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Download A phase 1/2 study of an adjuvanted varicella-zoster virus - E
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A phase 1/2 study of an adjuvanted varicella-zoster virus subunit vaccine in autologous cell transplant recipients Stadtmauer EA et al. Blood 2014; 124: 2921 -2929 Νικόλαος-ΑνδρέαςΑναστασόπουλος Μάθημα Επιλογής «Λευχαιμίες» Varicella-Zoster Virus DS DNA virus with the typical herpesviridae structure 7 glycoproteins (gB, gC, gE, gH, gI, gK, gL) typical nuclear inclusions and multinucleate giant cells identical to those of HSV -structure latent virus in neurones and satellite cells in sensory ganglia -pathogenicity -clinical manifestations reactivation age>60 – immunocompromised (T cell immunodeficiency) vesiculobullous erythema, disseminated skin infection, CNS infection, pneumonia, hepatitis, post-herpetic neuralgia, ophthalmic zoster (skin and ocular lesions), Ramsay-Hunt syndrome, blood disorders Mandell, Douglas and Bennett’s Principles and Practice of Infectious Disease 8th Edition Varicella-Zoster Virus VZV showing the virus envelope glycoprotein I (gE) labelled with monoclonal antibody and goat anti-mouse IgG conjugated with 15 nm colloidal gold Greenwood, Slack, Berer, Irving Medical Microbiology, 18th edition Why was this study conducted? Edward A. Stadtmauer et al. Blood 2014;124:2921-2929 HCTx recipients are susceptible to early VZV infection Studies have demonstrated that live attenuated VZV vaccines are immunogenic in these pts – safety? Is an adjuvanted gE vaccine immunogenic and safe enough to use in the early postHCTx period? NCT00920218 (clinicaltrials.gov) Phase 1/2a Study Design I Edward A. Stadtmauer et al. Blood 2014;124:2921-2929 Observer blind – Randomized – Placebo controlled N = 121 pts 121 pts were randomized - 1:1:1:1 – 1 pt not vaccinated Taking into account underlying disease Patient Characteristics Age>18 MM or B/T cell NHL or HL or AML Autologous HCT in the previous 50-70 days Women of non-child-bearing potential Exclusion Criteria Previous VZV/HZ vaccination Hx of VZV infection within the previous 12 months Exposure to VZV post HCTx Immunoglobulin Rx or vaccination post HCTx Acute infection upon enrollment Contraindication to vaccination (ie allergies) Receiving any investigational product 30 days ago – throughout the whole study Study Design II Edward A. Stadtmauer et al. Blood 2014;124:2921-2929 ©2014 by American Society of Hematology Demographics 110 pts completed study up until month 4 98 subjects completed follow up period (15) Recurrent malignancy -6 to 32 !!! Edward A. Stadtmauer et al. Blood 2014;124:2921-2929 Safety and Adverse events I Edward A. Stadtmauer et al. Blood 2014;124:2921-2929 Adverse events: solicited: local reactions (pain, redness, oedema) vs general (fever, headache, fatigue, myalgia, gi tract symptoms) – reported by “educated” pts on diary cards for 7 days after each vaccination unsolicited: reported by pts on cards throughout the study and up to 3o days after last vaccination – cause of AE investigated by researchers Recurrence of malignancy, new onset auto-immune disease, immune-mediated inflammatory disorders – documented throughout the study Safety and Adverse Events II Measuring Response to vaccination Edward A. Stadtmauer et al. Blood 2014;124:2921-2929 Serum anti-gE Ab concentration ELISA / cutoff value = 18 mIU/mL Intracellular cytokine staining VZV specific CD4+ & CD8+ T-cells Markers: IFN-gamma, IL-2, TNF-a, CD40L At least 2 of the above mentioned Results Safety and Adverse Events III TABLE 3 -Solicited – most common local: pain general: myalgia -Unsolicited – vaccine related: chills 54 SAE events in 33 pts 1 pneumonia event (2x gE/AS01B) 9 died – none due to to the vaccine NO autoimmune 4 VZV pts – 2 in the gE/AS01E & 2 in the saline Humoral, Cellular and Combined Immune Response Humoral: ALL but (1) had antigE before vac ALL had antigE after vac (4x increase in GMC or 4x Min conc in seroneg) peak in the 4th month (but not as high as expected after 2nd vac) better response: 3x DOSEs AFTER 15th month: 54.5% had antibodies DISEASE AFFECTS HUMORAL RESPONSE Cell-mediated: 2x increase in CD4+(2+) cells BEST 3x AS01B (100%) BUT none did signif. Better! Combined: 3x gE/AS01B > 2x AS01B>AS01E Antiglycoprotein E humoral and cell-mediated immune response rates. Edward A. Stadtmauer et al. Blood 2014;124:2921-2929 ©2014 by American Society of Hematology Take-home message live attenuated VZV vaccine is immunogenic in these pts BUT is not safe this vaccine was tested (safe and immunogenic) in immunocompetent patients 3 doses are better – not as effective as expected induces both humoral and cellular immunity immune response is reduced in B-cell NHL pts what can be done after the fist year post HCTx?