Vaccinia Immune Globulin Intravenous (Human) - VIGIV
Status: approved; in U.S. biodefense stockpile
Organizations involved:
DVC LLC – R&D; Tech.
DynPort Vaccine Co, LLC – Former
Computer Sciences Corp. (CSC) – Parent
Massachusetts Biological Labs. (MBL) – Manuf.
McKesson BioServices – Manuf. other
Joint Vaccine Acquisition Program (JVAP), DOD – U.S. mark.
Department of Defense (DOD) – Parent
New York Blood Center – Tech.
Porton International – Former
Ipsen S.A. – Former
Cross ref.: See the entry for Vaccinia Immune Globulin/Baxter for background information about vaccinia immune globulin. See also the Vaccinia Immune Globulin, i.v./Cangene, concerning another VIVIG product.
Description: Vaccinia Immune Globulin Intravenous (Human) or VIGIV is an aqueous formulation of high purity immune globulin (IgG) containing high levels of vaccinia virus neutralizing antibodies isolated from the pooled plasma of U.S. military personnel donors having previously received booster immunizations with the only FDA-licensed smallpox vaccine (Dryvax; live vaccinia virus; see related entry), with processing including solvent detergent viral inactivation and nanofiltration for viral reduction. VIGIV is stabilized with 5% sucrose and 1% Albumin (Human). This is the primary vaccinia immune globulin product for military (Department of Defense) use.
Although U.S. civilian smallpox (Dryvax) immunization was halted in the early 1970s, DOD continued immunization of those in the military into the early 1990s, and frozen Plasma from vaccinated soldiers is still in storage. This is the source Plasma for manufacture of VIGIV.
VIGIV is supplied in sterile vials containing 50 mL of solution with VIGIV at a concentration of 50 mg/mL (2,500 mg immunoglobulin per vial). VIGIV is stored at 2-8˚C (refrigerated). Each mL of VIGIV contains approximately 50 ± 10 mg immunoglobulin, primarily IgG, trace amounts of immunoglobulin A (IgA) and immunoglobulin M (IgM); 50 mg sucrose; and 10 mg Albumin (Human). The sodium content is 19.5 to 22.5 mEq per liter (i.e., 1.0 to 1.5 mEq per 50 mL). VIGIV has a dating period of 24 months from the date of manufacture when stored at 2-8˚C (refrigerated). The date of manufacture is the date of final sterile filtration of the formulated drug product. Sterile bulk material can be stored at 2-8ºC prior to filling for 104 days from the date of sterile filtration.
Biological.: VIGIV contains vaccinia virus-specific IgG representative of the immunized donors who contributed to the plasma pool from which the product is derived. VIGIV contains a relatively high concentration of antibodies directed against vaccinia virus. The potency of VIGIV is based on the ability of VIGIV to neutralize vaccinia virus as measured by the plaque reduction neutralization (PRN) assay. The concentration of anti-vaccinia antibodies in a sample, expressed in units/milliliter (U/mL), is defined as the inverse of the dilution of the sample that results in a 50% reduction in viral plaques (PRN50 titer). The circulating serum half-life of injected VIGIV has been shown to be ~22 days in adults, much like other immunoglobulin preparations.
Nomenclature: Vaccinia Immune Globulin, i.v. [SY]; Vaccinia Immune Globulin Intravenous (Human) [FDA]; VIGIV [SY]; smallpox vaccine immune globulin [SY]; accinia virus immune globulin [SY]; Vaccinia Immune Globulin (Human) [SY]
Companies.: The Joint Vaccine Acquisition Program (JVAP), Department of Defense (DOD), exclusively contracted with DynPort Vaccine Co, LLC (now DVC LLC) for development, manufacture, and maintenance of a stockpile of VIGIV. DVC is DOD’s prime contractor for biodefense vaccine R&D and manufacture. DynPort Vaccine Co, LLC was formerly a joint venture of DynCorp., a large government contractor and Porton International Ltd., a subsidiary of Ipsen S.A. Computer Sciences Corp. (CSC) acquired Porton’s portion of the joint venture in Aug. 2004 (assumed full ownership).
VIGIV is manufactured under (sub)contract from DVC by Massachusetts Biological Laboratories (MBL), CBER/FDA est. no. 0064. VIGIV is stored and distributed [presumably, under a (sub) contract from DVC] by McKesson BioServices.
The available information about VIGIV is limited, due to the product’s strategic biodefense importance and it being controlled by the DOD. For example, DVC did not (refused to) substantively respond when asked whether VIGIV be available/marketed to the private sector; whether it will seek further approvals in other countries and/or whether it will sell the product to other governments; and refused to disclose information about the number of doses manufactured (delivered to DOD) or to be manufactured under DOD contract. It can be presumed that DVC will market the product to other governments.
