Zoster vaccine live (Oka/Merck) - Zostavax; shingles vaccine; herpes zoster vaccine
Status: recently FDA approved
Organizations involved:
Merck & Co., Inc. – Manuf.; R&D; Tech.; World mark.
Research Foundation for Microbial Diseases of Osaka University (BIKEN) – Tech.
Cross ref: See the entry (#564) above for the well-established pediatric version of this vaccine, Varivax, used for prevention of chickenpox, for general and background information about varicella virus, disease and vaccines.
Description: Zoster vaccine live (Oka/Merck) or Zostavax is, like Varivax, 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 first and only medical option approved for the prevention of shingles.
Each 0.65 mL dose when reconstituted and stored at room temperature for up to 30 minutes contains a minimum of 19,400 PFU (plaque forming units; at the end of the vaccine’s shelf-life) of live Oka/Merck varicella-zoster virus; 31.16 mg of sucrose, 15.58 mg of hydrolyzed gelatin (porcine, source; porcine gelatin stabilizer; PGS), 3.99 mg of sodium chloride, 0.62 mg of monosodium L-glutamate monohydrate, 0.57 mg of sodium phosphate dibasic, 0.10 mg of potassium phosphate monobasic, 0.10 mg of potassium chloride; residual components of MRC-5 cells including DNA and protein; and trace quantities of neomycin, and bovine calf serum. The product contains no preservatives. The lyophilised vaccine must be stored frozen at -15ºC or colder, and the diluent should be stored refrigerated or at room temperature.
The product is shipped using a styrofoam box allowing packing the frozen component and the non-frozen component together. The frozen component is placed in the lower compartment where dry ice is used as the refrigerant. The non-frozen component is placed in the receptacle compartment in the lid, so it is not exposed to the freezing conditions of the dry ice.
Nomenclature: Varicella Virus Vaccine, adult [BIO]; Zostavax [TR]; zoster vaccine live (Oka/Merck) [FDA]; herpes zoster vaccine [SY]; shingles vaccine [SY]; NDC 0006-4963-00 and NDC 0006-4963-41 [NDC]
Companies.: Zostavax was developed and is manufactured and marketed by Merck & Co., Inc., CBER/FDA est. no. 0002. In 2006, a new vaccine manufacturing facility in Durham, NC, came came online, with completion/approval expected in 2010. M-M-R II, its component vaccines and Zostavax will be manufactured there.
The source OKA/Merck strain of VZV was developed by and licensed from the Research Institute for Microbial Diseases of Osaka University (BIKEN; Osaka, Japan).
Merck has constructed a new live viral vaccine manufacturing facility in Durham, NC, which is expected to assume Zostavax manufacture currently performed as Merck facilities in West Point, PA. The new facility has an automatic vial distribution system that can handle more than 100,000 doses of product per day in an aseptic manufacturing environment. The facility has an automated lyophilizer capable of handling 116,000 vials of frozen vaccine at a time, performing freeze-drying over a two-day period. The plant was expected to be fully operational in 2008.
Manufacture: The virus seeds, drug substance process and varicella vaccine bulk used are the same as for Varivax and the varicella virus component in Merck’s combination vaccine, ProQuad.
The OKA virus was initially obtained from a Japanese child with varicella, then introduced into human embryonic lung cell cultures, adapted to and propagated in embryonic guinea pig cell cultures, and finally propagated in human diploid cell cultures (WI-38). Further passage of the virus was performed by Merck in MRC-5 human diploid cell cultures. See the Varivax entry for further information.
EMEA/European Union has noted, “Although no clinical studies with ZOSTAVAX have been conducted using VZV from the passage levels intended for commercial production, varicella-zoster vaccine at the passage level for production was developed and evaluated in the setting of the applicant’s monovalent varicella vaccine, VARIVAX.” Process validation (for EU approval) was performed by comparing the results of three validation lots.
For manufacture, a vial from the Master Working Cell Bank (MWCB) of Oka/Merck VZV virus is thawed and planted into cell factories. Cells are cultured, trypsinized and the concentration of the working seed is adjusted. Each production roller bottle is planted with working infected cell suspension and incubated. The spent medium is removed and discarded, and each cell culture is rinsed. Porcine gelatin stabilizer (PGS) stabilizer is added; amd the suspension is removed and stored under appropriate conditions. Each resulting batch of varicella harvested virus fluid (HVFs) is composed of mechanically harvested VZV MRC-5 cells.
