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.

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.

Phase III comparison of an investigational quadrivalent meningococcal conjugate vaccine with the licensed meningococcal ACWY conjugate vaccine in adolescents.

BACKGROUND: Neisseria meningitidis is an important cause of invasive bacterial infection in the United States, and disease rates are higher for adolescents than for the general population. Quadrivalent meningococcal conjugate vaccine is recommended for routine vaccination of adolescents and high-risk groups. This study compares the safety and immunogenicity of the Novartis Vaccines investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM, with the licensed meningococcal conjugate vaccine, Menactra. METHODS: In this multicenter phase III study, 2180 adolescents 11-18 years of age were randomly assigned to 4 groups (1:1:1:1) to receive a single dose of 1 of 3 lots of MenACWY-CRM or a single dose of Menactra. Serum samples obtained before vaccination and 1 month after vaccination were tested for serogroup-specific serum bactericidal activity using human complement (hSBA). The hSBA titers after vaccination with MenACWY-CRM or Menactra were compared in noninferiority and superiority analyses. RESULTS: The hSBA geometric mean titers after MenACWY-CRM vaccination were higher than the hSBA geometric mean titers after Menactra vaccination, and criteria for superiority were met for this end point for all 4 serogroups. Also, the criteria for superiority of MenACWY-CRM, compared with Menactra, were met for the end points of proportion of subjects with postvaccination hSBA titers 1:8 and proportion of seroresponders for serogroups A, W-135, and Y. MenACWY-CRM was noninferior to Menactra for serogroup C for these end points. Reactogenicity was similar, with 64% of the MenACWY-CRM recipients and 70% of the Menactra recipients reporting mild and/or moderate solicited reactions. Neither vaccine was associated with a serious adverse event. CONCLUSIONS: MenACWY-CRM vaccine is well tolerated in adolescents and generates a stronger immune response than Menactra for all 4 serogroups. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00450437 .

A randomized trial to determine the tolerability and immunogenicity of a quadrivalent meningococcal glycoconjugate vaccine in healthy adolescents.

BACKGROUND: Because of the well-documented increased risk of meningococcal disease among adolescents, vaccination is recommended for this population in many countries, including the United States. This study compared the tolerability and immunogenicity in adolescents of a candidate quadrivalent meningococcal CRM197 glycoconjugate vaccine against serogroups A, C, W-135, and Y (MenACWY-CRM) with that of the licensed unconjugated quadrivalent polysaccharide vaccine (MPSV4). METHODS: This phase II study was conducted in the United States among 524 adolescents aged 11-17 years in 2 stages, with different randomization schemes. The first 334 participants, enrolled in Stage 1, were randomized (1:1) to receive either MenACWY-CRM(+) (with adjuvant) or MPSV4. The next 190 participants, enrolled in Stage 2, were randomized (4:1) to receive either MenACWY-CRM(-) (without adjuvant) or MPSV4. Safety data were collected using diary cards and active surveillance. Human complement serum bactericidal activity (hSBA) titers were measured 1 and 12 months postvaccination. RESULTS: MenACWY-CRM and MPSV4 vaccines were well tolerated (local reactions, 63%-71% vs. 60%-62%; systemic reactions, 44%-56% vs. 46%-59%, respectively). One month postvaccination, similar hSBA titers were observed with the adjuvanted and nonadjuvanted MenACWY-CRM. The immunogenicity of MenACWY-CRM(-), measured by geometric mean titer, was significantly (P < 0.05) greater than that of MPSV4 for all 4 vaccine serogroups at 1 month. The percentage of subjects with hSBA titers > or =1:4 was also significantly greater (P < 0.01) for MenACWY-CRM(-) recipients for serogroups A, C, and Y and noninferior for W-135. The proportions of MenACWY-CRM(-) recipients with hSBA titers > or =1:4 to the vaccine serogroups at 1 month were 84% to 96% and geometric mean titers were 34 to 100. The percentage of subjects with hSBA titers > or =1:4 was significantly (P < 0.01) greater than MPSV4 for serogroups C, W-135, and Y 12 months postvaccination. CONCLUSIONS: MenACWY-CRM was well tolerated and immunogenic, with evidence of persistence of bactericidal antibodies for at least 12 months postvaccination.

