Rotavirus Vaccine, Live, Oral, Tetravalent - Rota-Shield; Rotamune
Status: approvals withdrawn; new sponsor working on refiling for approvals
Organizations involved:
Wyeth Pharmaceuticals – Manuf.; R&D; Tech.; World mark.; Former
National Institute of Allergy and Infectious Diseases (NIAID), NIH – R&D; Tech.
National Institutes of Health (NIH) – Parent
Biovirx Inc. – R&D; Tech.; World mark.
Description: Rotavirus Vaccine, Live, Oral, Tetravalent or RotaShield is a formulation of live, attenuated (natural reassortant/recombinant, not genetically engineered), orally administered, tetravalent, lyophilized (freeze-dried), cell cultured [using an African green monkey kidney cell line and a fetal rhesus diploid cell line (FRhL-2)] natural recombinant rotaviruses designed to provide protection against the four rotavirus serotypes responsible for most rotavirus disease in infants and young children in the U.S. The vaccine contains four live viruses – a naturally attenuated rhesus rotavirus (MMU 18006; serotype 3) which provides protection against human rotavirus serotype 3; and three rhesus-human reas-sortant viruses – DxMMU18006 (sero-type 1), DS-1xMMU--18006 (serotype 2), and ST-3xMMU18006 (serotype 4). The rhesus-human reas-sortant viruses are each composed of ten rhesus rotavirus RNA segments and one segment of human rotavirus origin encoding the viral protein 7 (VP7) antigen of human rotavirus serotypes 1, 2 or 4. The resulting reassortant viruses provide human serotype-specific VP7 antigens identical to those of the human rotavirus serotypes 1, 2, and 4 (responsible for most disease in the U.S.). Human rotaviruses grow poorly in cell culture, one of the reasons why rhesus, rather than attenuated human viruses, were developed for the vaccine.
The vaccine, also referred to as rhesus rotavirus-tetravalent (RRV-TV), was approved for prevention of rotavirus gastroenteritis, the most common cause of severe diarrhea and potentially life-threatening diarrhea in infants. However, it was withdrawn within a year of its U.S. launch after its use was associated with an increased incidence of intussusception, a type of serious bowel obstruction (involving in-folding of segments of the lower intestinal tract into other segments), in infants within weeks after receiving the live vaccine. Natural rotavirus and other gastrointestinal infections have not been associated as a cause of intussusception. A new licensee is now working towards refiling for approval of the vaccine.
RotaShield was marketed as a two component package containing a single-dose vial of lyophilized vaccine and a pouch containing 2.5 mL of irradiated sterile sodium citrate buffer diluent (9.6 mg/ml of citric acid and 25.6 mg/ml of sodium bicarbonate). The buffer diluent was mixed with the powdered vaccine, and served to neutralize stomach acidity and protect the acid-labile rotaviruses from degradation. Each 2.5 mL dose contained equal quantities (1 x 105 or 100,000 pfu) of each rotavirus serotype, with 4 x 105 (400,000) pfu total virus present. Excipients used to stabilize the lyophilized vaccine included sucrose, monosodium glutamate, potassium monophosphate, and sodium disphosphate. The vaccine contains no preservatives. Neomycin sulfate and amphotericin B (antibiotics) were used during culture of the virus, but were present in the vaccine at less than 1 µg/dose. The vaccine had a dating period (shelf life) of 24 months from the date of manufacture when stored ≤ 25˚C (77˚F). The date of manufacture is the date of the formulation of the tetravalent bulk in the case of the vaccine; and as the date of fill for the diluent. The diluent had a shelf life of 30 months.
Nomenclature: Rotavirus Vaccine/Wyeth [BIO]; RotaShield [TR]; Rotavirus Vaccine, Live, Oral, Tetravalent [FDA]; rhesus rotavirus-tetravalent [SY]; RRV-TV [SY]; Rotamune [TR foreign]; NDC 0008-0847;0008-2562-01; 0008-2562-02 [NDC]
Biological.: Rotavirus, a member of the Reoviridae family of viruses, has a genome composed of 11 segments of double-stranded RNA, each encoding a viral protein. The two outer capsid proteins, VP7, a surface glycoprotein, and VP4, a protease-cleaved hemagglutinin (in some strains), are important for virus antibody induction, neutralization and immunity. Although there are many different strains of rotavirus, most disease in the U.S. is caused by four human serotypes of rotavirus group A, designated serotypes (G)1, 2, 3, and 4 based on serologic response to the VP7 (G) antigen.
