Status: new, replacement vaccines pending at FDA
Organizations involved:
Barr Labs. – R&D; Tech.; Manuf.
Teva Pharmaceutical Industries Ltd. – Parent
BioReliance Corp. – Manuf.
Wyeth – Former
Walter Reed Army Institute of Research (WRAIR), – R&D; Former
U.S. Army – Parent; Former
U.S. Department of Defense (DOD) – USA mark. Parent
National Institute of Allergy and Infectious Diseases (NIAID) – R&D; Former
National Institutes of Health (NIH) – Former
Cross ref: See the entries below for the two previously available Adenovirus Vaccines.
Description: Two Adenovirus Vaccines, serotypes 4 and 7, both live viral vaccines, had originally received FDA approval and generally were administered together. Neither vaccine is currently manufactured (production was halted in 1996). Both vaccines were manufactured by Wyeth-Ayerst Labs., American Home Product Corp. (now Wyeth), and sold exclusively to the U.S. Department of Defense (and perhaps the militaries of other countries) for vaccination of new recruits. These live oral vaccines are formulated as enteric coated tablets, and were designed to induce enteric (not respiratory) adenovirus infection.
New versions of these vaccines from Teva are now available. See related entries.
Each of the two original vaccines contained a strain of live adenovirus, either serotype 4 or 7, cultured in WI-38 human diploid fibroblast cells. Each tablet contains 4.5 log10 TCID50 (32,000 TCID50) of live infectious virus. Table excipients (additives/stabilizers) apparently included monosodium gluta-mate, sucrose, d-mannose, d-fructose, dextrose, lactose, Albumin (Human), potassium phosphate, and plasdone. The pills are 3/8 inch glossy white (type 4) or yellow (type 7) standard convex tablets. The yellow coloring of the type 7 tablet is FD&C Yellow 5 (tartrazine). In addition to live virus and excipients, tablets contain residual components from the growth and maintenance media for virus and cells, certain materials used in processing, and cellulose acetate phthalate, alcohol, acetone, castor oil, magnesium stearate, and amberlite.
Use of the original vaccines effectively prevented or minimized adenovirus epidemics that were routine, particularly in the fall-winter, among new military recruits. The last remaining stocks of these vaccines were depleted in 1999. Subsequently, there have been major adenovirus outbreaks among military recruits. Outbreaks have reached epidemic levels, defined as 1.5 cases per 100 people/week, at several military installations. New, replacement oral types 4 and 7 vaccines are in development.
Biological.: Intestinal adenovirus infection is asymptomatic and induces development of serum neutralizing antibodies. Resulting immunity provides a high degree of protection against adenovirus-associated respiratory disease. Live adenovirus is excreted in the stools of more than 90% of recipients. Trials in military recruits demonstrated that the vaccines induced asymp-tomatic infection that did not spread to susceptible recruits, and effectively prevented acute adenovirus respiratory infections.
Adenoviruses are nonenveloped, double-stranded DNA viruses capable of causing a variety of illnesses The viruses infect a variety of mammals, including dogs, fowl, mice, cattle, pigs, and monkeys. Human adenovirus respiratory infection and associated acute respiratory disease (ARD) is rather common, but generally remains unrecognized and undiagnosed. Symptoms are those of the “common cold.” Adeno-virus-es, along with rhinoviruses (the primary etiologic agents), are generally considered to be the main etiologic agents causing common colds. Adenovirus respiratory infection can lead to pneumonia, acute respiratory disease, fever, pharyngitis, cough, hoarseness and chest pain. There are no antiviral or other specific treatments available for adenovirus disease.
Adenoviruses are medium-sized, non-enveloped icosohedral viruses containing double-stranded DNA. There are at least 52 immunologically distinct types that can cause human infections. Adenoviruses are unusually stable to chemical and physical agents and to adverse pH conditions, thus allowing for prolonged survival outside of the body.