The cells in the HVF suspension are disrupted and clarified. The dispensed final bulk containers (dispensed bulk) comprise a batch of pooled active substance and are stored frozen. Final harvested control fluids are tested for sterility, mycoplasms, and tissue culture safety, while cells are tested for hemadsorption. Automatic machines aseptically fill vials, and then the vials are lyophilized. The filling and lyophilization are carried out comparable to the Varivax process. Inspected sealed vials are stored at ≤-20°C (maximum 6 months) until they are packaged. After packaging, the vaccine may be stored at -15°C or colder for a maximum of 18 months (according to the European Union approval).
Cell-substrate-derived impurities may include proteins derived from the host cell line. Cell-culture-derived impurities may include antibiotics (e.g., neomycin), serum, or other media components. VZV processing uses cell growth medium containing bovine calf serum (BSA). Serum protein clearance is provided by rinsing the cell layers to remove as much serum as possible prior to virus harvest. Each VZV final bulk is tested for BSA. Assays are performed at several stages of processing of vaccine bulks in order to confirm absence of extraneous agents, to verify potency and identity, and to provide a measure of quality and process consistency. Most assays performed on VZV vaccine bulks and bulk intermediates are qualitative methods for which the experimental outcome is only: growth or no growth, absence or presence etc. In many of these cases, the assay specifications are compendial. For quantitative assays, the acceptance criterion is based on historical data.
Several different vaccine lots were used in clinical trials with differences in VZV titers and lot sizes. The manufacturing process for the drug substance (DS; active agent, i.e, VZV) changed in 1998, and DS batches from the so-called 1994-1995 process and 1998 process (current manufacturing process) were used in the production of the lots used in clinical trials. For all clinical protocols, the target fill volume was 0.7 mL and the administered volume was 0.5 ml, except in in study (009) where 0.7 ml or 1.0 mL was filled and 0.65 mL of the reconstituted vaccine was administered. For one study (004), the vaccine was aged in refrigerator to reduce the number of PFU to mimic the product at the end of the shelf-life. Lots used in stability studies and manufacturing process validation studies have been produced with the current DS process. In 1998, three full-scale process validation DP batches were produced using the mew formulation and filling processes. In 2003, the formulation and filling processes were modified (specifics not disclosed). In 2004, three full-scale DP batches were produced to validate process and equipment improvements and pressure control during lyophilization.
The European Product Assessment Report (EPAR) states “the risk of BSE transmission in ZOSTAVAX is exceedingly remote.” Biological reagents used in the manufacture of the vaccine bulks or bulk intermediates include iron-enriched bovine calf serum (BCS), fetal bovine serum (FBS), porcine pancreatic trypsin, gelatin (porcine-derived hydrolyzed), and amino acids. Except for hydrolyzed porcine gelatin, the stabilizers used are compliant with all existing compendial monographs (relevant to EU approval). Gelatin, the only excipient of animal origin, is derived from non-ruminant sources, and therefore is in compliance with Ph. Eur. Chapter 5.2.8. Adventitious agent testing of hydrolyzed gelatin is performed by Merck.
Because this is a live virus vaccine that contains varicella-zoster virus, with a viral component that is strongly associated with the cell membrane, it is not a highly purified product. At least for EU-destined vaccine, to provide a marker for removal of residuals from the cell culture process, a quantitative test for residual bovine serum albumin (BSA) is conducted on the vaccine bulks used for filling. The BSA content in the final containers is a calculated value that is derived from the input volumes and the measured BSA concentration of the individual VZV bulks along with the input volume of PGS stabiliser. A specification exists for BSA content in filled container (≤500 ng BSA per single human dose) as per the Ph. Eur. monograph 0648 for the pediatric Varicella vaccine, even though filled container material is not directly tested. Because of the relatively high virus titer required for this vaccine, the specification for residual BSA deviates from the one of the Ph. Eur. monograph (650 ng per dose or 1 g/mL). Merck has proposed the development of a new Ph. Eur. Monograph for zoster vaccine. Two reference standards (house standards) have been used for potency assays of this product.
FDA class: Biologics BLA
Approvals: Date = 20060525; original BLA approval
Date = 20070706; BLA supplement; Indication = added a statement in the package insert regarding concomitant administration with inactivated influenza vaccine
Date = 20080618; BLA supplement; Indication = include changes to the package insert and patient product information for the frozen formulation
Date = 20081118; BLA supplement; Indication = changes to the package; updates to the Post-Marketing Section with the addition of “rash” based on post-marketing reports, reinserting the word “sterile” to Section 11 (Description) of the label, and replacing “lyophilized preparation” with “suspension” in the Highlights section of the label
Indications: full text of "INDICATIONS AND USAGE” section of product insert/labeling; 12/31/2008]:
ZOSTAVAX is indicated for prevention of herpes zoster (shingles) in individuals 60 years of age and older.
