Prakash K. Bhuyan

Safety, tolerability and immunogenicity of a recombinant hepatitis B vaccine manufactured by a modified process in healthy young adults.

Background: Merck has developed a manufacturing process modification for RECOMBIVAX HB™. Three lots of modified process hepatitis B vaccine (mpHBV) were studied in a randomized, blinded trial to demonstrate similarity of the 3 lots of mpHBV and noninferiority to RECOMBIVAX HB™ (control vaccine) with regard to immunogenicity. Methods: Healthy 20- to 35-year-old subjects (N=860) received a 1-mL intramuscular dose (10 mcg hepatitis B surface antigen [HBsAg]) of mpHBV from 1 of 3 lots or control at Day 1, and Months 1 and 6. Serum antibody to HBsAg (anti-HBs) was assayed Predose 1 and 1 month Postdose 3 (Month 7) using a quantitative hepatitis B antibody assay (Ortho VITROS ECi assay). Anti-HBs geometric mean titers (GMTs) and seroprotection rates (SPRs) (% of subjects with an anti-HBs titer ≥10 mIU/mL) were compared at Month 7. After each dose, injection-site adverse experiences (AEs) and oral temperature were recorded for 5 days; systemic AEs were recorded for 15 days. Results: Month 7 SPRs for the mpHBV groups ranged from 97.8 to 98.9% (98.2% for the mpHBV groups combined). The SPR for the control group was 98.5%. The estimated GMT was 1761 mIU/mL for the mpHBV groups combined and 1108 mIU/mL for the control group. The GMT ratio (mpHBV/control) was 1.6 (95% confidence interval [CI]: 1.2 to 2.1), indicating superiority of mpHBV compared with control. The percentages of subjects reporting any AE, injection-site AEs, or systemic AEs were similar across the 4 vaccination groups. There were no serious AEs. Conclusions: The SPRs for the mpHBV groups and the control group were high; responses were consistent across the mpHBV groups. The mpHBV and control vaccines were generally well tolerated.

Safety and immunogenicity of a hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B vaccine at 2, 3, 4, and 12-14 months of age.

Combination vaccines improve parental and provider satisfaction and schedule compliance by decreasing the number of injections. In a Phase 2, randomized, double-blind, multicenter study, we compared four formulations of a liquid, hexavalent diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B virus (DTaP-IPV-Hib-HBV) vaccine in 708 infants immunized at 2, 3, 4, and 12-14 months of age. The formulations contained identical DTaP and IPV components, differing in the contents of Hib polyribosylribitol phosphate (PRP) conjugate component (tetanus-toxoid [PRP-T, 12microg] or Neisseria meningitidis outer-membrane-protein-complex [PRP-OMPC, 3microg or 6microg]), and in hepatitis B surface antigen (HBsAg, 10microg or 15microg). A minimum acceptable postdose 3 antibody response rate was defined by the lower limit of the 95% confidence interval exceeding a prespecified target. Rates of adverse events (AEs) were similar among groups, with a trend for increased solicited injection-site reactions (pain, redness, swelling) with increasing PRP-OMPC and HBsAg concentration. Serious AEs reported by eight subjects were not considered to be vaccine related. All PRP-OMPC formulations met prespecified acceptability criteria for postdose 3 immunogenicity for all antigens: PRP, HBsAg, pertussis, diphtheria, tetanus and polio. Apart from the Hib response, the postdose 3 responses obtained with the PRP-T formulation met the acceptability criterion for each antigen. Postdose 4 responses were acceptable for all antigens in all formulations. All vaccine formulations were well tolerated. The three PRP-OMPC formulations met prespecified immunogenicity criteria, and the one with the lowest PRP-OMPC concentration was selected for further optimization of immunogenicity.

Immunogenicity, Tolerability and Safety in Adolescents of Bivalent rLP2086, a Meningococcal Serogroup B Vaccine, Coadministered with Quadrivalent Human Papilloma Virus Vaccine.

