Varicella Virus Vaccine Live (Oka/Merck) - Varivax; chickenpox vaccine
Status: approved; marketed
Organizations involved:
Merck & Co., Inc. – Manuf.; R&D; World mark.
Research Foundation for Microbial Diseases of Osaka University (BIKEN) – R&D; Tech.
Sanofi Pasteur MSD – Europe mark.
Cross ref: See the entry for Varicella-Zoster Immune Globulin (Human) (#791), and the entry (#565) for a modified version of this vaccine for use in adults for prevention and allevation of symptoms associated with herpes zoster (shingles).
Description: Varicella Virus Vaccine Live (Oka/Merck) or Varivax is a lyophilized (freeze-dried) formulation of live attenuated varicella-zoster virus (VZV; chickenpox virus), Oka/Merck strain, cultured in MRC-5 human diploid fibroblast cells. This is the only vaccine available against any human herpes-virus. The vaccine has been shown to be 85% effective for protecting against all cases of chickenpox and nearly 100% effective in preventing severe cases, with only rare, mild side effects, such as soreness and swelling at the injection site.
Varicella vaccine contains live virus and is less stable than most other vaccines. Varivax is packaged as lyophilized powder in single-dose vials in both a newer “refrigerator stable” and original frozen formulation. For both, after reconstitution for subcutaneous injection, each 0.5 mL dose contains not less than 1,350 PFU (plaque forming units) of Oka/Merck VZV at expiration. The “refrigerator stable” formulation must be stored at 2-8˚C (refrigerated), and has a shelf life of 18 months; and may also be stored frozen (but can not be refrozen, if thawed).
For the frozen formulation, the vaccine must be kept at 15°C (+5°F) or colder. Potency of the vaccine begins to decline within minutes of exposure to temperatures above 5˚F, and the vaccine should be kept at freezer temperature at all times (or may be refrigerated for up to 72 hours). The dating period for the vaccine is 18 months at -15˚C, starting at the date of removal by Merck from -20˚C for packaging. The vaccine potency (virus titer) decreases by an estimated 18% after 18 months storage at -15˚C.
For the “refrigerator stable” formulation, excipients in each 0.5 mL dose are sucrose, 18 mg; hydroly-zed gelatin (porcine); porcine gelatin stabilizer (PGS), 8.9 mg; urea. 3.6 mg; sodium chloride, 2.3 mg; monosodium glu-ta-mate, 0.36 mg; sodium phosphate, 0.33 mg; potassium phosphate monobasic, 57 µg; and potassium chloride, 57 µg. For the frozen formulation, inactive ingredient in each 0.5 mL dose are sucrose, 25 mg; hydrolyzed gelatin (porcine origin; PGS), 12.5 mg; sodium chloride, 3.2 mg; monosodium glutamate, 0.5 mg; sodium phosphate dibasic, 0.45 mg; potassium phosphate monobasic, 0.08 mg; potassium chloride, 0.08 mg.
Both formulations also contain residual components of MRC-5 cells, including DNA and protein; and trace quantities of sodium phosphate monobasic EDTA, neomycin (antibiotic), and bovine calf serum (FBS) from MRC-5 culture media. The vaccine contains no preservatives. The nearly 2 µg of unmodified human DNA (from MRC-5 cells) present in each dose is reported to be the highest level in any approved pediatric vaccine.
Nomenclature: Varicella Virus Vaccine [BIO]; Varivax [TR]; Varicella Virus Vaccine Live (Oka/Merck) [FDA]; chickenpox vaccine [SY]; NDC 0006-4826-00; NDC 0006-4827-00 [NDC]
Biological.: No adequate animal model for human VZV infection is available. Varivax induces VZV-neutralizing antibodies and VZV-specific cell-mediated immune responses. The relative contributions of humoral immunity and cell-mediated immunity to protection from chickenpox are unknown.
