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.

M-M-R(®)II manufactured using recombinant human albumin (rHA) and M-M-R(®)II manufactured using human serum albumin (HSA) exhibit similar safety and immunogenicity profiles when administered as a 2-dose regimen to healthy children.

Prior to 2006, M-M-R(®)II (measles, mumps, and rubella virus vaccine live) was manufactured using human serum albumin (HSA) and each dose of the vaccine contained a relatively small amount (≤0.3mg) of HSA. Because of specific regulatory requirements and limited suppliers of HSA acceptable for human use, there was a need to replace HSA with recombinant human albumin (rHA) to mitigate any potential risk to the availability of M-M-R(®)II. Two different formulations of M-M-R(®)II manufactured using either rHA or HSA were clinically evaluated for safety and immunogenicity when administered as a 2-dose regimen to healthy children 12-18 months and 3-4 years of age. Adverse events, including those indicative of a possible hypersensitivity reaction, were collected for 42 days after each dose. Antibodies to measles, mumps, and rubella were measured before and approximately 6 weeks after dose 1. Antibodies to rHA were measured before and approximately 6 weeks after dose 1 and dose 2. Antibody seroconversion rates to measles, mumps, and rubella were 97.0%, 99.5%, and 99.7%, respectively, for recipients of M-M-R(®)II with rHA and 97.2%, 97.9%, and 99.6%, respectively, for recipients of M-M-R(®)II with HSA, and geometric mean titers to all 3 vaccine viral antigens were comparable between the 2 vaccination groups. The proportions of subjects who reported adverse events, including those suggestive of hypersensitivity reactions, after each dose of study vaccine were comparable between the 2 vaccination groups. No subject had detectable antibodies to rHA immediately prior to or following receipt of either the first or second dose of study vaccine. Given the comparable immunogenicity and safety profiles of both formulations, rHA is an acceptable replacement for HSA in the manufacture of M-M-R(®)II.

A dose-ranging study of MF59(®)-adjuvanted and non-adjuvanted A/H1N1 pandemic influenza vaccine in young to middle-aged and older adult populations to assess safety, immunogenicity, and antibody persistence one year after vaccination.

BACKGROUND: During development of an A/H1N1 pandemic influenza vaccine, this study was performed to identify the antigen and adjuvant content which would provide optimal antibody response and persistence in adults and the elderly. Dose-sparing strategies, such as inclusion of adjuvants, are critical in ensuring the widest possible population coverage in the event of an influenza pandemic, despite a limited global capacity for vaccine manufacture. METHODS: Healthy subjects aged 18-64 years (n = 1240) and ≥65 years (n = 1352) were vaccinated with 1 of 8 investigational vaccine formulations varying in antigen quantity (3.75 µg to 30 µg of hemagglutinin) and MF59(®) adjuvant (none, half dose, or full dose). All subjects received 2 vaccine doses administered 3 weeks apart. Antibody response was assessed by hemagglutination inhibition assay 1 and 3 weeks after administration of first and second doses. Antibody persistence was assessed after 6 and 12 mo. Vaccine safety was monitored over 12 mo. RESULTS: All 8 investigational A/H1N1 vaccine formulations were well tolerated, and rapidly induced high antibody titers which met all of the Center for Biologics Evaluation and Research (CBER) and Committee for Medicinal Products for Human Use (CHMP) licensure criteria 3 weeks after one dose. The highest antibody titers were observed in participants vaccinated with higher quantities of antigen and adjuvant. CONCLUSION: A single vaccine dose containing 3.75 µg of A/California/7/2009 (H1N1) antigen with MF59 adjuvant was identified as optimal for young to middle-aged (18-64 years) and older (≥65 years) adult populations.

Analysis of safety data in children after receiving two doses of ProQuad® (MMRV).

