Status: U.S. approval withdrawn; prior main U.S. VIG

Organizations involved:

Baxter Hyland Immuno – Manuf.; R&D; Tech.; Former

Joint Vaccine Acquisition Program, DOD – Former

U.S. Department of Defense (DOD) – Parent

Cross ref: See the entries below for the two intravenously-administered vaccinia immune globulin products being added to the U.S. biodefense stockpile (replacing this product). See the entry for Smallpox Vaccine Products (#535), involving live vaccinia virus used for prevention of smallpox. See the Immune Globulin Products entry (#743).

Description: Vaccinia Immune Globulin (Human) or VIG is an isotonic solution of immune globulin for intramuscular administration obtained from pooled fractionated Plasma from selected high vaccinia virus antibody titer donors having received vaccination with a smallpox vaccine (containing live vaccinia virus). VIG consists primarily of immune globulin G (IgG) in polymerized form, containing polyclonal human antibodies against vaccinia virus. VIG contains 15-18% protein, at least 90% IgG, has potency of about 10,000 IU/mL, and is preserved with thimerosal.

Biological.: VIG is considered essential and required to be available for any smallpox vaccine (live vaccinia virus vaccine) testing and use. VIG is the only product shown effective for treatment of major adverse events, e.g., systemic infection, resulting from vaccinia virus infection due to smallpox vaccination. VIG is effective for treatment of vaccine-associated eczema vacci-natum and some cases of progressive vaccinia virus infections, but it is not effective against postvaccination encephalitis. VIG was developed in the 1950s and found to be effective for treating eczema vaccinatum, generalized vaccinia, progressive vaccinia, and accidental implantation of vaccinia. However, VIG was never tested in controlled studies before routine smallpox vaccination was discontinued in 1972.

The Centers for Disease Control and Prevention (CDC) estimates that vaccination of the entire U.S. population would generate a need for 33,000-49,000 doses of VIG. However, the CDC reports VIG was historically used only 47 times per million first-time vaccinations, which suggests need for much fewer doses. However, no one knows how many severe vaccine reactions would occur in today’s population or whether/how people at risk for these complications can be screened out.

The only current practical alternative to VIG for treating smallpox vaccine reactions is the antiviral drug cidofovir (Vistide) from Gilead Sciences, approved only for the treatment of cytomegalovirus retinitis. However, cidofovir can cause kidney damage, and current IND rules specify that the drug can be used for vaccinia adverse reactions only when VIG is ineffective.

As discussed in the entries below, two companies under government contracts are developing new/replacement VIG products for intravenous administration (VIG-IV). The Cangene product has potency similar to prior intramuscular VIG from Baxter. Intravenous immune globulins require more careful and intricate manufacture, e.g., to avoid polymerization, than immune globulin products administered intramuscularly, and are generally purer than older products administered intramuscularly.s

Nomenclature: Vaccinia Immune Globulin, i.m. [BIO]; Vaccinia Immune Globulin (Human) [FDA]; Vaccinia Immune Human Globulin [former USAN]; Vaccinia Immune Globulin USP [USAN]; cowpox virus immune globulin [SY]; VIG [SY]; VIG-IM [SY] vaccinia virus immune globulin [SY]; smallpox vaccine immune globulin [SY]

Biological.: Vaccinia virus (cowpox virus), like variola virus, is a double-stranded DNA virus, a member of the Poxviridae (poxvirus) family and Orthopoxvirus genus. However, vaccinia virus lacks the extreme pathogenicity of variola virus, and live vaccinia virus has long been used as a vaccine for smallpox prevention and post-exposure treatment. However, these vaccines can cause serious, even life-threatening, vaccinia virus infections. See the Smallpox Vaccine Products entry (#535) for further information about variola and vaccinia viruses.

VIG is used for passive immunization or transient protection against or modification of infection with vaccinia virus from use of live vaccinia virus vaccine (for prevention of smallpox), and against infection with laboratory-acquired and wild vaccinia virus (which is rare). Antibodies in the product with specificity for vaccinia virus attach to and neutralize the virus in the bloodstream. Protective levels of vaccinia virus-neutralizing antibody have not been established. VIG, like many other immune globulin products, has an in vivo half life of about 21 days, and is primarily eliminated by metabolic breakdown.

Companies.: The current very limited stocks (see Status section) of VIG were manufactured by Baxter Hyland Immuno, CBER/FDA est. no. 0140. Current stocks of VIG are primarily controlled by the Department of Defense (DOD), presumably the Joint Vaccine Acquisition Program (JVAP), DOD.

History: A VIG product derived from human plasma was first reported in 1950. A Vaccinia Immune Human Globulin product was reportedly formerly manufactured by Alpha Therapeutic Corp. This product does not appear on CBER/FDA approval lists or in its databases of approved products (which are unreliable prior to the mid/late-1970s, when FDA assumed biologics regulation from NIH).

Manufacture: VIG is produced much like most other hyperimmune plasmas, with Plasma obtained from donors with a high titer of vaccinia virus-neutralizing antibodies, e.g., from having received Dryvax. The plasma is pooled and subjected to Cohn-Oncley cold-ethanol fractionation. The existing product was apparently not subjected to specific viral inactivation steps (beyond the viral inactivation and partitioning inherent in the manufacturing process).