Background: This study in healthy adolescents (11 to <18 years) evaluated coadministration of quadrivalent human papillomavirus vaccine (HPV-4), with bivalent rLP2086, a meningococcal serogroup B (MnB) vaccine. Methods: Subjects received bivalent rLP2086 + HPV-4, bivalent rLP2086 + saline or saline + HPV-4 at 0, 2 and 6 months. Immune responses to HPV-4 antigens were assessed 1 month after doses 2 and 3. Serum bactericidal assays using human complement (hSBAs) with 4 MnB test strains expressing vaccine-heterologous human complement factor H binding protein (fHBP) variants determined immune responses to bivalent rLP2086. Coprimary objectives were to demonstrate noninferior immune responses with concomitant administration compared with either vaccine alone. Additional endpoints included the proportions of subjects achieving prespecified protective hSBA titers to all 4 MnB test strains (composite response) and ≥4-fold increases in hSBA titer from baseline for each test strain after dose 3; these endpoints served as the basis of licensure of bivalent rLP2086 in the US. Results: The noninferiority criteria were met for all MnB test strains and HPV antigens except HPV-18; ≥99% of subjects seroconverted for all 4 HPV antigens. Bivalent rLP2086 elicited a composite response in >80% of subjects and increased hSBA titers ≥4-fold in ≥77% of subjects for each test strain after dose 3. A substantial bactericidal response was also observed in a large proportion of subjects after dose 2. Local reactions and systemic events did not increase with concomitant administration. Conclusions: Concomitant administration of bivalent rLP2086 and HPV-4 elicits robust immune responses to both vaccines without increasing reactogenicity compared with bivalent rLP2086 alone. Concurrent administration may increase compliance with both vaccine schedules.

Safety and immunogenicity of three different formulations of a liquid hexavalent diphtheria–tetanus–acellular pertussis–inactivated poliovirus–Haemophilus influenzae b conjugate–hepatitis B vaccine at 2, 4, 6 and 12–14 months of age☆☆☆

The current recommended infant vaccination schedules require many injections at multiple sites, which increase stress for infants and parents and may create challenges to vaccination compliance. Therefore, combination vaccines, which reduce the number of injections at each medical visit, can be an essential method to improve compliance. The objective of this study was to assess the safety and immunogenicity of an investigational, liquid, hexavalent, pediatric vaccine at 2, 4, 6, and 12-14 months of age. In this multicenter, open-label controlled study, 756 infants were randomized in approximately equal numbers to receive 0.5mL intramuscular dose of diptheria-tetanus-pertussis-polio-Haemophilus influenzae type b+hepatitis B vaccine, or 1 of 3 double-blind investigational formulations. All formulations included a hepatitis B surface antigen (HBsAg) concentration of 10μg/0.5mL. The three hexavalent vaccine formulations used in this study contained either Hib polyribosylribitol phosphate (PRP) conjugate component (tetanus toxoid [PRP-T, 12μg] or Neisseria meningitidis outer membrane protein complex [PRP-OPMC, 3μg or 6μg]): a minimum acceptable postdose 3 antibody response rate for each antigen was defined by the lower limit of a 95% confidence interval exceeding a prespecified target. Rates of adverse events (AEs) were similar among groups, with a trend for increased solicited vaccine-related injection-site reactions (pain, erythema, swelling) with increasing PRP-OMPC dose. No serious vaccine-related AEs were reported in the investigational groups. Both PRP-OMPC formulations met prespecified acceptability criteria for all antigens: PRP, HBsAg, pertussis, diphtheria, tetanus and poliovirus. The PRP-T formulation met the acceptability criterion for antibody responses to all antigens other than PRP at postdose 3. Postdose 4 responses were adequate for all antigens in all formulations. All vaccine formulations were well-tolerated. Both PRP-OMPC formulations met prespecified immunogenicity criteria of PRP-OMPC evaluation.

Safety and immunogenicity of a hexavalent vaccine administered at 2, 4 and 6 months of age with or without a heptavalent pneumococcal conjugate vaccine: a randomized, open-label study.