BACKGROUND: In randomized clinical studies, over 11,800 children, 12 months to 6 years of age, were administered ProQuad(®), a combination measles, mumps, rubella, and varicella vaccine (MMRV). This paper describes the safety following a 2-dose regimen of MMRV administered to children in the second year of life. METHODS: Safety data from five clinical studies were combined for all children who were scheduled to receive two doses of MMRV ∼3-6 months apart. All vaccinated children were followed for safety following each dose of MMRV. RESULTS: Of 3112 children who received a first dose of MMRV, 2780 (89.3%) received a second dose of MMRV. Overall, 70.5% and 57.7% of children reported ≥1 adverse experiences following first and second doses of MMRV, respectively. Injection-site redness was statistically significantly higher postdose 2 than postdose 1, while injection-site pain/tenderness was statistically significantly higher postdose 1 compared to postdose 2. Rashes were statistically significantly lower postdose 2 compared to postdose 1. Ten febrile seizures (8 postdose 1, 2 postdose 2) were reported following MMRV vaccination. The incidence of febrile seizures postdose 1 of MMRV was 0.26% (8/3019) compared to 0.07% (2/2695) postdose 2 of MMRV. CONCLUSIONS: Administration of two doses of MMRV has an acceptable safety profile in children 12 to 23 months of age. There is a small increase in the risk of febrile seizures following the first dose of MMRV as compared to the component vaccines, but the risk for any individual child is relatively low.

Long-term study of a quadrivalent human papillomavirus vaccine.

BACKGROUND: We present a long-term safety, immunogenicity, and effectiveness study of a quadrivalent human papillomavirus (HPV4) vaccine. METHODS: Sexually naive boys and girls aged 9 to 15 years (N = 1781) were assigned (2:1) to receive HPV4 vaccine or saline placebo at day 1 and months 2 and 6. At month 30, the placebo group (n = 482) received HPV4 vaccine following the same regimen and both cohorts were followed through month 96. Subjects ≥ 16 years were eligible for effectiveness evaluations. The primary objective was to evaluate the long-term anti-HPV6/11/16/18 serological levels. The secondary objective was to estimate vaccine effectiveness against HPV6/11/16/18-related persistent infection or disease. RESULTS: For each of the HPV4 vaccine types, vaccination-induced anti-HPV response persisted through month 96. Among 429 subjects who received HPV4 vaccine at a mean age of 12, none developed HPV6/11/16/18-related disease or persistent infection of ≥ 12 months' duration. Acquisition of new sexual partners (among those ≥ 16 years) was ∼1 per year. Subjects receiving HPV4 vaccine at month 30 (mean age 15 years) had a similar baseline rate of seropositivity to ≥ 1 of the 4 HPV types to those vaccinated at day 1 (mean age 12 years; 1.9% [9 of 474] vs 1.7% [20 of 1157]); however, 4 of the 9 subjects vaccinated at the later age were seropositive to 3 vaccine types, indicating previous HPV exposure. No new significant serious adverse events were observed for 8 years postvaccination in both genders. CONCLUSIONS: When administered to adolescents, the HPV4 vaccine demonstrated durability in clinically effective protection and sustained antibody titers over 8 years.

Antibody persistence after primary and booster doses of a quadrivalent meningococcal conjugate vaccine in adolescents.

