Measles Virus Vaccine Live - Attenuvax
Status: approved; marketed
Organizations involved:
Merck & Co., Inc. – Manuf.; R&D; Tech.; World mark.
Children’s Hospital (Boston) – R&D
Cross ref: See the entry for Measles, Mumps and Rubella Virus Vaccine Live (M-M-R II) (#493).
Description: Measles Virus Vaccine Live or Attenuvax is a lyo-philized (freeze-dried) formulation of live measles virus for prophylactic vaccination against measles virus infection and disease. Attenuvax contains a highly attenuated strain (Moraten) of measles virus, originally derived from Enders’ attenuated Edmonston strain, propagated in chick embryo cell culture. Each 0.5 mL dose contains not less than 1,000 TCID50 of live measles virus.
The vaccine induces long-term immunity to measles virus infection through induction of antibodies to the measles fusion (F) antigen. This is the only measles vaccine approved in the U.S. Most children receive measles vaccination via the measles, mumps and rubella (M-M-R II) combination vaccine (#493), rather than individual component vaccines.
The vaccine is packaged in boxes of 10 single-dose vials along with diluent for subcutaneous administration. Each dose of the vaccine contains sorbitol (14.5 mg), sodium phosphate, sucrose (1.9 mg), sodium chloride, hydrolyzed gelatin (14.5 mg; bovine origin), human albumin (0.3 mg), fetal bovine serum (<1 ppm), other buffer and media ingredients, and approximately 25 µg of neomycin. The vaccine contains no preservatives. A 50-dose vial of lyophilized vaccine is available only to government agencies/institutions. During shipment, to ensure that there is no loss of potency, the vaccine must be maintained at a temperature of 10°C (50°F) or colder. Freezing during shipment does not affect potency.
Nomenclature: Measles Virus Vaccine [BIO]; Attenuvax [TR]; Rubeovax [TR former]; Measles Virus Vaccine Live [FDA USAN]; Measles Virus Vaccine, Live, Attenuated [FDA former]; Measles Virus Vaccine Live USP [USP]; measles virus Edmonston strain [SY for Rubeovax]; measles virus Moraten strain [SY for Attenuvax ]; NDC 0006-4709-00; NDC 0006-4589-00; NDC 0006-4591-00 [NDC]
History: A killed (formaldehyde inactivated) measles virus vaccine from Pfizer & Co. was approved shortly before approval of Merck’s original live vaccine (although CBER/FDA has apparently lost and no longer reports either approval and revocation dates for this vaccine). This was effective in clinical trials, but children receiving the vaccine developed more serious atypical measles disease about a year later after exposure to wild (or live vaccine) virus. Long-term immunity to measles virus infection is dependent on antibody to the fusion (F) antigen. Formaldehyde inactivated measles virus induces antibodies to the viral hemagglutinin (HA) antigen but formaldehyde inactivation destroys the fusion antigen, and the resulting immunity is of short duration. The vaccine was withdrawn before mass marketing of the Merck vaccine began.
Chicken embryo tissue culture methods developed by Dr. J. Enders, Children’s Hospital (Boston, MA), and collaborators enabled development of the Merck measles vaccine. This allowed measles virus to be cultured and passaged (put through successive cell cultures) and reliably attenuated (mutated and weakened). Dr. Enders obtained a virus throat culture from Dr. Ed-monston and isolated the virus. This Edmonston strain was passaged into successive cultures in human kidney, human amnion, and adapted to culture in chick embryo cell culture. Merck Sharp & Dohme researchers further attenuated the Edmonston B strain by passage in human kidney cells (24 passages), embryonated chicken eggs (12 passages) and chick embyro cell culture (17 passages). Samples of the virus were stabilized, lyophilized (freeze-dried), and form the basis for the current vaccine.
