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STUDY DESIGN: Case report. BACKGROUND: A number of pain referral patterns for sacroiliac dysfunction have been reported in the literature. However, very little has been written about pain localized to the knee joint for cases involving sacroiliac dysfunction. CASE DESCRIPTION: A 25-year-old female runner was self-referred to physical therapy for medial knee pain of 4½ weeks' duration without a significant onset event. The pain completely curtailed her training for the Boston Marathon. Examination of the patient's knee and hip did not reveal any abnormal findings and there was no reproduction of pain with any test procedures except for medial knee joint tenderness to palpation. Additional, more proximal examination suggested significant asymmetry of sacral bony landmarks of the pelvic girdle without significant findings on the provocation tests of the sacroiliac joint. A single session of manual therapy procedures directed to the pubic symphysis and sacroiliac joint ipsilateral to the side of knee pain was provided. OUTCOMES: The patient was able to return to running without further incident of knee pain after a single therapy session. DISCUSSION: This case suggests the importance of regional interdependence in the examination of patients with an apparently common clinical problem. Furthermore, the case describes a previously unreported presentation of local knee pain possibly attributable to sacroiliac joint dysfunction. LEVEL OF EVIDENCE: Therapy, level 4. [ABSTRACT FROM AUTHOR]

Objective: Altered postural presentations have been associated with a variety of musculoskeletal disorders. Therapeutic exercise interventions are often utilized to manage patients with increased thoracic kyphosis or 'round shoulders', yet few controlled studies have evaluated their efficacy.Design: A prospective, randomized, controlled design was used to evaluate the influence of a home-based exercise regimen on these postural variances. Seventy-one patients with real or perceived concerns about their thoracic posture completed the 13-week study. Patients with 23-80 degrees of thoracic kyphosis entered the study. Pre- and post-intervention flexicurve measurements of thoracic kyphosis were made. Patients were randomly assigned to an exercise (n=32) or control group (n=39). A mixed design ANOVA tested main effects and interactions.Results: A statistically significant (p < 0.05) interaction was found between group assignment and delta kyphosis values. Post-hoc analysis of the multiple comparisons produced a marginal p-value (p =0.0557). Mean delta kyphosis values were (+) 0.5 degrees (+/-7.0 degrees) for the control group and (-) 3.0 degrees (+/-6.1 degrees) for the experimental group.Conclusions: This 13-week home exercise program targeting modification of thoracic kyphosis angles had a statistically significant impact. However, post-hoc statistical analyses and clinical implications are marginal. [ABSTRACT FROM AUTHOR]

Background: Japanese encephalitis virus (JEV), although confined to Asia, causes about 35000-50000 cases and 10000 deaths every year, and is the most important cause of encephalitis worldwide. There is no known antiviral treatment for any flavivirus. Results from in-vitro studies and work in animals have shown inteferon alfa has antiviral activity on Japanese encephalitis and other flaviviruses; therefore, we aimed to assess the efficacy of inteferon alfa-2a in Japanese encephalitis.Methods: We did a randomised double-blind placebo-controlled trial of interferon alfa-2a (10 million units/m2, daily for 7 days) in 112 Vietnamese children with suspected Japanese encephalitis, 87 of whom had serologically confirmed infections. Our primary endpoints were hospital death or severe sequelae at discharge. Analysis was by intention to treat.Findings: Overall, 21 children (19%) died, and 17 (15%) had severe sequelae. Outcome at discharge and 3 months did not differ between the two treatment groups; 20 children in the interferon group had a poor outcome (death or severe sequelae), compared with 18 in the placebo group (p=0.85, difference 0.1%, 95% CI -17.5 to 17.6%), there were no long-term side effects of interferon.Interpretation: The doses of interferon alfa-2a given in this regimen did not improve the outcome of patients with Japanese encephalitis. [ABSTRACT FROM AUTHOR]

Vaccination of the global population against COVID-19 is a great scientific, logistical, and moral challenge. Despite the rapid development and authorization of several full-length Spike (S) protein vaccines, the global demand outweighs the current supply and there is a need for safe, potent, high-volume, affordable vaccines that can fill this gap, especially in low- and middle-income countries. Whether SARS-CoV-2 S-protein receptor-binding domain (RBD)-based vaccines could fill this gap has been debated, especially with regards to its suitability to protect against emerging viral variants of concern. Given a predominance for elicitation of neutralizing antibodies (nAbs) that target RBD following natural infection or vaccination, a key biomarker of protection, there is merit for selection of RBD as a sole vaccine immunogen. With its high-yielding production and manufacturing potential, RBD-based vaccines offer an abundance of temperature-stable doses at an affordable cost. In addition, as the RBD preferentially focuses the immune response to potent and recently recognized cross-protective determinants, this domain may be central to the development of future pan-sarbecovirus vaccines. In this study, we review the data supporting the non-inferiority of RBD as a vaccine immunogen compared to full-length S-protein vaccines with respect to humoral and cellular immune responses against both the prototype pandemic SARS-CoV-2 isolate and emerging variants of concern., (© 2021. The Author(s).)

Background: This phase 2 observer-blind, randomized, multicenter, dose-ranging study evaluated immunogenicity and safety of different formulations of an AS03-adjuvanted H5N1 influenza vaccine in children 6-35 months of age., Methods: One hundred eighty-five children randomized into 5 groups [1.9 µg hemagglutinin (HA)/AS03B, 0.9 µg HA/AS03C, 1.9 µg HA/AS03C, 3.75 µg HA/AS03C or 3.75 µg HA/AS03D] were to receive 2 doses administered 21 days apart (primary vaccination). AS03 was classified by amount of DL-α-tocopherol, with AS03B the highest amount. One year later, all subjects were to receive unadjuvanted 3.75 µg HA as antigen challenge. Immunogenicity was assessed 21 days after primary vaccination (day 42) and 7 days after antigen challenge (day 392). Immunogenicity-fever index, based on hemagglutination inhibition and microneutralization antibody titers at day 42 and fever 7 days after each vaccination, was used to guide the selection of an acceptable formulation., Results: After primary vaccination, formulations elicited strong homologous immune responses with all subjects' hemagglutination inhibition titers ≥1:40 post-vaccination. Immunogenicity-fever index based on hemagglutination inhibition and microneutralization assays showed that 1.9 µg HA/AS03B ranked the highest. Antibody levels persisted >4 times above baseline 12 months after primary vaccination with all formulations (day 385). Antibodies increased >4-fold after antigen challenge (day 392/day 385) with 1.9 µg HA/AS03B, 0.9 µg HA/AS03C and 1.9 µg HA/AS03C formulations. Overall per subject, the incidence of fever ranged from 28.6% (3.75 µg HA/AS03D) to 60.5% (1.9 µg HA/AS03B)., Conclusions: All formulations were highly immunogenic and demonstrated acceptable safety profiles, with the 1.9 µg HA/AS03B providing the most favorable balance of immunogenicity versus reactogenicity for use in children 6-35 months of age., Competing Interests: J.H.K., M.D., J.D., D.F. and B.S. are employees of the GSK group of companies. W.W., D.W.V., B.I. and A.S. were employees of the GSK group of companies during the conduct of the study. J.H.K., B.S., M.D., J.D., W.W. and A.S. hold shares from the GSK group of companies. T.P., N.-C.C., K.S. and L.-M.H. received funds from the GSK group of companies through their institution for the conduct of the study. L.-M.H. received personal fees from the GSK group of companies for educational lectures. J.H.K., M.D., T.P., N.-C.C., K.S., L.-M.H., J.D., D.F., B.S., W.W., D.W.V., B.I. and A.S. declare no other financial and nonfinancial relationships and activities. K.-P.H., P.-Y.C. and C.-H.C. declare no financial and nonfinancial relationships and activities and no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Hepatitis E (HE) during pregnancy can be fatal; there are no prospective risk estimates for HE and its complications during pregnancy. We followed 2,404 pregnant women for HE and pregnancy outcomes from 1996 to 1998. Subjects from Nepal were enrolled at an antenatal clinic with pregnancy of ≤ 24 weeks. Most women (65.1%) were anti-HE virus negative. There were 16 cases of HE (6.7 per 1,000); three mothers died (18.8%) having had intrauterine fetal death (IUFD). Thirteen mothers survived: five preterm and seven full-term deliveries, one IUFD. HE among seronegative women was the sole cause of maternal death and increased the risk of IUFD (relative risk [RR]: 10.6; 95% confidence interval [CI]: 4.29-26.3) and preterm delivery (RR: 17.1, 95% CI 7.56-38.5). HE vaccination of females in at-risk regions before or as they attain reproductive age would reduce their risk for preterm delivery, IUFD, and maternal death.