The Massachusetts Biologic Labs. completed manufacture of its first lot of VIGIV vials for DynPort (under DOD contract) in Sept. 1999. However, about 30% was unusable due to equipment failure during fill and finish operations. A second lot was manufactured in Feb. 2000, and a third lot was completed in June 2000. An IND for use of Lot 2 was filed in June 2000, and a Phase IIb trial began in July 2000. This trial was the pivotal trial supporting FDA approval. In July 2003, DynPort completed its second VIGIV Phase I trial. VIGIV development included validated assay for VIG potency (a requirement for approval).
Manufacture: Each lot of VIGIV contains vaccinia virus-specific antibody isolated from units of Source Plasma meeting minimum potency specifications as compared to a validated reference standard. All units of plasma were tested for alanine transaminase (ALT, an indicator of viral hepatitis), and found to be negative for hepatitis C virus antibody and hepatitis B virus surface antigen. All units of plasma were negative for HIV antibodies and negative for HIV RNA by reverse transcriptase polymerase chain reaction (RT-PCR; NAT). Potency (vaccinia virus antibody titer) of Source Plasma is reported as the inverse of the 50% plaque reduction neutralization (PRN50) titer, which is the dilution of test sample that results in a 50% reduction in viral plaques. Plasma units obtained from immunized individuals have been selected for pooling by two methods: determination of neutralization (PRN) titer of each plasma unit (known titer) and estimation of PRN titer using a bracketing method. A window of inclusion method, where all Source Plasma units collected between 2 and 26 weeks after smallpox vaccination are pooled, will be used for future lots of VIGIV.
Pooled plasma is fractionated by cold ethanol precipitation according to the Cohn Method 6 and the Oncley Method 9, modified to yield a product suitable for intravenous administration. The immunoglobulin is subjected to ultrafiltration and concentrated to 7% (range of 6.5% to 8%) protein. Immune globulin preparations for intravenous use must generally be of higher purity and contain less aggregated IgG than immune globulin products approved for intramuscular administration.
To assure virus removal/inactivation, ultrafiltration, the bulk immunoglobulin is filtered (nanofiltration) through a 75 nm filter and two 35-nm filters connected in series. The bulk immunoglobulin is subjected to solvent detergent viral inactivation by incubation with 1% Triton X-100 (octoxynol) and 0.3% tri-n-butyl phosphate to inactivate enveloped viruses. The mixture is filtered, stirred for at least 4 hours, and then passed through a hydrophobic chromatography column to remove the solvent and detergent. The virally inactivated globulin is formulated by adding sucrose (to 5%) and human albumin (to 1%) to the IgG solution. The final drug product is sterilized by 0.2-µm filtration and filled into 50 mL glass vials. After final vial inspection, lots are tested, labeled, and packaged.
Final product release tests are performed on every lot of VIGIV, including: sterility (21 CFR §610.12); IgG purity by electrophoresis; IgG and albumin protein concentration; heat stability (21 CFR §640.101); pH; prekallikrein activator activity; kallikrein activity; molecular size by high performance liquid chromatography; hepatitis B surface antigen and antibody content; nucleic acids for HIV-1 and hepatitis C virus; anticomplementary activity; pyrogen (21 CFR §610.13b); isoagglutinins content; Anti-D content; visual appearance; identity; and general safety tests (21 CFR §610.11). The product must also meet the established specification for sodium and contain the target amount of sucrose. Potency testing is performed by the validated PRN assay. The PRN assay is used to determine the neutralization capacity of samples of VIGIV Source Plasma and VIGIV drug product (at lot release and as part of the stability program). All PRN assays are performed by BioReliance Corp., a subsidiary of Invitrogen Corp.
Several steps in the manufacturing process have been validated for their ability to inactivate or remove viruses including Cohn/Oncley fractionation (Fraction I through Supzernatant III Filtrate); nanofiltration through one 75 nm and two 35 nm filters; and solvent/detergent viral inactivation. The viral reduction steps were validated in a series of in vitro experiments for their capacity to inactivate and/or remove HIV type 1 (HIV-1) and model viruses: bovine viral diarrhea virus (BVDV) as a model for hepatitis C virus; mouse encephalomyelitis virus (MEMV) as a model for hepatitis A virus; and pseudorabies virus (PRV), along with feline calicivirus (FCV), and Sindbis virus. Note, the first four viruses are enveloped, and the other two are non-enveloped. Total mean log10 reductions in viable virus count ranged from 6.07 to greater than 16.