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.

Characteristics of an ideal rotavirus vaccine.

Rotavirus gastroenteritis primarily affects children younger than 5 years of age and is the leading cause of diarrhea-related hospitalizations worldwide. The substantial morbidity associated with this disease and the major burden on healthcare resources underscore the need for an effective vaccine. Two recently developed vaccines (RotaTeq [rotavirus vaccine, live, oral, pentavalent], and Rotarix [rotavirus vaccine, live]) share some characteristics of an ideal rotavirus vaccine. High efficacy, excellent tolerability, and no increased risk of intussusception were shown in separate clinical trials of more than 60,000 infants for each trial, as well as in smaller phase 3 clinical trials of each vaccine. Vaccination against rotavirus will substantially reduce rotavirus gastroenteritis-associated morbidity and mortality and, in so doing, bring about a significant reduction in rotavirus gastroenteritis-associated healthcare utilization.

Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial.

OBJECTIVE: Administration of a quadrivalent HPV-6/ 1/16/18 vaccine to 16- to 26-year-old women was highly effective in preventing HPV-6/ 1/16/18-related cervical/vulvar/vaginal precancerous lesions and genital warts. As the risk of acquiring HPV significantly rises after sexual debut, HPV vaccines should have the greatest benefit in sexually naive adolescents. We evaluated the tolerability and immunogenicity of quadrivalent vaccine in males and females 9 to 15 years of age through 18 months postenrollment. METHODS: In this randomized, double-blind trial, 1781 sexually naive children were assigned (2:1) to quadrivalent HPV-6/11/16/18 vaccine or saline placebo administered at day 1 and months 2 and 6. Serum neutralizing anti-HPV-6/11/16/18 responses were summarized as geometric mean titers (GMTs) and seroconversion rates. Primary analyses were done per-protocol (subjects received 3 doses, had no major protocol violations and were HPV type-specific seronegative at day 1). Adverse experiences were collected by diary card. RESULTS: At month 7, seroconversion rates were > or =99.5% for the 4 vaccine-HPV-types. GMTs and seroconversion rates in boys were noninferior to those in girls (P < 0.001). At month 18, > or =91.5% of vaccine recipients were seropositive, regardless of gender. A higher proportion of vaccine recipients (75.3%) than placebo recipients (50.0%) reported one or more injection-site adverse experiences following any vaccination. Rates of fever were similar between vaccination groups. No serious vaccine-related adverse experiences were reported. CONCLUSIONS: In 9- to 15-year-old adolescents, the quadrivalent vaccine was generally well tolerated and induced persistent anti-HPV serologic responses in the majority of subjects for at least 12 months following completion of a three-dose regimen. The vaccine durability supports universal HPV vaccination programs in adolescents to reduce the burden of clinical HPV disease, particularly cervical cancer and precancers.

Programmatic issues in the implementation of an HPV vaccination program to prevent cervical cancer.

BACKGROUND: Cervical cancer remains an important health problem even in countries with effective cervical screening programs. HPV vaccines offer great potential for primary prevention of cervical cancer and other HPV-related diseases. PERSPECTIVES: Eventual implementation of an HPV vaccination program raises several key issues, including universal vs. targeted vaccinations, the age and gender of vaccine recipients, the acceptability of this vaccine to health care providers, adolescents, and parents, and the effect of this vaccine on cervical cancer screening. These issues were explored among symposium attendees during an interactive question-and-answer session using computerized voting pads. CONCLUSIONS: Preventative HPV vaccination programs should ideally be executed universally in both women and men with an emphasis on children and adolescents prior to their first sexual experience. Parent education on HPV disease and vaccine efficacy and safety will be critical to the acceptability of HPV vaccination for their children. HPV vaccination will not eliminate the need for Pap screening. Further research will be needed to develop rational and cost-effective cervical surveillance programs for women protected by HPV vaccines.