Background: Non-neutralizing antibodies inducing complement-dependent lysis (CDL) and antibody-dependent cell-mediated cytotoxicity (ADCC) activity may contribute to protection against influenza infection. We investigated CDL and ADCC responses in healthy adults randomized to receive either non-adjuvanted or AS03-adjuvanted monovalent A(H1N1)pdm09 vaccine (containing 15 µg/3.75 μg of hemagglutinin, respectively) on a 2-dose schedule 21 days apart., Methods: We conducted an exploratory analysis of a subset of 106 subjects having no prior history of A(H1N1)pdm09 infection or seasonal influenza vaccination enrolled in a previously reported study (NCT00985673). Antibody responses against the homologous A/California/7/2009 (H1N1) vaccine strain and a related A/Brisbane/59/2007 (H1N1) seasonal influenza strain were analyzed up to Day 42., Results: Baseline seropositivity determined with hemagglutination inhibition (HI), CDL and ADCC antibody titers against viral strains was high; A/California/7/2009 (HI [40.4-48.1%]; CDL [34.6-36.0%]; ADCC [92.1-92.3%]); A/Brisbane/59/2007 (HI [73.1-88.9%]; CDL [38.0-42.0%]; ADCC [86.8-97.0%]). CDL seropositivity increased following vaccination with both adjuvanted and non-adjuvanted formulations (A/California/7/2009 [95.9-100%]; A/Brisbane/59/2007 [75.5-79.6%]). At Day 21, increases in CDL and ADCC antibody geometric mean titers against both strains were observed for both formulations. After 2 doses of AS03-adjuvanted vaccine, vaccine responses of 95.8% (≥9-fold increase from baseline in CDL titers) and 34.3% (≥16-fold increase from baseline in ADCC titers) were seen against A/California/7/2009; and 22.4% and 42.9%, respectively, against A/Brisbane/59/2007. Vaccine responses after 2 doses of the non-adjuvanted vaccine were broadly similar., Conclusions: Broadly comparable non-neutralizing immune responses were observed following vaccination with non-adjuvanted and AS03-adjuvanted A(H1N1)pdm09 formulations; including activity against a related vaccine strain., (© 2020 Glaxosmithkline Biologicals. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Dengue disease and its causative agents, the dengue viruses (DENV-1-4), cause high morbidity in tropical and subtropical regions. We evaluated three dosing regimens of the investigational tetravalent AS03 B -adjuvanted dengue-purified inactivated vaccine (DPIV+AS03 B ). In this phase 1/2, observer-blind, placebo-controlled study (NCT02421367), 140 healthy adults were randomized 1:1:2 to receive DPIV+AS03 B according to the following regimens: 0-1 month (M), 0-1-6 M, or 0-3 M. Participants received DPIV+AS03 B or placebo at M0, M1, M3, and M6 according to their dosing schedule. Primary objectives were 1) to evaluate the safety of DPIV+AS03 B for 28 days (D) after each dose; 2) to demonstrate the added value of a booster dose (0-1-6 M versus 0-1 M) based on neutralizing antibody titers to each DENV type (DENV-1-4) at 28 D after the last dose; and, if this objective was met, 3) to demonstrate the benefit of a longer interval between the first and second doses (0-1 M versus 0-3 M). Adverse events (AEs) within 7 D after vaccination tended to be more frequent after DPIV+AS03 B doses than placebo; the number of grade 3 AEs was low (≤ 4.5% after DPIV+AS03 B ; ≤ 2.9% after placebo), with no obvious differences across groups. Within 28 D following each dose, the frequency of unsolicited AEs after DPIV+AS03 B appeared higher for three-dose (0-1-6 M) than two-dose (0-1 M and 0-3 M) regimens. No serious AEs were considered related to vaccination, and no potential immune-mediated diseases were reported during the study. All three schedules were well tolerated. Both primary immunogenicity objectives were demonstrated. The 0-3 M and 0-1-6 M regimens were more immunogenic than the 0-1 M regimen.

Four formulations of an investigational tetravalent dengue purified inactivated vaccine, administered as two doses one month (M) apart, were previously shown to be immunogenic and well-tolerated up to M13 of the phase I study NCT01702857. Here, we report results of the follow-up from M14 to year (Y) 3. One hundred healthy Puerto Rican adults, predominantly dengue virus (DENV)-primed, were randomized 1:1:1:1:1 to receive placebo or vaccine formulations: 1 μg/serotype/dose adjuvanted with aluminum, AS01 E or AS03 B , or aluminum-adjuvanted 4 μg/serotype/dose. No serious adverse events occurred. Two medically-attended potential immune-mediated disease cases, vaccination unrelated, were reported (groups 1 µg+Alum and 1 µg+AS03 B ). Of 14 instances of suspected dengue, none were laboratory confirmed. Geometric mean neutralizing antibody titers against DENV 1-4 waned from M14, but remained above pre-vaccination levels for DENV 1-3, with the highest values for group 1 µg+AS03 B : 1220.1, 920.5, 819.4, and 940.5 (Y2), and 1329.3, 1169.2, 1219.8, and 718.9 (Y3). All formulations appeared to be safe and immunogenic during the 3-year follow-up.

Dengue virus (DENV) is transmitted by infectious mosquitoes during blood-feeding via saliva containing biologically-active proteins. Here, we examined the effect of varying DENV infection modality in rhesus macaques in order to improve the DENV nonhuman primate (NHP) challenge model. NHPs were exposed to DENV-1 via subcutaneous or intradermal inoculation of virus only, intradermal inoculation of virus and salivary gland extract, or infectious mosquito feeding. The infectious mosquito feeding group exhibited delayed onset of viremia, greater viral loads, and altered clinical and immune responses compared to other groups. After 15 months, NHPs in the subcutaneous and infectious mosquito feeding groups were re-exposed to either DENV-1 or DENV-2. Viral replication and neutralizing antibody following homologous challenge were suggestive of sterilizing immunity, whereas heterologous challenge resulted in productive, yet reduced, DENV-2 replication and boosted neutralizing antibody. These results show that a more transmission-relevant exposure modality resulted in viral replication closer to that observed in humans., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: Yannick Vanloubbeeck, Clarisse Lorin, Marie-Pierre Malice, David Vaughn, and Lucile Warter are employees of the GSK group of companies.