Background: DTaP5-IPV-Hib-HepB, an investigational hexavalent combination vaccine, was evaluated for safety and immunogenicity, when administered to infants with heptavalent pneumococcal conjugate vaccine (PCV7). Methods: Infants were randomized to receive DTaP5-IPV-Hib-HepB plus PCV7, DTaP5-IPV-Hib-HepB with PCV7 administered 1 month later or DTaP5-IPV/Hib plus HepB plus PCV7 at 2, 4 and 6 months of age in an open-label, phase IIb trial. Vaccine responses were assessed by pertussis toxoid, filamentous hemagglutinin, pertactin and fimbriae types 2/3 seroconversion rates, Haemophilus influenzae type b polyribosylribitol phosphate capsular polysaccharide, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus types 1, 2 and 3 seroprotection rates and geometric mean titers. Solicited injection site and systemic reactions, serious adverse events, and other safety outcomes were reported. Results: Seroprotection rates to polyribosylribitol phosphate, hepatitis B surface antigen, diphtheria toxoid, tetanus toxoid and poliovirus antigens across all groups met or exceeded predetermined acceptability criteria. Seroconversion rates to pertussis toxoid, pertactin and fimbriae types 2/3, but not filamentous hemagglutinin, met such criteria. Antidiphtheria antibodies were significantly lower when PCV7 was coadministered. Geometric mean titers to the other antigens of the hexavalent and PCV7 vaccines were all high and similar in the 2 groups. No safety signals were noted. Conclusions: DTaP5-IPV-Hib-HepB administered at 2, 4 and 6 months of age concomitantly with PCV7 was well tolerated and elicited robust antibody responses to all but the antidiphtheria antigens for which there may be evidence of immune interference. Only filamentous hemagglutinin did not meet seroconversion rate acceptability criteria.

Safety and immunogenicity of a toddler dose following an infant series of a hexavalent diphtheria, tetanus, acellular pertussis, inactivated poliovirus, Haemophilus influenzae type b, hepatitis B vaccine administered concurrently or at separate visits with a heptavalent pneumococcal conjugate vaccine

BACKGROUND: Combination diphtheria-tetanus-5 component acellular pertussis-inactivated poliovirus-Haemophilus influenzae b conjugate-hepatitis B-vaccine (DTaP5-IPV-Hib-HepB) administered either concurrently with 7-valent pneumococcal conjugate vaccine (PCV7) or one month apart was generally safe and immunogenic at 2, 4, and 6 months of age. This study examined the effects of a booster dose at age 15 months. METHODS: Participants were randomized to DTaP5-IPV-Hib-HepB plus PCV7, DTaP5-IPV-Hib-HepB with PCV7 administered 1 month later, or a pentavalent DTaP5-IPV/Hib plus HepB plus PCV7 at 15 months of age in a randomized, open-label, phase IIb clinical trial. Immunogenicity endpoints were rates of seroresponse to pertussis toxoid, filamentous haemagglutinin, pertactin, and fimbriae types 2 and 3, and rates of seroprotection against (Hib) polyribosylribitol phosphate capsular polysaccharide (PRP), hepatitis B surface antigen (HBsAg), diphtheria toxoid, tetanus toxoid, and poliovirus types 1, 2, and 3; and geometric mean titers to all vaccine antigens. Safety endpoints included solicited injection site reactions and systemic and serious adverse events. RESULTS: Seroresponse/seroprotection rates for all antigens exceeded prespecified criteria in both groups that received the hexavalent DTaP5-IPV-Hib-HepB; in the group that received the currently licensed pentavalent vaccine, seroresponse/seroprotection rates exceeded the criteria for all antigens except filamentous hemagglutinin. Seroresponse rates were ≥88.9% for pertussis antigens and seroprotection rates against PRP, HBsAg, diphtheria toxoid, tetanus toxoid, and poliovirus antigens were ≥95.1% in recipients of DTaP5-IPV-Hib-HepB. CONCLUSIONS: DTaP5-IPV-Hib-HepB administered concomitantly with PCV7 or one month apart at 15 months of age following the infant series was well tolerated and elicited antibody responses to all vaccine antigens, with no significant interference from concomitant PCV7 administration. (clinicaltrials.gov registration number NCT00362427).