ZOSTAVAX is not indicated for the treatment of zoster or post-herpetic neuralgia (PHN).
Status: On April 25, 2005, Merck submitted a BLA for approval of Zostavax for prevention of herpes zoster (shingles) in adults; prevention of postherpetic neuralgia (PHN); and the reduction of acute and chronic shingles-associated pain in adults. The PDUFA dete (target BLA response date) was extended several times. The BLA was granted on May 25, 2006. As with the European Union approval (discussed below), Merck had sought approval for preventing herpes zoster and postherpetic neuralgia, and reducing
acute chronic zoster associated pain in adults ages 50 and above, but only received approval for those age 60 and above.
In Dec. 2005, the Vaccines and Related Biological Products Advisory Committee, FDA, agreed that the clinical trials in more than 40,000 people support the efficacy and safety of Zostavax to prevent shingles in adults aged 60 and over. The Committee did not agree that available data also support the efficacy and safety of Zostavax in adults aged 50-59, as Merck had requested. The Committee also suggested areas for additional analysis. Merck’s data were not compelling enough to back approval in those aged 50 to 59. However, only about 150 of the ~38,000 patients in Merck’s pivotal Zostavax study were in the 50-59 year age range. This suggested that, the vaccine would receive an indication restricted to those ≥60 years of age.
In May 2006, the European Union (EU) and Australia approved Zostavax, and applications are pending in other countries. The EU MAA filing had sought approval for preventing herpes zoster and postherpetic neuralgia, and reducing acute chronic zoster associated pain in adults ages 50 and above. However, approval was granted for prevention of herpes zoster (shingles) in adults 60 years or older.
Merck first launched the vaccine in the U.S. in 2006, followed by the EU and other territories in 2007.
In Oct. 2006, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), recommended that all persons age 60 and older receive vaccination to prevent herpes zoster/shingle (i.e., receive Zostavax), including those who have had a previous episode of shingles.
The European Union (EMEA) has formally recognized that “The Drug substance (DS) is equivalent to that in the approved monovalent VZV vaccine, VARIVAX, and the VZV component in the tetravalent vaccine, ProQuad.”
In Feb. 2007, CDC received notice from Merck 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 (pediatric VZV vaccine; see related entry) and Zostavax over production of ProQuad (MMR-V combination vaccine; see related entry), and that there will be a shortage of ProQuad to the end of 2007. In May 2007, CDC received further notice from Merck that the supply of Zostavax is expected to be adequate for routine vaccination of adults aged >60 years.
In May 2008, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), recommended use of Zostavax for the prevention of shingles in adults aged 60 and older. The ACIP recommendations call for routine vaccination of all appropriate people 60 years of age and older with a single dose.
Tech. transfer: See the Tech. transfer section of the entry above for Varivax.
Trials: The clinical development program for Zostavax consisted mainly of eight protocols in which approximately 40,000 subjects were enrolled and vaccinated. Before routine administration, it is not necessary to ask patients about their history of varicella (chickenpox) or to conduct serologic (blood) tests for varicella immunity. Shingles vaccination was also included on the CDC's 2007-2008 Recommended Adult Immunization Schedule.
In Nov. 2003, the National Institute of Allergy and Infectious Diseases (NIAID), NIH, began a 5-year Phase III study, the Shingles Prevention Study (SPS; Study 004), using a Zostavax in adults for prevention of shingles. In July 2004, enrollment enrollment was closed with 38,359 volunteers ge 60 and over. Participants were randomized to groups given either Zostavax (n=19,270) or a placebo (n=19,276) and followed for the development of shingles for a median duration of 3.1 years. Suspected cases of shingles were assessed by polymerase-chain-reaction (PCR) assay, virus culture and clinically by an evaluation committee consisting of five physicians with expertise in shingles. The vaccine cut the rate of varicella infection by about half in people 60 and older and help curb related pain. However, Zostavax did not significantly reduce rates of death or hospitalization, and it became less effective after three years, particularly in older persons, e.g., those over age 70. Zostavax met the primary endpoint. The overall BOI score, a measure of the average severity, incidence and duration of disease among all patients, was 2.21 for the Zostavax group vs. 5.68 with placebo (p <0.001), a reduction of 61.1% over the first 6 months. Zostavax also met the secondary endpoints. Viral infections were reduced by 63.9% in those 60 to 69 years old, compared with 37.6% in those ages 70 and older. Illness-related pain dropped 65.5% in 60-69 year-olds and by 55.5% in those 70 and older. There were 27 cases of PHN in the vaccine group vs. 80 with placebo (p <0.001). There were 315 cases of shingles in the vaccine group vs. 642 with placebo (p <0.001). Zostavax significantly reduced the incidence of persistent nerve pain after shingles (PHN) by 66.5% (p <0.001); 27 cases of PHN occurred in the vaccine group (N=19,254) compared to 80 cases in the placebo group (N=19,247). Zostavax significantly reduced the overall incidence of shingles by 51.3% (p <0.001); and 315 cases of shingles occurred in the vaccine group (N=19,254) compared to 642 cases in the placebo group (N=19,247). The vaccine also was “generally well tolerated.” The rates of serious adverse events, systemic adverse events and hospitalization were low. While the ability of the vaccine to prevent shingles declined with age, the risk of chronic pain among those older vaccinated persons who still developed shingles was lowered.
