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Lehtinen M.,University of Tampere | Paavonen J.,University of Helsinki | Wheeler C.M.,University of New Mexico | Jaisamrarn U.,Chulalongkorn University | And 27 more authors.
The Lancet Oncology | Year: 2012

Background: Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults). Methods: Healthy women aged 15-25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681. Findings: Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5-100) in the TVC-naive and 45·7% (22·9-62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9-98·7) in the TVC-naive and 45·6% (28·8-58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15-17 year age group and progressively decreased in the 18-20 year and 21-25 year age groups. Vaccine efficacy against all AIS was 100% (31·0-100) and 76·9% (16·0-95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. Interpretation: PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. Funding: GlaxoSmithKline Biologicals. © 2012 Elsevier Ltd.


Block S.L.,Kentucky Pediatric and Adult Research | Falloon J.,MedImmune LLC | Hirschfield J.A.,Score Physician Alliance | Krilov L.R.,Winthrop University | And 3 more authors.
Pediatric Infectious Disease Journal | Year: 2012

Background: Influenza B viruses from 2 lineages cocirculate annually. Because the single B strain contained in trivalent vaccines may not match the major circulating strain, adding a second B virus could enhance protection. This study compared the safety and immunogenicity of an investigational quadrivalent Ann Arbor strain live attenuated influenza vaccine (Q/LAIV) with that of 2 trivalent vaccines (T/LAIV), each containing a B strain from a different lineage. Methods: This randomized, double-blind study was designed to demonstrate the immunologic noninferiority of Q/LAIV compared with T/LAIV in children 2-17 years of age by comparing postdose geometric mean titers of hemagglutination inhibition antibodies. Children were randomized 3:1:1 to receive Q/LAIV or 1 of 2 T/LAIV vaccines. Those subjects who were 9-17 years of age received 1 dose, and those 2-8 years of age received 2 doses 1 month apart. Serum immune responses were evaluated 1 month after dose 1 (dose 2 for influenza vaccine-naive subjects aged 2-8 years). Results: Q/LAIV was noninferior to T/LAIV: upper bounds for all four 95% confidence intervals for the postdose geometric mean titer ratios (T/LAIV divided by Q/LAIV) were ≤1.5, the predefined noninferiority margin. The overall seroresponse rates (4-fold rise) were comparable between treatment groups. Safety events were comparable, except that fever was more common after dose 1 in Q/LAIV subjects (5.1%) than in T/LAIV subjects (3.1%) 2-8 years of age. Conclusions: The immunogenicity of Q/LAIV was noninferior to that of T/LAIV in children aged 2-17 years; safety was also comparable. Q/LAIV may broaden the protection against influenza B strains provided by current trivalent influenza vaccines. © 2012 by Lippincott Williams ∧ Wilkins.


Block S.L.,Kentucky Pediatric and Adult Research | Szenborn L.,Wroclaw Medical University | Daly W.,Bluegrass Clinical Research Inc | D'Agostino D.,Novartis | And 3 more authors.
Vaccine | Year: 2015

Background: A meningococcal vaccine protective against all major disease-associated serogroups (A, B, C, W and Y) is an unmet public health need. In this phase 2 observer-blinded, randomized, controlled study, two investigational meningococcal ABCWY vaccine formulations were evaluated to assess their immunological noninferiority to a licensed quadrivalent meningococcal ACWY glycoconjugate vaccine (MenACWY-CRM) for serogroups ACWY and immunogenicity against serogroup B test strains, as well as for formulation selection based on a desirability index (DI). Each investigational MenABCWY formulation contained recombinant protein and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine (4CMenB) combined with components of MenACWY-CRM. Methods: A total of 484 healthy 10-25 year-old participants were randomized to receive two doses, two months apart, of an investigational MenABCWY formulation that contained either a full or one-quarter dose of OMV, 4CMenB alone, or a Placebo followed by MenACWY-CRM. Immunogenicity against each of serogroups ACWY and four serogroup B test strains was assessed by serum bactericidal assay with human complement (hSBA). MenABCWY formulations were compared by a DI based on key immunogenicity and reactogenicity parameters. Results: Seroresponse rates for serogroups ACWY were significantly higher after two doses of either MenABCWY formulation than after one dose of MenACWY-CRM: respectively, A: 90-92% vs. 73%; C: 93-95% vs. 63%; W: 80-84% vs. 65%; and Y: 90-92% vs. 75%. Prespecified noninferiority criteria were met. Both MenABCWY formulations induced substantial immune responses against serogroup B test strains, although 4CMenB responses were higher. Overall DIs for both MenABCWY formulations were similar. Reactogenicity profiles of the MenABCWY formulations were similar to each other and to that of 4CMenB. No vaccine-related serious adverse events were reported. Conclusions: Both investigational MenABCWY formulations elicited robust immune responses against serogroups ACWY and serogroup B test strains, and had acceptable reactogenicity profiles, with no safety concerns identified. © 2015 Elsevier Ltd.


