Andrew W. Lee

Vaniprevir With Pegylated Interferon Alpha-2a and Ribavirin in Treatment-Naive Patients With Chronic Hepatitis C: A Randomized Phase II Study

Vaniprevir (MK‐7009) is a macrocyclic hepatitis C virus (HCV) nonstructural protein 3/4A protease inhibitor. The aim of the present phase II study was to examine virologic response rates with vaniprevir in combination with pegylated interferon alpha‐2a (Peg‐IFN‐α‐2a) plus ribavirin (RBV). In this double‐blind, placebo‐controlled, dose‐ranging study, treatment‐naïve patients with HCV genotype 1 infection (n = 94) were randomized to receive open‐label Peg‐IFN‐α‐2a (180 μg/week) and RBV (1,000‐1,200 mg/day) in combination with blinded placebo or vaniprevir (300 mg twice‐daily [BID], 600 mg BID, 600 mg once‐daily [QD], or 800 mg QD) for 28 days, then open‐label Peg‐IFN‐α‐2a and RBV for an additional 44 weeks. The primary efficacy endpoint was rapid viral response (RVR), defined as undetectable plasma HCV RNA at week 4. Across all doses, vaniprevir was associated with a rapid two‐phase decline in viral load, with HCV RNA levels approximately 3log10 IU/mL lower in vaniprevir‐treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%‐83.3% versus 5.6%; P < 0.001 for all comparisons). There were numerically higher, but not statistically significant, early and sustained virologic response rates with vaniprevir, as compared to placebo. Resistance profile was predictable, with variants at R155 and D168 detected in a small number of patients. No relationship between interleukin‐28B genotype and treatment outcomes was demonstrated in this study. The incidence of adverse events was generally comparable between vaniprevir and placebo recipients; however, vomiting appeared to be more common at higher vaniprevir doses. Conclusion: Vaniprevir is a potent HCV protease inhibitor with a predictable resistance profile and favorable safety profile that is suitable for QD or BID administration. (HEPATOLOGY 2012;56:884–893)

Long-term Durability of Immune Responses After Hepatitis A Vaccination Among HIV-Infected Adults

BACKGROUND Vaccination provides long-term immunity to hepatitis A virus (HAV) among the general population, but there are no such data regarding vaccine durability among human immunodeficiency virus (HIV)-infected adults. METHODS We retrospectively studied HIV-infected adults who had received 2 doses of HAV vaccine. We analyzed blood specimens taken at 1 year, 3 years, and, when available, 6-10 years postvaccination. HAV immunoglobulin G (IgG) values of ≥10 mIU/mL were considered seropositive. RESULTS We evaluated specimens from 130 HIV-infected adults with a median age of 35 years and a median CD4 cell count of 461 cells/mm(3) at or before time of vaccination. Of these, 49% had an HIV RNA load <1000 copies/mL. Initial vaccine responses were achieved in 89% of HIV-infected adults (95% confidence interval [CI], 83%-94%), compared with 100% (95% CI, 99%-100%) of historical HIV-uninfected adults. Among initial HIV-infected responders with available specimens, 90% (104 of 116; 95% CI, 83%-95%) remained seropositive at 3 years and 85% (63 of 74; 95% CI, 75%-92%) at 6-10 years. Geometric mean concentrations (GMCs) among HIV-infected adults were 154, 111, and 64 mIU/mL at 1, 3, and 6-10 years, respectively, compared with 1734, 687, and 684 mIU/mL among HIV-uninfected persons. Higher GMCs over time among HIV-infected adults were associated with lower log(10) HIV RNA levels (β = -.12, P = .04). CONCLUSIONS Most adults with well-controlled HIV infections had durable seropositive responses up to 6-10 years after HAV vaccination. Suppressed HIV RNA levels are associated with durable HAV responses.