Shortly before approval of the Merck vaccine, the company discovered that the chick-embryo cells used for passage and attenuation of the virus were contaminated with an oncogenic (cancer-causing) virus – avian leukosis (chicken leukemia) -virus. FDA was not concerned, as a similarly contaminated yellow fever vaccine had long been in use with no signs of human carcinogenicity. Dr. H. Rubin, Univ. of California, had developed the RIF (Resistance Inducing Factor) test and found that hens with sufficient levels of avian leukosis virus antibodies produced uninfected eggs/offspring. Merck found a source for avian leukosis virus-free chickens at Kimber Farms (Niles, CA) and adopted eggs from these flocks for vaccine manufacture.
The original experimental Merck vaccine (trade name Rubeovax) was highly reactogenic – causing fever, sore arms, and other symptoms. Merck Sharp & Dohme researchers found that intramuscular injection of Immune Globulin (Human) or IGIM (see #743) into one arm, followed immediately by injection of the vaccine in the other arm, reduced reactogenicity without reducing the vaccines immunogenicity. As originally approved in 1963, Rubeovax was administered with Immune Globulin (Human), trade name Gammagee, from Merck.
Dow Chemical Co. (est. no 0110) was licensed to manufacture Measles Virus Vaccine Live from Feb. 1965-June 1978. This vaccine contained attenuated virus cultured in dog kidney cells. It was found to be too reactogenic and was withdrawn from the market.
Merck & Co., Inc. was licensed to manufacture Measles Live and Smallpox Vaccine, a combination vaccine, from Nov. 1967-March 1987. This vaccine contained a lyophilized Rube-ovax and live smallpox vaccine (vaccinia virus-infected calf lymph) from Wyeth (see Dryvax, #536).
In 1968, Merck received supplemental approval for a more attenuated live measles virus vaccine, Attenuvax, that was found to be less reactogenic than Rubeovax. Attenu-vax could be administered without simultaneous co-administration of immune globulin, a factor simplifying vaccination and reducing risks of blood-borne viral and other infections. Merck had put this vaccine strain through 40 additional passages in chick-embryo cell culture, resulting in the current Moraten strain. Clinical trials involved about 20,000 children.
Measles Immune Globulin (Human) was previously manufactured in the U.S. by Centeon LLC (Jan. 1974-Aug. 1982); Lederle Labs. (April 1964-Nov. 1980); and Parke-Davis div., Warner-Lambert Co. (May 1964-Nov. 1977).
Companies.:
Companies.: The vaccine was developed and is manufactured by Merck & Co., Inc. (West Point, PA), CBER/FDA est. no. 0002. It is marketed in the U.S. by Merck & Co., and internationally by Merck affiliates. In 2006, a new vaccine manufacturing facility in Durham, NC, came online, with completion/approval expected in 2010. M-M-R II, its component vaccines and Zostavax will be manufactured there.
Manufacture: manufacture (as originally approved for Atten-u-vax) involves removal of embryos from the eggs of avian leukosis virus-free chickens; mincing, washing, and trypsinization (use of trypsin enzyme to break up tissue) of the embryonic torsos to obtain suspended independent cells; placement of a specific number of cells in culture bottles; infection of the cells with measles virus; and culture of the virus. The growth medium for measles virus is Medium 199 (a buffered salt solution containing vitamins and amino acids and supplemented with fetal bovine serum) containing SPGA (sucrose, phosphate, glutamate, and human albumin) as stabilizer, and neomycin. About 20% of culture bottles are used as controls to test for contamination. After culture, fluids are harvested, clarified, stored, and lyophilized (freeze-dried). The cells, virus pools, fetal bovine serum, gelatin, and human albumin [Albumin (Human)] used in the vaccine are all screened for the absence of adventitious agents.
FDA class: Biologic PLA
CBER class: Viral And Rickettsial Vaccines
Approvals: Date = 19630321; PLA, granted to live measles virus vaccine (Rubeovax) to be used in combination with immune globulin (Gammagee) from Merck
Date = 19680000; PLA supplement; Indication = approval of Attenuvax
Date = 19860106; product license revoked under old proper name and granted (reissued) under new proper name
Date = 20070131; BLA supplement; Indication = package insert revisions (not affecting the approved indications:)
Indications: [portions of the "INDICATIONS AND USAGE” section of the product insert/labeling]:
Recommended Vaccination Schedule
ATTENUVAX is indicated for vaccination against measles in persons 12 months of age or older.