History: The seed virus used for manufacture was originally isolated by Dr. M. Taka-hashi, et al., Research Institute for Microbial Diseases of Osaka University (BIKEN), from a Japanese child with chicken-pox.
During clinical testing by Merck using vaccine lots manufactured in 1982, 1984, 1987, and 1991, the manufacturing process was improved to increase the yield, viability and stability of the live attenuated virus in the final product. Vaccine preparations used in clinical trials varied in terms of live virus titer (PFU) and the ratio of live:dead virus. Virus strains from these different manufacturing campaigns produced similar quantities of viral glycoproteins, induced similar titers of antibodies, and retained restriction endonuclease cleavage sites and sequences in regions potentially variable among VZV strains (i.e., the virus did not vary significantly in terms of immunogenicity and genotype).
Companies.: Varivax was developed and is manufactured by Merck & Co., Inc. (West Point, PA), CBER/FDA est. no. 0002. Varivax is marketed in the U.S. by Merck & Co., and internationally by Merck & Co. affiliates. The source VZV strain was developed by and licensed from the Research Institute for Microbial Diseases of Osaka University (BIKEN; Osaka, Japan). BIKEN has manufactured a similar VZV vaccine marketed in Japan since 1987. The vaccine is marketed in Europe by Sanofi Pasteur MSD, joint venture of Sanofi Pasteur S.A. and Merck.
Manufacture: Varivax is produced from culture of attenuated varicella-zoster virus (strain Oka/Merck) derived by Merck & Co. from the Oka/BIKEN VZV strain (from BIKEN). Subsequent passage has been in MRC-5 human diploid cells. The complete sequence of the Oka/Merck strain and wild-type Oka parent have been determined.
The Oka strain of VZV was originally isolated from fluid taken from the vesicles of a 3-year-old Japanese boy with a case of chicken pox. The virus was isolated in primary human, embryonic lung cells (HEL) and was passaged 11 times. The strain was further passaged 12 times in guinea pig embryo fibroblasts (GPE) to attenuate the strain and once in human diploid cells (WI-38) to passage 24. One vial of frozen infected cells of the passage 24 Oka VZV strain was received by Merck on March 1984 from Osaka University (BIKEN)
In the process of isolating virus from culture in MRC-5 cells, cell-derived proteins and DNA are included in the vaccine. Testing of the host MRC-5 cells has indicated no evidence for tumorigenicity in nude mice, and normal senescence in tissue culture. The ~2 µg of VZV DNA/dose of vaccine was determined to be unlikely to integrate into host cells and cause harm under the conditions of vaccination. The Vaccines and Related Biological Products Advisory Committee, FDA, concluded on Aug. 23, 1994, that this residual DNA does not pose a safety risk exceeding the known benefits of the vaccine.
The vaccine is manufactured using a robotic system which performs manipulations and provides a high degree of aseptic processing and sterility assurance. It was reported in 1995 that manufacture of a single lot of vaccine requires 22,400 robotic manipulations over 37 days.
Sterility of the pooled bulk vaccine is ensured by controlled aseptic processing throughout the manufacturing process. Control of viral adventitious agents is based on testing of the Master Seed, Stock Seeds, and manufacturer’s Working Cell Banks to ensure absence of other viral agents (including adeno-associated viruses and retroviruses) as well as other microbial agents. Each batch of vaccine is tested to verify absence of adventitious viral agents. Other than vaccine virus [at the time of approval], no viral agents had been detected in any of the batches tested. Prior to packaging, Merck may store the bulk vaccine at -20˚C or colder for 24 months.
Prior to filling into the final containers, stored clarified bulk vaccine is thawed and diluted to the target potency level. The final formulated bulk is tested for sterility. Filled vials are frozen and lyophilized (freeze-dried) to minimize potency loss. The vials are sealed and stored at -20˚C or colder prior to labeling and packaging. Filled containers are tested for sterility, potency, identity, moisture, restoration, pH, and general safety. These tests have been shown to be appropriate for controlling safety, freedom from contamination, and immunogenicity.
