The n e w e ng l a n d j o u r na l of m e dic i n e c or r e sp ondence Vaccine for Prevention of Influenza in Children To the Editor: Jain et al. (Dec. 26 issue)1 claim that a quadrivalent influenza vaccine (QIV) is efficacious in preventing influenza in children, although their efficacy data are similar to those obtained with the use of the traditional trivalent influenza vaccine (TIV).2 What additional benefit does QIV offer over TIV? Why did they randomly assign patients to receive QIV or hepatitis A vaccine rather than QIV or TIV? We do not think that developing vaccines simply on the basis of including the hemagglutinin antigens of “best guess” A and B strains is sufficient for the global prevention of influenza because it does not avoid the risk of a mismatch between the influenza A strains selected for the vaccine and those actually circulating during the influenza season,3 nor does it reduce the delay in the availability of pandemic vaccines.4 Cross-reactive human B-cell and T-cell epitopes between influenza A and B strains have been identified recently in humans.5 Would it not be more appropriate to consider new strategies on the basis of conserved vaccine targets as a means of providing global protection against influenza? Susanna Esposito, M.D. Università degli Studi di Milano Milan, Italy [email protected] Nicola Principi, M.D. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico Milan, Italy No potential conflict of interest relevant to this letter was reported. 1. Jain VK, Rivera L, Zaman K, et al. Vaccine for prevention of mild and moderate-to-severe influenza in children. N Engl J Med 2013;369:2481-91. 2. DiazGranados CA, Denis M, Plotkin S. Seasonal influenza vaccine efficacy and its determinants in children and non-elderly adults: a systematic review with meta-analyses of controlled trials. Vaccine 2012;31:49-57. 3. Chen J, Deng YM. Influenza virus antigenic variation, host antibody production and new approach to control epidemics. Virol J 2009;6:30. 4. Partridge J, Kieny MP. Global production of seasonal and pandemic (H1N1) influenza vaccines in 2009-2010 and comparison with previous estimates and global action plan targets. Vaccine 2010;28:4709-12. 5. Terajima M, Babon JA, Co MD, Ennis FA. Cross-reactive human B cell and T cell epitopes between influenza A and B viruses. Virol J 2013;10:244. DOI: 10.1056/NEJMc1400874 The Authors Reply: Because efficacy estimates of inactivated TIV in children were not robust, we evaluated the benefit of inactivated QIV measured as absolute efficacy (as compared with hepatitis A vaccine, not TIV) to show the underappreciated benefits of vaccinating healthy children to prevent moderate-to-severe influenza and to reduce clinic visits, hospitalization, and school and parental-work absenteeism. The A subtype and B lineage–specific vaccine efficacy estimates that we generated also apply to TIV made by the same process. The additional benefit of QIV is direct protection against both B types in the vaccine. This is supported by its efficacy against the three strains prevalent in the trial and its similar immunogenicity for all four vaccine strains, whereas, in children 3 to 8 years old, TIV is far less immunogenic than QIV against the added B strain in QIV.1,2 We acknowledge that inactivated influenza vaccines are limited because they immunize prethis week’s letters 1167 Vaccine for Prevention of Influenza in Children 1168 JAK Inhibitor in CALR-Mutant Myelofibrosis 1170 Acute Liver Failure 1171 Increased Phenylephrine Plasma Levels with Administration of Acetaminophen 1172 Speech in an Orally Intubated Patient n engl j med 370;12 nejm.org march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org by GHASSAN DBAIBO DBAIBO on March 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved. 1167 The n e w e ng l a n d j o u r na l of m e dic i n e dominantly against the globular head of hemag- Bruce L. Innis, M.D. glutinin, which drifts.3 We agree that the ulti- GlaxoSmithKline Vaccines mate goal is a vaccine that is based on conserved King of Prussia, PA Since publication of their article, the authors report no furtargets that could eliminate annual vaccination. Nevertheless, our study shows the health ther potential conflict of interest. gains accruable now by administering QIV to 1. Langley JM, Carmona Martinez A, Chatterjee A, et al. Immunogenicity and safety of an inactivated quadrivalent influenchildren. za vaccine candidate: a phase III randomized controlled trial in children. J Infect Dis 2013;208:544-53. 2. Domachowske JB, Pankow-Culot H, Bautista M, et al. A randomized trial of candidate inactivated quadrivalent influenza vaccine versus trivalent influenza vaccines in children aged 3-17 years. J Infect Dis 2013;207:1878-87. 3. Krammer F, Palese P. Universal influenza virus vaccines: need for clinical trials. Nat Immunol 2014;15:3-5. Varsha K. Jain, M.D., M.P.H. GlaxoSmithKline Vaccines King of Prussia, PA Ghassan Dbaibo, M.D. American University of Beirut Beirut, Lebanon [email protected] DOI: 10.1056/NEJMc1400874 JAK Inhibitor in CALR-Mutant Myelofibrosis 1168 30 160 140 25 Platelets (×10−3/mm3) 20 15 Spleen size (cm BCM) 120 100 80 60 10 Hemoglobin(g/dl) Platelets White Cells, Hemoglobin, Spleen Size 40 5 0 White cells 0 (×10−3/mm3) 4 8 12 20 16 20 24 0 Weeks from Baseline B Patient with p.L367fs*48 Mutation 35 Platelets (×10−3/mm3) 140 30 120 25 100 20 80 Spleen size (cm BCM) 15 60 10 Hemoglobin(g/dl) 40 5 0 160 Platelets Figure 1. Effect of JAK Inhibitor Fedratinib in Two Patients with CALR-Mutated Myelofibrosis. The graphs show the white-cell count, hemoglobin level, platelet count, and spleen size (as measured in centimeters below the costal margin [cm BCM]) over a period of 6 months in two patients with CALR mutations who received the JAK inhibitor fedratinib. The treatment is currently interrupted owing to a hold on clinical trials due to safety concerns. Patients were evaluated with the Dynamic International Prognostic Scoring System (DIPSS),5 which uses five risk factors to predict survival: an age older than 65 years, a hemoglobin level of less than 10 g per deciliter, a white-cell count of more than 25,000 per cubic millimeter, circulating blasts of at least 1%, and constitutional symptoms. Panel A shows results from a 38-year-old man who had received a diagnosis of primary myelofibrosis 11 years before enrollment in our study. He received fedratinib when the DIPSS score indicated intermediate-2 risk (hemoglobin, 8.3 g per deciliter; blasts, 2%). Panel B shows results from a 67-year-old woman who had received a diagnosis of primary myelofibrosis 7 years before enrollment. She received fedratinib when the DIPSS score indicated high risk (age, 67 years; hemoglobin, 8.6 g per deciliter; blasts, 6%; and night sweats). A Patient with p.L367fs*46 Mutation White Cells, Hemoglobin, Spleen Size To the Editor: Janus kinase (JAK) inhibitors are new targeted therapies for myelofibrosis that reduce the palpable spleen size to 50% of the baseline measurement in approximately 40% of patients and improve symptoms in the majority of them.1,2 In studies of myelofibrosis, Klampfl et al.3 and Nangalia et al.4 (Dec. 19 issue) found that mutations in CALR (the gene encoding calreticulin) 20 White cells (×10−3/mm3) 0 4 8 12 16 20 24 0 Weeks from Baseline n engl j med 370;12 nejm.org march 20, 2014 The New England Journal of Medicine Downloaded from nejm.org by GHASSAN DBAIBO DBAIBO on March 24, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.