Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. METHODS: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5-60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010-020150-34). FINDINGS: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4-74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI -5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, -1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5-26·6; p<0·0001). INTERPRETATION: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. FUNDING: Merck & Co., Inc.

Safety and Immunogenicity of Inactivated Varicella-Zoster Virus Vaccine in Adults With Autoimmune Disease: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: Immunogenicity and safety of inactivated zoster vaccine (ZVIN) were evaluated in adults with autoimmune disease. METHODS: Adults with autoimmune disease treated with immunosuppressive therapy (biologic or nonbiologic) were randomized to receive 4 doses of ZVIN, ZVIN containing a higher quantity of antigen, or placebo. To measure varicella-zoster virus (VZV)-specific immune responses using glycoprotein enzyme-linked immunosorbent assay (gpELISA) and interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT), blood samples were collected at baseline, post-doses 2, 3, and 4. The primary hypothesis was that ZVIN would elicit significant VZV-specific immune responses, measured by gpELISA or ELISPOT, at approximately 28 days post-dose 4. Safety and tolerability was assessed through 28 days post-dose 4. RESULTS: ZVIN elicited a statistically significant VZV-specific immune response approximately 28 days post-dose 4, measured by gpELISA (estimated geometric mean fold rise from baseline [GMFR] = 1.6 [95% confidence interval [CI], 1.4,1.7], P value < .0001) and IFN-γ ELISPOT (estimated GMFR = 2.0 [95% CI, 1.6,2.6], P value < .0001); both results met the prespecified success criterion. Overall, 57% (164/289) of all ZVIN and 21% (13/62) of placebo recipients reported ≥1 injection-site adverse events (AEs), and 52% (149/289) and 47% (29/62) reported ≥1 systemic AEs, respectively. Eight ZVIN and 1 placebo recipients experienced serious AEs, including 2 events (ZVIN group) determined by the investigator to be vaccine related (keratitis; amnesia). Overall frequency of AEs decreased with subsequent doses of vaccine. CONCLUSIONS: In adults with autoimmune disease, ZVIN was well tolerated and elicited statistically significant VZV-specific immune responses approximately 28 days post-dose 4, measured by gpELISA and IFN-γ ELISPOT. CLINICAL TRIALS REGISTRATION: NCT01527383.

Safety and immunogenicity of heat-treated zoster vaccine (ZVHT) in immunocompromised adults.

BACKGROUND: Safety and immunogenicity of heat-treated zoster vaccine (ZVHT) were assessed in immunocompromised adults. METHODS: In a randomized, double-blind, placebo-controlled, multicenter study, 4 doses ZVHT or placebo were administered approximately 30 days apart to adults with either solid tumor malignancy (STM); hematologic malignancy (HM); human immunodeficiency virus (HIV) with CD4(+) ≤200; autologous hematopoietic stem-cell transplant (HCT) or allogeneic-HCT recipients. Varicella-zoster virus (VZV) T-cell responses by interferon-γ enzyme-linked immunospot (IFN-γ ELISPOT) and VZV antibody concentrations by glycoprotein enzyme-linked immunosorbent assay (gpELISA) were measured at baseline and approximately 28 days after each dose. RESULTS: No safety signals were found in any group. IFN-γ ELISPOT geometric mean fold rises (GMFR) after dose 4 in STM, HM, HIV, and autologous-HCT patients were 3.00 (P < .0001), 2.23 (P = .004), 1.76 (P = .026), and 9.01 (P = NA), respectively. Similarly, antibody GMFR were 2.35 (P < .0001), 1.28 (P = .003), 1.37 (P = .017), and 0.90 (P = NA), respectively. T-cell and antibody responses were poor after 4 doses of ZVHT in allogeneic-HCT patients. CONCLUSION: ZVHT was generally safe and immunogenic through 28 days post-dose 4 in adults with STM, HM, and HIV. Autologous-HCT but not allogeneic-HCT patients had a rise in T-cell response; antibody responses were not increased in either HCT population. Study identification. V212-002 Clinical Trials Registration. NCT00535236.