Cohn/Oncley fractionation reduced BVDV by 6.25 log; Sindbis by 6.6 log; HIV-1 by >9.44 log; PRV by >10.37; MEMV by 4.06; and FCV (N.A.). Nanofiltration reduced BVDV by ≥5.4 log; Sindbis by ≥6.84 log; HIV-1 (N.A.); PRV (N.A.); MEMV (N.A.); and FCV (N.A.). Solvent-detergent viral inactivation reduced BVDV by >4.85 log; Sindbis (N.A.); HIV-1 by >4.51 log; PRV by >5.53; MEMV by 0.57; and FCV (N.A.). For all three processes, the cumulative reduction was BVDV by ≥16.5 log; Sindbis by ≥13.44 log; HIV-1 by 13.95 log; PRV by >15.9; MEMV by 4.06; and FCV by ≥6.92. Additional testing with bovine parvovirus (as a model for parvovirus B19) showed a mean cumulative reduction factor of greater than 7.34 log10 for Cohn/Oncley fractionation and solvent-detergent treatment followed by hydrophobic chromatography. A mean cumulative reduction factor of 2.55 log10 was observed for removal of porcine parvovirus by nanofiltration.
Based on the size (350 x 270 nm) of vaccinia virus, which is a large virus, it is anticipated to be removed by the nanofiltration steps and inactivated by the presence of anti-vaccinia antibodies in the product. In addition, solvent-detergent treatment of bulk VIGIV material is capable of reducing vaccinia virus to undetectable levels. Treatment of bulk VIGIV material with solvent and detergent at the same concentrations used in the VIGIV manufacturing process led to a greater than 4 log10 reduction in vaccinia virus titers. Robust viral reduction was also observed after treatment at half-strength concentrations of both solvent and detergent.
The first three lots of VIGIV manufactured by the Mass. Biological Labs. were lyophilized, with the second lot used in a clinical trial. All subsequent lots and those provided under contract are aqueous formulation in vials.
FDA class: Biologic BLA
Approval Date: 20050218; original BLA (BL 125093); orphan designation (granted 6/18/2004)
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:
VIGIV is indicated for the treatment and/or modification of the following conditions: Aberrant infections induced by vaccinia virus that include its accidental implantation in eyes (except in cases of isolated keratitis), mouth, or other areas where vaccinia infection would constitute a special hazard; Eczema vaccinatum; Progressive vaccinia; Severe generalized vaccinia; and Vaccinia infections in individuals who have skin conditions such as burns, impetigo, varicella-zoster, or poison ivy; or in individuals who have eczematous skin lesions because of either the activity or extensiveness of such lesions.
Treatment of complications that include vaccinia keratitis with VIGIV should be performed with caution since a single study in rabbits has demonstrated increased corneal scarring with intramuscular VIG administration. VIGIV is not considered to be effective in the treatment of postvaccinial encephalitis.
Status: VIGIV was granted accelerated approval by FDA on Feb. 18, 2005. Approval with orphan designation was granted to DVC LLC (on behalf of the Department of Defense). Approval was granted without a proprietary (brand or trade name) at the request of DVC. The effectiveness of VIGIV for accelerated approval was based on a surrogate endpoint for efficacy – serum antibody concentrations 5 days after administration. There are no controlled trials demonstrating a clinical benefit, such as a reduction in the severity of complications or survival.
As part of the approval, DVC must conduct post-approval studies including the collection of clinical data from the first 100 patients treated with VIGIV for complications of vaccinia infection, including descriptions of treatment and clinical course. The purpose of data collection is to verify the ultimate clinical benefits of VIGIV, to further study the relationship of the surrogate endpoint (anti-vaccinia antibody levels day 5 post-infusion) to clinical benefit, and to provide information about adverse events in patients with vaccinia infection treated with VIGIV. DVC must also collect serum samples prior to VIGIV treatment and 5 days after treatment in the first 50 patients, which will subsequently be analyzed to determine anti-vaccinia antibody levels at both timepoints. These data will be analyzed to assess the correlation between day 5 antibody levels and clinical improvement for each complication. DVC agreed to work with FDA, and other public health agencies to design and implement a clinical study protocol to include VIGIV dose ranging, when such a study is feasible, due to the actual or impending widespread use of VIGIV.
Note, although substantially the same and used for the same indications:, but with differently worded indications:, both VIGIV from Cangene and DVC have orphan designation from FDA.
Tech. transfer: Solvent detergent viral inactivation technology was developed by and presumably nonexclusively licensed from the New York Blood Center. For example, see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) (#799) for further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses.