Clinical study 004 demonstrated that, compared to placebo, vaccination of adults, 60 years of age or older, with Zostavax decreases the incidence of herpes zoster (5.4 versus 11.1 per 1000 person-years) and PHN (0.5 versus 1.4 per 1000 person-years). The vaccine also showed efficacy with respect to the herpes zoster “Burden of illness”, which includes, besides the incidence of herpes zoster, duration and severity of pain as an indicator of vaccine efficacy. Results from this trial were reported in the June 2, 2005, issue of the New England Journal of Medicine.
Based on a relatively large safety database consisting of more than 20,000 exposed individuals from controlled clinical trials with an average follow up time of about three years, Zostavax showed a good safety profile. The vaccine was generally well tolerated in adults ≥60 years of age. The most commonly observed adverse reactions were injection site reactions and headache. Injection-site reactions were more frequent among zoster vaccine recipients compared to placebo recipients, but they were generally mild in intensity and of short duration. The overall incidence of systemic clinical adverse events following a dose of zoster vaccine was similar to that following a dose of placebo.
So far, the vaccine has been shown to be effective over a three or more year surveillance period (in the Shingles Prevention Study). If immunity eventually wanes in older vaccinated individuals, a booster inoculation may be required. For physicians and individuals, this makes it difficult to decide when the best time to vaccinate a patient might be. Vaccinating too early could result in the efficacy of Zostavax waning. Waiting too long runs the risk of an outbreak occurring before vaccination.
Disease: VZV, like other herpesviruses, establishes a latent state in sensory nerves and may be reactivated later in life. Reactivation in middle or old age results in herpes zoster or shingles, with vesicles forming in the area of the skin innervated by the infected sensory nerve ganglia, usually on the trunk or on the face (e.g, trigeminal nerve). Pain is very severe and may persist for several weeks or longer. In patients over 60, it may last many months, and pain can be severe enough to be incapacitating. Herpes zoster is currently usually treated with anti-herpesvirus drugs, e.g., valacyclovir (Valtrex), famciclovir (Famvir), or acyclovir.
Shingles may first appear as tingling, itching or pain on one side of the body or face. It then progresses to a blistering rash accompanied by pain in almost every case that varies in intensity and duration. Shingles also can lead to complications, including persistent, often debilitating nerve pain (post-herpetic neuralgia or PHN). This persistent, long-term nerve pain is the most common complication of shingles.
Shingles can affect anyone who has had chickenpox -- currently more than 90% of adults in the U.S. (with Varivax, the pediatric chickenpox vaccine for varicella prevention launched in 1995). Shingles most frequently affects those over the age of 50. Up to half of all people living to age 85 will develop shingles during their lifetime. It is estimated that up to 800,000 or 1 million people in the U.S. suffer from shingles each year, and the incidence is expected to increase as the population ages. The incidence rate for shingles have been increasing in adults in recent years, with many associating this with universal Varivax vaccination (see next paragraph). Approximately 25-50% of shingles patients older than 50 years of age develop chronic pain after shingles (PHN).
There are more than 1 million new cases of shingles in the U.S. every year; over half in people 60 and older.
There is evidence that adult exposure to children with chickenpox reinforces immunity, much like a booster vaccination would, but cases of pediatric chickenpox and such booster effects are now rare. This may result in an increased incidence of shingles as Zostavax-vaccinated persons reach late adulthood. Some have suggested that vaccination (with live virus) of adults might actually result in an increase in the incidence of shingles.