The need for improved dengue vaccines remains since the only licensed vaccine, Dengvaxia, shows variable efficacy depending on the infecting dengue virus (DENV) type, and increases the risk of hospitalization for severe dengue in children not exposed to DENV before vaccination. Here, we developed a tetravalent dengue purified and inactivated vaccine (DPIV) candidate and characterized, in rhesus macaques, its immunogenicity and efficacy to control DENV infection by analyzing, after challenge, both viral replication and changes in biological markers associated with dengue in humans. Although DPIV elicited cross-type and long-lasting DENV-neutralizing antibody responses, it failed to control DENV infection. Increased levels of viremia/RNAemia (correlating with serum capacity at enhancing DENV infection in vitro), AST, IL-10, IL-18 and IFN-γ, and decreased levels of IL-12 were detected in some vaccinated compared to non-vaccinated monkeys, indicating the vaccination may have triggered antibody-dependent enhancement of DENV infection. The dengue macaque model has been considered imperfect due to the lack of DENV-associated clinical signs. However, here we show that post-vaccination enhanced DENV infection can be detected in this model when integrating several parameters, including characterization of DENV-enhancing antibodies, viremia/RNAemia, and biomarkers relevant to dengue in humans. This improved dengue macaque model may be crucial for early assessment of efficacy and safety of future dengue vaccines., Competing Interests: The authors declare the following conflicts: MAC, OT, SB, KS-O, YV, CL and LW are employees of the GSK group of companies. DWV used to be an employee of the GSK group of companies at the time when the study was performed. M-PM worked under contract with GSK at the time when the study was performed. KS-O, DWV, YV, CL and LW report owning shares and/or restricted shares in the GSK group of companies. MBB, RSM, RCP, YDSM, LGAM, LD-M, MF, AH and EC are employees of Fiocruz which was contracted by GSK in the context of this study.

Background: Avian influenza A H9N2 strains have pandemic potential., Methods: In this randomized, observer-blind study (ClinicalTrials.gov: NCT01659086), 420 healthy adults, 18-64years of age, received 1 of 10 H9N2 inactivated split-virus vaccination regimens (30 participants per group), or saline placebo (120 participants). H9N2 groups received 2 doses (days 0, 21) of 15µg hemagglutinin (HA) without adjuvant, or 1.9µgHA+AS03 A , 1.9µgHA+AS03 B , 3.75µgHA+AS03 A , or 3.75µgHA+AS03 B ; followed by the same H9N2 formulation or placebo (day 182). AS03 is an adjuvant system containing α-tocopherol (AS03 A : 11.86mg; AS03 B : 5.93mg) and squalene in an oil-in-water emulsion. Immunogenicity (hemagglutination inhibition [HI] and microneutralization assays) and safety were assessed up to day 546., Results: All adjuvanted formulations exceeded regulatory immunogenicity criteria at days 21 and 42 (HI assay), with seroprotection and seroconversion rates of ≥94.9% and ≥89.8% at day 21, and 100% and ≥98.1% at day 42. Immunogenicity criteria were also met for unadjuvanted vaccine, with lower geometric mean titers. In groups administered a third vaccine dose (day 182), an anamnestic immune response was elicited with robust increases in HI and microneutralization titers. Injection site pain was reported more frequently with adjuvanted vaccines. No vaccine-related serious adverse events were observed., Conclusions: All H9N2 vaccine formulations were immunogenic with a clinically acceptable safety profile; adjuvanted formulations were 4-8 times dose-sparing (3.75-1.9vs 15µgHA)., Trial Registration: Registered on ClinicalTrials.gov: NCT01659086., (Copyright © 2017. Published by Elsevier Ltd.)

We investigated the role of AS03 A (here AS03), an α-tocopherol oil-in-water emulsion-based adjuvant system, on the long-term persistence of humoral and cell-mediated immune responses to A(H1N1)pdm09 influenza vaccines. In two studies, a total of 261 healthy adults (≤60 years old) were randomized to receive two doses of AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin (HA) or nonadjuvanted vaccine containing 15 μg of hemagglutinin (in study A) or 3.75 μg of hemagglutinin (in study B) 21 days apart. Hemagglutination inhibition (HI) antibody, memory B-cell, and CD4 + /CD8 + T-cell responses were characterized up to 1 year following dose 1. We also assessed the effects of age and seasonal influenza vaccination history. AS03-adjuvanted (3.75 μg HA) vaccine and nonadjuvanted vaccine at 15 μg but not at 3.75 μg HA elicited HI antibody responses persisting at levels that continued to meet European licensure criteria through month 12. At month 12, the geometric mean titer for AS03-adjuvanted vaccine was similar to that for nonadjuvanted (15-μg) vaccine in study A (1:86 and 1:88, respectively) and higher than that for nonadjuvanted (3.75-μg) vaccine in study B (1:77 and 1:35, respectively). A(H1N1)pdm09-specific CD4 + T-cell and B-cell responses were stronger in AS03-adjuvanted groups and persisted only in these groups for 12 months at levels exceeding prevaccination frequencies. Advancing age and a seasonal vaccination history tended to reduce HI antibody and memory B-cell responses and, albeit less consistently, CD4 + T-cell responses. Thus, AS03 seemed to enhance the persistence of humoral and cell-mediated responses to A(H1N1)pdm09 vaccine, allowing for antigen sparing and mitigating potential negative effects of age and previous seasonal vaccination. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00968539 and NCT00989287.)., (Copyright © 2017 van der Most et al.)

Background: Better population data on respiratory viruses in children in tropical and southern hemisphere countries is needed., Methods: The epidemiology of respiratory viruses among healthy children (6 months to <10 years) with influenza-like illness (ILI) was determined in a population sample derived from an influenza vaccine trial (NCT01051661) in 17 centers in eight countries (Australia, South East Asia and Latin America). Active surveillance for ILI was conducted for approximately 1 year (between February 2010 and August 2011), with PCR analysis of nasal and throat swabs., Results: 6266 children were included, of whom 2421 experienced 3717 ILI episodes. Rhinovirus/enterovirus had the highest prevalence (41.5%), followed by influenza (15.8%), adenovirus (9.8%), parainfluenza and respiratory syncytial virus (RSV) (both 9.7%), coronavirus (5.6%), human metapneumovirus (5.5%) and human bocavirus (HBov) (2.0%). Corresponding incidence per 100 person-years was 29.78, 11.34, 7.03, 6.96, 6.94, 4.00, 3.98 and 1.41. Except for influenza, respiratory virus prevalence declined with age. The incidence of medically-attended ILI associated with viral infection ranged from 1.03 (HBov) to 23.69 (rhinovirus/enterovirus). The percentage of children missing school or daycare ranged from 21.4% (HBov) to 52.1% (influenza)., Conclusions: Active surveillance of healthy children provided evidence of respiratory illness burden associated with several viruses, with a substantial burden in older children., (Copyright © 2016. Published by Elsevier Ltd.)