Reassortment of rotavirus segments occurs naturally, i.e., when different rotaviruses are mixed in the same medium, the virus’ genome segments reassort (recombine) by natural (not recombinant DNA) methods. This phenomenon was used to develop RotaShield. This is similar to the reassortment of influenza virus used to develop FluMist, a live intranasal influenza virus vaccine (see related entry). Reassortment is accomplished in vitro by mixed culture of different viruses, with coinfection of the same cells with two different but similar strains of rotavirus (having poor RNA editing capability). This allows the viral genetic material to naturally recombine. Resulting reassorted viruses have a mixture of gene segments from the co-cultured strains, and those with desired features (phenotype and genotype) may be selected. Wild-type rotaviruses grow poorly in cell culture, one of the reasons why reassortants were necessary for vaccine development.
Because rotaviruses only or primarily infects the small intestine of humans, immunity is presumed to be due to immunoglobulin A (IgA; mucosal immunity) antibodies at the mucosal surface. However, this local immunity is difficult to measure in infants and children. Circulating IgA rotavirus antibodies rise and then return to baseline several weeks after rotavirus vaccination. Because of this, the level of serum IgG-type rotavirus antibodies is the primary surrogate marker for measuring rotavirus immunity.
See the Disease section below for discussion of rotavirus disease. The pathogenic mechanisms of rotavirus disease are not fully clear. The rotavirus NSP4 protein may act as an enterotoxin, triggering a signal transduction pathway leading to an increase in intracellular calcium (Ca2+), which potentiates chloride ion (Cl-) secretion by a Ca2+ dependent pathway. This mechanism may be similar to that of E. coli heat-labile enterotoxin-beta and some other bacterial enterotoxins (and other diarrhea-causing viruses).
This live vaccine virus induces IgG antibodies capable of neutralizing human rotavirus serotypes 1, 2, 3 and 4, and specific IgA (mucosal) antibodies that are presumed to provide the vaccine’s protective efficacy against rotavirus infection.
History: Dr. A.Z. Kapikian, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH; Bethesda, MD), and collaborators first reported electron microscopy identification of rotavirus. In 1984, NIAID researchers developed the first monovalent reassortant vaccine. Clinical trials with monovalent vaccines indicated that additional immunogens were needed for better protection against other rotavirus serotypes causing disease in the U.S. Several years later, NIAID researchers developed the additional reas-sort-ment components of the current vaccine. [A timeline of advances in rotavirus molecular biology and vaccine development and other rotavirus-related articles were published in the Journal of Infectious Diseases, vol. 174, suppl. 1, Sept. 1996].
Companies.: The vaccine was commercially developed and manufactured by Wyeth (Marietta, PA), CBER/FDA est. no. 0003, formerly a subsidiary of American Home Products Corp. (AHP). It was marketed in the U.S. by Wyeth.
In the 2nd quarter of 1999, AHP wrote off a special charge (loss) of $53.0 million for the estimated costs of the suspension of shipments and its voluntary market withdrawal and disposals of stocks of RotaShield.
In May 2004, as discussed in the “Tech. transfer” section below, Biovirx Inc. (Minneapolis, MN) licensed exclusive worldwide rights to Rotashield-related inventions and clinical data from the National Institutes of Health (NIH), with the intension of refiling for approvals of RotaShield (or a substantially similar follow-on) vaccine and marketing it worldwide. Impfstoffwerk Dessau-Tornau GmbH (Tornau, Germany) is Biovirx’s contract manufacturer for Rotashield.
Manufacture: The viruses are first cultured individually in African green monkey kidney cells. Fetal bovine serum (FBS) is used in the culture medium. Virus is then transferred to fetal rhesus diploid cell line (FRhL-2) in a Minimum Essential Medium (MEM) for large-scale culture. After the rotavirus is harvested, residual cellular debris is removed by filtration. Sucrose, monosodium glutamate, potassium monophosphate, and potassium diphosphate are added to the virus-containing medium to stabilize the rotavirus. Neomycin sulfate and ampho-tericin B (antibiotics) are present during cell culture growth, but are removed during processing, and are present in the final product at a concentration of less than 1 µg per dose. All growth media and ingredients are tested for viral and other microbial contamination.
FDA class: Biologic BLA
Approvals: Date = 19980831; first approval, BLA ref. no. 97-0111 and 97-0924
Date = 19991015; BLA voluntarily withdrawn
Indications: for immunization at 2, 4, and 6 months of age for the prevention of rotavirus gastroenteritis in infants
Status: An estimated one million U.S. infants received 1.5 million doses of RotaShield during the less than one year the vaccine was available in the U.S.