BACKGROUND: The aim of this study was to evaluate antibody persistence 5 years after primary vaccination with the quadrivalent meningococcal conjugate vaccines MenACWY-CRM or MenACWY-D and 2 years after a booster dose of MenACWY-CRM, in the context of a phase 3 study. METHODS: Subjects (aged 19.2 ± 2.3 years) were assigned to 5 groups according to whether they had previously received primary vaccination (at 14.2 ± 2.2 years) with MenACWY-CRM (N = 131) or MenACWY-D (N = 76), a booster dose of MenACWY-CRM 3 years after primary vaccination with MenACWY-CRM (N = 44) or MenACWY-D (N = 31) or no vaccination (N = 107). The immunogenicity measures were percentages of subjects with serum bactericidal activity (hSBA) ≥ 1:8 for serogroups A, C, W and Y and hSBA geometric mean titers. Comparisons with age-matched, vaccine-naive subjects were performed. RESULTS: A majority of subjects vaccinated 5 years previously maintained hSBA ≥ 1:8 against serogroups C, W and Y in the MenACWY-CRM (59%-82%) and MenACWY-D groups (54%-73%); this was lower for serogroup A in both groups. There was a decline in antibody titers after primary vaccination, especially in the first 2 years postprimary vaccination, with steady concentrations during the next 3 years. Two years after MenACWY-CRM booster vaccination the percentages of subjects with hSBA ≥ 1:8 ranged from 77% to 100% across serogroups and geometric mean titers were 2.5- to 8-fold higher than prebooster values across serogroups. CONCLUSIONS: Booster vaccination with MenACWY-CRM elicited a robust immune response during the 2-year follow-up period, irrespective of previous vaccination.

Antibody persistence and booster response of a quadrivalent meningococcal conjugate vaccine in adolescents.

OBJECTIVE: To evaluate the tolerability and immunogenicity of a booster dose of the quadrivalent meningococcal conjugate vaccine MenACWY-CRM (Menveo, Novartis Vaccines and Diagnostics, Siena, Italy) administered 3 years after primary vaccination of adolescents enrolled in a phase 3 study with either MenACWY-CRM or MenACWY-D (Menactra, Sanofi Pasteur, Swiftwater, Pennsylvania). STUDY DESIGN: A total of 730 healthy adolescents participated, including 622 initial study participants who received primary vaccination with MenACWY-CRM (n = 367) or MenACWY-D (n = 255) 3 years previously and 108 age-matched vaccine-naïve controls. A subset of MenACWY-CRM (n = 83) and MenACWY-D (n = 77) recipients were administered a MenACWY-CRM booster dose 3 years postprimary vaccination. Immunogenicity prior to and after the booster dose of MenACWY-CRM was measured by serum bactericidal assay with human complement (hSBA). Local and systemic reactions and adverse events were monitored in subjects receiving the booster dose. RESULTS: At 3 years postprimary vaccination, 64%, 82%, and 65% of subjects initially vaccinated with MenACWY-CRM (n = 367) showed hSBA titers ≥8 against serogroups C, W-135, and Y, respectively; this was lower for serogroup A (28%). Significantly more MenACWY-CRM recipients had hSBA titers ≥8 for serogroups W-135 and Y than MenACWY-D recipients (n = 255). A MenACWY-CRM booster dose resulted in 99%-100% of subjects demonstrating hSBA titers ≥8 against all serogroups, irrespective of primary vaccination (MenACWY-CRM, n = 83; MenACWY-D, n = 77). The booster dose was well tolerated without significant adverse events. CONCLUSIONS: MenACWY-CRM can be used to boost adolescents who have received a primary vaccination with either MenACWY-CRM or MenACWY-D.

Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate: a phase III randomized controlled trial in children.

BACKGROUND: Mismatch between circulating influenza B viruses (Yamagata and Victoria lineages) and vaccine strains occurs frequently. METHODS: In a randomized controlled trial, immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate (QIV) versus trivalent inactivated influenza vaccine (TIV)-Victoria(Vic) and TIV-Yamagata(Yam) in children 3-17 years of age was evaluated. In an open-label study arm, QIV only was assessed in children 6-35 months of age. RESULTS: A total of 3094 children (932 QIV, 929 TIV-Vic, 932 TIV-Yam, and 301 QIV only) were vaccinated. QIV was noninferior to the TIVs for shared strains (A/H3N2 and A/H1N1) based on hemagglutination-inhibition (HI) antibodies 28 days after last vaccination, and superior for the unique B strains Victoria and Yamagata (geometric mean titer ratios 2.61, 3.78; seroconversion rate differences 33.96%, 44.63%). Among children in the randomized trial, adverse event rates were similar except for injection site pain (dose 1: 65.4% QIV, 54.6% TIV-Vic, 55.7% TIV-Yam). CONCLUSION: QIV elicited superior HI responses to the added B strains compared to TIV controls, potentially improving its effectiveness against influenza B. HI responses were similar between QIV and TIV controls for the shared strains. QIV had an acceptable safety profile relative to TIVs. CLINICAL TRIALS REGISTRATION: NCT01198756.