FDA class: Biologic PLA
CBER class: Viral And Rickettsial Vaccines
Approvals: Date = 19950317; PLA 93-0395
Date = 20050405; BLA supplement; Indication = approval of optional second (booster) dose for children 12 months to 12 years of age
Indications: [full text of "INDICATIONS AND USAGE” section of the product insert/labeling; Insert at Merck Web site not updates (to reflect optional second dose) as of April 22, 2005]:
VARIVAX is indicated for vaccination against varicella in individuals 12 months of age and older.
Revaccination: The duration of protection of VARIVAX is unknown at present and the need for booster doses is not defined. However, a boost in antibody levels has been observed in vaccinees following exposure to natural varicella as well as following a booster dose of VARIVAX administered four to six years postvaccination.
In a highly vaccinated population, immunity for some individuals may wane due to lack of exposure to natural varicella as a result of shifting epidemiology. Post-marketing surveillance studies are ongoing to evaluate the need and timing for booster vaccination. Vaccination with VARIVAX may not result in protection of all healthy, susceptible children, adolescents, and adults (see CLINICAL PHARMACOLOGY).
Status: Universal pediatric varicella vaccination was recommended in 1996 by the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC); American Academy of Family Physicians (AAFP); and American Academy of Pediatrics (AAP). See “Prevention of Varicella: Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP),” MMWR, May 28, 1999/48(RR06);1-5. As a required/universal vaccine, Varivax vaccination is required for entry into most school systems; and is covered by the federal vaccine liability insurance program (see #400).
In June 2005, ACIP, CDC, recommended varicella vaccine booster shots for children during outbreaks of the disease, and mandatory immunization for all students entering middle school, high school and college. ACIP stopped short of recommending booster shots for all children between the ages of 4-6, but may take up that issue again. Boosters are needed during outbreaks, because some of the many children who routinely get one dose (of the three-inoculation regimen) before age 2 still develop the disease. School-based outbreaks in children continue, often triggered by children who develop chickenpox that is milder but can still spread to others, particularly those not or not fully immunized. ACIP suggested all states enact school entry varicella vaccination requirements. ACIP also recommended that physicians ask pregnant women and adults born since 1965 whether they have had chickenpox or the vaccine; and if not, they should be tested or given the shots (but not during pregnancy).
In Feb. 2007, CDC received notice from Merck & Co., Inc., that because of lower than expected titers of varicella-zoster virus (VZV) in its recently-Manufactured bulk varicella virus vaccine, Merck was prioritizing production of Varivax and zoster vaccines (Zostavax; see related entry) over production of ProQuad (MMR-V vaccine; see related entry), i.e., available bulk vaccine would be used for Varivax and Zostavax. In May 2007, CDC received notice from Merck that current projections of orders indicate ProQuad would likely be unavailable beginning in July 2007 to the end of the year. Merck requested that customers begin transitioning from ProQuad to Varivax.
Tech. transfer: Merck has received various patents related to Varivax, (and Zostavax) including U.S. 4,000,256 (expired), “ Varicella vaccine and process for its preparation;” related to its original invention/development; 5,360,736, “ Process for attenuated varicella zoster virus vaccine production,” a “ process [that] makes mass production of a live VZV vaccine more practical,” involving fully rather than partially confluent cell-monolayer culture. U.S. 5,997,880, “ Method for alleviating varicella related post-herpetic neuralgia,” and 6,214,354, a continuation, “Method for preventing zoster or alleviating varicella related post-herpetic neuralgia,” cover use of Zostavax for reducing PHN, with 5,997,880 having just one claim -- “A method for reducing the severity of post-herpetic neuralgia in people older than fifty which comprises immunizing an individual older than fifty who has had varicella or who has had a live varicella vaccine with an immunologically effective amount of attenuated varicella zoster virus Oka strain.” U.S. 6,251,653, “ Method of improved mixing of a varicella-infected cell culture in roller bottles,” claiming methods for enhancing the mixing of a varicella-infected cell culture in roller bottles by the introduction of controlled cross-sectional flow perturbations in roller bottle rotation.