Wyeth-Ayerst filed its BLA on April 9, 1997, and the vaccine was approved on Aug. 31, 1999; a review time of ~1.5 years. The Centers for Disease Control and Prevention (CDC) and other organizations recommended universal rotavirus vaccination of all infants in the U.S. with the vaccine (prior to its withdrawal). As part of approval, Wyeth committed to conduct post-marketing studies in at least 20,000 children, and IND studies to examine safety in older infants and immune interference with other concurrently administered vaccines.
On July 16, 1999, Wyeth temporarily suspended further distribution and administration of RotaShield until more data on the potential association the vaccine and intussusception became available. This action followed anecdotal reports of cases of intussusception, a serious type of bowel obstruction in which one segment of the bowel (large intestine) becomes enfolded within another segment, blocking bowel movements. The action was taken in consultation with the FDA following a recommendation from the CDC to postpone administration because of reports to the Vaccine Adverse Events Reporting System (VAERS) of a possible association between Rota-Shield and intussusception. On Oct.15, 1999,
Wyeth voluntary withdrew Rotashield from the U.S. market, and halted further manufacture and development. Rota-Shield was the first rotavirus vaccine to be approved anywhere, and it was the first case of withdrawal from the U.S. market of a vaccine accepted for universal pediatric use. Wyeth’s withdrawal of the vaccine from the U.S. market effectively halted the vaccine’s development for use in lesser-developed countries where rotavirus disease has a much higher mortality rate and an effective rotavirus vaccine is desperately needed (see Disease section). [In hind-sight, particularly from the perspective of worldwide need and markets, it appears that Wyeth made a miscalculation in initially developing RotaShield as a universal pediatric vaccine for the U.S. and other highly developed/affluent countries, rather than first or in parallel seeking approvals in lesser-developed countries, where even the worse-case increases in intussusception would be considered negligible/irrelevant compared to the risks. Presumably, Wyeth planned to first ramp up manufacturing and marketing for the U.S. and other major pharmaceutical markets, and then obtain approvals and market it in lesser-developed countries (requiring lower prices, dependent on economies-of-scale). Even though considered safe and effective and highly desired by many developing countries, Wyeth’s U.S. market-driven decision to withdraw and abandon the vaccine halted its potential availability outside the U.S.].
Tech. transfer: Commercial development began in 1987 though a Collaborative Research & Development Agreement (CRADA) between Wyeth-Ayerst and NIAID, NIH. Patents exclusively licensed by NIH to Wyeth included U.S. 4,751,080 and U.S. 4,704,275, both covering the source strains, including rhesus rotavirus serotype 3 strain MMU 18006 (ATCC VR 954; also described in Lab. Animal Science, vol. 29, p. 610-6, 1979). The vaccine reassortants DxMMU18006 (sero-type 1), DS-1xMMU--18006 (serotype 2), and ST-3xMMU18006 (serotype 4) were derived from MMU 18006. Besides developing the base and reassortant strains used in RotaShield, NIAID also conducted and assisted with clinical trials. Wyeth returned rights to its licensed technology after the vaccine’s withdrawal.
In May 2004, Biovirx Inc. licensed exclusive worldwide rights to Rotashield-related inventions and clinical data from the NIH, with the intension of refiling for approvals of Rota-Shield and marketing it worldwide. Biovirx plans to confer with FDA regarding the need, if any, for additional clinical trials; and was raising ~$10 million from a private placement to secure and validate a manufacturing facility.
Trials: The vaccine’s safety and efficacy were studied in several large-scale placebo-controlled trials. RotaShield was administered to nearly 18,000 subjects in various clinical studies conducted in nine countries. Overall, RotaShield prevented at least 50% of all cases of rotavirus disease and at least 70% of severe cases. This included 5,733 infants who received the vaccine in placebo-controlled trials. In clinical trials involving almost 7,000 infants in the U.S. and Europe, intussusception occurred at a rate of 5 per 10,0000 vaccine recipients. At the time of the product’s approval, this incidence rate was not judged to be a significant risk compared to the normal incidence rate of infant intussusception.