Immunogenicity and safety of an investigational hepatitis B vaccine with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40-70 years of age.

BACKGROUND: The currently licensed hepatitis B vaccines have limitations including hyporesponsiveness in older adults, poor compliance, and the extended time for most persons to develop seroprotection (e.g. >6months). A vaccine containing HBsAg combined with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) has been developed to overcome these limitations. METHODS: A Phase 3, multicenter, randomized, subject- and observer-blinded, active-controlled trial was conducted among healthy subjects 40-70years of age comparing the immunogenicity and safety of two doses of HBsAg-1018 at 0 and 4weeks to three doses of licensed hepatitis B vaccine, HBsAg-Eng, at 0, 4, and 24weeks. The primary immunogenicity endpoint was noninferiority of the seroprotection rate (SPR; % with anti-HBs≥10mIU/mL) of HBsAg-1018 compared to the SPR of HBsAg-Eng at 8 weeks following the last dose of vaccine. Conditional upon meeting noninferiority, superiority of HBsAg-1018 over HBsAg-Eng was assessed. Safety was compared between the two vaccines. RESULTS: At the primary endpoint, the SPR for the HBsAg-1018 group (90.0%) was superior to the SPR for the HBsAg-Eng group (70.5%) with an SPR difference of 19.5% (95% CI, 14.7%, 24.7%). At week 28 when the SPR peaked in the HBsAg-Eng group (72.8%), the SPR in the HBsAg-1018 group (94.8%) was significantly higher than in the HBsAg-Eng group. The SPR in the HBsAg-1018 group was significantly higher than in the HBsAg-Eng group at each study visit from week 4 through week 52. The safety profiles for the two vaccines were similar. CONCLUSION: When compared to the HBsAg-Eng three-dose regimen given at 0, 1, and 6months, HBsAg-1018 demonstrated superior seroprotection with only two doses at 0 and 1month. The safety profile of HBsAg-1018 was comparable to that of the licensed vaccine, HBsAg-Eng. HBsAg-1018 would provide a significant public health contribution toward the prevention of hepatitis B infection.

Safety and tolerability of a 6-week course of oseltamivir prophylaxis for seasonal influenza in children.

In an open-label study, 49 children aged 1-12 years received oseltamivir (30-75 mg once daily depending on bodyweight) for 6 weeks for influenza prophylaxis. Seventeen participants reported 22 adverse events (AEs); in three participants, AEs were considered probably drug related (nausea or vomiting). No serious AEs were reported. The tolerability profile was similar to pooled safety data from treatment studies (duration of 5 days) in children.

Antibody responses to routine pediatric vaccines administered with 13-valent pneumococcal conjugate vaccine.

