Relative Efficacy of AS03-Adjuvanted Pandemic Influenza A(H1N1) Vaccine in Children: Results of a Controlled, Randomized Efficacy Trial

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.GlaxoSmithKline BiologicalsUniv Melbourne, Murdoch Childrens Res Inst, Carlton, Vic 3010, AustraliaUniv Melbourne, Melbourne Sch Populat & Global Hlth, Carlton, Vic 3010, AustraliaGlaxoSmithKline Vaccines, King of Prussia, PA USANovavax, Rockville, MD USAMary Chiles Gen Hosp, Dept Pediat, Manila, PhilippinesDe La Salle Hlth Sci Inst, Dept Pediat, Dasmarinas City, PhilippinesRes Inst Trop Med, Dept Hlth, Muntinlupa, PhilippinesUniversidade Federal de São Paulo, Dept Pediat, São Paulo, BrazilFac Ciencias Med Santa Casa São Paulo, Dept Pediat, São Paulo, BrazilAssoc Fundo Incent Pesquisa, São Paulo, BrazilInst Costarricense Invest Clin, San Jose, Costa RicaNatl Inst Publ Hlth Mexico, Cuernavaca, Morelos, MexicoUniv Autonoma Nuevo Leon, Serv Med, Monterrey, MexicoInst Nacl Pediat Mexico, Mexico City, DF, MexicoHosp Gen Durango, Durango, MexicoPhramongkutklao Hosp, Infect Dis Unit, Dept Pediat, Bangkok, ThailandKhon Kaen Univ, Dept Pediat, Fac Med, Khon Kaen, ThailandNatl Healthcare Grp Polyclin, Singapore, SingaporeCtr Estudios Infect Pediat, Cali, ColombiaGlaxoSmithKline Vaccines, Wavre, BelgiumGlaxoSmithKline Vaccines, Rixensart, BelgiumUniversidade Federal de São Paulo, Dept Pediat, São Paulo, BrazilWeb of Scienc

Immunogenicity and Safety of a Trivalent Inactivated Influenza Vaccine in Children 6 Months to 17 Years of Age, Previously Vaccinated with an AS03-Adjuvanted A(H1N1)Pdm09 Vaccine: Two Open-label, Randomized Trials.

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

A phase I, open-label, dose-finding study of GSK2636771, a PI3Kb inhibitor, administered with enzalutamide in patients with metastatic castration-resistant prostate cancer

PurposeIn patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR) targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory phosphatase and tensin homolog (PTEN) activates phosphoinositide 3-kinase (PI3K)/AKT signaling and contributes to resistance to androgen-deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance.Patients and methodsIn this Phase I study (NCT02215096), patients with PTEN-deficient mCRPC, who progressed on prior enzalutamide, received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100 mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended Phase II dose (RP2D), and assess the 12-week non-progressive disease (PD) rate.ResultsOverall, 37 patients were enrolled; 36 received {greater than or equal to}1 dose of GSK2636771 (200 mg: n=22, 300 mg: n=12; 400 mg: n=2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n=1; 300 mg: n=2, 400 mg: n=2). No new or unexpected adverse events nor evidence of drug-drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% CI: 28.2-71.8%, n=22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. 4/34 (12%) patients had prostate-specific antigen reduction of {greater than or equal to}50%.ConclusionsAlthough there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed

IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility to herpesvirus infection and hematologic malignancy as well as a deficiency of NK cell function. It is caused by defective WAS protein (WASp). WASp facilitates filamentous actin (F-actin) branching and is required for F-actin accumulation at the NK cell immunological synapse and NK cell cytotoxicity ex vivo. Importantly, the function of WASp-deficient NK cells can be restored in vitro after exposure to IL-2, but the mechanisms underlying this remain unknown. Using a WASp inhibitor as well as cells from patients with WAS, we have defined a direct effect of IL-2 signaling upon F-actin that is independent of WASp function. We found that IL-2 treatment of a patient with WAS enhanced the cytotoxicity of their NK cells and the F-actin content at the immunological synapses formed by their NK cells. IL-2 stimulation of NK cells in vitro activated the WASp homolog WAVE2, which was required for inducing WASp-independent NK cell function, but not for baseline activity. Thus, WAVE2 and WASp define parallel pathways to F-actin reorganization and function in human NK cells; although WAVE2 was not required for NK cell innate function, it was accessible through adaptive immunity via IL-2. These results demonstrate how overlapping cytoskeletal activities can utilize immunologically distinct pathways to achieve synonymous immune function

Respiratory viruses and influenza-like illness: Epidemiology and outcomes in children aged 6 months to 10 years in a multi-country population sample

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 medicallyattended 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. (C) 2016 Published by Elsevier Ltd on behalf of The British Infection Association.GlaxoSmithKline Biologicals S.AGSK Vaccines, 20 Ave Fleming, B-1330 Wavre, BelgiumCtr Estudios Infectol Pediat, Cali, ColombiaUniv Fed Sao Paulo, Dept Pediat, Pediat Infect Dis, Sao Paulo, BrazilRes Inst Trop Med, Dept Hlth, Muntinlupa, PhilippinesInst Costarricense Invest Clin, San Jose, Costa RicaNatl Inst Publ Hlth Mexico, Cuernavaca, Morelos, MexicoPhramongkutklao Hosp, Dept Pediat, Infect Dis Unit, Bangkok, ThailandInst Nacl Pediat Mexico, Mexico City, DF, MexicoUniv Autonoma Nuevo Leon, Med Serv, Monterrey, MexicoHosp Gen Durango, Durango, MexicoFac Ciencias Med Santa Casa Sao Paulo, Sao Paulo, BrazilAssoc Fundo Incent Pesquisa, Dept Pediat, Sao Paulo, BrazilNatl Univ Singapore, Natl Healthcare Grp Polyclin, Singapore, SingaporeGSK Vaccines, King Of Prussia, PA USAUniv Melbourne, Murdoch Childrens Res Inst, Carlton, Vic, AustraliaUniv Melbourne, Melbourne Sch Populat & Global Hlth, Carlton, Vic, AustraliaPediatric Infectious Diseases, Department of Pediatrics, Universidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Relative efficacy of AS03-adjuvanted pandemic influenza A(H1N1) vaccine in children: Results of a controlled, randomized efficacy trial

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 /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. © 2014 The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America