Immunogenicity, Safety, and Tolerability of a Hexavalent Vaccine in Infants

BACKGROUND: DTaP5-IPV-Hib-HepB is a fully liquid investigational hexavalent vaccine directed against 6 diseases. METHODS: This multicenter, open-label, comparator-controlled, phase III study randomly assigned healthy infants 2-to-1 as follows: group 1 received DTaP5-IPV-Hib-HepB, PCV13, and RV5 at 2, 4, and 6 months of age followed by DTaP5, Hib-OMP, and PCV13 at 15 months of age; group 2 received DTaP5-IPV/Hib, PCV13, and RV5 at 2, 4, and 6 months of age, with HepB at 2 and 6 months of age, followed by DTaP5, Hib-TT, and PCV13 at 15 months of age. RESULTS: Overall, 981 participants were vaccinated in group 1 and 484 in group 2. Immune responses in group 1 to all antigens contained in DTaP5-IPV-Hib-HepB 1 month after dose 3 and for concomitant rotavirus vaccine were noninferior to those in group 2, with the exception of antipertussis filamentous hemagglutinin (FHA) geometric mean concentrations (GMCs). Vaccine response rates for FHA were noninferior to control. After the toddler dose, group 1 immune responses were noninferior to group 2 for all pertussis antigens. Solicited adverse event rates after any dose were similar in both groups, with the exceptions of increased injection-site erythema, increased fever, and decreased appetite in group 1. Fever was not associated with hospitalization or seizures. CONCLUSIONS: The safety and immunogenicity of DTaP5-IPV-Hib-HepB are comparable with the analogous licensed component vaccines. Decreased FHA GMCs and increased injection-site reactions and fever are unlikely to be clinically significant. DTaP5-IPV-Hib-HepB provides a new combination vaccine option aligned with the recommended US infant immunization schedule.

1056 MK-7009 SIGNIFICANTLY IMPROVES RAPID VIRAL RESPONSE (RVR) IN COMBINATION WITH PEGYLATED INTERFERON ALFA-2A AND RIBAVIRIN IN PATIENTS WITH CHRONIC HEPATITIS C (CHC) GENOTYPE 1 INFECTION

MK-7009 Significantly Improves Rapid Viral Response (RVR) in Combination with Pegylated Interferon Alfa-2a and Ribavirin in Patients with Chronic Hepatitis C (CHC) Genotype 1 Infection Michael P. Manns,1 Edward Gane,2 Maribel Rodriguez-Torres,3 Albrecht Stoehr,4 Chau-Ting Yeh,5 Richard T. Wiedmann,6 Peggy M. Hwang,7 Erin Quirk,6 Jeffrey Silber,6 and Andrew W. Lee6* 1Medical School of Hannover, Hannover, Germany, 2Auckland Clinical Studies, Auckland, New Zealand, 3Fundacion de Investigacion de Diego, San Juan, and Ponce School of Medicine, Ponce, Puerto Rico, 4ifi-institute for interdisciplinary medicine, Hamburg, Germany, 5Liver Research Unit, Chang Gung Medical Center, Taipei, Taiwan, 6ID/Vaccines Clinical Research, Merck Research Laboratories, West Point, PA, USA, 7Biostatistics, Merck Research Laboratories, West Point, PA, USA *for the MK-7009 Protocol 007 Study Group

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.

A Phase III randomized, double-blind, clinical trial of an investigational hexavalent vaccine given at 2, 4, and 11-12 months.