Heikkinen T.,University of Turku | Block S.L.,Kentucky Pediatric and Adult Research | Toback S.L.,MedImmune | Toback S.L.,Gilead Sciences Inc. | And 2 more authors.
Pediatric Infectious Disease Journal | Year: 2013

Background: Acute otitis media (AOM) is a frequent complication of influenza in children, and influenza vaccination helps protect against influenza-associated AOM. A live attenuated influenza vaccine (LAIV) approved for eligible children aged ≥2 years for the prevention of influenza also effectively reduces influenza-associated AOM. However, the annual effectiveness of LAIV against all-cause AOM is unknown. Methods: AOM rates in children aged 6-83 months from 6 randomized, placebo-controlled trials and 2 randomized, inactivated influenza vaccinecontrolled trials were pooled and analyzed. To enable comparison with studies of AOM prevention by pneumococcal conjugate vaccines, 12-month effectiveness was calculated assuming that LAIV had no effect outside of influenza seasons. Results: During influenza seasons, LAIV efficacy compared with placebo against all-cause AOM in children aged 6-71 months (N = 9497) was 12.4% (95% confidence interval [CI]: 2.0%, 21.6%) in year 1. In year 2, the efficacy in children aged 18-83 months (N = 4142) was 6.2% (95% CI: -12.4%, 21.7%). Compared with inactivated influenza vaccine, the efficacy of LAIV in children aged 6-71 months (N = 9901) against febrile all-cause AOM was 9.7% (95% CI: -2.1%, 20.1%). The estimated 12-month effectiveness of LAIV compared with placebo against all-cause AOM was 7.5% (95% CI: -2.4%, 16.2%). Conclusions: LAIV reduced the incidence of all-cause AOM compared with placebo in children. The estimated 12-month effectiveness of LAIV was comparable with 7-valent pneumococcal conjugate vaccine. The effects of the vaccines will overlap somewhat; however, because pneumococcal conjugate vaccines only prevent a fraction of all pneumococcal AOM and influenza-associated AOM can be caused by other pathogens, LAIV could further reduce the incidence of AOM in children. Copyright © 2013 by Lippincott Williams & Wilkins.


Block S.L.,Kentucky Pediatric and Adult Research | Heikkinen T.,University of Turku | Toback S.L.,MedImmune | Zheng W.,MedImmune | Ambrose C.S.,MedImmune
Pediatric Infectious Disease Journal | Year: 2011

BACKGROUND: Acute otitis media (AOM) is a frequent complication of influenza in young children. Influenza vaccination is known to protect against AOM by preventing influenza illness. We sought to determine the efficacy of the live attenuated influenza vaccine (LAIV) against influenza-associated AOM compared with placebo and trivalent inactivated influenza vaccine (TIV). LAIV is approved for eligible children aged ≥2 years in the United States and in several other countries. METHODS: AOM incidence data from 6 randomized, double-blind, placebo-controlled trials and 2 randomized, double-blind, TIV-controlled trials in children 6 to 83 months of age were pooled and analyzed. RESULTS: A total of 290 cases of AOM were identified in 24,046 study subjects. LAIV efficacy against influenza-associated AOM was 85.0% (95% confidence interval [CI], 78.3%-89.8%) compared with placebo and 54.0% (95% CI, 27.0%-71.7%) compared with TIV. Efficacy trended higher in those ≥24 months of age compared with those aged 6 to 23 months. In placebo-controlled trials, among children who acquired influenza despite vaccination, AOM was diagnosed in 10.3% of LAIV recipients and 16.8% of placebo recipients, representing a 38.2% (95% CI, 11.0%-58.2%) relative reduction in the development of AOM. In TIV-controlled studies, among subjects with breakthrough influenza illness, the proportions of LAIV and TIV recipients who developed AOM were similar. CONCLUSIONS: Children receiving LAIV had a high level of protection against influenza-associated AOM when compared with placebo or TIV. This was most evident in children older than 2 years, for whom LAIV is indicated. LAIV recipients who contracted breakthrough influenza illness despite vaccination developed AOM at a significantly lower rate than did unvaccinated children who developed influenza. © 2011 Lippincott Williams & Wilkins, Inc.


Toback S.L.,MedImmune LLC | Levin M.J.,University of Colorado at Denver | Block S.L.,Kentucky Pediatric and Adult Research | Belshe R.B.,Saint Louis University | And 2 more authors.
Expert Review of Vaccines | Year: 2012

Influenza B is responsible for significant morbidity in children and adults worldwide. For more than 25 years, two antigenically distinct lineages of influenza B viruses, B/Yamagata and B/Victoria, have cocirculated globally. Current influenza vaccine formulations are trivalent and contain two influenza subtype A strains (A/H1N1 and A/H3N2) but only one B strain. In a half of recent influenza seasons, the predominant circulating influenza B lineage was different from that contained in trivalent influenza vaccines. A quadrivalent live attenuated influenza vaccine (Q/LAIV) that contains two B strains, one from each lineage, has been developed to help provide broad protection against influenza B. Q/LAIV was recently approved for use in the USA in eligible individuals 2-49 years of age. This review summarizes clinical trial data in support of Q/LAIV. © 2012 2012 Expert Reviews Ltd.