The immune response to dengue virus (DENV) infection is complex and not fully understood. Using longitudinal data from 181 children with dengue in Thailand who were followed for up to 3 years, we describe neutralizing antibody kinetics following symptomatic DENV infection. We observed that antibody titers varied by serotype, homotypic vs heterotypic responses, and primary versus postprimary infections. The rates of change in antibody titers over time varied between primary and postprimary responses. For primary infections, titers increased from convalescence to 6 months. By comparing homotypic and heterotypic antibody titers, we saw an increase in type specificity from convalescence to 6 months for primary DENV3 infections but not primary DENV1 infections. In postprimary cases, there was a decrease in titers from convalescence up until 6 months after infection. Beginning 1 year after both primary and postprimary infections, there was evidence of increasing antibody titers, with greater increases in children with lower titers, suggesting that antibody titers were boosted due to infection and that higher levels of neutralizing antibody may be more likely to confer a sterilizing immune response. These findings may help to model virus transmission dynamics and provide baseline data to support the development of vaccines and therapeutics., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Heterologous prime-boost vaccination is a pandemic response strategy utilizing subtype-matched vaccine at pandemic onset followed by strain-matched vaccine once available. Persistence of immune response and safety of influenza A (H5N1) vaccine adjuvanted with adjuvant system containing α-tocopherol and squalene in an oil-in-water emulsion (AS03B) were evaluated., Methods: An open phase 3 active-controlled study (www.clinicaltrials.gov NCT01379937) assessed immunogenicity and reactogenicity of a heterologous booster dose of A/turkey/Turkey/1/2005-H5N1-AS03B in children 3 to <18 years of age, given 6 months after 2-dose priming with A/Indonesia/05/2005-H5N1-AS03B (H5N1(2) -H5N1 group) compared with a single dose of A/turkey/Turkey/1/2005-H5N1-AS03B in unprimed subjects (hepatitis A vaccine (HAV)-H5N1 group). Hemagglutinin inhibition responses and microneutralization antibodies were assessed to 6 months after booster vaccination., Results: Hemagglutinin inhibition antibody responses against A/turkey/Turkey/1/2005-H5N1 were superior in the H5N1(2)-H5N1 versus the hepatitis A vaccine-H5N1 group overall and in each age strata (3 to <10 and 10 to <18 years). Anamnestic immune responses were demonstrated against vaccine-homologous/heterologous strains in the H5N1(2)-H5N1 group. Injection site pain and fever increased with consecutive doses for children <6 years (H5N1(2)-H5N1). Immune responses to vaccine-homologous/heterologous strains persisted to 6 months after booster vaccination in the H5N1(2)-H5N1 group., Conclusions: Heterologous H5N1-AS03B-adjuvanted booster vaccination in children/adolescents was immunogenic for vaccine-homologous and heterologous strains following 2-dose priming, with immune persistence for at least 6 months. Prime-boost strategies using H5N1-AS03 could be effectively employed in this age group.

Background: During the influenza pandemic 2009-2010, an AS03-adjuvanted A(H1N1)pdm09 vaccine was used extensively in children 6 months of age and older, and during the 2010-2011 influenza season, the A(H1N1)pdm09 strain was included in the seasonal trivalent inactivated influenza vaccine (TIV) without adjuvant. We evaluated the immunogenicity and safety of TIV in children previously vaccinated with the AS03-adjuvanted A(H1N1)pdm09 vaccine., Methods: Healthy children were randomized (1:1) to receive TIV or a control vaccine. Children were aged 6 months to 9 years (n = 154) and adolescents 10-17 years (n = 77) when they received AS03-adjuvanted A(H1N1)pdm09 vaccine at least 6 months before study enrolment. Hemagglutination inhibition (HI) and neutralizing antibody responses against the A(H1N1)pdm09 strain were evaluated before (day 0) and at day 28 and month 6 after study vaccination. Reactogenicity was assessed during the 7 day postvaccination period, and safety was assessed for 6 months., Results: At day 0, >93.9% of all children had HI titers ≥1:40 for the A(H1N1)pdm09 strain, which increased to 100% at both day 28 and month 6 in the TIV group. Between days 0 and 28, HI antibody geometric mean titers against A(H1N1)pdm09 increased by 9-fold and 4-fold in children 6 months to 9 years of age and 10-17 years of age, respectively., Conclusion: AS03-adjuvanted A(H1N1)pdm09 vaccine-induced robust immune responses in children that persisted into the next season, yet were still boosted by TIV containing A(H1N1)pdm09. The reactogenicity and safety profile of TIV did not appear compromised by prior receipt of AS03-adjuvanted A(H1N1)pdm09 vaccine.

