1. 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-Ανδρέας Αναστασόπουλος Μάθημα Επιλογής «Λευχαιμίες»

2. 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 latent virus in neurones and satellite cells in sensory ganglia 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 -structure -pathogenicity -clinical manifestations Mandell, Douglas and Bennett’s Principles and Practice of Infectious Disease 8 th Edition

3. 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, 18 th edition

4. Why was this study conducted? 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) Edward A. Stadtmauer et al. Blood 2014;124:2921-2929

5. Study Design I Phase 1/2a 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 Edward A. Stadtmauer et al. Blood 2014;124:2921-2929

6. ©2014 by American Society of Hematology Study Design II

7. 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

8. Safety and Adverse events I 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 Edward A. Stadtmauer et al. Blood 2014;124:2921-2929

9. Safety and Adverse Events II

10. Measuring Response to vaccination 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 Edward A. Stadtmauer et al. Blood 2014;124:2921-2929

11. Results

12. 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

13. 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 4 th month (but not as high as expected after 2 nd vac) better response: 3x DOSEs AFTER 15 th 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

14. Edward A. Stadtmauer et al. Blood 2014;124:2921-2929 ©2014 by American Society of Hematology Antiglycoprotein E humoral and cell-mediated immune response rates.

15. Take-home message live attenuated VZV vaccine is immunogenic in these pts BUT is not safe this vaccine was tested (safe and immunogenic) in immuno- competent 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?