Safety, tolerability and immunogenicity of VAQTA given concomitantly versus nonconcomitantly with other pediatric vaccines in healthy 12-month-old children.

BACKGROUND: The objective of this study is to assess whether hepatitis A vaccine is immunogenic and well tolerated when administered to 12-month-old children alone or concomitantly with other routinely administered pediatric vaccines. METHODS: Six hundred seventeen healthy 12-month-old children were randomized to receive dose 1 of hepatitis A vaccine given alone or concomitantly with measles-mumps-rubella vaccine and varicella vaccine and dose 2 of hepatitis A vaccine given alone or concomitantly with diphtheria-tetanus-acellular pertussis vaccine and optionally with oral or inactivated poliovirus vaccine. Participants were followed for clinical adverse experiences and serologic responses to all vaccine antigens. Antibody responses were compared with historical controls for some indices. RESULTS: The safety profile was generally comparable whether hepatitis A vaccine was administered alone or concomitantly with other vaccines. When administered alone, the hepatitis A seropositivity rate was 98.3% and 100% for dose 1 and dose 2, respectively, and after dose 2 was similar to historical rates and the geometric mean titers were similar between initially seropositive and initially seronegative subjects (6207 and 6810 mIU/mL, respectively). After concomitant administration with hepatitis A vaccine, antibody responses to measles, mumps, rubella, diphtheria, tetanus and filamentous hemagglutinin (98.8%, 99.6%, 100%, 98.6%, 100% and 83.3%, respectively) were similar to historical controls and response to poliovirus was demonstrated, but immune responses to varicella zoster virus (79%) and pertussis toxoid (76%) were inferior to historical controls. CONCLUSIONS: Hepatitis A vaccine is highly immunogenic and generally well tolerated when administered to healthy children as young as 12 months of age regardless of initial hepatitis A serostatus and can be administered concomitantly with measles-mumps-rubella vaccine and oral or inactivated poliovirus vaccine.

Safety and immunogenicity of a measles, mumps, rubella and varicella vaccine given with combined Haemophilus influenzae type b conjugate/hepatitis B vaccines and combined diphtheria-tetanus-acellular pertussis vaccines.

BACKGROUND: A study was conducted to assess administration of a combination measles, mumps, rubella and varicella vaccine (MMRV) with other childhood vaccines. METHODS: In this open, multicenter trial, 1915 healthy children ages 12-15 months were randomized into 3 groups: group 1, MMRV, combined Haemophilus influenzae type b conjugate-hepatitis B vaccines (Hib/HepB) and combined diphtheria-tetanus-acellular pertussis vaccines (DTaP) concomitantly; group 2, MMRV followed by Hib/HepB and DTaP 42 days later; group 3, MMR and varicella vaccine followed by Hib/HepB and DTaP 42 days later. RESULTS: Antibody responses to measles, mumps, rubella, varicella, Hib, HepB, diphtheria and tetanus were similar between groups 1 and 2 (all >95%, except varicella, 89.7% in group 1 and 90.9% in group 2). Pertussis toxin and filamentous hemagglutinin responses were significantly lower in group 1 than in group 2 (group 1, 74.1 and 67.1%; group 2, 90.4 and 86.8%, respectively). An exploratory analysis suggested that the difference in and pertussis toxin and filamentous hemagglutinin responses was likely the result of study design rather than interference among vaccine components because the groups differed in age of receipt of DTaP (group 1, approximately 12 months; group 2, approximately 13.5 months). When the groups were matched for age, sample size was sufficient for comparison only in children > or =13.5 months old. Pertussis toxin and filamentous hemagglutinin responses were similar in these children. The safety profiles for each vaccination regimen were comparable. CONCLUSIONS: The immunogenicity data support concomitant administration of MMRV with Hib/HepB. Limited data from an exploratory analysis indicate that MMRV can be administered concomitantly with DTaP. Concomitant administration of MMRV, Hib/HepB and DTaP is well-tolerated.

Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children.