However, post-approval reports of serious intussusception caused the vaccine to be withdrawn from the market. Vaccine-associated intussusception primarily occurred within 1-2 weeks after administration of this live vaccine. Cases of intussusception were often severe and required surgery (about one-half of vaccine-associated cases), while most normal cases of intussusception can be treated with enemas. Several post-approval studies found a temporal association between use of RotaShield and the development of intussusception, particularly within 1-2 weeks after the first dose; and the Centers for Disease Control and Prevention (CDC) concluded that there was a “strong significant” association between vaccination and intussusception. At the time, it was reported that intussusception normally occurs in about 1 of every 1,900 infants in the U.S. in their first year of life. The disease sometimes requires surgery and is rarely fatal in the U.S. After introduction of the vaccine, the CDC projected a vaccine-associated increase in the rate of intussusception due to RotaShield of one case per 2,500 to 5,000 infants vaccinated. This increased risk, combined with anecdotal reports of serious intussusception, was enough to cause the withdrawal of the vaccine in the U.S., a highly litigation-prone environment for vaccines.
In the Oct. 2001 issue of Lancet (vol. 358, p. 1224-29), NIAID, NIH, researchers confirmed increased risk in the first few weeks after inoculation, but found decreased risk after this period, with the overall risk for intussusception actually appearing to be lower in vaccinated infants. The study examined hospital admissions for intussusception among infants less than one year of age from Oct. 1998 to July 1999, when the vaccine was available in the U.S., compared to comparable periods going back as far as 1993. Hospital discharge data were examined from 10 states, including over one-fourth of the 3.8 million infants born annually in the U.S. and ~300,000 infants having received RotaShield. The study found that the risk for hospitalization due to intussusception was actually decreased by 4-10% among infants less than one year old during the period when RotaShield was available, compared to analogous time periods before the vaccine’s introduction; and that the increased risk for intussusception in the weeks after initial vaccination was offset, or more than offset, by a decreased risk for intussusception in later infancy, i.e., the vaccine was associated with an increase in intussusception above normal for several weeks after vaccination, but this risk decreased to below normal after this period. Also after the vaccine’s withdrawal, the CDC revised its original estimate of the projected increase in incidence of vaccine-related intussusception, decreasing this by about one-half. With continuing debate and controversy, the risk of vaccine-associated intussusception came to be widely accepted to be about 1 excess case per 10,000 vaccinated infants (lower than the original estimate).
By 2003, NIAID researchers had reviewed additional data and revised the estimated the risk of vaccine-associated intussusception to be 1 excess case per 32,000 infants in the target population, infants 45-210 days old (see “Reappraisal of the association of intussusception with the licensed live rotavirus vaccine challenges initial conclusions,” Journal of Infectious Diseases, 187:1301-08, 2003). Excess risk/cases apparently occurred because physicians often gave the vaccine to infants older than indicated/officially approved, with some physicians administering the product in patients up to 9 months of age. Intussusception normally peaks at 4-9 months of age. The availability of more data with time showed that intussusception rates were not significantly increased by the vaccine. In fact, the study reported an overall decrease in intussusception observed among infants less than 1 year old during the rotavirus vaccine exposure period. The background rate of intussusception in the U.S. was recalculated to be 1 case per 3,000 infants during the first year of life (within the range originally associated with RotaShield).
Medical: Infants were recommended to receive the oral vaccine at 2, 4 and 6 months of age.
Disease: Rotavirus is highly contagious and infects nearly all children by the age of four. Epidemiological studies confirm that rotavirus gastroenteritis, especially severe rotavirus disease, occurs primarily in infants younger than two years of age. Although older children and adults experience rotavirus infection and reinfection, most do not become sick or have only mild illness (a reason the vaccine was not recommended for adults). There are no antiviral therapeutics available for treatment of rotavirus infections. Treatment involves alleviating associated dehydration and other symptoms.
Rotavirus is the single most important cause of epidemic severe acute gastroenteritis (diarrhea and vomiting) in infants and young children both in developed and developing countries. Untreated severe rotavirus diarrhea in infants can be rapidly fatal unless dehydration is corrected by oral or intravenous replacement of fluids. In temperate climates, the disease is seasonal, with a peak in the winter months. In tropical and subtropical areas, it is generally endemic.
Rotavirus infection affects an estimated 3.5 million children annually in the U.S. It is estimated that in the U.S. each year 411,000 infants under one year of age and 1.5 million between 1-2 years of age require treatment for rotaviral gastroenteritis. About on-half of affected children develop severe diarrhea. An estimated U.S. annual 55,000 hospitalizations of infants for severe diarrhea are diagnosed as rotavirus infection, and about 20 to 40 of these children die each year. Overall, rotavirus causes about 5% of diarrheal disease in the community and nearly 40% of severe dehydrating illness.