Trials: Varivax has been shown to be 85% effective for protecting against all cases of chickenpox, and nearly 100% effective in preventing severe cases, with only rare, mild side effects, such as soreness and swelling at the injection site.
The duration of the prophylactic efficacy induced following vaccination with Varivax is an unresolved issue. It is unknown whether immunized children develop lifelong immunity. Most of the clinical trials conducted by Merck were designed to monitor short-term efficacy. If the protective effects of immunization wanes, a program of universal booster immunization might be needed for older children, adolescents, and for adults at risk for herpes zoster (shingles; resulting from VZV reactivation or infection in adults) and other serious VZV illness. Studies are ongoing to assess the vaccine’s long-term efficacy. Also, a large-scale clinical trial is underway to determine the efficacy of the vaccine (re)administered to adults for the prevention of herpes zoster.
Recent field studies have shown that pediatric efficacy may be less than expected. A booster regimen may need to be formally adopted, but this will be costly, inconvenient, and controversial. For example, an outbreak in a New Hampshire day-care center reported in late 2002 found the vaccine to be only 44% effective among vaccinated children. A case-controlled study in 339 children having received Varivax was reported in the Feb. 18, 2004 issue of the Journal of the American Medical Association. It was concluded that although the vaccine was 99% effective in the first year, but its effectiveness significantly decreased after one year (to 84%; still considered excellent) and remained steady after that for the 8-year period studied. Most cases of pediatric breakthrough diseases were mild. In May 2004, a study of a 2003 Michigan chicken-pox outbreak was reported by CDC (MMWR, 5/14/2004), finding 12% of vaccinated children had contracted chickenpox compared to 76% of unvaccinated children. Vaccinated children had limited rash and less severe disease than their unvaccinated peers. Ironically, the vaccine may have contributed to this outbreak (and others), because many infected children (carriers) were not sick enough to have stayed out of school.
A study published in the Sept. 2004 issue of Pediatrics reported that varicella vaccination in the U.S. resulted in a 59% or almost $100 million drop in hospital expenses related to the disease between 1993 and 2001; and that hospitalization rates for the disease and its complications fell 74% between 1995 and 2001.
Disease: Varicella zoster virus (VZV) infection is a highly communicable and serious disease. VZV infection of children (chicken-pox) is usually a self-limited disease lasting 4-5 days characterized by fever, malaise, and a generalized vesicular rash, typically 250-500 lesions, some of which may leave permanent pock marks. Infants, adolescents, adults, and immune compromised persons are at higher risk for serious complications from VZV, including infection of internal organs. Although it is generally a benign, self-limiting disease, varicella may be associated with serious complications (e.g., bacterial superinfection, pneumonia, encephalitis, Reye’s Syndrome), and/or death. Adults who develop the disease are more likely to succumb to life-threatening VZV pneumonia. VZV infection in pregnant woman often results in congenital malformations in the fetus.
The U.S. incidence rate of chickenpox, has fallen ~85% since the introduction of Varivax in 1995. Before the availability of the vaccine, varicella disease was responsible for an estimated 4 million cases, 11,000-12,000 hospitalizations, and 100 deaths each year in the U.S., with ~90% of cases in children. Before the vaccine, at least 61% of all children contracted varicella. Efforts to increase vaccination have been hindered by the perception by many primary care physicians and parents that chickenpox is a mild and inconsequential disease, and a normal part of childhood (as it was before the vaccine).
See the Zostavax entry (#565) for information about herpes zoster (shingles), involving reactivation of latent virus infection in adults.