Nomenclature: Adenovirus Vaccine, Live, Oral, Type 4 [FDA]; Adenovirus Vaccine, Live, Oral, Type 7 [FDA]
History: Adenoviruses were first discovered in the adenoidal tissue of U.S. soldiers in the 1950s. Infection was associated with rhinitis, pharyngitis, conjunctivitis, pneumonitis, and atypical pneumonia. Historically, adenovirus types 4 and 7 have been the major causes of acute respiratory disease in the U.S. military. Among military recruits, adenoviral disease is highest during winter, accounting for about 90% of all recruits hospitalized with pneumonia and 72% of all respiratory disease. In 1958, adenovirus infection caused hospitalization of an estimated 10% of military recruits. Basic combat training, generally about 8 weeks, brings together thousands of soldiers from all over the U.S. into a setting (close contact, barracks) in which respiratory viruses can easily spread. Most infections occur during the first 3 weeks of basic training (boot camp). Of the 47 adenoviral serotypes, types 4 and 7 have accounted for most military respiratory disease epidemics, while studies show that acute respiratory disease in the general population may be caused by a wider variety of microorganisms. A 1965 study of a typical epidemic at Fort Dix, NJ, established the need for and efficacy of adenovirus vaccines.
The Parke-Davis div. of Warner-Lambert Co. (now part of Pfizer) previously held approval for Adenovirus & Influenza Virus Vaccines Combined Aluminum Phosphate Adsorbed; approval granted on Sept. 22, 1957 and revoked on July 29, 1980 (shortly after approval of the Wyeth vaccines). Clinical studies with such inactivated vaccines from 1956-1960 found these ineffective in preventing adenovirus disease. Subsequent discovery that inactivated vaccines may be contaminated with adventitious simian viruses (from host cell lines) and that adeno-viruses can hybridize with oncogenic simian virus 40 (SV-40) raised safety concerns with inactivated adenovirus vaccines.
Dr. R.M. Chanock and co-workers, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH; Bethesda, MD), in 1965 developed a live adenovirus type 4 vaccine cultured in human diploid cells (Journal of the American Medical Association, 445-452, 1966). Wyeth Labs. manufactured experimental vaccines under contracts sponsored by NIAID and the Army, and trials were sponsored by NIAID and the Army under INDs 71, 294, 265, and 359. In 1971, the Department of Defense (DOD) began routine use of adenovirus types 4 and 7 vaccines. Vaccine development for other serotypes that cause only infrequent epidemics was undertaken, but no other vaccines were ever licensed.
These vaccines were widely used by the military before their approval by FDA. Wyeth applied for approval of type 4 vaccine in 1967, and for type 7 in 1974. Immunization of U.S. military recruits with type 4 vaccine began in 1967 (Vietnam War) and with type 7 in 1971. In 1971 (still nearly a decade before FDA approval), the Department of Defense (DOD) began routine use of live, enteric-coated types 4 and 7 vaccines. The vaccines were manufactured by Wyeth under contract to and distributed by the Walter Reed Army Institute of Research (WRAIR; Washington, DC). This DOD use of the vaccines was based on the results of what FDA considered to be extensive clinical trials. At the time, DOD and other federal agencies were exempt from FDA regulations. More recently, the DOD has voluntarily pledged to use only FDA-approved products for treatment of military personnel.
The DOD policy to vaccinate all male trainees during basic combat training drastically reduced adenovirus type 4- and type 7-associated acute respiratory disease. Adenovirus vaccines were administered to male trainees entering basic combat training between Oct. and April, the period for most adenovirus outbreaks. Year-round use of the two vaccines began in 1984, and resulted in the elimination of outbreaks due to adenovirus types 4 and type 7.
In 1994, use of the two vaccines was temporarily interrupted. Shortly thereafter, in 1995, a limited outbreak occurred among basic trainees at Fort Jackson, SC. This confirmed the utility of the vaccines. The epidemic stopped about 5-6 weeks after the administration of adenovirus vaccines was reinstated, and was centered in one military unit that had not received the vaccines. Concern about the continued threat of adenoviruses was validated by serologic studies, which revealed that the adenoviral susceptibility of personnel entering the military in the 1990s was similar to that of personnel who entered in the 1970s.