Varicella-zoster virus-specific antibody responses in 50-59-year-old recipients of zoster vaccine.

Prevaccination and 6-week postvaccination samples from the immunogenicity substudy (n = 2269) of the zoster vaccine (ZV) efficacy trial (N = 22 439) in 50-59-year-old subjects were examined for varicella-zoster virus-specific antibody responses to vaccination. The varicella-zoster virus geometric mean titer (GMT) and geometric mean fold rise were higher in ZV recipients than in placebo recipients (GMT, 660.0 vs 293.1 glycoprotein enzyme-linked immunosorbent assay units/mL [P < .001], respectively; geometric mean fold rise, 2.31 vs 1.00 [P < .025]). In each group there was a strong inverse correlation between postvaccination GMT and risk of subsequent herpes zoster. Although these data provide strong evidence that relates ZV-induced antibody and the risk of herpes zoster, a protective threshold was not determined. Clinical Trials Registration. NCT00534248.

A phase 3, multicenter, randomized, double-blind, active-comparator-controlled study to evaluate the safety, tolerability, and immunogenicity of a 4-dose regimen of V114, a 15-valent pneumococcal conjugate vaccine, in healthy infants (PNEU-PED).

BACKGROUND: Pneumococcal disease (PD) remains a major health concern with considerable morbidity and mortality in children. Currently licensed pneumococcal conjugate vaccines (PCVs) confer protection against PD caused by most vaccine serotypes, but non-vaccine serotypes contribute to residual disease. V114 is a 15-valent PCV containing all 13 serotypes in Prevnar 13™ (PCV13) and additional serotypes 22F and 33F. This pivotal phase 3 study compared safety and immunogenicity of V114 and PCV13. METHODS: 1720 healthy infants were randomized 1:1 to receive a 4-dose regimen of V114 or PCV13 concomitantly with other routine pediatric vaccines. Safety was evaluated after each dose as proportion of participants with adverse events (AEs). Serotype-specific anti-pneumococcal immunoglobulin G (IgG) was measured at 1-month post-dose 3 (PD3), pre-dose 4, and 1-month post-dose 4 (PD4). IgG response rates, geometric mean concentrations (GMCs), and opsonophagocytic activity (OPA) were compared between vaccination groups. RESULTS: The proportion, maximum intensity, and duration of injection-site, systemic, and serious AEs were generally comparable between V114 and PCV13 groups. In comparison to PCV13, V114 met non-inferiority criteria for all 15 serotypes based on IgG response rates at PD3. V114 met non-inferiority criteria by IgG GMCs for all serotypes at PD3 and PD4, except for serotype 6A at PD3. V114-induced antibodies had bactericidal activity as assessed by OPA. Further, V114 met superiority criteria for shared serotype 3 and unique serotypes 22F and 33F compared to PCV13 by serotype-specific IgG GMCs at both PD3 and PD4. Immunogenicity of concomitantly administered routine pediatric vaccines was comparable in V114 and PCV13 groups. CONCLUSIONS: In healthy infants, V114 displays acceptable safety and tolerability profiles and generates comparable immune responses to PCV13. V114 also met superiority criteria for serotypes 3, 22F, and 33F. These results support use of V114 for prevention of PD as part of routine infant vaccination schedules. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03893448; EudraCT: 2018-004109-21.

Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years.

