Title: Vaccinia Immune Globulins: Characteristics, Supply, Clinical Use and Licensure
1Vaccinia 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
2Vaccinia Immune Globulin Issues
- 1. Current Products VIG and VIGIV
- Supply Potency - Licensing
- Anti-vaccinia antibody activity in
- licensed IGIV products
3Estimated 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
4Estimated VIG Needs CDC 5/2002
- Uncertainties
- Prophylaxis (pregnancy, eczema,
immunocompromised) - Complication rates in elderly
- Dose that will de facto be used
- Real scenario
5Range 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)
6Vaccinia 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
7VIG 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
8Comparison of VIG and VIGIV (Product 1)
HPLC (CBER, FDA) PRN titers (2 Collaborating
Laboratories) Lethality Prevention in SCID Mice
9Characterization 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
10Anti-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
11SCID 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.
12In vivo Vaccinia Neutralization by VIG Products
VIG 5
13Summary 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)
14VIG 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.
15Additional 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
16Current 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
17Current 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
18Current 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
19Additional 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
20Does 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)
21IGIV 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
22IGIV Product
23IGIV Product
24IGIV Product
25Summary 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
26Amount 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)
27Caveats/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.