A phase I randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and immunogenicity of a live-attenuated quadrivalent dengue vaccine in flavivirus-naïve and flavivirus-experienced healthy adults.

Dengue (DENV) is a mosquito-borne virus with four serotypes causing substantial morbidity in tropical and subtropical areas worldwide. V181 is an investigational, live, attenuated, quadrivalent dengue vaccine. In this phase 1 double-blind, placebo-controlled study, the safety, tolerability, and immunogenicity of V181 in baseline flavivirus-naïve (BFN) and flavivirus-experienced (BFE) healthy adults were evaluated in two formulations: TV003 and TV005. TV005 contains a 10-fold higher DENV2 level than TV003. Two-hundred adults were randomized 2:2:1 to receive TV003, TV005, or placebo on Days 1 and 180. Immunogenicity against the 4 DENV serotypes was measured using a Virus Reduction Neutralization Test (VRNT60) after each vaccination and out to 1 year after the second dose. There were no discontinuations due to adverse events (AE) or serious vaccine-related AEs in the study. Most common AEs after TV003 or TV005 were headache, rash, fatigue, and myalgia. Tri- or tetravalent vaccine-viremia was detected in 63.9% and 25.6% of BFN TV003 and TV005 participants, respectively, post-dose 1 (PD1). Tri- or tetravalent dengue VRNT60 seropositivity was demonstrated in 92.6% of BFN TV003, 74.2% of BFN TV005, and 100% of BFE TV003 and TV005 participants PD1. Increases in VRNT60 GMTs were observed after the first vaccination with TV003 and TV005 in both flavivirus subgroups for all dengue serotypes, and minimal increases were measured PD2. GMTs in the TV003 and TV005 BFE and BFN groups remained above the respective baselines and placebo through 1-year PD2. These data support further development of V181 as a single-dose vaccine for the prevention of dengue disease.

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 y) 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 y and ≥65 y was conducted. Serum antibody to HBsAg (anti-HBs) was measured Predose 1 and 1 mo Postdose 3. RESULTS: For subjects ≥50 y, 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 y, 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 y, 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 y old achieved seroprotection. The sub-population ≥65 y had lower vaccination responses than the 50-64 y sub-population. For subjects ≥65 y, 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.

Using the power law model to predict the long-term persistence and duration of detectable hepatitis A antibody after receipt of hepatitis A vaccine (VAQTA™).

VAQTA™ (Hepatitis A Vaccine, inactivated [HAVi]; Merck & Co., Inc., Kenilworth, NJ, USA) is currently licensed for prevention of disease caused by hepatitis A virus in persons ≥12 months of age. This report summarizes statistical models developed to evaluate the long-term persistence and duration of detectable hepatitis A antibody (total antibody levels with no distinction on class) after receipt of HAVi in healthy children and adolescents (V251-023 and V251-035) and in healthy adults (V251-034). The statistical models presented, conducted separately for each of the three studies, are based on models that have been used in the literature to estimate the duration of antibody to protect against human papillomavirus (HPV) disease. In the absence of observed study data on hepatitis A antibody persistence for vaccine recipients over several decades, an extrapolation from a kinetic model of antibody decay was used to estimate the duration of detectable antibody. Extrapolation of observed antibody titers from postvaccination, Year 2.5-3.5, Year 5-6, and Year 10 in 165 children and adolescents who received HAVi at Day 0 and Week 24 in V251-023 suggests that detectable levels of antibody may persist after the second dose for many years. This model suggests that 25 to 50 years Postdose 1 in a two-dose series of HAVi, 99.4% of the study population will have detectable levels of hepatitis A antibody.

Sequential administration of Prevnar 13™ and PNEUMOVAX™ 23 in healthy participants 50 years of age and older.

