions among co-administered vaccines are complex. Therefore, co-administration data are critical before a vaccination regimen can be recommended. Co-administration of DTaP-HBV-IPV/Hib with other routinely administered vaccines was associated with high percentages of children achieving seroprotection/vaccine response against DTaP-HBV-IPV/Hib antigens. In addition, co-administration was not associated with clinically significant interference in immune responses to co-administered vaccines and was well tolerated. Increased systemic reactions observed with some combinations (DTaP-HBV-IPV/Hib + pneumococcal conjugate or meningococcal serogroup B vaccines) were mitigated by prophylactic paracetamol administration. The data reported here, which represent the most frequently used co-administrations of DTaP-HBV-IPV/Hib worldwide, support the concomitant administration of DTaP-HBV-IPV/Hib with other routinely recommended infant vaccines.

Immunogenicity and safety of a combined DTPa-IPV/Hib vaccine administered as a three-dose primary vaccination course and a booster dose in healthy children in Russia: a phase III, non-randomized, open-label study.

We assessed the immunogenicity and safety of the combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in children in Russian Federation aiming to support the registration of the vaccine in Russia. In this phase 3, non-randomized, open-label study (NCT02858440), healthy children received three primary doses at 3, 4.5, and 6 months of age (N = 235) and a booster dose at 18 months of age (N = 225). Seroprotection rates against diphtheria, tetanus, Hib, and poliovirus 1-3, seropositivity rates against pertussis antigens, and antibody geometric mean concentrations/titers for all antigens were evaluated one month post-primary and post-booster vaccinations. Solicited local and general adverse events (AEs) were collected during a 4-day period and unsolicited AEs during a 31-day period post-vaccination. Serious AEs were recorded throughout the study. At post-primary vaccination, all infants were seroprotected against diphtheria, tetanus, and poliovirus 1 and 2, 99.3% against poliovirus 3, and 98.4% against Hib. At least 98.9% of participants were seropositive for the three pertussis antigens. At post-booster vaccination, all toddlers were seroprotected/seropositive against all vaccine components. The most frequent local and general solicited AEs were redness, reported for 52.6% and 44.9% of children, and irritability, reported for 64.7% and 39.1% of children, post-primary and post-booster vaccination, respectively. Unsolicited AEs were reported for 20.4% (post-primary) and 5.8% of children (post-booster vaccination). Most AEs were mild or moderate in intensity. Six serious AEs were reported in three (0.4%) children; none were fatal or assessed as vaccination-related. DTPa-IPV/Hib proved immunogenic and well tolerated in the Russian pediatric population.

Integration of hexavalent diphtheria, tetanus, acellular pertussis, hepatitis B virus, inactivated poliomyelitis and Haemophilus influenzae type b conjugate vaccine within existing national recommendations following a birth dose of monovalent hepatitis B virus vaccine: results of a systematic review in the Asia Pacific region.

Introduction: In Asia Pacific, most countries recommend a monovalent hepatitis B virus (HBV) vaccine dose at birth followed by primary vaccination series including three or four doses of combination vaccines against diphtheria, tetanus, and pertussis, with or without Haemophilus influenzae type b (Hib), HBV or poliomyelitis antigens. If hexavalent conjugate vaccines against diphtheria-tetanus-acellular pertussis-HBV-inactivated poliovirus-Hib (DTPa-HBV-IPV/Hib) replace the vaccines included in the primary vaccination series, co-administration of lower-valent vaccines would be avoided but infants would receive ≥4 doses of HBV-containing vaccines before the age of 2 years. Areas covered: We searched for clinical trials conducted in the South-East Asia and Western Pacific Regions (World Health Organization geographic definition), investigating vaccination regimens with >3 doses of HBV-containing vaccines in infants, including a monovalent HBV vaccine birth dose and ≥1 dose of GSK's hexavalent DTPa-HBV-IPV/Hib vaccine. Expert opinion: The six clinical trials included in this review showed that infants who received the monovalent HBV vaccine at birth and three or four doses of DTPa-HBV-IPV/Hib vaccine achieved protective immunogenic titers with a clinically acceptable safety profile. Our results support the integration of hexavalent DTPa-HBV-IPV/Hib vaccine within existing national recommendations in the Asia Pacific region to reduce the number of injections during infancy.

Long-term antibody persistence against hepatitis B in adolescents 14-15-years of age vaccinated with 4 doses of hexavalent DTPa-HBV-IPV/Hib vaccine in infancy.