BACKGROUND: A quadrivalent measles, mumps, rubella and varicella vaccine would facilitate universal immunization against all 4 diseases, improve compliance and immunization rates and decrease the number of injections given to children and visits to physicians' offices. OBJECTIVES: To evaluate 1- and 2-dose regimens of a combined measles, mumps, rubella and varicella vaccine (ProQuad, referred to as MMRV) manufactured with a varicella component of increased potency. METHODS: In this partially blind, multicenter study, 480 healthy 12- to 23-month-old children were randomized to receive either MMRV and placebo or M-M-RII and VARIVAX. Injections were given concomitantly at separate sites. Subjects randomized to receive MMRV and placebo received a second dose of MMRV 90 days later. Subjects were followed for 42 days after each vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after each vaccination. RESULTS: Measles-like rash and fever during days 5-12 were more common after the first dose of MMRV (rash, 5.9%; fever, 27.7%) than after M-M-RII and VARIVAX (rash, 1.9%; fever, 18.7%). The incidence of other adverse events were similar between groups. Response rates were >90% to all vaccine components in both groups. Geometric mean titers to measles and mumps were significantly higher after 1 dose of MMRV than after administration of M-M-RII and VARIVAX. The second dose of MMRV elicited slight to moderate increases in measles, mumps and rubella antibody titers and a substantial increase in varicella antibody titer (from 13.0 to 588.1 glycoprotein antigen-based enzyme-linked immunosorbent assay units/mL). CONCLUSION: A 1- or 2-dose regimen of MMRV is generally well-tolerated when administered to 12- to 23-month-old children and has a safety and immunogenicity profile similar to that of M-M-RII and VARIVAX administered concomitantly.

Dose-response study of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children.

BACKGROUND: A combined measles, mumps, rubella and varicella (MMRV) vaccine would facilitate universal immunization against 4 diseases by decreasing the number of injections and thus enhancing compliance and coverage rates. If a second dose of varicella vaccine were to be recommended, MMRV could be used to administer a routine second dose of M-M-RII with the added advantage of boosting varicella-zoster virus (VZV) antibody titers. METHODS: Subjects 12-23 months of age received a single injection of 1 of 3 lots of an MMRV vaccine (ProQuad) containing high, middle or low VZV potency, or VARIVAX given concomitantly with M-M-RII. Recipients of MMRV received a second injection of MMRV approximately 90 days later. RESULTS: We enrolled 1559 subjects in the study. Antibody response rates to VZV 6 weeks after 1 injection of high potency MMRV (88.6%) or 2 injections of MMRV of any varicella potency (99.7-100%) were similar to the response rates after concomitant administration of M-M-RII and VARIVAX (93.1%). The second injection of MMRV boosted VZV antibody titers. Antibody responses to measles, mumps and rubella were >or=98%, similar to the control, after 1 or 2 injections of MMRV. MMRV was generally well-tolerated during the 42 days after vaccination. CONCLUSIONS: One injection of high potency MMRV resulted in antibody responses to the 4 vaccine components equivalent to those found after concomitant administration of M-M-RII and VARIVAX. A second injection of MMRV resulted in a significant boost in VZV antibody. This boost may translate into enhanced immunogenicity against varicella, which is known to correlate with increased protection.

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.

Measuring antibody responses to a live attenuated influenza vaccine in children.

