a phase 1/2 study of an adjuvanted varicella-zoster virus subunit vaccine in autologous cell...
TRANSCRIPT
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»
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
BRIEF INTRODUCTION –
REFRESH YOUR MEMORY
Suggested Rx:
iv acyclovir 10 mg/kgBW/8hrs or 500 mg/m2/8 hrs X 7-10 days Eur Respir J 2003; 21: 886-91 J Support Oncol 2012; 10: 55-9
Bone Marrow Transpl 2011; 46: 294-9 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? 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
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 studyEdward A. Stadtmauer et al. Blood 2014;124:2921-
2929
pts born before 1980 – tested
for serological evidence of
VZV infection
Edward A. Stadtmauer et al. Blood 2014;124:2921-2929
©2014 by American Society of Hematology
Study Design II
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
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
Safety and Adverse Events II
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
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
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.
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?
THANK YOU