BACKGROUND Combination vaccines simplify vaccination visits and improve coverage and timeliness. DTaP5-HB-IPV-Hib is a new investigational, fully-liquid, combination vaccine designed to protect against 6 infectious diseases, including 5 pertussis antigens and OMPC instead of PT as conjugated protein for Hib component. METHODS In this multicenter, double-blind, comparator-controlled, Phase III study (NCT01480258) conducted in Sweden, Italy, and Finland, healthy infants were randomized 1:1 to receive one two immunization regimens. The DTaP5-HB-IPV-Hib Group received the investigational hexavalent vaccine (DTaP5-HB-IPV-Hib) and the Control Group received Infanrix-hexa (DTPa3-HBV-IPV/Hib) at 2, 4 and 11-12months of age. Both groups received concomitantly Prevnar 13 (PCV13) and Rotateq (RV5) or Rotarix (RV1) at 2, 4months of age and PCV13 at 11-12months. Subjects administered RV5 received a 3rd dose at 5months of age. RESULTS A total of 656 subjects were randomized to the DTaP5-HB-IPV-Hib Group and 659 subjects to Control Group. Immune responses to all vaccine antigens post-toddler dose were non-inferior in the DTaP5-HB-IPV-Hib Group as compared to the Control Group. Additionally, the post-dose 2 and pre-toddler DTaP5-HB-IPV-Hib anti-PRP responses were superior. The DTaP5-HB-IPV-Hib Group responses to concomitant RV1 were non-inferior compared to the Control Group. Solicited adverse event rates after any dose were similar in both groups, except for higher rates of pyrexia (6.4% difference; 95% CI: 1.5,11.3) and somnolence (5.8% difference; 95% CI: 1.7,9.8) in the DTaP5-HB-IPV-Hib Group. Vaccine-related serious adverse events occurred infrequently in the DTaP5-HB-IPV-Hib Group (0.3%) and the Control Group (0.5%). CONCLUSIONS The safety and immunogenicity of DTaP5-HB-IPV-Hib is generally comparable to Control when administered in the 2, 4, 11-12month schedule. Early Hib responses were superior versus Control. DTaP5-HB-IPV-Hib could provide a new hexavalent option for pediatric combination vaccines, aligned with recommended immunizations in Europe. STUDY IDENTIFICATION V419-008 CLINICALTRIALS.GOV identifier: NCT01480258.

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).

Concomitant administration of hepatitis A vaccine with measles/mumps/rubella/varicella and pneumococcal vaccines in healthy 12- to 23-month-old children

This open-label, multicenter, randomized, comparative study evaluated immunogenicity, safety and tolerability of concomitant (Group 1; n = 330) vs. non-concomitant (Group 2; n = 323) VAQTA™ (25U/0.5 mL) (hepatitis A vaccine; HAV) with ProQuad™ (measles/mumps/rubella/varicella; MMRV) and Prevnar™ (7-valent pneumococcal; PCV-7) in healthy, 12–23 mo old children. Group 1 received HAV/MMRV/PCV-7 concomitantly on Day 1 and second doses of HAV/MMRV at Week 24. Group 2 received MMRV/PCV-7 on Day 1, HAV at Weeks 6 and 30 and MMRV at Week 34. Hepatitis A seropositivity rate (SPR: ≥10 mIU/mL; 4 weeks postdose 2), varicella zoster-virus (VZV) SPR (≥5 gpELISA units/mL) and geometric mean titers (GMT) to S. pneumoniae were examined. Injection-site and systemic adverse experiences (AEs) and daily temperatures were collected. Hepatitis A SPR were 100% for Group 1 and 99.4% for Group 2 after two HAV doses; risk difference = 0.7 (95%CI: −1.4,3.8, non-inferior) regardless of initial serostatus. VZV SPR was 93.3% for Group 1 and 98.3% for Group 2; risk difference = −5.1 (95%CI: −9.3,−1.4; non-inferior). S. pneumoniae GMT fold-difference (7 serotypes) ranged from 0.9 to 1.1; non-inferior. No statistically significant differences in the incidence of individual AEs were seen when HAV was administered concomitantly vs. non-concomitantly. Three (all Group 2 post-administration of MMRV/PCV-7) of 11 serious AEs were considered possibly vaccine-related: dehydration and gastroenteritis (same subject) on Day 52; febrile seizure on Day 9. No deaths were reported. Antibody responses to each vaccine given concomitantly were non-inferior to HAV given non-concomitantly with MMRV and PCV-7. Administration of HAV with PCV-7 and MMRV had an acceptable safety profile in 12- to 23-mo-old children.