BACKGROUND: A 13-valent pneumococcal conjugate vaccine (PCV13) has been licensed in >100 countries to broaden coverage against pneumococcal disease. We assessed whether PCV13 interferes with immune responses to concomitantly administered routine pediatric vaccines. METHODS: Healthy US infants were randomly assigned in 2 studies to receive PCV13 or 7-valent PCV (PCV7) at age 2, 4 and 6 months concomitantly with diphtheria, tetanus, acellular pertussis, inactivated polio virus, hepatitis B and Haemophilus influenzae type b, and at age 12-15 months with measles, mumps, rubella, varicella and hepatitus A. Antibodies to pertussis antigens, diphtheria, tetanus toxoid, poliovirus types 1-3, Haemophilus influenzae type b polyribosylribitol phosphate capsular polysaccharide and polyribosylribitol phosphate capsular polysaccharide were measured 1 month after the infant series; measles, mumps, rubella, varicella and polyribosylribitol phosphate capsular polysaccharide were determined 1 month after the toddler dose. Both the percentages of responders (subjects reaching a prespecified antibody concentration) and immunoglobulin G antibody geometric mean concentrations/titers were calculated for each concomitant vaccine antigen. RESULTS: Not all assays were performed on all subjects. Data were available from 153 to 239 infants and 163-230 toddlers in the PCV13 group and 173-240 infants and 167-214 toddlers in the PCV7 group. One month after both infant series and the toddler dose, noninferiority criteria were met for all antigens with respect to percentage of responders in both PCV7 and PCV13 groups. Immunoglobulin G antibody geometric mean concentration/titer ratios (PCV13/PCV7) were 0.91-1.33 and 0.83-1.03 at 1 month after the infant series and toddler dose, respectively, and met predetermined noninferiority criteria. CONCLUSIONS: Immune responses to routine pediatric vaccines concomitantly administered with PCV13 were noninferior to responses achieved when administered with PCV7.

Antibody persistence and response to a booster dose of a quadrivalent conjugate vaccine for meningococcal disease in adolescents.

BACKGROUND: In a previous randomized phase 2 study in adolescents, a CRM197 meningococcal conjugate vaccine against serogroups A, C, W-135 and Y (MenACWY-CRM) was well tolerated and immunogenic, compared with a plain polysaccharide vaccine (MenACWY-PS). METHODS: This extension study assessed antibody persistence 5 years after primary vaccination with MenACWY-CRM (n = 50) or MenACWY-PS (n = 51), and the immunogenicity and reactogenicity of a dose of MenACWY-CRM given 5 years after primary vaccination; antibody response was also compared with vaccine-naive controls (n = 54). The primary endpoints were the percentage of subjects with titers ≥8 by serum bactericidal activity assay using human complement (hSBA) 5 years after primary vaccination and hSBA geometric mean titers 1 month after the MenACWY-CRM dose given in the current study. RESULTS: Five years after primary vaccination, over 70% of subjects who had received MenACWY-CRM were seropositive (hSBA titers ≥8) for serogroups C, W-135 and Y; for serogroups C and Y, the percentages of seropositive subjects were significantly higher in subjects previously vaccinated with MenACWY-CRM than in subjects previously vaccinated with MenACWY-PS. The MenACWY-CRM dose given 5 years postprimary vaccination elicited an anamnestic response across serogroups in those previously vaccinated with MenACWY-CRM. Responses in those previously vaccinated with MenACWY-PS were less robust but adequate and similar to that seen in the vaccine-naive group, both in magnitude and kinetics. MenACWY-CRM was well tolerated in all 3 groups. CONCLUSION: MenACWY-CRM provided a broad and persistent immune response in adolescents. A subsequent dose of MenACWY-CRM elicited an adequate antibody response, regardless of vaccine history.

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 novel quadrivalent meningococcal CRM-conjugate vaccine given concomitantly with routine vaccinations in infants.

BACKGROUND: In phase II studies, MenACWY-CRM elicited robust immunologic responses in young infants. We now present results from our pivotal phase III infant immunogenicity/safety study. METHODS: In this open-label phase III study, we randomized full-term 2-month-old infants to 4 doses of MenACWY-CRM coadministered with routine vaccines at 2, 4, 6, and 12 months of age or with routine vaccines alone. We monitored for local and systemic reactions and serious adverse events among all study participants and evaluated for sufficiency of the immune responses to MenACWY-CRM through serum bactericidal activity assay with human complement. RESULTS: Bactericidal antibodies were present in 94% to 100% of subjects against each of the serogroups in MenACWY-CRM after the 4-dose series and were 67% to 97% after the first 3 doses. Geometric mean titers were higher after the fourth dose of MenACWY-CRM compared with a single dose of MenACWY-CRM at 12 months of age for all serogroups (range of ratios, 4.5-38). Responses to 3 doses of routine vaccines coadministered with MenACWY-CRM were noninferior to routine vaccinations alone, except for small differences in pneumococcal serotype 6B responses after dose 3 but not dose 4 and pertactin after dose 3. Inclusion of MenACWY-CRM did not affect the safety or reactogenicity profiles of the routine infant vaccine series. CONCLUSIONS: A 4-dose series of MenACWY-CRM was highly immunogenic and well tolerated in young infants, and it can be coadministered with routine infant vaccines. Substantial immunity was conferred after the first 3 doses administered at 2, 4, and 6 months of age.