Safety and immunogenicity of a modified process hepatitis B vaccine in healthy adults ≥ 50 years

Background: Generating protective immune responses in older adults (particularly ≥65 years) remains challenging for vaccines in general. This study examined the immune response engendered in older adults by RECOMBIVAX HB™ manufactured using a modified adjuvant (modified-process hepatitis B vaccine; mpHBV), RECOMBIVAX-HB™, and ENGERIX-B™. Methods: Randomized, double-blind, multicenter study enrolled healthy, seronegative subjects (N=538) to receive mpHBV (10 µg hepatitis B surface antigen [HBsAg]), RECOMBIVAX-HB™ (10 µg HBsAg), or ENGERIX-B™ (20 µg HBsAg) at Day 1, Month 1, and Month 6. Prespecified analysis of subpopulations 50-64 years and ≥65 years was conducted. Serum antibody to HBsAg (anti-HBs) was measured Predose 1 and 1 month Postdose 3. Results: For subjects ≥50 years, seroprotection rates (SPR, anti-HBs titer ≥10 mIU/mL) were 75.7% (95% CI: 68.0,82.2) for mpHBV, 68.0% (95% CI: 59.8,75.5) for RECOMBIVAX HB™, and 84.0% (95% CI: 77.0,89.6) for ENGERIX-B™. For subjects 50-64 years, SPRs were 82.1% (95% CI: 73.8,88.7) for mpHBV, 77.4% (95% CI: 68.7,84.7) for RECOMBIVAX-HB™, and 88.5% (95% CI: 81.1,93.7) for ENGERIX-B™. For subjects ≥65 years, SPRs were 57.5% (95% CI: 40.9,73.0) for mpHBV, 34.4% (95% CI: 18.6,53.2) for RECOMBIVAX-HB™, and 67.7% (95% CI: 48.6,83.3) for ENGERIX-B™. There were 6 non-vaccine related serious adverse events reported. Conclusions: The majority of subjects ≥50 years old achieved seroprotection. The sub-population ≥65 years had lower vaccination responses than the 50-64 years sub-population. For subjects ≥65 years, mpHBV and ENGERIX-B™ groups achieved higher seroprotection rates than the RECOMBIVAX-HB group. The safety profile of mpHBV was consistent with the other groups.

Safety and immunogenicity of a modified process hepatitis B vaccine in healthy infants.

Background: A modified process hepatitis B vaccine (mpHBV) uses higher phosphate content in the manufacturing process relative to the current product, Recombivax-HB. The higher phosphate is thought to improve antigen presentation, and thereby, increase antibody production. The mpHBV was previously shown to be well tolerated and immunogenic in adults. The current study tested a 2-, 4-, 6-month vaccination schedule and a higher dose formulation (10 &mgr;g mpHBV) in healthy infants. Methods: In a randomized, double-blind study, healthy infants (N = 1718), approximately 2 months of age, received a 0.5-mL intramuscular dose of 5-&mgr;g mpHBV, Recombivax-HB (5 &mgr;g), 10-&mgr;g mpHBV, or Engerix-B (10 &mgr;g) at day 1, month 2, and month 4 (2, 4, 6 months of age). Serum antibody to hepatitis B surface antigen (anti-HBs) was analyzed at month 7. The geometric mean titer (GMT) and seroprotection rate (SPR; % subjects with anti-HBs titer ≥10 mIU/mL) were determined 1 month after the third dose. Results: Month 7 SPRs were 99.3% (402/405, 95% confidence interval [CI]: 98.3, 100) in the 5 &mgr;g mpHBV group, 100.0% (398/398, 95% CI: 99.9, 100) in the 10 &mgr;g mpHBV group, 98.5% (400/406, 95% CI: 97.2, 99.8) in the Recombivax-HB group, and 99.5% (398/400, 95% CI: 98.7, 100) in the Engerix-B group. Month 7 GMTs (mIU/mL) were 748.2 (95% CI: 672.0, 833.1) in the 5 &mgr;g mpHBV group, 981.5 (95% CI: 891.0, 1081.2) in the 10 &mgr;g mpHBV group, 376.8 (95% CI: 331.4, 428.5) in the Recombivax-HB group, and 556.6 (95% CI: 491.8, 629.9) in the Engerix-B group. The percentages of subjects reporting injection-site or systemic adverse events were similar across the vaccination groups. Conclusions: All 4 hepatitis B vaccines elicited high anti-HBs SPRs. After dose 3, anti-HBs GMT were highest in the 10 &mgr;g mpHBV group, but did not meet the predefined criteria for superiority. All vaccines were well tolerated.