A Phase Iii Randomized, Double-blind, Clinical Trial of an Investigational Hexavalent Vaccine Given at Two, Three, Four and Twelve Months

Background: Combination vaccines simplify vaccination visits and improve coverage and timeliness. Diphtheria–tetanus toxoids–acellular pertussis 5, hepatitis B, inactivated poliovirus vaccine and Haemophilus influenzae type b (DTaP5–HB–IPV–Hib) is a new investigational, fully liquid, combination vaccine containing a 5-antigen pertussis component and is designed to protect against 6 infectious diseases. Methods: In this multicenter, double-blind, comparator-controlled, phase III study (NCT01341639) conducted in Finland, Germany and Belgium, healthy infants were randomized 1:1 to receive 1 of 2 immunization regimens. The DTaP5–HB–IPV–Hib group received the investigational hexavalent vaccine (DTaP–HB–IPV–Hib) and the Control group received Infanrix-hexa (DTPa3–HBV–IPV/Hib) at 2, 3, 4 and 12 months of age. Both groups received concomitantly Prevnar 13 (PCV13) and Rotateq (RV5) at 2, 3 and 4 months of age and ProqQad (MMRV) at 12 months of age. MMRV was also administered to all study subjects at 13 months of age. Results: A total of 628 subjects in the DTaP5–HB–IPV–Hib group and 622 subjects in the Control group were randomized. In a per-protocol analysis, immune responses to vaccine antigens 1 month after dose 3 and after the toddler dose were noninferior in the DTaP5–HB–IPV–Hib group as compared with the Control group. The DTaP5–HB–IPV–Hib group responses to MMRV given concomitantly at 12 months were all noninferior compared with the Control group. Solicited adverse event rates after any dose, including fever, were similar in both groups. Most adverse events were mild-to-moderate and did not lead to subject withdrawal. Vaccine-related serious adverse events occurred infrequently in the DTaP5–HB–IPV–Hib group (0.3%) and the Control group (0.2%). Conclusions: The safety and immunogenicity of DTaP5–HB–IPV–Hib is comparable to Control when administered in the 2-month, 3-month, 4-month and 12-month schedule. DTaP5–HB–IPV–Hib has the potential to provide a new hexavalent option for pediatric combination vaccines, aligned with recommended immunizations in Europe.

Lot-to-lot Consistency, Safety, Tolerability and Immunogenicity of an Investigational Hexavalent Vaccine in Us Infants

Background: This multicenter phase III study (NCT01340937) evaluated the consistency of immune responses to 3 separate lots of diphtheria–tetanus toxoids–acellular pertussis 5, inactivated poliovirus vaccine, Haemophilus influenzae type b, and hepatitis B (DTaP5-IPV-Hib-HepB), an investigational hexavalent vaccine (HV). Methods: Healthy infants were randomized (2:2:2:1) to receive HV or Pentacel (Control). Groups 1, 2 and 3 received HV at 2, 4 and 6 months, and Control at 15 months. Group 4 received Control at 2, 4, 6 and 15 months, plus Recombivax HB (HepB) at 2 and 6 months. Concomitant Prevnar 13 was given to all groups at 2, 4, 6 and 15 months; pentavalent rotavirus vaccine (RV5) was given to all groups at 2, 4 and 6 months. Blood specimens (3–5 mL) were collected immediately before administration of dose 1, postdose 3, immediately before toddler dose, and after toddler dose. Adverse events were recorded after each vaccination. Results: The 3 manufacturing lots of HV induced consistent antibody responses to all antigens. Immunogenicity of HV was noninferior to Control for all antibodies, except for pertussis filamentous hemagglutinin geometric mean concentration postdose 3, and pertussis pertactin (PRN) geometric mean concentration after toddler dose. Postdose 3 immunogenicity of concomitantly administered Prevnar 13 was generally similar (except for serotype 6B) when given with HV or Control. Adverse events of HV were similar to Control, except for a higher rate of fever ≥38.0°C [49.2% vs. 35.4%, estimated difference 13.7% (8.4, 18.8)]. Conclusions: HV demonstrated lot-to-lot manufacturing consistency; safety and immunogenicity were comparable with the licensed vaccines. HV provides a new combination vaccine option within the US 2-month, 4-month and 6-month vaccine series.