A phase 1/2 study of an adjuvanted varicella-zoster virus subunit vaccine in autologous cell...

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


©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 !!!


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


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


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

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

A phase 1/2 study of an adjuvanted varicella-zoster virus subunit vaccine in autologous cell...

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