BACKGROUND: Herpes zoster (HZ) adversely affects individuals aged 50-59, but vaccine efficacy has not been assessed in this population. This study was designed to determine the efficacy, safety, and tolerability of zoster vaccine for preventing HZ in persons aged 50-59 years. METHODS: This was a randomized, double-blind, placebo-controlled study of 22 439 subjects aged 50-59 years conducted in North America and Europe. Subjects were given 1 dose of licensed zoster vaccine (ZV) (Zostavax; Merck) and followed for occurrence of HZ for ≥1 year (mean, 1.3 years) postvaccination until accrual of ≥96 confirmed HZ cases (as determined by testing lesions swabs for varicella zoster virus DNA by polymerase chain reaction). Subjects were followed for all adverse events (AEs) from day 1 to day 42 postvaccination and for serious AEs (SAEs) through day 182 postvaccination. RESULTS: The ZV reduced the incidence of HZ (30 cases in vaccine group, 1.99/1000 person-years vs 99 cases in placebo group, 6.57/1000 person-years). Vaccine efficacy for preventing HZ was 69.8% (95% confidence interval, 54.1-80.6). AEs were reported by 72.8% of subjects in the ZV group and 41.5% in the placebo group, with the difference primarily due to higher rates of injection-site AEs and headache. The proportion of subjects reporting SAEs occurring within 42 days postvaccination (ZV, 0.6%; placebo, 0.5%) and 182 days postvaccination (ZV, 2.1%; placebo, 1.9%) was similar between groups. CONCLUSIONS: In subjects aged 50-59 years, the ZV significantly reduced the incidence of HZ and was well tolerated. CLINICAL TRIALS REGISTRATION: NCT00534248.

Safety and tolerability of zoster vaccine in adults ≥60 years old.

OBJECTIVE: To evaluate the general safety of zoster vaccine (ZV) in adults ≥60 years old. PATIENTS/METHODS: Subjects were enrolled in a 1:1 ratio to receive 1 dose of ZV or placebo. Subjects were followed for serious adverse experiences (SAEs) for 42 days (primary follow-up period) and 182 days (secondary follow-up period) postvaccination. Relative-risks (ZV/placebo) for SAEs during both safety periods were calculated. STUDY PERIOD: 17-Sep­2007 to 09-Jan-2009. RESULTS: Overall, 5,983 subjects received ZV and 5,997 received placebo. Within the primary 42-day follow-up period, 84 ZV subjects and 67 placebo subjects reported SAEs. The estimated risk of SAEs within 42 days was 1.41% for ZV versus 1.12% for placebo, with a relative-risk of 1.26 (95% CI 0.91,1.73); indicating no statistically significant difference between groups, meeting the pre-specified success criterion. During the 182-day follow-up period, 340 ZV subjects and 300 placebo subjects reported SAEs. The estimated risk of SAEs within 182 days was 5.68% for ZV versus 5.01% for placebo, with a relative-risk of 1.13 (95% CI 0.98,1.32), indicating no statistically significant difference between groups. Two subjects in the ZV group reported SAEs deemed by the investigator to be vaccine-related (uveitis and sciatica; onset Day 5 and 4, respectively). One subject in the placebo group reported a SAE deemed by the investigator to be vaccine-related (lumbar radiculopathy; onset Day 51). There were 24 fatal SAEs in the ZV group and 17 in the placebo group (relative risk = 1.41; CI: 0.77, 2.60); 6 and 5, respectively, with SAE onset during the primary 42-day follow-up period. No deaths were deemed vaccine-related. CONCLUSIONS: ZV and placebo groups had similar safety profiles in terms of SAEs during the primary (Day 1 to 42) and secondary (Day 1 to 182) follow-up periods.

Protective immune responses against Haemophilus influenza type b elicited by a fully-liquid DTaP-IPV-Hib-HepB vaccine (VAXELIS™).