In 1996, Wyeth-Ayerst, the sole manufacturer of the two vaccines, ceased their manufacture. Wyeth had requested $5 million considered essential to updating its Marietta, PA, adenovirus vaccine manufacturing facilities. Wyeth had warned as early as 1984 that it would stop churning out pills costing $1 each unless DOD allocated $5 million to repair its deteriorating production plant. However, DOD declined, citing budgetary considerations. Wyeth shuttered the facility in 1996. DOD’s unwillingness to spend $5 million has resulted in tens of millions of dollars being spent to restart adenovirus vaccines manufacture. As discussed below, the DOD is now sponsoring development of new, replacement oral live adenovirus serotype 4 or 7 virus vaccines. In Fall 2001, Assistant Secretary of Defense William Winkenwerder Jr. remarked, “This is one of the most disappointing facts and stories that I’ve learned upon coming into my position...I don’t want to cast aspersions on anybody who had responsibility in the past, but to be blunt this is a major screw-up.”
To conserve the remaining vaccine lots, the military restricted use of adenovirus vaccines to the period of Sept. 1 through March 31, the peak season for acute respiratory diseases. Subsequently, routine administration of adeno-virus vaccines to military trainees was suspended on March 31, 1997 at all basic training centers.
Companies.: Wyeth ceased manufacture of adenovirus vaccines in 1996.
Manufacture: For the original vaccines, live adenovirus serotype 4 or 7 virus is cultured in WI-38 human diploid fibroblast cells. First, cells are derived from a frozen cell bank documented with respect to karyological analysis, lack of adventitious agents, and absence of hetero-transplantability. The culture medium is Minimum Essential Medium, Eagle’s containing a balanced salt solution, fetal calf serum and several antibiotics (maximum concentration per mL of 50 µg gentamicin sulfate, 50 µg neomycin sulfate and 2.5 µg ampho-tericin B). The human diploid WI-38 cell line is subjected to karyological analysis (J. Biol. Stand., 7, 397-404, 1979). The cell bank is tested for hetero-transplant-ability in ALS-treated newborn hamsters, for safety in weanling and adult mice, guinea pigs, rabbits and embryonated eggs, and shown to be free of myco-plasma. The cell cultures used for vaccine production are tested for mycoplasma, hemad-sor-bing agents, and for other extraneous agents in human diploid and green monkey kidney cell lines.
Adenovirus seed stock was stored frozen, then removed, and added to the cell cultures. A maintenance medium of antibiotics in a balanced salt solution is used for virus production. WI-38 cell monolayers are inoculated with virus and incubated. The medium containing live virus is harvested from each incubation bottle, pooled, filtered, and frozen. Individual harvests are combined (pooled) to form a finished liquid bulk to which stabilizers are added to preserve viability of the virus. Cultured virus is harvested, particulate cellular material is removed by filtration, and is the filtrate is dried by lyophilization (freeze-dried). Viability is preserved during drying by incorporation of additives/stabilizers, including monosodium glutamate, sucrose, d-mannose, d-fructose, dextrose, Albumin (Human), potassium phosphate, and plasdone. The virus preparation is diluted by admixture with lactose powder and processed by conventional methods into enteric-coated tablets for oral administration.
Prior to filtration, the harvest is tested for infectivity and mycoplasma. Following filtration, the harvest is tested for bacterial and fungal sterility, safety in suckling pigs and adult mice, guinea pigs and rabbits, and freedom from extraneous agents in cell cultures of human diploid origin, primary human embryonic kidney and green monkey kidney cells. Tablets are tested for appearance, thickness, weight, hardness, rate of disintegration, infectivity, identity, and general safety in mice and guinea pigs.
Status: Neither vaccine is currently manufactured, although their approvals remained valid until recently. Wyeth ceased manufacture of adenovirus vaccines in 1996, and the Dept. of Defense exhausted its supplies in 1999. At the time, the FDA still considered the vaccines safe and highly effective in interrupting epidemic acute respiratory disease (ARD) and reducing ARD rates in basic combat trainees. Subsequently, Wyeth withdrew its PLAs for the vaccines. See the R&D section below for information about replacement vaccines in development.
With no vaccines available prior to approval of the new replacments, it had been reported that on the order of 2,500 U.S. military recruits develop adenovirus infections each month.