Medical: Vaccination of children aged 12 months to 12 years old involves subcutaneous administration of a single dose, 0.5 mL. Vaccination of persons age 13 year of age and older involves two doses, 0.5 mL each, administered subcutaneously 4-8 weeks apart.
According to the U.S. Centers for Disease Control and Prevention (CDC), since introduced in 1995, nearly all states have added Varivax to the list of requirements for school enrollment and the nationwide rate of vaccination has climbed to 85% for children aged 19 months to 35 months. However, this vaccination rate is still below that for some other vaccines,
In the Aug. 11, 2004 issue of the Journal of the American Medical Association, a study of the effectiveness of Varivax was reported based on 6,316 cases in a Los Angeles County community of 320,000 between 1997 and 2001. Varivax was shown to prevent most cases of the chickenpox, and even when the vaccine fails, children tend to have a less severe case and are less likely to be contagious (a factor likely to figure in the debate about instituting a booster vaccination program). Varivax was 100% effective in preventing severe disease, 92-100 effective in preventing moderate or severe disease, and 80% effective in preventing all forms of chickenpox. With vaccination, the transmission rate to other family members was 15%, and without vaccination the transmission rate was 72%.
In March 2007, the Advisory Committee for Immu-nization Practices (ACIP), CDC, and in April 2007, the American Academy of Pediatrics (AAP) revised their recommendations for use of varicella vaccines, including switching from the current 1-dose to a 2-dose regimen. Despite widespread vaccination, the number of reported cases of varicella has remained relatively constant during the past 5 to 6 years. Since vaccination offers effectiveness between 80% to 85%, a large number of cases of varicella continue to occur among people who already have received the vaccine (breakthrough varicella) and increasing outbreaks of varicella have been reported among highly immunized populations of school children. The peak age-specific incidence has shifted from 3- to 6-year-old children in the prevaccine era to 9- to 11-year-old children in the postvaccine era for cases in both immunized and unimmunized children during these outbreaks.
With less varicella being spread, fewer persons are encountering those infected and receiving the equivalent of a nature booster inoculation. Outbreaks of varicella are considered likely to continue with the prior 1-dose immunization strategy. After administration of 2 doses of varicella vaccine in children, the immune response is markedly enhanced, with >99% of children achieving an antibody concentration (determined by glycoprotein enzyme-linked immunosorbent assay [gpELISA]) of >=5 U/mL (an approximate correlate of protection) and a marked increase in geometric mean antibody titers. The estimated vaccine efficacy over a 10-year observation period of 2 doses for prevention of any varicella disease is 98% (compared with 94% for 1 dose), with 100% efficacy for prevention of severe disease. Recipients of two doses are 3.3-fold less likely to have breakthrough varicella, compared with those given 1 dose, during the first 10 years following immunization.
According to current guidelines, children 12 months through 12 years of age should receive two 0.5-mL doses of varicella vaccine administered subcutaneously, separated by at least 3 months; if the second dose inadvertently is administered between 28 days and 3 months after the first dose, the second dose does not need to be repeated. All children routinely should receive the first dose at 12 to 15 months of age. The second dose of varicella-containing vaccine is recommended routinely when children are 4 to 6 years of age (i.e., before a child enters kindergarten or first grade), but can be administered at an earlier age. A second dose catch-up vaccination was recommended for children, adolescents and young adults who previously received just one dose. Varivax or any combination vaccine containing it may be used.
A second dose will certainly provide extra protection, but it is not clear how much. Instead of the current single inoculation with 80-85% efficacy, CDC is hoping instead to see 90-95% with a second/booster dose. Other boosters as young adult or throughout one’s lifetime may be appropriate or needed (see the Zostavax entry).
In the March 14, 2007, edition of the New England Journal of Medicine, it was reported that with fewer natural cases of the disease going around, unvaccinated children or children in whom the current single dose of the vaccine fails to work have been catching the highly contagious disease later in life, when the risk of severe complications is greater. Among those unvaccinated who get infected later in life, there’s a 20-times greater risk of dying compared to a child who becomes infected, and a 10 to 15 times greater chance of being hospitalized.