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.

Lactose-free milk protein-based infant formula: impact on growth and gastrointestinal tolerance in infants.

Lactose, the major carbohydrate in human milk and standard milk-based formulas, provides energy for growth in infants. The use of lactose-free milk protein-based infant formulas has increased in the United States. However, clinical studies of their impact on growth, safety, and gastrointestinal tolerance in infants are limited. Thus, a prospective, blinded, randomized clinical trial was conducted in healthy, normal-term infants fed an experimental lactose-free milk protein-based formula (NoLAC; n = 63) versus a standard commercial lactose-containing milk-based formula (LAC; n = 65) for 112 days. Growth (weight, length, and head circumference) was similar and normal in both groups (weight gain: NoLAC = 31.1 ± 0.9 g/day, LAC = 29.4 ± 0.9 g/day, mean ± SEM; P = .895). Serum biochemistries for both groups were within infants' normal reference ranges. Both groups had comparable tolerance but the NoLAC group had softer stools and lower spit-ups. Thus, the study suggests that absence of lactose in milk-based formula does not adversely affect normal growth in term infants.

Comparison of the safety and immunogenicity of an investigational and a licensed quadrivalent meningococcal conjugate vaccine in children 2-10 years of age.

BACKGROUND: Routine administration of quadrivalent meningococcal conjugate vaccine to adolescents and certain high risk groups is recommended in the United States and Canada. We compared the immunogenicity and safety of an investigational quadrivalent meningococcal vaccine conjugated to CRM-197 (MenACWY-CRM) with a licensed quadrivalent vaccine conjugated to diphtheria toxoid (MCV4) in children aged 2-10 years. METHODS: Eligible 2-5-year-olds were randomized 1:2:2 to receive either 2 doses of MenACWY-CRM, or 1 dose of MenACWY-CRM or MCV4; 6-10-year-olds were randomized 1:1 to receive a single dose of MenACWY-CRM or MCV4. The primary immunogenicity assessment was seroresponse separately for the two age cohorts 28 days following a single dose of MenACWY-CRM or MCV4. Noninferiority and superiority criteria were predefined. Solicited injection-site and systemic reactions were collected for the 7 days postvaccination. RESULTS: A total of 2907 children were randomized to receive study vaccine. MenACWY-CRM met statistical superiority criteria vs. MCV4 for groups W and Y and was noninferior for group C in both age strata. For group A, noninferiority criteria were not met; the group A seroresponse rates for MenACWY-CRM and MCV4, respectively were 72% (95% confidence interval 68-75%) and 77% (73-80%) in 2-5-year-olds and 77% (73-80%) and 83% (79-86%) in 6-10-year-olds. When the two age strata were combined (2-10-year-old children), MenACWY-CRM was noninferior to MCV4 for all four groups, and statistically superior for groups C, W, and Y. Safety parameters were similar across age cohorts and vaccines groups. CONCLUSIONS: MenACWY-CRM and MCV4 were immunogenic and well tolerated in children aged 2-10 years. Seroresponse to MenACWY-CRM was statistically noninferior to MCV4 for all groups, and statistically superior for groups C, W, and Y. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00616421.