Trials: Documented military outbreaks show that both vaccines are necessary, e.g., vaccine prevention of type 4-associated acute respiratory disease alone results in the emergence of type 7-associated disease.
By 1967 (Vietnam War), more than 42,000 individuals had received enteric-coated type 4 tablets, mostly U.S. military recruits (with a few trials in other countries). At least 29,000 subjects had no prior measurable adenovirus type 4 neutralizing antibody at baseline. Almost all (85-95%) susceptible recruits developed neutralizing antibodies following administration of at least 4.2 log10 TCID50 live type 4 adenovirus. The 50% infectious dose of the vaccine for the lower respiratory tract appeared to be 1 to 2.7 log TCID50. Trials with type 7 vaccine showed that it similarly stimulated specific neutralizing antibody in 85% or more of vaccinated subjects, with antibody levels similar to that induced by type 4, and provided protection against type 7 natural infection.
Among nonvaccinated military recruits, more than 55% of 3,212 throat cultures from symptomatic trainees from Oct. 1996 to May 1998 yielded adenoviruses. Most prevalent were types 4 (46%), 7 (32%), 3 (13%), and 21 (5%). Among trainees with acute respiratory infection symptoms, nonvaccinated personnel were at much greater risk of having a culture positive for adenovirus types 4 or 7 (odds ratio = 41.2; 95% confidence interval = 18.7 to 113.2) than vaccinated personnel. Immunization of recruits in camps was repeatedly shown to abort early autumn epidemics.
In family studies, about 17% of susceptible unvaccinated contacts appeared to experience asymptomatic seroconversion (developed enteric, not respiratory, infection as a result of exposure to vaccinated individuals). Thus, the vaccines also provided some immunity in close contacts of those vaccinated (as they still shed live virus). These secondary infections occurred most often between marital partners, and more rarely from mothers to susceptible children. This contact infection generally did not occur in the closely associated groups of military recruits.
The most recent demonstration of the vaccines’ efficacy arises from intensive, laboratory-based surveillance of adenovirus infection initiated in late April 1997 (after halt of routine vaccination) at Fort Jackson, SC, the Army’s largest basic combat training center. See J. Infect. Dis., 1999;179:1531-3. An epidemic of adenovirus type 4-associated acute respiratory disease occurred among soldiers in basic combat training. More than 1,000 trainees were hospitalized, with 66.1% of those hospitalized having detectable adenovirus type 4 isolate. The first case appeared in late May, and the outbreak lasted until Dec. (after vaccination was resumed in Nov.), and then declined. This type of epidemic, not seen during the long use of the vaccines, and its control by vaccination demonstrated the efficacy of the vaccines.
The pivotal clinical data supporting the BLA for Types 4 and 7 vaccines resulted from a large placebo-controlled Phase III trial designed to evaluate the safety and efficacy of Type 4 oral vaccine to prevent wild type 4 adenovirus-associated Acute Respiratory Disease (ARD) and for the Type 7 ADV oral vaccine to induce neutralizing antibody to type 7 adenovirus. The study involved over 4,000 male and female recruits at Naval and Army training facilities. The trial results supported the safety and tolerability of the oral Type 4 and Type 7 ADV vaccines, the efficacy of the oral Type 4 ADV vaccine in reducing the attack rate of wild type 4 adenovirus-associated febrile ARD, and the ability of Type 7 ADV vaccine to produce neutralizing antibodies. Duramed/ completed its Phase I study in April 2006, and completed its Phase III program in April 2008.
Medical: Adenovirus vaccine is administered orally, as a single dose consisting of two tablets; one tablet of adenovirus type 4 (white tablet) and one tablet of adenovirus type 7 (light peach tablet). Each tablet must be swallowed whole and cannot be chewed or crushed.
Index Terms:
Companies involvement:
Full monograph
401 Adenovirus Vaccines
Nomenclature:
Adenovirus Vaccine, Live, Oral, Type 4 []
Adenovirus Vaccine, Live, Oral, Type 7 []
biopharmaceutical products
vaccines, live
vaccines, viral
NA
NA
US002 FDA application pending
US011 Approved Formerly in US/withdrawn
NA
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