Worldwide, approximately 870,000 infant deaths annually are attributed to rotaviral disease, particularly the associated diarrhea, with the vast majority of these deaths in developing countries where supportive treatment is often not available. Thus, the risk and incidence of death from infant rotavirus infection is far greater (about 5 orders of magnitude) in lesser-developed countries.
The WHO has recommended inclusion of rotavirus vaccines in national immunization programs of countries where clinical trials have demonstrated that the vaccines are safe and effective. In 2009, in order to make possible a worldwide push against rotavirus, additional clinical trials are necessary in impoverished populations in Africa and Asia because orally administered vaccines historically perform differently in various populations of the world. In 2004, the PATH Rotavirus Vaccine Program (a partnership between PATH, the US CDC, and the WHO with funding from the GAVI Alliance) took the unprecedented step of partnering with rotavirus vaccine manufacturers, GSK and Merck, to conduct rigorous clinical trials to determine the vaccines’ efficacy in those continents. Results from large trials in Africa and Asia are expected in 2009.
In March 2009, PATH published a briefling paper reporting that rotavirus vaccines have the potential to save more than 2.5 million lives by 2025..
Market: The average price paid by U.S. purchasers for RotaShield was $38/dose, or about $114 for a full course of three vaccinations. Some parents paid over $200.
An estimated 1.5 million doses were distributed in the U.S. prior to its voluntary withdrawal from the market. Total sales would have been ~$57 million.
R&D: As discussed above in the Tech. transfer section, Biovirx Inc. licensed RotaShield-related technology and clinical data from NIH in May 2004, and is pursuing RotaShield development and marketing worldwide.
Aridis Pharmaceutical, LLC, in collaboration with Wyeth, is developing Rotavax, a rotavirus vaccine delivered in a highly convenient oral, quick-dissolving thin film dosage form (e.g. Listerine breath freshener strip). In 2009, Rotavax has successfully completed six NIH and Wyeth sponsored Phase I and II clinical trials with strong safety and efficacy results. Aridis has exclusively licensed this vaccine from the NIH for the North American and European markets. Rotavax will require only two doses.
AMRAD Corp. Ltd. in collaboration with SmithKine Beecham S.A., now GlaxoSmithKline plc, halted development of an oral rotavirus vaccine in 1999 after equivocal immune responses were observed in a Phase II trial.
Companies involvement:
Full monograph
532 Rotavirus Vaccine, live/Wyeth
Nomenclature:
Rotavirus Vaccine, live/Wyeth [BIO]
RotaShield [TR]
Rotavirus Vaccine, Live, Oral, Tetravalent [FDA]
rhesus rotavirus-tetravalent [SY]
RRV-TV [SY]
Rotamune [TR non-U.S.]
NDC 0008-0847;0008-2562-01; 0008-2562-02 [NDC (for vaccine vials)]
FDA Class: Biologic BLA
Year of approval (FDA) = 1998
Date of 1st FDA approval = 19980831
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
live microorganisms (as active agent)
monkey source materials
rattlesnakes
vaccines, live
vaccines, oral
vaccines, viral
African green monkey kidney cells
amphotericin B
bovine serum
bovine serum, fetal (FBS)
fetal rhesus monkey diploid cells<!-- monkeycells -->
fetal rhesus monkey diploid cells<!-- monkeycells -->
FRhL-2 diploid fetal rhesus lung cells
human-rhesus rotavirus reassortant virus serotypes 1, 2, and 4
kidney cells, human neonatal
mammalian cell culture
Minimum Essential Medium (MEM)
monkey diploid cells, fetal rhesus<!-- monkeycells -->
monkey diploid cells, fetal rhesus<!-- monkeycells -->
monkey kidney cells<!-- monkeycells -->
neomycin
rhesus lung cells, diploid fetal
rhesus lung cells, diploid fetal
rhesus rotavirus (serotype 3)
rhesus-human rotavirus reassortant virus serotypes 1, 2, and 4
rotavirus
citric acid
lyophilized (freeze-dried)
monosodium glutamate
potassium monophosphate
rotavirus capsid protein 7 (VP7)
sodium bicarbonate
sodium citrate
sodium disphosphate
sucrose
VP7, rotavirus capsid protein
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
North American coral snake
EU000 Not yet/Never filed with EU
UM999 Not Available/Not Marketed in US
US011 Approved Formerly in US/withdrawn
EM999 Not Available/Not Marketed in EU
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