FDA class: Biologic PLA

Approvals: Date = 19681231, PLA, granted to Baxter

Indications: prevention and sometimes treatment of vaccinia virus infection in exposed persons and those with vaccinia virus infection, whether from natural sources or from vaccination with smallpox vaccine

Status: VIG from Baxter is no longer approved, and it has not been manufactured for decades. In late 2002, the CDC reported that the U.S. stockpile consisted of about 700 doses. This was considered enough to treat the reactions that would be expected if 4-6 million people were vaccinated with smallpox vaccine (handle adverse effects from a vaccination program for a small outbreak). The government’s supply of VIG is in the custody of the Department of Defense (DOD), but is available to the CDC for civilian use.

Trials: VIG is considered highly effective. A mortality rate of 7% was reported in one study using VIG for treatment of eczema vaccinatum (severe vaccinia virus infection-associated eczema) vs. 30-40% mortality in patients receiving only palliative treatment. Studies is the 1960s showed that VIG could reduce the number of deaths from severe smallpox vaccine-associated eczema vaccinatum by two-thirds and stop the spread of new sores. However, VIG has little or no effect on vaccinia necrosum, which is deadly in immune suppressed persons, or on potentially life-threatening vaccinia encephalitis. VIG has never been tested in controlled studies, e.g., before routine smallpox vaccination was discontinued in 1972.

Medical: VIG may be used for treatment of severe systemic and skin vaccinia virus infections. Vaccinia virus infections are rare but may occur due to contact with vaccinia virus, whether wild virus or smallpox vaccine, with the mouth, eyes, or other membranes susceptible to vaccinia virus infection; and from contact with a lesion of vaccinated or infected persons. HIV-infected patients, chemotherapy recipients, and others with depressed immunity are particularly susceptible to severe vaccinia virus infections. VIG is generally not effective or used for treatment of post vaccination-associated encephalitis. VIG is contraindicated for treatment of vaccinia-associated keratitis, since studies in rabbits indicate this may increase the risk of scarring.

VIG (Baxter) is generally administered by intramuscular injection (buttocks or thigh), 0.3 mL/kg, within 24 hours of known or likely exposure to vaccinia virus (previously, mostly in research labs.; now, due to smallpox vaccination). For post-infection treatment, 0.6 ml/kg is generally administered as soon as possible. Doses over 10 mL are divided for injection at separate sites. Additional doses may be administered, particularly for treatment of post-vaccination infections, with VIG readmi-nistered every 2-3 days until no new skin lesions appear.

Market: Other than treatment of vaccinia virus infections arising from smallpox vaccination, due to its limited and strategic use (link to bioterrorism/biological warfare defense), the need for reporting and control of vaccinia outbreaks, and other factors, VIG is available for civilian use in the U.S. only from the Centers for Disease Control and Prevention (CDC). Physicians contemplating use of VIG should contact CDC for guidance in diagnosis, prophylaxis and treatment. The product “is released from the CDC when indicated for the treatment of eczema vaccinatum, vaccinia necro-sum, ocular vaccinia, or severe generalized vaccinia in persons who receive the smallpox vaccine.”

Replenishing supplies of VIG is required for research, manufacture, testing, and use of any new smallpox vaccines. Using the ratio of vaccinations to VIG-treatable adverse events indicated by the CDC (i.e., 700 doses of VIG for 4-6 million vaccinees), smallpox vaccination of the entire U.S. population would generate a need for somewhere between 33,000-49,000 doses of VIG. However, the CDC reports that a survey showed that in the past, VIG was used only 47 times per million first-time vaccinations, which suggests a lower need. Considering the necessity of having VIG available for any testing or use of smallpox vaccines (see the Smallpox Vaccine Products entry #535), existing supplies and future stocks of VIG have considerable strategic value. Vaccinia virus-based smallpox vaccine testing and non-emergency use by U.S. and other countries can and will only be undertaken with the availability of an adequate, safe, and effective VIG supply. VIG will also be required for determining the potency of smallpox vaccines.

The Centers for Disease Control and Prevention (CDC) has recommended stockpiling of VIG-IV at a rate of 1 dose of VIG per 10,000 doses of stockpiled smallpox vaccine. Presuming a U.S. population of about 290 million, with enough vaccine doses stockpiled for each person, about 30,000 doses of VIG-IV should be available, in case the entire population needed to be vaccinated against smallpox.

Once the U.S. government obtains adequate supplies of intravenous VIG, the likely U.S.-approved manufacturers, Cangene and DynPort/MBL (see entries below), may be expected to market VIG internationally, particularly to the military and public health establishments of U.S. allies (for use along with smallpox vaccine supplies many countries are acquiring/stockpiling).

R&D: Omrix S.A is developed an intravenous VIG. Omrix has a supply agreement with the Israeli Ministry of Health and the Israeli Defense Force (IDF). Its first batch was supplied in Jan. 2003, and a further batch was expected to be delivered in late 2005. Omrix has been investigating sales to other governments.

BioFactura Inc. is developing a smallpox therepeutic, a human or humanized vaccinia virus monoclonal antibody, derived from the antibodies of a smallpox survivor.

Investigators with the National Institute of Allergy and Infectious Diseases (NIAID), NIH), are developing a recombinant chimeric human-monkey monoclonal antibody for treatment of smallpox.