BACKGROUND: DTaP-IPV-Hib-HepB is a fully-liquid, hexavalent combination vaccine (Vaxelis™) approved for vaccination against diphtheria, tetanus, pertussis, poliomyelitis, hepatitis B, and invasive disease due to Haemophilus influenzae type b (Hib). Hib capsular polysaccharide, polyribosylribitol phosphate (PRP), is conjugated to Neisseria meningitidis outer membrane protein complex (OMPC). Safety and immunogenicity of DTaP-IPV-Hib-HepB were evaluated in 6 Phase III clinical studies including > 5,200 children. Studies included vaccination schedules in the United States (2, 4, 6 months of age) and Europe (2, 3, 4, 12 months of age and 2,4,11-12 months of age). METHODS: Data pertaining to anti-PRP responses of DTaP-IPV-Hib-Hep B compared to control vaccines from 5 Phase III studies are summarized. RESULTS: Post-infant series, the percentage of participants that achieved protective antibody thresholds for PRP (anti-PRP titer ≥ 0.15 µg/mL and ≥ 1.0 µg/mL, respectively) were higher in DTaP-IPV-Hib-HepB recipients compared to recipients who received control vaccines. A high level of protective responses (96.6% at ≥ 0.15 µg/mL [95% CI:94.8, 97.9%]; 72.9% at ≥ 1.0 µg/mL [95% CI:69.2,76.4%]) were seen post-dose 2 of the 2 + 1 vaccination schedule and met superiority criteria over comparator, p-value < 0.001. In the same schedule, prior to administration of the toddler dose (in the second year of life), anti-PRP titers were higher in DTaP-IPV-Hib-HepB recipients (91.4% at ≥ 0.15 µg/mL; 46.8% at ≥ 1.0 µg/mL) as compared to recipients who received control vaccines (63.4% at ≥ 0.15 µg/mL; 17.1% at ≥ 1.0 µg/mL). One-month post-toddler dose, high levels of anti-PRP titers were achieved in both DTaP-IPV-Hib-HepB recipients (99.8% at ≥ 0.15 µg/mL; 96.6% at ≥ 1.0 µg/mL) and recipients who received control vaccines (99.5% at ≥ 0.15 µg/mL; 94.9% at ≥ 1.0 µg/mL). CONCLUSIONS: These results support that DTaP-IPV-Hib-HepB induces a robust and sustained early Hib response. During the high-risk period for Hib disease after the infant vaccine and prior to the toddler dose; >90% of recipients maintained superior protective anti-PRP levels compared to control.

Safety and immunogenicity of a fully-liquid DTaP-IPV-Hib-HepB vaccine (Vaxelis™) in premature infants.

Background: Immune immaturity may put premature infants at increased risk for infections. DTaP-IPV-Hib-HepB vaccine (Vaxelis™), a hexavalent vaccine studied in >6,800 children, has acceptable safety and immunogenicity profiles generally similar to control vaccines. Here we evaluate safety and immunogenicity of DTaP-IPV-Hib-HepB vaccine in premature infants. Methods: Premature infants were identified using prior medical conditions terms "premature baby/delivery" and/or "low birth weight baby". Immunogenicity and safety data were summarized across one Phase II and four Phase III randomized, active-comparator-controlled clinical trials (Protocol 004 in Canada [Control: PENTACEL™]; Protocols 005 and 006 in the US [Control: PENTACEL™]; and Protocols 007 and 008 in the EU [Control: INFANRIX™ hexa]) and one Phase III clinical trial in the UK (PRI01C); no formal statistical comparisons were performed. Results: Overall, 160 infants were considered premature (DTaP-IPV-Hib-HepB = 111 Control = 49). The incidence of adverse events (AEs) for DTaP-IPV-Hib-HepB was comparable between overall and premature populations for all AEs days 1-15 postvaccination (Overall = 96.3%; Premature = 97.3%;), solicited injection-site AEs days 1-5 postvaccination (Overall = 84.1%; Premature = 75.5%), and solicited systemic AEs days 1-5 postvaccination (Overall = 93.7%; Premature = 94.5%). A high percentage of premature infants mounted protective immune responses to antigens contained in DTaP-IPV-Hib-HepB vaccine. Response rates in preterm infants for all antigens (80-99%) were in a similar range to all infants (80-99%) for both DTaP-IPV-Hib-HepB and control vaccines. Conclusions: DTaP-IPV-Hib-HepB vaccine has a low incidence of AEs, an acceptable safety profile, and elicited satisfactory immune responses in premature infants comparable to the overall study population. These findings support vaccination with DTaP-IPV-Hib-HepB vaccine in healthy premature infants.

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 administration of zoster and pneumococcal vaccines in adults ≥60 years old.