We evaluated antibody persistence against hepatitis B virus (HBV) in adolescents previously vaccinated with a hexavalent diphtheria-tetanus-acellular pertussis-HBV-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine (DTPa-HBV-IPV/Hib), as part of the national newborn immunization program in Germany. We also assessed the anamnestic response to a challenge dose of a monovalent HBV vaccine. In this phase 4, open-label, non-randomized study (NCT02798952), 302 adolescents aged 14-15 years, primed in their first 2 years of life with 4 DTPa-HBV-IPV/Hib doses, received one challenge dose of monovalent HBV vaccine. Blood samples were taken before and one month post-vaccination and used to determine antibody levels against hepatitis B surface antigen (HBs). Reactogenicity and safety were also assessed post-challenge dose. Pre-challenge dose, 53.7% of 268 participants included in the according-to-protocol cohort for immunogenicity had anti-HBs antibody concentrations ≥10 mIU/mL (seroprotection cut-off) and 16.8% had anti-HBs antibody concentrations ≥100 mIU/mL. One month post-challenge dose, 93.3% of adolescents had anti-HBs antibody concentrations ≥10 mIU/mL and 87.3% had antibody concentrations ≥100 mIU/mL. An anamnestic response was mounted in 92.5% of adolescents. Injection site pain (in 33.6% of participants) and fatigue (30.2%) were the most frequently reported solicited local and general symptoms, respectively. Six of the 55 unsolicited adverse events reported were considered vaccination-related. Two vaccination-unrelated serious adverse events were reported during the study. Long-term antibody persistence against hepatitis B was observed in 14-15 years old adolescents previously primed in infancy with DTPa-HBV-IPV/Hib. A challenge dose of monovalent HBV vaccine induced strong anamnestic response, with no safety concerns.

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.

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.

Hexavalent vaccines: increasing options for policy-makers and providers. A review of the data supporting interchangeability (substitution with vaccines containing fewer antigens) and mixed schedules from the same manufacturer.

INTRODUCTION: Combination vaccines improve vaccine uptake and open the infant immunization space for additional vaccines. Hexavalent vaccines have been marketed since 2000. Infanrix hexa (combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b conjugate vaccine, DTPa-HBV-IPV/Hib, GSK) is longest on the market, providing 16 years post-marketing experience. Each DTPa-HBV-IPV/Hib vaccine component is licensed alone and/or in smaller combination vaccines. Programmatic considerations sometimes require an interchange between vaccines due to unavailability, program change or mixed schedules (when the number of required antigens differs across scheduled primary vaccination visits). AREAS COVERED: Immunogenicity and safety data from 11 GSK-sponsored clinical trials support the interchangeability of DTPa-HBV-IPV/Hib within the same vaccines family, and use of DTPa-HBV-IPV/Hib in mixed primary vaccination schedules. EXPERT COMMENTARY: Data show acceptability of interchange of DTPa-HBV-IPV/Hib with other products within the same vaccines family and its use in mixed immunization schedules. This aligns with WHO recommendations that vaccines of the same family from the same manufacturer be used to complete the infant vaccination schedule. Interchangeability and suitability for use in mixed schedules is of interest for policy-makers/providers in the framework of vaccination recommendations as it provides flexibility. Given the complexity of larger combination vaccines, interchangeability or sequential use needs careful assessment.

Immunogenicity and safety of primary and booster vaccination with 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens in a hexavalent DTPa-HBV-IPV/Hib combination vaccine in comparison with the licensed Infanrix hexa.

Safety and immunogenicity of 2 investigational formulations of diphtheria, tetanus and Haemophilus influenzae type b antigens of the combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliomyelitis-Hib vaccine (DTPa-HBV-IPV/Hib) were evaluated in a Primary (NCT01248884) and a Booster vaccination (NCT01453998) study. In the Primary study, 721 healthy infants (randomized 1:1:1) received 3 doses of DTPa-HBV-IPV/Hib formulation A (DATAPa-HBV-IPV/Hib), or B (DBTBPa-HBV-IPV/Hib) or the licensed DTPa-HBV-IPV/Hib vaccine (Infanrix hexa, GSK; control group) at 2, 3, 4 months of age. Infants were planned to receive a booster dose at 12-15 months of age with the same formulation received in the Primary study; however, following high incidence of fever associated with the investigational formulations in the Primary study, the Booster study protocol was amended and all infants yet to receive a booster dose (N = 385) received the licensed vaccine. In the Primary study, non-inferiority of 3-dose vaccination with investigational formulations compared with the licensed vaccine was not demonstrated due to anti-pertactin failing to meet the non-inferiority criterion. Post-primary vaccination, most infants had seroprotective levels of anti-diphtheria (100% of infants), anti-tetanus antigens (100%), against hepatitis B (≥ 97.5% across groups), polyribosyl-ribitol-phosphate (≥ 88.0%) and poliovirus types 1-3 (≥ 90.5%). Seropositivity rates for each pertussis antigen were 100% in all groups. Higher incidence of fever (> 38°C) was reported in infants receiving the investigational formulations (Primary study: 75.0% [A] and 72.1% [B] vs 58.8% [control]; Booster study, before amendment: 49.4% and 46.6% vs 37.4%, respectively). The development of the investigational formulations was not further pursued.