BACKGROUND: Hemagglutination inhibition (HAI) assay is the standard method for evaluating inactivated influenza vaccines, but no standard assay has been established for evaluating live attenuated influenza vaccines (LAIV). LAIV containing A/Beijing/262/95(H1N1) induced low serum HAI antibody responses to the antigenic variant, A/New Caledonia/20/99(H1N1) in a serologic study but provided protection against the A/New Caledonia-like viruses in a community study. Neutralization and HAI assays were compared by measuring H1N1 cross-reactive antibody responses to the LAIV in children. METHODS: Sera were collected from 50 children 1-8 years of age before vaccination and 4-6 weeks after each dose of the LAIV. Antibody titers to the 3 vaccine viruses were measured by the HAI assay, whereas antibody titers against the H1N1 vaccine virus (A/Beijing/262/95) and 2 H1N1 antigenic variants (A/Shenzhen/227/95 and A/New Caledonia/20/99) were measured by the HAI and neutralization assays. RESULTS: Initially seronegative participants were more likely to develop HAI seroconversion responses to the 3 vaccine viruses than the baseline seropositive participants (77% versus 14% for H1N1, 100% versus 20% for H3N2, 100% versus 19% for B, P < 0.01, Fisher's exact test). For the H1N1 cross-reactive antibody responses, seroconversion rates measured by the neutralization assay were significantly higher than those measured by the HAI assay (95% versus 78%, P = 0.0485 for A/Beijing/262/95; 75% versus 24%, P < 0.0001 for A/Shenzhen/227/95; 51% versus 5%, P < 0.0001 for A/New Caledonia/20/99). CONCLUSIONS: The neutralization assay was more sensitive than the HAI assay for measuring H1N1 antibody responses after vaccination of children with the LAIV and may provide a better correlate of clinical protection provided by the LAIV.

Concomitant administration of a bivalent Haemophilus influenzae type b-hepatitis B vaccine, measles-mumps-rubella vaccine and varicella vaccine: safety, tolerability and immunogenicity.

BACKGROUND: The study was done to verify that concomitant administration of a bivalent Haemophilus influenzae type b-hepatitis B vaccine (Comvax), measles-mumps-rubella vaccine (M-M-RII) and varicella vaccine (Varivax) would be well-tolerated and suitably immunogenic with respect to all vaccine antigens. METHODS: We randomized 822 healthy 12- to 15-month-old children (1:1) to receive concomitant injections of Comvax, M-M-RII and Varivax (concomitant group) or Comvax followed 6 weeks later by injections of M-M-RII and Varivax (nonconcomitant group). Blood samples taken before and 6 weeks after vaccination were tested for antibodies to all vaccine antigens. RESULTS: Vaccinations were generally well-tolerated. Children in the concomitant and nonconcomitant treatment groups were similar with respect to the safety endpoint of primary interest (16.1 and 19.5%, respectively, had a fever > or =103 degree F rectally at any time within 14 days after either of two clinic visits). Fifteen serious adverse events were reported (eight in the concomitant group and seven in the nonconcomitant group); all resolved. Elements of two serious adverse events (fever, fever and measles-like rash; both in concomitant group children) were considered possibly related to vaccination. One child was withdrawn from the study because of a nonserious adverse event subsequently judged to be unrelated to vaccination. Similar proportions of vaccinees in the concomitant and nonconcomitant groups developed satisfactory antibody responses to the H. influenzae polysaccharide, polyribosylribitol phosphate (97.8 to 98.7%), hepatitis B surface antigen (99.2 to 100%), measles virus (99.4 to 99.6%), mumps virus (98.4 to 99.2%), rubella virus (100%) and varicella virus (93.2 to 94.6%). CONCLUSION: Concomitant administration of Comvax, M-M-RII and VARIVAX at the 12- or 15-month clinic visit is one satisfactory way of delivering some of the multiple vaccines indicated during the second year of life.

Ten year follow-up of healthy children who received one or two injections of varicella vaccine.

BACKGROUND: The rate of varicella and persistence of varicella antibody after a one dose vs. a two dose regimen of varicella virus vaccine live Oka/Merck (VARIVAX; Merck & Co., Inc., West Point, PA) in approximately 2000 children were compared during a 9- to 10-year follow-up period. METHODS: Children 12 months to 12 years of age with a negative history of varicella were randomized in late 1991 to early 1993 to receive either one or two injections of varicella vaccine given 3 months apart. Subjects were actively followed for varicella, any varicella-like illness or zoster and any exposures to varicella or zoster on a yearly basis for 10 years after vaccination. Persistence of varicella antibody was measured yearly for 9 years. RESULTS: Most cases of varicella reported in recipients of one or two injections of vaccine were mild. The risk of developing varicella >42 days postvaccination during the 10-year observation period was 3.3-fold lower (P < 0.001) in children who received two injections than in those who received one injection (2.2% vs. 7.3%, respectively). The estimated vaccine efficacy for the 10-year observation period was 94.4% for one injection and 98.3% for two injections (P < 0.001). Measurable serum antibody persisted for 9 years in all subjects. CONCLUSIONS: Administration of either one or two injections of varicella vaccine to healthy children results in long term protection against most varicella disease. The two dose regimen was significantly more effective than a single injection.