This study evaluated safety & immunogenicity of ZOSTAVAX® (zoster vaccine: ZV) administered concomitantly versus nonconcomitantly with PNEUMOVAX® 23 (pneumococcal vaccine: PPV23). This randomized, double-blind, placebo-controlled study enrolled 473 subjects ≥60 years old in 1:1 ratio to receive ZV & PPV23 concomitantly (Day 1) or nonconcomitantly (PPV23 Day 1, ZV Week 4). Blood samples obtained for pneumococcal polysaccharide (PnPs) antibody (Ab) testing by enzyme-linked immunosorbent assay (ELISA) and varicella-zoster virus (VZV) Ab testing by glycoprotein ELISA. Subjects followed for adverse experiences (AEs) for 28 days postvaccination. Mean baseline VZV geometric mean titers (GMT) in nonconcomitant group were lower than concomitant group. Four weeks postvaccination with ZV, VZV Ab response in concomitant group was not similar to nonconcomitant group; estimated VZV GMT ratio [concomitant/nonconcomitant] was 0.70 (95% CI, 0.61-0.80). VZV Ab response was acceptable in concomitant group; estimated geometric mean foldrise (GMFR) from baseline was 1.9 (95% CI, 1.7-2.1). PnPs serotype-specific Ab responses were similar in both groups. All 6 reported serious AEs were deemed not related to study vaccine. Postvaccination of ZV, incidence of injection-site AEs was similar in both groups; clinical AEs were numerically but not significantly higher in nonconcomitant group. In summary, VZV GMT Ab response induced by ZV administered concomitantly with PPV23 was inferior to that induced nonconcomitantly. These results indicate that, to avoid a potential decrease in ZV immunogenicity, ZV & PPV23 should not be given concomitantly. Concomitant administration did not affect response to PPV23 serotypes tested. When administered concomitantly, ZV & PPV23 vaccines were generally well tolerated.

Integrated Safety Profile of a New Approved, Fully Liquid DTaP5-HB-IPV-Hib Vaccine.

BACKGROUND: DTaP5-HB-IPV-Hib is a fully liquid, hexavalent vaccine containing a 5-antigen pertussis component, approved since 2016 in Europe [Vaxelis; DTaP5-HB-IPV-Hib vaccine: Diphtheria, tetanus, pertussis (5 acellular components: pertussis toxoid [PT], filamentous haemagglutinin [FHA], pertactin (PRN), and fimbriae Types 2 and 3 [FIM]), hepatitis B (recombinant DNA: rDNA), poliomyelitis (inactivated) and Haemophilus influenzae type b conjugate vaccine (adsorbed); MCM Vaccine B.V., The Netherlands] for primary and booster vaccination in infants and toddlers against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive diseases caused by Haemophilus influenzae type b. The comparator vaccine (control) was INFANRIX hexa (GlaxoSmithKline Biologics S.A., Rixensart, Belgium) (DTaP3-IPV-HepB/Hib) in European studies and PENTACEL (DTaP5-IPV/Hib) (Sanofi Pasteur, Swiftwater, PA) in US studies. METHODS: Data from 6 studies were integrated and analyzed to provide a comprehensive safety profile. Numbers and proportions of subjects with adverse events (AEs) were summarized by treatment group. Group differences in proportion of AEs were calculated. RESULTS: Among the DTaP5-HB-IPV-Hib (N = 5223) and 2295 control (N = 2295) groups, solicited injection-site and systemic AEs were very common. Serious AEs were reported by 3.9% of DTaP5-HB-IPV-Hib and 3.7% of control subjects. Vaccine-related serious AEs occurred infrequently, 0.2% for both groups. Most AEs were mild-to-moderate and did not lead to subject withdrawal. Group differences for solicited systemic AEs were small (<3%) and not statistically significant, except for pyrexia (estimated difference 9.4% [95% CI: 6.7%-12%]). The difference was driven by the 2 US studies where the PENTACEL control group had a lower fever rate. Among European studies, there was no significant difference in rates of pyrexia between DTaP5-HB-IPV-Hib and INFANRIX hexa. CONCLUSIONS: The safety of DTaP5-HB-IPV-Hib is consistent with the safety profile of its components and similar to comparator vaccines, including INFANRIX hexa. The vaccine provides a new, fully liquid and convenient hexavalent vaccination option for use with various vaccination schedules in Europe.