Baxter R.,Kaiser Permanente | Reisinger K.,Primary Physicians Research | Block S.L.,Kentucky Pediatric and Adult Research | Izu A.,Novartis | And 2 more authors.
Journal of Pediatrics | Year: 2014

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. © 2014 Elsevier Inc. All rights reserved.


Block S.L.,Kentucky Pediatric and Adult Research | Yi T.,MedImmune LLC | Sheldon E.,Miami Research Associates | Dubovsky F.,MedImmune LLC | Falloon J.,MedImmune LLC
Vaccine | Year: 2011

Background: Trivalent seasonal influenza vaccines contain 2 A strains and 1 B strain. B strains of 2 antigenically distinct lineages, Yamagata and Victoria, have been co-circulating annually, and the B strain included in vaccines often has not been a lineage match to the major circulating strain. Thus, a vaccine containing B strains from both lineages could broaden protection against influenza. Quadrivalent live attenuated influenza vaccine (Q/LAIV) is an investigational 4-strain formulation of LAIV that contains 2 A strains, A/H1N1 and A/H3N2, and 2 B strains, 1 from each lineage. Methods: A randomized, double-blind, active-controlled study of Q/LAIV was conducted in 1800 adults aged 18-49 years to compare the immunogenicity and safety of Q/LAIV to trivalent LAIV (T/LAIV). Subjects were randomized 4:1:1 to receive an intranasal dose of Q/LAIV (. n=. 1200) or 1 of 2 matching T/LAIV vaccines, each containing 1 of the B strains included in Q/LAIV (. n=. 600 total). The primary endpoint was the comparison of the post-vaccination strain-specific geometric mean titers (GMT) of hemagglutination inhibition antibody in Q/LAIV recipients to those in T/LAIV recipients, with immunologic noninferiority of Q/LAIV to be demonstrated if the upper bound of the 2-sided 95% confidence interval (CI) for the ratio of the GMTs [T/LAIV divided by Q/LAIV] was ≤1.5 for all strains. Results and Conclusion: Q/LAIV met the criteria for noninferiority: the ratios of the GMTs for the A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 1.09 (95% CI, 1.01-1.18), 1.05 (95% CI, 0.96-1.14), 1.10 (95% CI, 0.97-1.25), and 0.92 (95% CI, 0.82-1.03), respectively. Solicited symptoms and adverse events were similar in the Q/LAIV and T/LAIV arms. Q/LAIV may confer increased protection against influenza by targeting B strains from both lineages. © 2011 Elsevier Ltd.


Hedrick J.A.,Kentucky Pediatric and Adult Research
Expert Review of Anti-Infective Therapy | Year: 2010

Common community-acquired infections include those of the upper respiratory tract. In the 1990s, the antimicrobial treatment of upper respiratory tract infections focused on penicillin-resistant Streptococcus pneumoniae. However, following the introduction of a pneumococcal conjugate vaccine, a decrease in invasive pneumococcal disease occurred, and in the case of otitis media a shift towards Haemophilus influenzae as the predominant causative pathogen was observed. Future antimicrobial therapy for outpatient upper respiratory tract infections may need to focus on pathogens such as penicillin-susceptible S. pneumoniae,-lactamase-producing H. influenzae,-lactamase-negative amoxicillin-resistant H. influenzae and Moraxella catarrhalis. In these circumstances, third-generation oral cephalosporins, such as cefixime and cefdinir, could be increasingly used as an optional first-line therapy in community practice for upper respiratory tract infections suspected to be caused by these key pathogens, as an alternative to amoxicillin-clavulanate. © 2010 Expert Reviews Ltd.


Block S.L.,Kentucky Pediatric and Adult Research | Toback S.L.,MedImmune | Ambrose C.S.,MedImmune
Clinical Pediatrics | Year: 2010

In the United States, annual influenza vaccine is now recommended for all children 6 months through 18 years of age. This 2-year observational study of US outpatient pediatricians offices captured office demographics and characteristics, recorded all influenza vaccinations administered and vaccination-related activities during the influenza season, and correlated office characteristics and activities associated with increased vaccine uptake. Offices generally offered the influenza vaccine from September through February and March; however, approximately 80% of vaccinations occurred in October through December. In 2008-2009 compared with 2007-2008, offices administered the vaccine earlier and later into the season. Estimated in-office rates of first-dose administration, 2-dose compliance, and use of the intranasal vaccine also increased. Qualitative analyses suggest that increased first-dose administration and 2-dose compliance rates are associated with smaller office size and a greater duration of vaccine availability, respectively, during both seasons. © 2010 The Author(s).

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