Trials: Two clinical studies, VIGIV-001 and VIGIV-03 (BB-IND 9141), involving 111 subjects treated in two studies supported the BLA. The effectiveness of VIGIV was evaluated on the basis of the serum vaccinia virus antibody concentrations in healthy volunteers five days after administration of VIGIV, and by a comparison with the estimated (modeled) serum antibody concentration five days after administration of the previous/comparator product [Vaccinia Immune Globulin Intramuscular (VIGIM)]. With smallpox vaccination and related and other vaccinia virus infections being too rare, there are no controlled trials demonstrating a clinical benefit, such as a reduction in mortality or in the severity of smallpox complications.
Results from two studies of with lyophilized (VIGIV-lyo) and liquid (VIGIV-liq) formulation of DVC]s VIGIV were published in fall 2004 [Clin. Infect. Dis. 2004 Sep 15;39(6):759-66]. The VIGIV-001 study was an open-label, single-center, ascending-dose, Phase IIB trial evaluating the safety and pharmacokinetics of three VIGIV dose levels (lyophilized formulation) in 78 healthy, normal, adult volunteers at doses of 100 mg/kg (2 mL/kg), 200 mg/kg (4 mL/kg), or 500 mg/kg (10 mL/kg) VIGIV. No serious adverse events or deaths were reported, and no subjects withdrew because of adverse events. Serum neutralizing antibody levels for vaccinia five days after administration of VIGIV were shown to greater than those expected following a similar dose of VIGIM. The adverse events profiles were comparable among doses. The geometric mean titer of VIG (antibodies) at the target dose (100 mg/kg) after intravenous administration of either formulation was 2.5 times higher than the predicted geometric mean titer after intramuscular injection (p < .001). The pharmacokinetics of VIGIV-lyo were linear for doses from 100- 500 mg/kg. Administration of the 200- and 500-mg/kg doses of VIGIV-lyo did not result in markedly higher adverse event rates. Adverse event rates observed with the liquid product were comparable to those seen with the lyophilized product.
The VIGIV-03 study was an open-label, single-center, Phase 1 trial to evaluate the safety of 100 mg/kg (2 mL/kg) of a liquid formulation of VIGIV in 33 healthy adult volunteers. The primary objective was to collect initial tolerability and safety data for the current liquid formulation of VIGIV. A secondary objective of this study was to compare the safety of the liquid formulation of VIGIV with the safety of the lyophilized formulation of VIGIV and three other liquid immune globulin intravenous products. No serious adverse events or deaths were reported, and no subjects withdrew because of adverse events.
These studies indicated that intravenous VIVIG as either a lyophilized powder or aqueous formulation is well tolerated and results in a more favorable pharmacokinetic profile than VIG administered intramuscularly.
Medical: The recommended total dosage of DVC’s VIGIV is 2 mL/kg (100 mg/kg) by intravenous infusion, when the clinical diagnosis of a severe vaccinia-related infection is established. This dose may be repeated, depending on the severity of the symptoms and response to treatment. Higher doses (200 or 500 mg/kg), if the patient does not respond to the initial 100 mg/kg dose.
Market: VIGIV distribution is controlled by the Department of Defense. It is available for use to treat systemic vaccinia virus infections arising from smallpox vaccination (which is based on establishing a localized skin infection with vaccinia virus, a poxvirus related to smallpox virus, to induce antibodies that cross-react and neutralize smallpox virus).
Companies involvement:
Full monograph
790 Vaccinia Immune Globulin, i.v./DVC
Nomenclature:
Vaccinia Immune Globulin, i.v./DVC [SY]
Vaccinia Immune Globulin Intravenous (Human) [FDA]
smallpox vaccine immune globulin [SY]
Vaccinia Immune Globulin (Human) [SY]
vaccinia virus immune globulin [SY]
VIGIV [SY]
FDA Class: Biologic BLA
Year of approval (FDA) = 2005
Date of 1st FDA approval = 20050218
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
DNA, mammalian
vaccinia virus vaccine
Albumin (Human)
Namalva cells
octoxynol (Triton X-100)
Plasma (Human)
sucrose
tri-n-butyl phosphate (TNBP)
viral (nano)filtration
viral inactivation, solvent detergent
accelerated approval (based on surrogate endpoints) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
BHK-21 (C-13)
conjugates
implants
North American coral snake
orphan status
EU000 Not yet/Never filed with EU
UM100 Controlled/Gov't Distribution in US
US200 Currently Approved in US
US666 Biodefense stockpile
EM999 Not Available/Not Marketed in EU
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