A double-blind, randomized, controlled, multi-center safety and immunogenicity study of a refrigerator-stable formulation of VARIVAX®.

OBJECTIVE: VARIVAX® (varicella virus vaccine, live Oka/Merck, Merck & Co., Inc., Kenilworth, NJ, USA) was originally licensed as a frozen formulation. A refrigerator-stable formulation of VARIVAX was subsequently developed to allow for increased availability of the product around the world. The objective of this study (V210-051) was to demonstrate that the safety, tolerability and immunogenicity profile of the refrigerator-stable formulation of VARIVAX was similar to the frozen formulation. METHODS: In this double-blind, randomized, multicenter study, healthy 12- to 23-month-old children with negative vaccination and clinical histories for measles, mumps, rubella, varicella, and zoster were vaccinated with either a refrigerator-stable formulation of VARIVAX (at two dosage levels; 8000 PFU [N = 320] or 25,000 PFU [N = 315]) or the frozen formulation of VARIVAX (10,000 PFU, N = 323) given concomitantly with M-M-RII® (measles, mumps, and rubella virus vaccine live, Merck & Co., Inc., Kenilworth, NJ, USA). Children were followed for 42 days after vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after vaccination. RESULTS: The refrigerator-stable formulation of VARIVAX was generally well tolerated. The incidence of adverse experiences was similar between all three groups. No vaccine-related serious adverse experiences were reported with any of the vaccine formulations. The immune response (percentage of subjects with varicella antibody titers ≥5 gpELISA units) for both refrigerator-stable formulations of VARIVAX at 6 weeks postvaccination was similar to that of the frozen formulation. Administration of either refrigerator-stable formulation of VARIVAX with M-M-RII yielded seroconversion rates and GMTs for measles, mumps and rubella that were comparable to those achieved after administration of the frozen formulation of VARIVAX with M-M-RII. CONCLUSION: The safety, tolerability, and immunogenicity profile of the refrigerator-stable varicella vaccine was similar to that of the frozen formulation.

Safety and immunogenicity of VAQTA® in children 12-to-23 months of age with and without administration of other US pediatric vaccines.

Safety and immunogenicity data from 5 clinical trials conducted in the US in children 12-to-23 months old where HAVi was administered alone or concomitantly with other pediatric vaccines (M-M-R®II, Varivax®, TRIPEDIA®, Prevnar®, ProQuad®, PedvaxHIB®, and INFANRIX®) were combined. Among 4,374 participants receiving ≥ 1 dose of HAVi, 4,222 (97%) had safety follow-up and the proportions reporting adverse events (AE) were comparable when administered alone (69.4%) or concomitantly with other pediatric vaccines (71.1%). The most common solicited injection-site AEs were pain/tenderness (Postdose 1: 25.8%; Postdose 2: 26.1%) and redness (Postdose 1: 13.6%; Postdose 2: 15.1%). The most common vaccine-related systemic AEs were fever (≥ 100.4ºF, 12.2%) and irritability (8.1%). Serious AEs (SAEs) were observed at a rate of 0.4%; 0.1% were considered vaccine-related. No deaths were reported within 14 days following a dose of HAVi. These integrated analyses also showed that protective antibody concentrations were elicited in 100% of toddlers after two doses and 92% after a single dose, regardless of whether HAVi was given concomitantly with other vaccines or alone. These results demonstrate that HAVi was well-tolerated whether given alone or concomitantly with other vaccines, with a low incidence of vaccine-related SAEs. HAVi was immunogenic in this age group regardless of whether administered with or without other pediatric vaccines and whether 1 or 2 doses were administered. HAVi did not impact the immune response to other vaccines. These data continue to support the routine use of HAVi with other pediatric vaccines in children ≥ 12 months of age.