Safety and immunogenicity of a recombinant hepatitis B vaccine manufactured by a modified process in renal pre-dialysis and dialysis patients.

BACKGROUND Patients with renal insufficiency are hyporesponsive to vaccination, including to hepatitis B vaccines. A manufacturing process modification for a hepatitis B vaccine (mpHBV) was studied in renal pre-dialysis and dialysis patients. METHODS This randomized, open-label, multicenter, estimation study enrolled previously unvaccinated, HBV-seronegative adult dialysis and pre-dialysis patients (N=276, median age 72.0 years). At 0, 1, 6, and 8 months, group 1 received a 1 mL intramuscular dose of mpHBV (containing 40 μg HBsAg) as a single injection, while group 2 received a 1 mL intramuscular dose of a licensed hepatitis B vaccine as two injections (each containing 20 μg HBsAg; 40 μg HBsAg total). Serum antibody to HBsAg (anti-HBs) was measured predose 1, and 1 month postdose 3 and 4. Anti-HBs geometric mean concentration (GMC) and seroprotection rate (SPR, % of subjects with anti-HBs titer ≥10 mIU/mL) were estimated at months 7 and 9. RESULTS For group 1, month 7 SPR was 48.5% (49/101, 95% CI: 38.4%, 58.7%); with an additional dose, month 9 SPR increased to 66.7% (66/99, 95% CI: 56.5%, 75.8%). For group 2, month 7 SPR was 57.7% (64/111, 95% CI: 47.9%, 67.0%); with an additional dose, month 9 SPR increased to 69.2% (72/104, 95% CI: 59.4%, 77.9%). group 1 GMCs at months 7 and 9 were 27.5 mIU/mL (95% CI: 15.7, 48.0) and 61.7 mIU/mL (95% CI: 34.2, 111.5), respectively. group 2 GMCs at months 7 and 9 were 48.7 mIU/mL (95% CI: 28.7, 82.7) and 115.8 mIU/mL (95% CI: 65.2, 205.5), respectively. There were 22 serious adverse events; none were considered related to study vaccine. CONCLUSIONS Both formulations were immunogenic in this population but required more vaccinations to reach seroprotective levels than comparable regimens in healthy individuals, as expected. The relatively reduced SPRs seen in this population support the need for routine screening and re-dosing in this population.

Safety and immunogenicity of a modified process hepatitis B vaccine in healthy neonates

BACKGROUND A manufacturing process using a modified adjuvant was developed to optimize the consistency and immunogenicity for recombinant hepatitis B vaccine (control: RECOMBIVAX-HB™). This modified process hepatitis B vaccine (mpHBV), which was previously shown to have an acceptable safety and immunogenicity profile in young adults, has now been studied in newborn infants. METHODS Healthy 1-10-day-old neonates (N=566) received 3 intramuscular doses (5μg hepatitis B surface antigen [HBsAg] per dose) of either mpHBV or control at Day 1, and Months 1 and 6. Serum antibody to HBsAg (anti-HBs) was assayed at Month 7 (1 month Postdose 3). Anti-HBs geometric mean titers (GMTs) and seroprotection rates (SPRs) (% of subjects with an anti-HBs titer ≥10mIU/mL) were compared at Month 7. After each dose, injection-site adverse experiences (AEs) and axillary temperatures were recorded for 5 days; systemic AEs were recorded for Days 1-14. RESULTS Month 7 SPR was 97.9% for the mpHBV group and 98.9% for the control. The GMT was 843.7mIU/mL for the mpHBV group and 670.1mIU/mL for the control. The GMT ratio (mpHBV/control) was 1.26 (95% confidence interval [CI]: 0.94, 1.69), meeting the prespecified non-inferiority criteria. The percentages of subjects reporting any AE, injection-site AEs, or systemic AEs were similar across the 2 vaccination groups. There were no serious AEs. CONCLUSIONS The safety profile of mpHBV was comparable to that of the control vaccine. The geometric mean antibody titer for mpHBV was higher than control vaccine in this infant population, but the difference did not meet the predefined statistical criterion for superiority.