Background: AS03-adjuvanted H5N1 pandemic influenza vaccines have been assessed in an extensive clinical development program conducted in North America, Europe, and Asia including children from 6 months of age, adults, and elderly adults. We evaluated AS03-H5N1 in Korean adults 18 through 60 years of age., Methods: This Phase IV, randomized, study was conducted to assess the immunogenicity, reactogenicity, and safety of two doses (3.75μg of hemagglutinin antigen) of A/Indonesia/5/2005 (H5N1) adjuvanted with AS03 given 21 days apart in Korean adults. Antibody responses were assessed using hemagglutination-inhibition (HI) assays against the vaccine strain and a vaccine-heterologous strain (A/Vietnam/1194/2004) 21 days after the second dose. A control group (safety) received a licensed seasonal inactivated trivalent influenza vaccine (TIV). Reactogenicity was assessed for 7 days after each vaccination, and unsolicited adverse events were assessed for 182 days following vaccination in both study groups (NCT01730378)., Results: AS03-H5N1 was immunogenic and elicited robust HI antibody responses with seroconversion rates of 100% for the vaccine strain and 69.1% for the heterologous strain (N=81). HI antibody responses fulfilled the European licensure criteria for immunogenicity (primary endpoint). The incidence of local and systemic solicited adverse events (reactogenicity) was higher with AS03-H5N1 than TIV. There was no apparent difference in the rate of unsolicited adverse events in the AS03-H5N1 and TIV groups., Conclusion: The results indicate that AS03-H5N1 vaccine is immunogenic with reactogenicity and safety findings that are consistent with the established profile of AS03-H5N1 vaccine., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The high burden of respiratory syncytial virus (RSV)-associated morbidity and mortality makes vaccine development a priority., Methods: As part of an efficacy trial of pandemic influenza vaccines (NCT01051661), RSV epidemiology in healthy children aged 6 months to <10 years at first vaccination with influenza-like illness (ILI) was evaluated in Australia, Brazil, Colombia, Costa Rica, Mexico, the Philippines, Singapore, and Thailand between February 2010 and August 2011. Active surveillance for ILI was conducted for approximately 1 year, with nasal and throat swabs analyzed by polymerase chain reaction. The prevalence and incidence of RSV among ILI episodes were calculated., Results: A total of 6266 children were included, of whom 2421 experienced 3717 ILI episodes with a respiratory sample available. RSV was detected for 359 ILI episodes, a prevalence of 9.7% (95% confidence interval: 8.7-10.7). The highest prevalence was in children aged 12-23 or 24-35 months in all countries except the Philippines, where it was in children aged 6-11 months. The incidence of RSV-associated ILI was 7.0 (6.3-7.7) per 100 person-years (PY). Eighty-eight ILI episodes resulted in hospitalization, of which 8 were associated with RSV (prevalence 9.1% [4.0-17.1]; incidence 0.2 [0.1-0.3] per 100 PY). The incidence of RSV-associated ILI resulting in medical attendance was 6.0 (5.4-6.7) per 100 PY. RSV B subtypes were observed more frequently than A subtypes., Conclusions: Active surveillance demonstrated the considerable burden of RSV-associated illness that would not be identified through hospital-based surveillance, with a substantial part of the burden occurring in older infants and children., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Stockpiling vaccine for deployment in the event of an influenza pandemic is an important mitigation strategy. A necessary aspect of stockpiling is to determine the shelf-life of the stored vaccine., Methods: In this Phase II, open-label study we assessed the immunogenicity and safety of H5N1 A/Indonesia/5/2005 vaccine adjuvanted with AS03A. The AS03A-H5N1 vaccine was prepared from bulk antigen that had been stored for 4 years, and adjuvant that had been stored for 2.5 years. Both the antigen and adjuvant were filled in separate multi-dose vials within 4 months of use, and on the day of vaccination, the contents of antigen and adjuvant vials were mixed. Seventy-eight adults aged 18-64 years were scheduled to receive two doses of hemagglutinin-antigen (3.75μg) given 21 days apart. Antibody responses were assessed by hemagglutination-inhibition (HI) assay according to age (18-30 years, 31-40 years, 41-50 years, and 51-64 years). Reactogenicity was assessed for 7 days after each vaccination, and safety was assessed for 385 days post-vaccination (NCT01416571)., Results: The vaccine was immunogenic. Twenty-one days after the second dose of vaccine in the overall population, the HI seroconversion rate and seroprotection rate (SPR; titer ≥1:40) was 96.0% and 98.7%, respectively. At Day 182 after vaccination, the SPR was 76.7% in the overall population. Injection site pain was the most frequent solicited adverse event (91.0%), and no safety concerns were raised., Conclusion: The immunogenicity and safety observed with AS03A-H5N1 vaccine formulated with bulk antigen which had been stockpiled before vialing and administration was consistent with that previously observed with newly manufactured AS03A-H5N1 vaccine. This suggests that stockpiling bulk antigen for 4 years does not compromise the immunogenicity or reactogenicity of the vaccine., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This phase 2/3, randomized, placebo-controlled, observer-blinded study assessed the immunogenicity, reactogenicity, and safety of an inactivated, split-virion H5N1 influenza vaccine (A/Indonesia/5/2005) in children aged 6 months through 17 years., Methods: Children received 2 influenza vaccine doses 21 days apart, each containing 1.9 µg of hemagglutinin and AS03B adjuvant (5.93 mg of α-tocopherol). The randomization ratio was 8:3 for vaccine to placebo, with equal allocation between 3 age strata (6-35 months, 3-8 years, and 9-17 years). Immunogenicity against the vaccine strain was assessed 21 days after the first and second vaccine doses for all vaccinees, at day 182 for half, and at day 385 for the remaining half. Reactogenicity after each dose and safety up to 1 year after vaccination were evaluated., Results: Within each age stratum, the lower limit of the 98.3% confidence interval for the day 42 seroprotection rate was ≥70%, thus fulfilling the US and European licensure criteria. The immune responses elicited by vaccine persisted well above baseline levels for 1 year. The vaccine was more reactogenic than placebo, but no major safety concerns were identified., Conclusions: AS03B-adjuvanted H5N1 influenza vaccine was immunogenic and showed an acceptable safety profile in all age groups studied. Clinical Trials Registration: NCT01310413., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Highly pathogenic avian influenza A/H5N1 viruses continue to circulate in birds and infect humans causing serious illness and death., Methods: In this randomized, observer-blinded study, adults ≥18 years of age (n=841) received 3.75 or 7.5 μg hemagglutinin antigen (HA) of an AS03-adjuvanted (AS03A or AS03B) A/Indonesia/5/2005 H5N1 (subclade 2.1) vaccine (priming), followed by the same HA dose of AS03-adjuvanted A/turkey/Turkey/1/05 H5N1 (clade 2.2) influenza vaccine as a booster 6 or 18 months after priming; an unprimed group received placebo at Day 0, and 3.75 μg HA of AS03A-adjuvanted booster vaccine at 6 and 18 months. Antibody responses were assessed by hemagglutination-inhibition assay (HI). Microneutralization (MN) antibody and cellular immunoassays were assessed in a subset of participants., Results: Geometric mean titers (GMTs) and seroconversion rates (SCRs) were higher in primed vs. unprimed subjects against the booster strain 10 days following booster vaccination at month 6 and month 18. After the booster at 18 months, the lower limit of the 97.5% confidence interval for the difference in SCR and GMT ratios between primed and unprimed subjects was >15% and >2.0, respectively, fulfilling the primary endpoint criteria for superiority against the booster strain. MN and cellular immune responses corresponded with the immunogenicity seen in HI measures., Conclusions: Adults primed with a dose-sparing oil-in-water adjuvanted H5N1 subclade vaccine had rapid and durable antibody responses to a heterologous subclade boosting vaccine given 6 or 18 months later., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Protecting young children from pandemic influenza should also reduce transmission to susceptible adults, including pregnant women., Methods: An open study assessed immunogenicity and reactogenicity of a heterologous booster dose of A/turkey/Turkey/1/2005(H5N1)-AS03B (AS03B is an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion [5.93 mg tocopherol]) in infants and children aged 6 to <36 months that was given 6 months following 2-dose primary vaccination with A/Indonesia/05/2005(H5N1)-AS03B. Vaccines contained 1.9 µg of hemagglutinin antigen and AS03B. Hemagglutinin inhibition (HI) responses, microneutralization titers, and antineuraminidase antibody levels were assessed for 6 months following the booster vaccination., Results: For each age stratum (defined on the basis of the subject's age at first vaccination as 6 to <12 months, 12 to <24 months, and 24 to <36 months) and overall (n=113), European influenza vaccine licensure criteria were fulfilled for responses to A/turkey/Turkey/1/2005(H5N1) 10 days following the booster vaccination. Local pain and fever increased with consecutive doses. Anamnestic immune responses were demonstrated for HI, neutralizing, and antineuraminidase antibodies against vaccine-homologous/heterologous strains. Antibody responses to vaccine-homologous/heterologous strains persisted in all children 6 months following the booster vaccination., Conclusions: Prevaccination of young children with a clade 2 strain influenza A(H5N1) AS03-adjuvanted vaccine followed by heterologous booster vaccination boosted immune responses to the homologous strain and a related clade, with persistence for at least 6 months. The results support a prime-boost vaccination approach in young children for pandemic influenza preparedness., Clinical Trials Registration: NCT01323946., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Prior receipt of a trivalent seasonal influenza vaccine (TIV) can affect hemagglutination inhibition (HI) antibody responses to pandemic influenza vaccines. We investigated the effect of TIV priming on humoral responses to AS03-adjuvanted and nonadjuvanted A(H1N1)pdm09 vaccines, the role of AS03 on cell-mediated immune (CMI) responses, and vaccine safety., Methods: Healthy adults (aged 19-40 years) were randomized 1:1:1:1 to receive TIV or saline followed 4 months later by 2 doses, 3 weeks apart, of adjuvanted or nonadjuvanted A(H1N1)pdm09 vaccine and followed up to study end (day 507). Pre- and postvaccination responses of HI and neutralizing antibody, CD4(+)/CD8(+) T cells, memory B cells, and plasmablasts were assessed., Results: Ninety-nine of the 133 participants enrolled completed the study. No vaccine-related serious adverse events were recorded. In TIV-primed participants, A(H1N1)pdm09-specific antibody and CD4(+) T-cell and memory B-cell responses to the pandemic vaccine tended to be diminished. Vaccine adjuvantation led to increased responses of vaccine-homologous and -heterologous HI and neutralizing antibodies and CD4(+) T cells, homologous memory B cells, and plasmablasts., Conclusions: In healthy adults, prior TIV administration decreased humoral and CMI responses to A(H1N1)pdm09 vaccine. Adjuvantation of A(H1N1)pdm09 antigen helped to overcome immune interference between the influenza vaccines. No safety concerns were observed., Registration: Clinical Trials.gov identifier NCT00707967., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: The vaccine efficacy (VE) of 1 or 2 doses of AS03-adjuvanted influenza A(H1N1) vaccine relative to that of 2 doses of nonadjuvanted influenza A(H1N1) vaccine in children 6 months to <10 years of age in a multinational study conducted during 2010-2011., Methods: A total of 6145 children were randomly assigned at a ratio of 1:1:1 to receive 2 injections 21 days apart of A/California/7/2009(H1N1)-AS03 vaccine at dose 1 and saline placebo at dose 2, 2 doses 21 days apart of A/California/7/2009(H1N1)-AS03 vaccine (the Ad2 group), or 2 doses 21 days apart of nonadjuvanted A/California/7/2009(H1N1) vaccine (the NAd2 group). Active surveillance for influenza-like illnesses continued from days 14 to 385. Nose and throat samples obtained during influenza-like illnesses were tested for A/California/7/2009(H1N1), using reverse-transcriptase polymerase chain reaction. Immunogenicity, reactogenicity, and safety were assessed., Results: There were 23 cases of confirmed 2009 pandemic influenza A(H1N1) (A[H1N1]pdm09) infection for the primary relative VE analysis. The VE in the Ad2 group relative to that in the NAd2 group was 76.8% (95% confidence interval, 18.5%-93.4%). The benefit of the AS03 adjuvant was demonstrated in terms of the greater immunogenicity observed in the Ad2 group, compared with the NAd2 group., Conclusion: The 4-8-fold antigen-sparing adjuvanted pandemic influenza vaccine demonstrated superior and clinically important prevention of A(H1N1)pdm09 infection, compared with nonadjuvanted vaccine, with no observed increase in medically attended or serious adverse events. These data support the use of adjuvanted influenza vaccines during influenza pandemics. Clinical Trials Registration. NCT01051661., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

