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Vaccinia Immune Globulins: Characteristics, Supply, Clinical Use and Licensure

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SCID mouse Model. SCID B and T cell deficiency. Macrophages, ... Vaccinia infection in SCID mice- onset clinical symptoms: 2 weeks. Mean Mortality (FDA Expts. ... – PowerPoint PPT presentation

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Title: Vaccinia Immune Globulins: Characteristics, Supply, Clinical Use and Licensure


1
Vaccinia Immune Globulins Characteristics,
Supply, Clinical Use and Licensure
  • May 8, 2002
  • Dorothy Scott, M.D.
  • Laboratory of Plasma Derivatives
  • Division of Hematology, OBRR, CBER, FDA

2
Vaccinia Immune Globulin Issues
  • 1. Current Products VIG and VIGIV
  • Supply Potency - Licensing
  • Anti-vaccinia antibody activity in
  • licensed IGIV products

3
Estimated VIG Product Needs CDC 5/2002
  • Depends upon scenario
  • mass vaccination (no contraindications)
  • 70,620 doses (includes pregnant women)
  • 30,032 (not including pregnant women)
  • Selective vaccination pre-event
    (contraindications adhered to HIV testing done
    pregnancy testing) assume 80 non-pregnancy
    contraindications detected
  • 6,006 doses
  • Selective vaccination post-event (smallpox
    contacts deferral secondary contacts with
    contraindications)
  • Estimate depends upon exposures

4
Estimated VIG Needs CDC 5/2002
  • Uncertainties
  • Prophylaxis (pregnancy, eczema,
    immunocompromised)
  • Complication rates in elderly
  • Dose that will de facto be used
  • Real scenario

5
Range of VIG Needs
  • CDC estimate 21 - 247 VIG-treatable
    complications/million vaccinees
  • 6,000 70,600 doses VIG
  • (presuming 100 mg/kg X 1 dose, and 70 kg
    patients 1 dose 7 grams)

6
Vaccinia Immune Globulins- current availability
  • VIG
  • I.m. preparation
  • Available from CDC under IND
  • Source plasma from vaccinated military recruits
  • Manufactured 1994 (Baxter)
  • VIGIV Product 1
  • I.v. preparation
  • IND studies under way
  • Same Source plasma as VIG
  • VIGIV Product 2
  • I.v. preparation
  • IND development under way

7
VIG Products Current and Near-Future
Availability
  • Scenario
  • Selective vaccination pre-event
    (contraindications adhered to HIV testing done
    pregnancy testing) 6,006 doses 24 - gt100
  • mass vaccination (no contraindications)
  • 70,620 doses ( pregnant women) 2.1- 10.5
  • 30,032 (not pregnant women) 4.8 - 25
  • Selective vaccination post-event (smallpox
    contacts deferral secondary contacts with
    contraindications)
  • Range depends upon exposures

8
Comparison of VIG and VIGIV (Product 1)
HPLC (CBER, FDA) PRN titers (2 Collaborating
Laboratories) Lethality Prevention in SCID Mice
9
Characterization of VIG/VIGIV Preparations HPLC
1/10/02
Monomer Dimer Aggregates Fragments VIG 4
81 14 5 0 VIG -20 79 14 7
0 VIGIV 1 92 6 2 0.0
10
Anti-vaccinia Titers by PRN 50 Neutralization
(µg/ml)
Lab 1 Lab 2 Lab 2 VIG 17 58 28 V
IGIV 18 5.5 32 16 Ratio 1.0 1.8 1.7 VIG/
VIGIV
11
SCID mouse Model
SCID B and T cell deficiency Macrophages,
APC, NK cells, complement activity unaffected G
reatly increased susceptibility to murine
pathogens More severe immunodeficiency than
nudes Vaccinia infection in SCID mice- onset
clinical symptoms 2 weeks Mean Mortality (FDA
Expts.) 27 4 days (literature 29 6
days) Vaccinia (WR) IGIV, 1h at RT
Inject I.p.
12
In vivo Vaccinia Neutralization by VIG Products
VIG 5
13
Summary SCID Experiments VIG vs. VIGIV (product
1)
Mouse Survival VIG VIG VIGIV 16.5 mg 5
mg 5 mg 3/12 0/12 17/18 Surviving mice
pox-free (55- 117 days after challenge)
14
VIG vs. VIGIV
  • VIG expected to lose potency over time
  • In vitro tests (current standard) no
    conclusively demonstrated difference (low n)
  • VIGIV(1) more activity in SCID neutralization
    model
  • More relevant in vivo studies desirable
  • Additional research may clarify whether
    prioritization VIG products should be considered.