Individuals first vaccinated with ATTENUVAX at 12 months of age or older should be revaccinated with M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live) prior to elementary school entry. Revaccination is intended to seroconvert those who do not respond to the first dose. The Advisory Committee on Immunization Practices (ACIP) recommends administration of the first dose of M-M-R II at 12-15 months of age and administration of the second dose of M-M-R II at 4-6 years of age. In addition, some public health jurisdictions mandate the age for revaccination. Consult the complete text of applicable guidelines regarding routine revaccination including that of high-risk adult populations.
Measles Outbreak Schedule; Infants Between 6-12 Months of Age: Local health authorities may recommend measles vaccination of infants between 6-12 months of age in outbreak situations. This population may fail to respond to the measles component of the vaccine. The younger the infant, the lower the likelihood of seroconversion (see CLINICAL PHARMACOLOGY). Such infants should receive a second dose of M-M-R II between 12 to 15 months of age followed by revaccination prior to elementary school entry.
Other Populations: Individuals planning travel outside the United States, if not immune, can acquire measles, mumps, or rubella and import these diseases into the United States. Therefore, prior to international travel, individuals known to be susceptible to one or more of these diseases can receive either a monovalent vaccine (measles, mumps or rubella), or a combination vaccine as appropriate. However, M-M-R II is preferred for persons likely to be susceptible to mumps and rubella; and if monovalent measles vaccine is not readily available, travelers should receive M-M-R II regardless of their immune status to mumps or rubella.
Vaccination is recommended for susceptible individuals in high-risk groups such as college students, health care workers, and military personnel.15
According to ACIP recommendations, most persons born in 1956 or earlier are likely to have been infected with measles naturally and generally need not be considered susceptible. All children, adolescents, and adults born after 1956 are considered susceptible and should be vaccinated, if there are no contraindications:...[truncated].
Disease: Measles can cause pneumonia, diarrhea, encephalitis and death in people who are not immunized. Most people in the U.S. are now immune because of vaccination with measles vaccine or M-M-R. Before vaccinations became common in 1963, there were between 3- 4 million cases and 450 deaths annually in the U.S.
In 2000, CDC declared that measles could no longer be naturally found in the U.S., with most cases can be traced to people who have recently been in Europe and Asia, where the disease still is present.
Primarily due to adoption of universal vaccination against measles in the U.S., in summer 2004 and again in Dec. 2005, the Centers for Disease Control and Prevention (CDC) reported that the incidence of measles is at it lowest in since 1912. Only 37 cases of measles were reported to CDC in 2004, down from the 44 cases in 2002, and a huge drop from the 4 million or so cases every year before routine vaccination began in 1963. Confirmed measles cases occurred predominantly among preschool-aged children (aged 1-4 years). As is now the common pattern, in 2004, nearly all the cases were imported from lesser-developed countries or were linked to imported cases, with four not linked to any one cause.
Measles is still a major health concern internationally, and a number of programs have been supporting and conducting vaccination programs in lesser-developed countries. The number of deaths from measles worldwide has dropped by 39% to an estimated 530,000 in 2003 from 873,000 in 1999. The largest reduction occurred in Africa, where the disease hits hardest. Many of those not killed by measles are severely affected, e.g., an estimated 30 million survivors are left blind or with other debilitating complications. The World Health Organization (WHO) recommends that >90% of infants at nine months of age or soon thereafter receive vaccination through routine health services, with another immunization every 3-4 years, to reach children who missed vaccination in the first round and to stimulate the immune systems of the 10-15 percent of children who fail to develop immunity after a single inoculation. Almost all nonimmunized children will contract measles upon exposure to the virus.