The study of influenza vaccines has revealed potential interactions between preexisting immunological memory and antigenic context and/or adjuvantation. In the face of antigenic diversity, the process of generating B cell adaptability is driven by cross-reactive CD4 memory cells, such as T follicular helper cells from previous infections or vaccinations. Although such "helped" B cells are capable of adapting to variant antigens, lack of CD4 help could lead to a suboptimal antibody response. Collectively, this indicates an interplay between CD4 T cells, adjuvant, and B cell adaptability., (Copyright © 2014, American Association for the Advancement of Science.)

Discordance between the measured levels of dengue virus neutralizing antibody and clinical outcomes in the first-ever efficacy study of a dengue tetravalent vaccine (Lancet, Nov 2012) suggests a need to re-evaluate the process of pre-screening dengue vaccine candidates to better predict clinical benefit prior to large-scale vaccine trials. In the absence of a reliable animal model and established correlates of protection for dengue, a human dengue virus challenge model may provide an approach to down-select vaccine candidates based on their ability to reduce risk of illness following dengue virus challenge. We report here the challenge of flavivirus-naïve adults with cell culture-passaged dengue viruses (DENV) in a controlled setting that resulted in uncomplicated dengue fever (DF). This sets the stage for proof-of-concept efficacy studies that allow the evaluation of dengue vaccine candidates in healthy adult volunteers using qualified DENV challenge strains well before they reach field efficacy trials involving children. Fifteen flavivirus-naïve adult volunteers received 1 of 7 DENV challenge strains (n=12) or placebo (n=3). Of the twelve volunteers who received challenge strains, five (two DENV-1 45AZ5 and three DENV-3 CH53489 cl24/28 recipients) developed DF, prospectively defined as ≥2 typical symptoms, ≥48h of sustained fever (>100.4°F) and concurrent viremia. Based on our study and historical data, we conclude that the DENV-1 and DENV-3 strains can be advanced as human challenge strains. Both of the DENV-2 strains and one DENV-4 strain failed to meet the protocol case definition of DF. The other two DENV-4 strains require additional testing as the illness approximated but did not satisfy the case definition of DF. Three volunteers exhibited effusions (1 pleural/ascites, 2 pericardial) and 1 volunteer exhibited features of dengue (rash, lymphadenopathy, neutropenia and thrombocytopenia), though in the absence of fever and symptoms. The occurrence of effusions in milder DENV infections counters the long-held belief that plasma leakage syndromes are restricted to dengue hemorrhagic fever/dengue shock syndromes (DHF/DSS). Hence, the human dengue challenge model may be useful not only for predicting the efficacy of vaccine and therapeutic candidates in small adult cohorts, but also for contributing to our further understanding of the mechanisms behind protection and virulence., (Published by Elsevier Ltd.)

Clinical trials have shown that AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines are highly immunogenic, although with an increased reactogenicity profile relative to non-adjuvanted vaccines in terms of the incidence of common injection site and systemic adverse events (AEs). We evaluated pooled safety data from 22,521 adults who had received an AS03-adjuvanted H5N1 or A(H1N1)pdm09 influenza or control vaccine with the purpose to identify medically-attended AEs (MAEs), including subsets of serious AEs (SAEs), potentially immune-mediated diseases (pIMDs), and AEs of special interest (AESI), and to explore a potential association of these AEs with the administration of an AS03-adjuvanted influenza vaccine. For participants who had received an AS03-adjuvanted vaccine, the relative risks (RRs) for experiencing a MAE or a SAE compared to control group (participants who had received a non-adjuvanted vaccine or saline placebo) were 1.0 (95% confidence interval [CI]: 0.9; 1.1) and 1.1 (95% CI: 0.9; 1.4), respectively. The overall RRs for experiencing an AESI or a pIMD (AS03-adjuvanted vaccine/control) were 1.2 (95% CI: 0.9; 1.6) and 1.7 (95% CI: 0.8; 3.8), respectively. Thirty-8 participants in the AS03-adjuvanted vaccine group had a pIMD reported after vaccine administration, yielding an incidence rate (IR) of 351.9 (95% CI: 249.1; 483.1) per 100,000 person-years. The estimated IRs in the AS03-adjuvanted vaccine group were greater than the literature reported rates for: facial paresis/VIIth nerve paralysis, celiac disease, thrombocytopenia and ulcerative colitis. These results do not support an association between AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines and the AEs collected in the trials included in the analysis.

This paper describes an international collaboration to carry out studies that contributed to the understanding of pathogenesis, diagnosis, treatment, and prevention of several diseases of public health importance for Thailand and the United States. In Kamphaeng Phet Province, Thailand, febrile syndromes, including encephalitis, hepatitis, hemorrhagic fever, and influenza-like illnesses, occurred commonly and were clinically diagnosed, but the etiology was rarely confirmed. Since 1982, the Kamphaeng Phet Provincial Hospital, the Thai Ministry of Public Health, and the US Army Component of the Armed Forces Research Institute of Medical Sciences, along with vaccine manufacturers and universities, have collaborated on studies that evaluated and capitalized on improved diagnostic capabilities for infections caused by Japanese encephalitis, hepatitis A, dengue, and influenza viruses. The collaboration clarified clinical and epidemiological features of these infections and, in large clinical trials, demonstrated that vaccines against Japanese encephalitis and hepatitis A viruses were over 90% efficacious, supporting licensure of both vaccines. With the introduction of Japanese encephalitis vaccines in Thailand's Expanded Program on Immunization, reported encephalitis rates dropped substantially. Similarly, in the US, particularly in the military populations, rates of hepatitis A disease have dropped with the use of hepatitis A vaccine. Studies of the pathogenesis of dengue infections have increased understanding of the role of cellular immunity in responding to these infections, and epidemiological studies have prepared the province for studies of dengue vaccines. Approximately 80 publications resulted from this collaboration. Studies conducted in Kamphaeng Phet provided experience that contributed to clinical trials of hepatitis E and HIV vaccines, conducted elsewhere. To provide a base for continuing studies, The Kamphaeng Phet-AFRIMS Virology Research Unit (KAVRU) was established. This paper reviews the origins of the collaboration and the scientific observations made between 1982 and 2012., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Pandemic influenza vaccine manufacturing capacity and distribution agility is enhanced through the availability of equivalent antigen-sparing vaccines. We evaluated equivalence in terms of immunogenicity between GlaxoSmithKline Vaccines' A/California/7/2009 (H1N1)v-like-AS03 vaccines manufactured in Dresden (D-Pan), and Quebec (Q-Pan)., Methods: In two studies, 334 adults 18-60 years of age received 2 doses of D-Pan or Q-Pan containing 3.75 μg haemagglutinin antigen (HA) adjuvanted with AS03A administered 21 days apart, and 209 children 3-9 years of age received 1 reduced dose of D-Panor Q-Pan (0.9 μg HA) or Q-Pan (1.9 μg HA) with AS03B. Haemagglutination inhibition (HI) titres were assessed before and 21 days post-vaccination. HI persistence was assessed after 12 months in adults and 6 months in children., Results: Pre-defined criteria for immunological equivalence of Q-Pan versus D-Pan were achieved in both populations. After one vaccine dose, ≥97.6% of adults and children had HI titres ≥1:40, with increases in titre ≥25.7-fold. CHMP and CBER regulatory acceptance criteria for influenza vaccines were exceeded by all groups in both studies at Day 21. In adults,the percentage with HI titres ≥1:40 at Month 12 was 82.9% (Q-Pan) and 84.0% (D-Pan). In children, the percentages at Month 6 were 75.3.3% (Q-Pan0.9), 85.1% (D-Pan0.9) and 79.3% (Q-Pan1.9). Safety profile of the study vaccines was consistent with previously published data., Conclusion: Two studies indicate that A/California/7/2009 (H1N1)v-like HA manufactured at two sites and combined with AS03 are equivalent in terms of immunogenicity in adults and children and highly immunogenic. Different HA doses elicited an adequate immune response through 180 days post-vaccination in children 3-9 years of age., Trial Registration: ClinicalTrials.gov: NCT00979407 and NCT01161160.