Safety, tolerability, and immunogenicity of gardasil given concomitantly with Menactra and Adacel.

OBJECTIVES: Multinational phase III trials of a human papillomavirus vaccine, Gardasil, have shown the vaccine to be generally well-tolerated, efficacious, and immunogenic. We evaluated the immunogenicity and safety of Gardasil administered concomitantly with Menactra and Adacel. METHODS: In this open-label study, boys (n = 394) and girls (n = 648) aged 10 to 17 were randomly assigned in a 1:1 ratio as follows: group A (concomitant administration) received a 0.5-mL dose of Gardasil at day 1, month 2, and month 6 and a 0.5-mL dose of Menactra and Adacel on day 1; group B (nonconcomitant administration) received Gardasil at day 1, month 2, and month 6 and Menactra and Adacel at month 1. Antibody levels for all vaccine components were measured. Systemic, injection-site, and serious adverse experiences (AEs) were monitored. RESULTS: Immune responses after concomitant administration of the 3 vaccines were noninferior to nonconcomitant administration. Seroconversion for Gardasil was > or = 99% in both groups A and B. For Menactra and Adacel, concomitant administration of the vaccines was demonstrated to be noninferior to nonconcomitant administration. Concomitant administration was generally well-tolerated. No participants withdrew because of an AE. One serious AE of transient muscular weakness of <24 hours' duration after the third Gardasil injection was reported in group B and was deemed possibly vaccine-related by the investigator. CONCLUSIONS: Overall, concomitant administration was generally well-tolerated and did not interfere with the immune response to the respective vaccines. Concomitant administration should minimize the number of visits required to deliver each vaccine individually, leading to increased compliance and more effective disease prevention.

A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD.

GARDASIL has been shown to reduce the incidence of pre-cancerous cervical, vulvar, and vaginal lesions, and external genital warts causally related to HPV6/11/16/18. Because of its expected public health benefit on reduction of cervical cancer and other HPV-related diseases, this vaccine has been rapidly implemented in the routine vaccination programs of several countries. It is therefore essential to assess its impact and safety through post-licensure surveillance programs. Here, we present a summary of 16 post-licensure safety and impact studies across 20 countries. These studies address general safety, including autoimmune disorders, long-term effectiveness, and type replacement. A summary of the surveillance efforts of the Unites States Centers for Disease Control and Prevention can be found in the accompanying article by Markowitz et al.

Impact of oseltamivir treatment on the incidence and course of acute otitis media in children with influenza.

OBJECTIVE: Acute otitis media (AOM) is the most common complication of pediatric influenza, and imposes a substantial health care burden. We examined the influence of oseltamivir treatment on the incidence and course of AOM in children with influenza. METHODS: In the original study, 695 children 1-12 years who presented within 48h of the onset of influenza-like symptoms were randomized to oseltamivir (2mg/kg) or placebo given twice daily for 5 days. AOM was assessed at enrollment and days 3, 6 (+/-1), 10 (+/-2) and 28 (+/-7). AOM was clinically diagnosed by the participating primary care provider, supported by tympanometry when possible. We performed a retrospective analysis of those participants with laboratory-confirmed influenza (LCI). Assessments included the incidence and clinical course of new AOM cases. RESULTS: In all, 452 children had LCI; 217 received oseltamivir and 235 placebo. AOM was diagnosed on or after study day 3 at a significantly lower frequency in the oseltamivir versus placebo group (12.4% versus 21.7%; relative risk [RR]: 0.57 [95% CI: 0.37, 0.88], respectively). Treatment effects were greatest for children 1-2 years (RR=0.42 [95% CI: 0.20, 0.89]) and 3-5 years (RR=0.45 [95% CI: 0.19, 1.04]), in whom the incidence of AOM was highest. CONCLUSIONS: Oseltamivir treatment significantly reduces the emergence of new AOM infections in children with LCI; effects are most pronounced in those <5 years. CLINICAL TRIAL NUMBER: WV15758.