Lack of a significant drug interaction between raltegravir and tenofovir.

Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with raltegravir monotherapy versus raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on raltegravir. The raltegravir area under the concentration time curve from 0 to 12 h (AUC(0-12)) and peak plasma drug concentration (C(max)) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on raltegravir concentration at 12 h postdose (C(12)) in healthy subjects (GMR [TDF plus raltegravir-raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C(24), AUC, and C(max) GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments.

Immunogenicity and safety of zoster vaccine live administered with quadrivalent influenza virus vaccine.

OBJECTIVES: Randomized, blinded, placebo-controlled trial to evaluate the safety and immunogenicity of ZOSTAVAX™ (ZV) administered concomitantly with quadrivalent inactivated influenza vaccine (IIV4) in adults≥50years of age (NCT02519855). METHODS: Overall, 440 participants were randomized into the Concomitant Group (CG) and 442 into the Sequential Group (SG). The CG received ZV and IIV4 at separate injection sites on Day 1 and matching placebo at Week 4. The SG received placebo and IIV4 (2015-2016 influenza season) at separate injection sites on Day 1 and ZV at Week 4. IMMUNOGENICITY ENDPOINTS: Varicella-zoster virus (VZV) antibody geometric mean titer (GMT) and geometric mean fold-rise (GMFR) from baseline to 4weeks postvaccination, measured by glycoprotein enzyme-linked immunosorbent assay (gpELISA) and adjusted for age and prevaccination titer. Influenza strain-specific GMT at baseline and 4weeks postvaccination was measured by hemagglutination inhibition (HAI) assay. SAFETY ENDPOINTS: Injection-site and systemic adverse experiences (AEs) within 28days following any vaccination and serious AEs throughout the study. RESULTS: The adjusted VZV antibody GMT ratio (CG/SG) was 0.87 (95%CI: 0.80, 0.95), meeting the prespecified noninferiority criterion. The VZV antibody GMFR in the CG was 1.9 (95%CI: 1.76, 2.05), meeting the acceptability criterion. Influenza antibody GMT ratios for A/H1N1, A/H3N2, B/Yamagata and B/Victoria were 1.02 (95%CI: 0.88, 1.18), 1.10 (95%CI: 0.94, 1.29), 1.00 (95%CI: 0.88, 1.14), and 0.99 (95%CI: 0.87, 1.13), respectively. The frequency of vaccine-related injection-site and systemic AEs was comparable between groups. No vaccine-related serious AE was observed. CONCLUSION: The concomitant administration of ZV and IIV4 to adults≥50years of age induced VZV-specific and influenza-specific antibody responses that were comparable to those following administration of either vaccine alone, and was generally well tolerated.

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naïve adults ≥50 years of age.

BACKGROUND: Pneumococcal disease remains a public health priority in adults. Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) containing 13 serotypes included in 13-valent pneumococcal conjugate vaccine (PCV13) plus 2 additional serotypes (22F and 33F) was evaluated in adults ≥50 years old (NCT01513551). METHODS: 691 adults received one dose of PCV15, PCV13, or 23-valent pneumococcal polysaccharide vaccine (PPV23) and were followed 14 days for safety. Serotype-specific IgG geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured immediately prior and 1-month postvaccination. RESULTS: Safety profiles were comparable across vaccination groups. PCV15 induced comparable levels of IgG GMCs and OPA GMTs to PCV13 and PPV23 for shared serotypes. Serotype-specific antibodies were numerically higher among recipients of PCV15 than PCV13 and PPV23 for 7 and 12 shared serotypes, respectively; and lower for 4 and 1 serotype(s), respectively. PCV15 induced higher IgG and OPA antibodies than PCV13 or PPV23 for serotypes unique to PCV15 (22F and 33F not in PCV13; 6A not in PPV23). CONCLUSIONS: PCV15 displayed an acceptable safety profile and induced IgG and OPA to all 15 serotypes included in the vaccine, at levels comparable to PCV13 and PPV23 for shared serotypes with these vaccines. Study identification: V114-002. CLINICALTRIALS.GOV identifier: NCT01513551. © 2018 Merck & Co., Inc.

Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV15) in healthy infants.

BACKGROUND: Pediatric use of pneumococcal conjugate vaccines (PCV) has been associated with significant decrease in disease burden. However, disease caused by non-vaccine serotypes has increased. Safety and immunogenicity of 15-valent PCV (PCV15) containing serotypes included in 13-valent PCV (PCV13) plus serotypes 22F and 33F were evaluated in infants (NCT01215188). METHODS: Infants received adjuvanted PCV15, nonadjuvanted PCV15, or PCV13 at 2, 4, 6, and 12-15 months of age. Safety was monitored for 14 days after each dose. Serotype-specific IgG geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) were measured at postdose-3, predose-4, and postdose-4. RESULTS: Safety profiles were comparable across vaccination groups. At postdose-3, both PCV15 formulations were non-inferior to PCV13 for 10 of 13 shared serotypes but failed non-inferiority for 3 serotypes (6A, 6B, and 19A) based on proportion of subjects achieving IgG GMC ≥0.35 µg/mL. Adjuvanted PCV15 and nonadjuvanted PCV15 were non-inferior to PCV13 for 11 and 8 shared serotypes, respectively, based on postdose 3 comparisons of GMC ratios. PCV15 induced higher antibodies to serotypes 3, 22F, and 33F than PCV13. CONCLUSIONS: PCV15 displayed acceptable safety profile and induced IgG and OPA to all 15 vaccine serotypes at levels comparable to PCV13 for 10 of 13 shared serotypes. Study identification: V114-003. CLINICALTRIALS.GOV identifier: NCT01215188.

Concomitant use of an oral live pentavalent human-bovine reassortant rotavirus vaccine with licensed parenteral pediatric vaccines in the United States.

BACKGROUND: A live pentavalent rotavirus vaccine (PRV) containing 5 human-bovine (WC3) reassortants expressing human serotypes G1, G2, G3, G4 and P1A[8] was evaluated in a blinded, placebo-controlled study. Possible interactions between PRV and concomitantly administered licensed pediatric vaccines were investigated in a United States-based nested substudy (Concomitant Use Study) of the Rotavirus Efficacy and Safety Trial. METHODS: From 2002 to 2003, healthy infants approximately 6 to 12 weeks of age at entry were randomized to receive either 3 oral doses of PRV or placebo at 4- to 10-week intervals. Subjects were also to receive combined Haemophilus influenzae type b and hepatitis B vaccine (2 doses), diphtheria and tetanus toxoids and acellular pertussis vaccine (3 doses), inactivated poliovirus vaccine (2 doses) and pneumococcal conjugate vaccine (3 doses) on the same day; oral poliovirus vaccine was not administered. Immunogenicity was assessed by measuring antibody responses to PRV and antigens contained in the licensed vaccines. Cases of rotavirus gastroenteritis were defined by forceful vomiting and/or -3 watery or looser-than-normal stools within a 24-hour period, and detection of rotavirus antigen in the stool. Safety was assessed by reporting of adverse events using diary cards. RESULTS: The Concomitant Use Study enrolled 662 subjects in the PRV group and 696 subjects in the placebo group. For the 17 antigens in the concomitantly administered vaccines, antibody responses were similar in PRV and placebo recipients, except for moderately diminished antibody responses to the pertactin component of pertussis vaccine. Efficacy of PRV against rotavirus gastroenteritis of any severity was 89.5% (95% CI = 26.5-99.8%). PRV was generally well tolerated when given concomitantly with the prespecified vaccines. CONCLUSIONS: In this study, antibody responses to the concomitantly administered vaccines were generally similar in PRV and placebo recipients. PRV was efficacious and well tolerated when given concomitantly with pediatric vaccines licensed in the United States.