Recent research shows that the incidence of shingles in U.S. adults has been increasing since the 1995 recommendation that all children receive chichen pox vaccine. Even though Varivax was launched in 1995, little remains known about the effects of widespread pediatric varicella vaccination on shingles (herpes zoster), including those having had chickempox as a child and in younger adults having received the vaccine as infants. Natural exposure to varicella virus, e.g., from infected children, acts to boost immunity in exposed children and adults. But the universal varicella vaccination program in the U.S. will nearly eradicate this natural boosting mechanism, leaving the population more vulnerable to shingles epidemics. In one study, it was estimated that if chickenpox were to be nearly eradicated by vaccination, a higher number of shingles cases could continue in the U.S. for up to 50 years; and that while death rates from chickenpox are already very low, any deaths prevented by vaccination will be offset by deaths from increasing shingles disease. This is one of the reasons or the rationale for adult varicella zoster/shingles vaccination. Some critics/skeptics point to the record of failures of U.S. adult vaccination programs, and cite this, combined with the loss of natural boosting sources, as likely to result in higher incidence rates and mortality from shingles even after introduction of Zostavax.
Medical: Zostavax is administered subcutaneously as a single dose.
Market:
First-half 2013 sales were $224 million, indicating a decrease from 2012.
Total sales were $651 million in 2012; $332 million in 2011; $243 million in 2010; $277 million in 2009; and $312 million in 2008.
As reported by the National Immunization Pro-gram (NIP), Centers for Disease Control and Prevention (CDC; 7/2007), the Private Sector Cost/Dose (average cost) per dose is $145.35 for packages of 10 1-dose vials, and $152.50 for single 0.65 mL vials. The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $107.935 for packages of 10 1-dose vials, and $113.24 for single 0.65 mL vials. These prices include the $3.00/dose ($.75/covered component vaccine) Federal Excise Tax charged by the manufacturer for the federal vaccine injury compensation program. Sanofi Pasteur’s contract with NIP, CDC, expires on March 31, 2008.
The 2007 Average Wholesale Price (AWP) is $$183.00/single-dose vial, with a Direct Price (Manufacturer’s discount price) of $152.50; and $1,744.20/10 vials, with a Direct Price of $1,453.50 (Red Book, 2007).
The Merck 2006 catalog price wais $145.35/dose purchased as a 10-pack of single-dose vials and $152.50 purchased as a single-dose vial.
The U.S. and EU approvals for use in those age 60 vs. 50 years and older have been estimated to reduce the total potential market for Zostavax by about 25%.
About 75% of eligible U.S. recipients are enrolled in Medicare, and the policies of the Centers for Medicare & Medicaid Services (CMS) could be key to vaccine reimbursement and sales in the U.S. The primary economic benefit from the vaccine is prevention of PHN, which could favor use in the more elderly segment of the population.
Friedman Billings & Ramsey (FBR) analysts have projected the total market for Zostavax to be $700 million in 2010, with this presuming significant expenditures for marketing the product.
There is no straightforward route to market Zostavax to those over the age of 60, with most vaccinations administered to infants/children. Merck may need to devote significant marketing resources to reach patients. Insurers could be reluctant to reimburse Zostavax, given that many patients quickly recover from shingles and the vaccine is not 100% effective.
However, uptake of the vaccine has been slow, and the market has remained small. In Jan 2008, In Jan. 2008, the CDC reported that the National Immunization Survey showed immunization to prevent shingles among people 60 and over was only 1.9%. In April 2013, CDC reported just 15.8% of those over 60 had been vaccinated.
Companies involvement:
Full monograph
565 Varicella Virus Vaccine, adult
Nomenclature:
Varicella Virus Vaccine, adult [BIO]
Zostavax [TR]
zoster vaccine live (Oka/Merck) [FDA]
herpes zoster vaccine [SY]
shingles vaccine [SY]
NDC 0006-4963-00 and NDC 0006-4963-41 [NDC]
FDA Class: BLA Biologic
Year of approval (FDA) = 2006
Date of 1st FDA approval = 20060525
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
bovine materials used<!-- bovinesource -->
human materials used<!-- humansource -->
live microorganisms (as active agent)
porcine plasma
rodent source materials
vaccines, live
vaccines, viral
cells, human
fibroblasts, human
human diploid cells
mammalian cell culture
MRC-5 human diploid fibroblast cells
octoxynol (Triton X-100)
trisodium citrate
varicella-zoster virus strain Oka/Merck
virus culture
bovine serum
gelatin (bovine source)
lyophilized (freeze-dried)
monosodium glutamate
neomycin
porcine endogenous retroviruses (PERV)
potassium chloride
potassium phosphate
sodium chloride
sodium phosphate, dibasic
sucrose
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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