Background: This study (NCT00979602) evaluated the immunogenicity and relative protective efficacy of one dose of influenza A(H1N1)pdm09 vaccine with or without AS03 (an α-tocopherol oil-in-water emulsion based Adjuvant System)., Methods: Four thousands and forty-eight healthy adults aged ≥ 18 years were randomized (1:1) to receive one dose of either the adjuvanted split virion (3.75 μg hemagglutinin antigen [HA]/AS03) or non-adjuvanted (15 μg HA) vaccine. Hemagglutination inhibition [HI] antibody response was evaluated before vaccination and at Days 21, 42 and 182 (Month 6). Safety of the study vaccines was evaluated during the entire study duration., Results: At Day 21, both study vaccines induced HI immune responses meeting the US regulatory criteria in subjects 18-64 years (seroprotection rate [SPR]: 98.0% [97.1-98.6]; seroconversion rate [SCR]: 89.7% [88.0-91.2] in the AS03-adjuvanted group; SPR: 91.4% [89.9-92.8]; SCR: 74.6% [72.3-76.9] in the non-adjuvanted group) and >64 years of age (SPR: 86.0% [82.5-89.0]; SCR: 75.3% [71.1-79.2] in the AS03-adjuvanted group; SPR: 69.1% [64.6-73.3]; SCR: 56.7% [52.0-61.3] in the non-adjuvanted group). The AS03-adjuvanted vaccine induced higher HI geometric mean titers than the non-adjuvanted vaccine at all time points. At Month 6, only subjects 18-64 years of age from both vaccine groups still met the US regulatory criteria (SPR: 82.1% [80.0-84.1]; SCR: 62.3% [59.6-64.8] in the AS03-adjuvanted group; SPR: 75.3% [72.9-77.5]; SCR: 53.7% [51.0-56.4] in the non-adjuvanted group). Protective efficacy was not evaluated due to low number of RT-qPCR-confirmed A(H1N1)pdm09 influenza cases. Through Month 12, 216 serious adverse events (in 157 subjects: 84 in the AS03-adjuvanted and 73 in the non-adjuvanted group) and 12 potentially immune mediated diseases (5 in the AS03-adjuvanted and 7 in the non-adjuvanted group) were reported., Conclusion: A single dose of either adjuvanted or non-adjuvanted influenza A(H1N1)pdm09 vaccine induced protective HI antibody levels against the A/California/7/2009 strain that persisted through Month 6 in the 18-64 years population., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Unlabelled: Conservative non-surgical management of a herniated lumbar intervertebral disc (HLD) in athletes is a complex task due to the dramatic forces imparted on the spine during sport participation. The demands placed upon the athlete during rehabilitation and return to sport are unique not only from a sport specific perspective, but also regarding return to the sport strength and conditioning programs utilized for sport preparation. Many prescriptions fail to address postural and motor control faults specific to athletic development, which may prevent full return to sport after suffering a HLD or predispose the athlete to future exacerbations of a HLD. Strength exercises involving squatting, deadlifting, and Olympic power lifts are large components of the typical athlete's conditioning program, therefore some progressions are provided to address potential underlying problems in the athlete's technique that may have contributed to their HLD in the first place. The purpose of this clinical commentary is to propose a framework for rehabilitation that is built around the phases of healing of the disc. Phase I: Non-Rotational/Non-Flexion Phase (Acute Inflammatory Phase), Phase II: Counter rotation/Flexion Phase (Repair Phase), Phase III: Rotational Phase/Power development (Remodeling Phase), and Phase IV: Full return to sport. This clinical commentary provides a theoretical basis for these phases based on available literature as well as reviewing many popular current practice trends in the management of an HLD. The authors recognize the limits of any general exercise rehabilitation recommendation with regard to return to sport, as well as any general strength and conditioning program. It is vital that an individual assessment and prescription is made for every athlete which reviews and addresses movement in all planes of motion under all necessary extrinsic and intrinsic demands to that athlete., Level of Evidence: 5.

Background: Protection against dengue requires immunity against all 4 serotypes of dengue virus (DENV). Experimental challenge may be useful in evaluating vaccine-induced immunity., Methods: Ten subjects previously vaccinated with a live attenuated tetravalent dengue vaccine (TDV) and 4 DENV-naive control subjects were challenged by subcutaneous inoculation of either 10(3) plaque-forming units (PFU) of DENV-1 or 10(5) PFU of DENV-3. Two additional subjects who did not develop DENV-3 neutralizing antibody (NAb) from TDV were revaccinated with 10(4) PFU of live attenuated DENV-3 vaccine to evaluate memory response., Results: All 5 TDV recipients were protected against DENV-1 challenge. Of the 5 TDV recipients challenged with DENV-3, 2 were protected. All DENV-3-challenge subjects who developed viremia also developed elevated liver enzyme levels, and 2 had values that were >10 times greater than normal. Of the 2 subjects revaccinated with DENV-3 vaccine, 1 showed a secondary response to DENV-2, while neither showed such response to DENV-3. All 4 control subjects developed dengue fever from challenge. Protection was associated with presence of NAb, although 1 subject was protected despite a lack of measurable NAb at the time of DENV-1 challenge., Conclusions: Vaccination with TDV induced variable protection against subcutaneous challenge. DENV-3 experimental challenge was associated with transient but marked elevations of transaminases.

