A phase 1/2 study of an adjuvanted varicella-zoster virus - E Download

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-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?