In the Nov. 15, 2005, issue of the Journal of Infectious Diseases, CDC investigators reported that measles vaccine does not cause subacute sclerosing panencephalitis (SSPE), a deadly brain infection linked to measles. Rather, the infection is believed to result from contact with the disease prior to vaccination. It was reported that vaccination can prevent SSPE and that the incidence of infection is higher than previously thought. With 12 SSPE patients identified in the study having measles between 1989 and 1991, this raised the incidence of measles-induced SSPE to a level approximately 10 times higher than the prior incidence rate, from 8.5 in 1 million persons to be between 7 and 11 per 100,000. The study concluded that measles vaccination programs prevent many more of the fatal brain infections than previously thought.
Market: As of early 2001, pediatric measles vaccine coverage worldwide was about 75%.
In Nov. 2004, the Centers for Disease Control and Prevention (CDC) reported that measles vaccine coverage (the percentage of those vaccinated) among U.S. children entering school (kindergarten) in 2003-2004 was 95.4%.
The 2007 Average Wholesale Price (AWP) is $166.96 for 10 single-dose vials, with a Direct Cost (Manufacturer’s discount price) of $132.88(Red Book, 2005). The 2004 AWP was $15.91/vial; $161.57 for 10, with a DC of $128.39/10 (Red Book, 2004). This includes the $.75/dose federal excise tax funding vaccine liability insurance) charged by the manufacturer.
The Centers for Disease Control and Prevention (CDC) had purchased the vaccine in bulk for $6.69/dose (contract ended March 31, 2001). This included the $.75/dose federal excise tax. CDC now preferentially purchases M-M-R II and ProQuad, rather than monovalent Attenuvax.
The World Health Organization (WHO) has cited $.26/dose as its cost for measles vaccine [apparently, highly subsidized, discounted and/or foreign biogeneric copies of Merck’s vaccine].
Competition: Other measles vaccines in the world marketplace, not marketed in the U.S., include vaccines manufactured by Sanofi Pasteur Ltd. (Canada); Eisai/Research Foundation for Microbial Diseases of Osaka University (BIKEN) (Japan); Sanofi Pasteur S.A. (France); Chiron Vaccines (Italy); Serum Institute of India; GlaxoSmithKline Biologicals (Belgi-um); and Berna Biotech Ltd. (Switzerland; now merged into Crucell N.V.). PT Bio Farma (Indonesia) is bringing to market a measles vaccine manufactured under contract by Panacea Biotec Ltd. (India).
In Dec. 2005, the Measles Initiative (supported by the American Red Cross, UN Foundation, CDC, UNICEF and WHO) attained its original goal of vaccinating 200 million children in more than 40 countries, with this preventing and estimated 1 million children from dying from measles over five years. Measles deaths have fallen 60 percent between 1999 and 2004 in Africa.
Companies involvement:
Full monograph
491 Measles Virus Vaccine
Nomenclature:
Measles Virus Vaccine [BIO]
Attenuvax [TR]
Rubeovax [TR at time of original approval]
Measles Virus Vaccine Live [FDA USAN]
Measles Virus Vaccine, Live, Attenuated [FDA former]
Measles Virus Vaccine Live USP [USP]
measles virus Edmonston strain [SY for Rubeovax]
measles virus Moraten strain [SY for ATTENUVAX]
NDC 0006-4709-00; NDC 0006-4589-00; NDC 0006-4591-00 [NUM NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1963
Date of 1st FDA approval = 19630321
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
chicken source materials
human materials used<!-- humansource -->
live microorganisms (as active agent)
vaccines, live
Albumin (Human)
bovine serum
chicken embryo (egg) culture
Edmonston strain, measles virus
Ender strain, measles virus
glutamate
mammalian cell culture
measles virus, Edmonston strain
measles virus, Ender strain
Medium 199 (M-199; Hank's medium)
neomycin
SPGA (sucrose, phosphate, glutamate, albumin)
virus culture
Albumin (Human)
bovine serum, fetal (FBS)
ethanol
gelatin (bovine source)
lyophilized (freeze-dried)
neomycin
sodium chloride
sodium phosphate
sorbitol
sucrose
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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