Chikungunya virus, transmitted by mosquitoes to man, causes an acute illness characterized by fever, rash and striking joint symptoms. US Military investigators developed, manufactured at The Salk Institute-Government Services Division (TSI-GSD), and tested the live, attenuated Chikungunya Vaccine TSI-GSD-218. The manufacturing facility stopped production in 1994. The Chikungunya Vaccine TSI-GSD-218 development effort was terminated in 1998, and materials were archived. In 2005, an alarming outbreak of chikungunya disease began in Africa and spread to islands in the Indian Ocean and throughout much of Asia. Abrupt epidemics with high attack rates and serious, even fatal, complications were reported, and travelers carried the virus to Europe and the Americas. In response to urgent requests, the US Military offered assistance by providing non-exclusive access to the previously stored vaccine production seed materials, bulk vaccine, regulatory documentation, and reports of previous clinical trials. Five companies requested technology transfers. This experience provides lessons about epidemiological unpredictability, preparedness, vaccine manufacturing, the potential global importance of vaccine seed materials and the advisability of a global strategic plan. Consideration should be given to banking of vaccine production seeds, cell substrates, and manufacturing instructions. In view of the manufacturability, attenuation, and immunogenicity of Chikungunya Vaccine TSI-GSD-218, authorities may wish to consider this product as a possible candidate itself, as a comparator vaccine to improve upon, as a seed for inactivated vaccine, or as a source of virus or antigen for neutralization assays or immunoassays., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Although much has been written about the efficacy of manual therapy interventions for adults with headaches or spinal pain, little research has focused on the use of these interventions in pediatric patients. The purpose of this systematic review was to evaluate the evidence for spinal manual therapy (SMT) interventions in patients 4-17 years old with headaches and/or mechanical spinal pain., Methods: A search for relevant studies published in the past 15 years was conducted on MEDLINE, CINAHL, Cochrane Central Register of Randomized Control Trials, PEDro, PubMed, and Sports Discus. Only English language articles were reviewed. Studies had to include at least one outcome measure for pain, function, or quality of life. Studies evaluating post-operative interventions, or those in which the interventions were directed at influencing excessive spinal curvatures, were excluded. Case reports and studies that did not limit analysis of the results to the pediatric population were also excluded., Results: Two randomized control trials and two studies offering lower levels of evidence were identified in the literature search. The latter studies were prospective cohort studies. The four studies were evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria., Discussion: There are very little data in the literature to support or refute the use of SMT interventions in pediatric patients. Further research is required to establish a strong evidence-based foundation for use of these interventions in children.

Background: During the 2009-2010 influenza pandemic, we evaluated the immunogenicity and safety of different H1N1 2009 pandemic influenza vaccines delivering various viral hemagglutinin (HA) doses with or without AS03 (a tocopherol oil-in-water emulsion-based adjuvant system) in children (NCT00976820)., Methods: Three hundred twenty-two healthy children 6 months to <9 years of age were randomized to receive 2 doses of nonadjuvanted (15 µg or 7.5 µg HA) or adjuvanted vaccine (3.75 µg HA/AS03A or 1.9 µg HA/AS03B), 21 days apart. Blood samples before and after each dose were tested for immune responses using hemagglutination inhibition and microneutralization assays. Safety assessments were done up to day 385., Results: The first dose of both AS03-adjuvanted vaccines elicited strong immune responses (seroprotection rates: 98.3%/99.0%; seroconversion rates: 94.9%/97.0%; geometric mean fold rises: 36.2/33.6), which were higher post-dose 2 (seroprotection rate: 100.0%/100%; seroconversion rate: 100.0%/98.8%; geometric mean fold rise: 157.1/151.6), meeting European regulatory criteria on days 21 and 42. The nonadjuvanted 15 µg HA vaccine also met the regulatory criteria after each dose; the 7.5 µg HA vaccine met them only post-dose 2. Six months post-dose 1, all vaccines except the nonadjuvanted 7.5 µg HA vaccine met European regulatory criteria. Neutralizing antibody response paralleled the hemagglutination inhibition immune response after each dose. Pain at the injection site, lasting 2-3 days, was more common following adjuvanted than nonadjuvanted vaccination., Conclusions: AS03-adjuvanted H1N1 2009 pandemic influenza vaccine (3.75 µg or 1.9 µg HA), administered as 2 doses, was highly immunogenic, induced long-term immune response to 6 months, with a clinically acceptable safety profile in children aged 6 months to <9 years of age.

This study evaluated the long-term persistence of immune response and safety of two doses of an A/California/7/2009 H1N1 pandemic influenza vaccine adjuvanted with AS03 (an α-tocopherol oil-in-water emulsion-based Adjuvant System) in Japanese children (NCT01001169). Sixty healthy subjects aged 6 mo-17 y were enrolled (1:1) into two study groups to receive 21 d apart, two doses of 1.9 µg haemagglutinin [HA]+AS03B (5.93 mg α-tocopherol) vaccine (6 mo-9 y) and 3.75 µg HA+AS03A (11.86 mg α-tocopherol) vaccine (10-17 y), respectively. Immunogenicity data (by haemagglutination inhibition [HI] and microneutralisation assays) to six months after the first vaccine dose are reported here. It was observed that following Dose 2, the HI immune response against the vaccine homologous strain induced by the two different dosages of the AS03-adjuvanted vaccine met and exceeded the US and European regulatory guidance criteria for pandemic influenza vaccines (seroprotection rate[SPR]/seroconversion rate[SCR]: 100%/100%; geometric mean fold rise GMFR: 146.8/57.1). Further, the immune response persisted for at least six months after the first vaccine dose wherein these regulatory criteria were still met (SPR: 100%/100%; SCR: 96.4%/89.7%; GMFR: 25.3/23.5). The neutralising antibody response was comparable to the HI immune response at Day 42 (vaccine response rate [VRR]: 100%/100%) and at Day 182 (VRR: 96.4%/82.8%). Overall, both vaccine dosages had a clinically acceptable safety profile. Thus, two doses of a 1.9 µg or 3.75 µg HA AS03-adjuvanted H1N1 2009 pandemic influenza vaccine in children aged 6 mo-17 y induced strong immune responses against the vaccine homologous strain that persisted for at least six months after the first vaccine dose.

AS03 is an Adjuvant System composed of α-tocopherol, squalene and polysorbate 80 in an oil-in-water emulsion. In various nonclinical and clinical studies, high levels of antigen-specific antibodies were obtained after administration of an AS03-adjuvanted vaccine, permitting antigen-sparing strategies. AS03 has been shown to enhance the vaccine antigen-specific adaptive response by activating the innate immune system locally and by increasing antigen uptake and presentation in draining lymph nodes, a process that is modulated by the presence of α-tocopherol in AS03. In nonclinical models of the AS03-adjuvanted prepandemic H5N1 influenza vaccine, increased levels of anti-influenza antibody afforded protection against disease and against virus replication of influenza strains homologous and heterologous to the vaccine strain. By incorporating AS03 in the pandemic H1N1/2009 vaccine, vaccine immunogenicity was increased compared with nonadjuvanted H1N1 vaccines. High H1N1/2009/AS03 vaccine effectiveness was demonstrated in several assessments in multiple populations. Altogether, the nonclinical and clinical data illustrate the ability of AS03 to induce superior adaptive responses against the vaccine antigen, principally in terms of antibody levels and immune memory. In general, these results support the concept of Adjuvant Systems as a plausible approach to develop new effective vaccines.

One influenza pandemic preparedness strategy involves priming a population with a pre-pandemic subtype-specific vaccine and boosting the immunological response at the time of the pandemic with a strain-matched vaccine. In the current study, adults (n=469) randomised 15 months previously to receive an A/Indonesia/5/2005 (H5N1) influenza vaccine (3.75 μg haemagglutinin antigen [HA]) administered alone or in combination with an oil-in-water emulsion based Adjuvant System containing 11.86 mg (AS03(A)) or 5.93 mg (AS03(B)) tocopherol per dose, received one booster dose of A/turkey/Turkey/1/2005 (H5N1) vaccine (3.75 μg HA) with or without AS03(A). An anamnestic antibody response that met US regulatory acceptance criteria was observed 15 months after priming. Although superior immunogenicity of AS03-adjuvanted compared to unadjuvanted priming was not demonstrated, higher antibody titres which persisted longer were seen when both priming and boosting regimens were adjuvanted. This may affect duration of response or heterologous immunity. The booster vaccines had a clinically acceptable safety/reactogenicity profile after adjuvanted or unadjuvanted priming. This study has been registered at www.clinicaltrials.gov NCT00771615., (Copyright © 2011 Elsevier Ltd. All rights reserved.)