Impact of a birth dose of hepatitis B vaccine on the reactogenicity and immunogenicity of diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b combination vaccination.

OBJECTIVES: To assess the impact of a birth dose of hepatitis B vaccine (HepB) on the reactogenicity and immunogenicity of a novel diphtheria-tetanus-acellular pertussis (DTaP)- HepB-inactivated poliovirus (IPV)/ type b (Hib) combination vaccine administered subsequently at 2, 4 and 6 months of age. METHODS: Neonates ( = 550) were randomized into two groups with regard to receipt of HepB at birth. All subjects in both groups received DTaP-HepB-IPV/Hib at 2, 4 and 6 months of age. Solicited local and general adverse events were recorded for 8 days after each dose. Antibodies to hepatitis B surface antigen were measured 1 month after the third dose of DTaP-HepB-IPV/Hib in a subset of 170 infants; titers of at least 10 mIU/ml were considered protective. RESULTS: The DTaP-HepB-IPV/Hib combination vaccine was well-tolerated in both groups. Of the infants who received a birth dose of HepB, 22.6% had severe (Grade 3) reactions after any of the three doses of DTaP-HepB-IPV/Hib combination vaccine compared with 23.2% of subjects who did not receive a birth dose of HepB (difference, -0.5%; 90% confidence interval, -7.4 to 6.1). Antibody to hepatitis B surface antigen titers were > or =10 mIU/ml for all tested infants. Geometric mean titers were 2996.2 and 1240.1 mIU/ml with and without a birth dose of HepB, respectively. CONCLUSIONS: A HepB birth dose does not increase the reactogenicity of a combination DTaP-HepB-IPV/Hib vaccine administered at 2, 4 and 6 months of age, and all tested subjects achieved protective anti-HBs titers (> or =10 mIU/ml), although geometric mean titers were higher when a birth dose of HepB was given.

Effect of influenza treatment with oseltamivir on health outcome and costs in otherwise healthy children.

OBJECTIVE: To evaluate the effect of treating children with influenza with oseltamivir on health outcomes and costs to healthcare payers. PATIENTS AND DESIGN: Health outcome data from the oseltamivir paediatric clinical development programme plus data from the literature were used in an economic model developed to predict morbidity and mortality due to influenza and its specified complications. Published data on the cost of care in the UK were used to compare oseltamivir with usual care in children aged 1-12 and 1-5 years by estimating cost-effectiveness and cost-utility ratios. RESULTS: Oseltamivir reduced median time to return to normal health and activity by almost 2 days (40% reduction, 67.1 vs 111.7 hours; p < 0.0001) versus placebo. In children aged 1-5 years, a 48% reduction (63.5 vs 121.3 hours; p = 0.0003) was observed. Oseltamivir-treated children who developed otitis media returned to normal health and activity 30% faster (99.6 vs 141.5 hours; p = 0.0517) than the placebo group. In the economic model, oseltamivir in the base-case analysis (assuming 60% diagnostic accuracy, full compliance, and 100% receive and start treatment within 48 hours, standard discounting according to the UK National Institute of Clinical Excellence guidelines) resulted in favourable cost-utility ratios in children aged both 1-12 and 1-5 years, with incremental cost-utility rates of £11 173/quality-adjusted life year (QALY) and oseltamivir being dominant compared with usual care, respectively (year of costing, 2002). Even in conservative scenarios, most cost-utility ratios remained <£30 000/QALY. CONCLUSIONS: Oseltamivir is an effective treatment for children with influenza, allowing faster return to normal health and activity compared with usual care. From the healthcare payer perspective, oseltamivir is a potentially cost-effective strategy for otherwise healthy children.

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.