15
Additional Considerations Potency of VIG
products
  • NO known protective titer for treatment of
    vaccinia complications
  • Best guess VIG 0.1 mg/kg (Baxter dose when
    licensed)
  • NO standard for comparison until 5/2002 (prior
    standard degraded)
  • CBER interim standard in progress sent to
    testing laboratories (to obtain call D. Scott at
    301-496-4396)
  • NO validated potency tests
  • SOPs
  • Relationship between in vitro tests and clinical
    efficacy not assured

16
Current Thinking Clinical Trials for Licensure
of VIGIV (1)
  • Licensure based upon PK equivalence and safety
    data. PK not inferior (gt 0.8) to VIG given I.m.
  • Human surrogate markers (e.g. influence VIGIV on
    vaccine take, lesion size) not required
    pre-approval yet to be validated
  • Accelerated Approval designation desirable (21
    CFR 601.40 601.46)
  • expedited availability of licensed product
  • Phase IV commitments to human surrogate marker
    validation/efficacy

17
Current Thinking Clinical Trials for Licensure
of VIGIV (2)
  • New product indications limited to treatment of
    VIG-treatable vaccinia vaccine complications
    labeling specific to data provided by
    manufacturer of each product

18
Current Thinking Clinical Trials for Licensure
of VIGIV (3)
  • Animal model studies encouraged
  • Human surrogate efficacy studies encouraged
  • Licensure requirements may change as result of
    animal/human studies
  • Manufacturers of approved products may have to
    update data in accordance with new CBER standards

19
Additional VIG Product Supplies Current Efforts
  • FDA
  • - Streamlining regulatory aspects of development
    (e.g. current thinking on requirements for
    licensure)
  • IND involvement facilitating access to products
    proactively rapid IND review
  • CDC currently contracting for adequate VIGIV
    supply IND development

20
Does commercial IGIV contain anti-vaccinia
antibodies?If so, do licensed products have
similar anti-vaccinia activity?
  • Vaccinations in U.S. stopped
  • 1971 routine use (mortality concerns)
  • 1976 healthcare workers
  • 1982 travelers
  • 1994 military
  • Long-term antibody production possible in some
    donors after decades prevalence unknown (up to
    10 years after 1 dose 30 years after 3 doses)

21
IGIV Bank to Vaccinia Testing Laboratories for
Neutralization Titers
  • Laboratory 1
  • Plaque reduction neutralization
  • Vero cells, Dryvax
  • Laboratory 2
  • Plaque reduction neutralization
  • Vero cells, NYCBOH strain
  • Laboratory 3
  • ?-Galactosidase vaccinia strain
  • HeLa cells, vSC56 vaccinia

7 Products 5 Lots Each
22
IGIV Product
23
IGIV Product
24
IGIV Product
25
Summary Anti-vaccinia antibodies in licensed IGIV
  • IGIVs can neutralize vaccinia in vitro (?-gal
    and plaque reduction assays) At best 5-8 fold
    LESS potent than VIGIV (1)
  • IGIVs have neutralization activity against
    vaccinia in vivo (preliminary data), in presence
    or absence of excipients
  • Two products (C and D) have consistently best
    titers in 3/3 laboratories one product (E) has
    lowest titers in 3/3 laboratories
  • Manufacturing method and/or donors may account
    for differences

26
Amount of IGIV Required to Fill VIG/VIGIV
Shortfall
  • Product C or D IGIV potency 8 fold less than
    VIG/VIGIV
  • Dose of VIG/VIGIV for 70 Kg patient 7g
  • Dose of IGIV 7 x 8 56g/person
  • 10,000 complications x 56g/person 560 kg IGIV
  • 1 lot of Product C 20 Kg 28 lots needed per
    10,000 complications
  • 1 average lot of Product C sufficient for 357
    treatments
  • IGIV distribution in U.S. 22,000 kg in 2001
    product C D, 4,700 kg/year (84,000 doses)

27
Caveats/Plans
  • No current evidence suggesting equivalent
    activity in vivo of anti-vaccinia antibodies in
    IGIV and VIG products
  • Antibody subclasses, affinities may be different
  • How can this best be ascertained
  • Animal studies
  • Human studies
  • IGIV supply issues (feasibility)
  • Not assured that all C and D lots high titer
  • DHHS is discussing possibility of high-titer IGIV
    lot reserve.
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