Market: Total worldwide sales were $846 million in 2012 and $831 million in 2011.
As reported by the National Immunization Program (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the Private Sector Cost/Dose (average cost) per dose is $74.56 for packages of 10 single dose vials ($66.81 in 2006; $62.78 in 2005). The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $59.15 for packages of 10 single dose vials ($56.90/dose in 2006; $52.25 in 2005). These prices include the $0.75/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. Merck’s contract with NIP, CDC, expires on March 31, 2008.
The 2007 Average Wholesale Price (AWP) is $93.73/single-dose vial, with a Direct Price (Manufacturer’s discount price) of $78.23; and $893.20 for 10, with a Direct Price of $745.58 (Red Book, 2005). These prices include the $.75/dose federal excise tax charged by the manufacturer.
In its March 22, 2006 price list, FFF Enterprises, a major biologics distributor, reported 75.50/single-dose 0.5 mL vial ($70.71 in 2005 and 2004) and $713.00/package of 10 single-dose vials ($690.62 in 2005; $674.30 in 2004). These prices include the $.75/dose federal excise tax.
In Nov. 2004, the Centers for Disease Control and Prevention (CDC) reported that varicella vaccine coverage ( (percentage of infants receiving >1 dose) among U.S. children entering school (kindergarten) in 2003-2004 was 93.3%. Use of Varivax has been increasing. U.S. vaccination coverage of VZV vaccine was 84.8% (±0.8%) in 2003; 80.6% in 2002, 76.3% in 2001, 59% in 1999, 43% in 1998, and 37% in 1997 (CDC).
In its 1998 annual report, Merck reported that Varivax was expected to average about $177 million in annual revenue for the first 7 years of its sales.
Competition: Varivax has no competition in the U.S., but does compete with similar products internationally. Aventis Pasteur S.A., now Sanofi Aventis S.A., developed and markets a live VZV vaccine in Europe and internationally, e.g., under the name Merieux Varicella Vaccine in France. This is a live attenuated OKA strain of VZV. It was first approved in France in 1993. SmithKline Beecham, now GlaxoSmithKline, developed and markets another live VZV vaccine, Varilrix, in Europe and internationally. This vaccine has much better temperature stability (refrigerated at 2-8˚C for up to two years) compared to Varivax, which must be stored frozen.
Companies involvement:
Full monograph
564 Varicella Virus Vaccine
Nomenclature:
Varicella Virus Vaccine [BIO]
VARIVAX [TR]
Varicella Virus Vaccine Live (Oka/Merck) [FDA]
chickenpox vaccine [SY]
NDC 0006-4826-00; NDC 0006-4827-00 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1995
Date of 1st FDA approval = 19950317
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
human materials used<!-- humansource -->
live microorganisms (as active agent)
porcine plasma
rodent source materials
vaccines, live
vaccines, viral
bovine serum
cells, human
fibroblasts, guinea pig embryonic
fibroblasts, WI-38 human diploid
guinea pig embryonic fibroblast cells
human embryonic lung cells
lung cell cultures, human embryonic
mammalian cell culture
MRC-5 human diploid fibroblast cells
octoxynol (Triton X-100)
varicella-zoster virus strain Oka/Merck
virus culture
WI-38 human diploid fibroblasts
DNA, mammalian
ethylenediaminetetraacetic acid (EDTA)
gelatin (bovine source)
gelatin (bovine source)
lyophilized (freeze-dried)
monosodium glutamate
neomycin
porcine endogenous retroviruses (PERV)
potassium chloride
potassium phosphate
sodium chloride
sodium phosphate, dibasic
sodium phosphate, monobasic
sucrose
U.S. Standard Rabies Vaccine
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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