In most countries worldwide, pneumococcal conjugate vaccines have been included in the infant immunization program, resulting in a significant reduction in the burden of pneumococcal disease in children and adults. Shifting serotype distribution due to the indirect effect of infant vaccination with the 13-valent pneumococcal conjugate vaccine (PCV13) may continue to increase the gap between 23-valent pneumococcal polysaccharide vaccine (PPSV23) and PCV13 serotype coverage for older adults in the coming years. This clinical study (V110-029; NCT02225587) evaluated the safety and immunogenicity of sequential administration of PCV13 followed approximately 8 weeks later, or approximately 26 weeks later, by PPSV23 in healthy adults ≥50 years of age. Both dosing intervals were generally well tolerated as measured by the nature, frequency, and intensity of reported adverse events (AEs) in both vaccination groups. Serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) measured 30 days following receipt of PPSV23 in either group and at Week 30 were generally comparable between the 2 groups for 6 serotypes unique to PPSV23 and 12 serotypes shared between PCV13 and PPSV23, regardless of the interval between receipt of PCV13 and PPSV23. In addition, administration of PPSV23 given either 8 weeks or 26 weeks following PCV13 did not negatively impact immune responses induced by PCV13. Furthermore, administration of PPSV23 given either 8 weeks or 26 weeks after PCV13 elicited serotype-specific OPA GMTs to serotypes unique to PPSV23, which could provide earlier protection against pneumococcal disease caused by these serotypes in comparison with the current Advisory Committee on Immunization Practices recommended interval of at least 12 months.

Concomitant use of VAQTA with PedvaxHIB and Infanrix in 12 to 17 month old children.

Open-label, multicenter, randomized study (NCT00289913) evaluated immunogenicity, safety, and tolerability of Vaqta (hepatitis A vaccine) administered with PedvaxHIB (Haemophilus b conjugate vaccine [Meningococcal protein conjugate]) & Infanrix (diphtheria/tetanus/acellular pertussis vaccine) in healthy, 15-month-old children. Five groups were evaluated: Group 1 received Vaqta/Infanrix PedvaxHIB on Day-1 and Vaqta at Week-24; Group 2 received Infanrix PedvaxHIB on Day-1, Vaqta at Week-4, and Vaqta at Week-28; Group 3 received Vaqta/PedvaxHIB on Day-1 and Vaqta Week-24; Group 4 received PedvaxHIB on Day-1, Vaqta at Week-4, and Vaqta at Week-28; and Group 5 (safety only) received Vaqta on Day-1 and Vaqta at Week-24. Hepatitis A seropositivity rate (SPR: ≥10 mIU/mL), Hib capsular polyribosylribitol phosphate (PRP) antibody response (>1.0 µg/mL), and geometric mean titers (GMT) to pertussis toxin (PT), pertussis filamentous hemagglutinin antibody (FHA), and pertactin were examined. Non-inferiority statistical criteria required a difference >10% in Hepatitis A SPR, PRP >1.0 µg/mL, and a GMT ratio of >0.67 for pertussis antigens. Injection-site and systemic adverse events (AEs) and daily temperatures were collected. Hepatitis A SPRs were 100% for Groups 1-4, regardless of initial serostatus. Anti-PRP titers were comparable (98.1% - 97.0%) for Groups 1-4. GMT and mean fold-rise were comparable for all 3 pertussis antigen components between concomitant and nonconcomitant groups. Criteria for non-inferiority of immune responses for concomitant vs nonconcomitant administration were met for Hepatitis A, Hib, and pertussis antigens. No statistically significant incidence differences of individual AEs were found between concomitant and nonconcomitant groups. No serious vaccine-related AEs or deaths were reported; no subject discontinued due to an AE. Immune responses to Vaqta, PedvaxHIB, and Infanrix given concomitantly were non-inferior to nonconcomitant responses. Vaqta administered with PedvaxHIB & Infanrix had an acceptable safety profile in 15-month-old children.

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.

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 µg 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-µg mpHBV, Recombivax-HB (5 µg), 10-µg mpHBV, or Engerix-B (10 µg) 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 µg mpHBV group, 100.0% (398/398, 95% CI: 99.9, 100) in the 10 µg 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 µg mpHBV group, 981.5 (95% CI: 891.0, 1081.2) in the 10 µg 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 µg mpHBV group, but did not meet the predefined criteria for superiority. All vaccines were well tolerated.

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.

A randomized, multicenter, open-label clinical trial to assess the anamnestic immune response 4 to 8 years after a primary hepatitis B vaccination series.

This open-label, randomized study challenged 4- to 8-year-old children from Spain (N = 1478) with a single dose of hepatitis B vaccine to estimate anamnestic responses. At the time of preimmunization, 15.9% to 51.2% of subjects had antibody values ≥10 mIU/mL. One month postimmunization, 91.6% to 97.3% of subjects had antibody titers ≥10 mIU/mL. There were no serious, vaccine-related, adverse experiences, and no discontinuations as a result of adverse experience.

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.