Rotavirus Vaccine, Live, Oral, Pentavalent - RotaTeq; WC3 pentavalent vaccine
Status: marketed in U.S., EU and other countries
Organizations involved:
Merck & Co., Inc. – Manuf.; R&D; Tech.; World mark.
Children’s Hospital of Philadelphia – R&D; Tech.
Wistar Institute – R&D; Tech.
Paul Capital Partners – Tech.
Royalty Pharma, AG – Tech.
Cross ref.: See the entry for Rotavirus Vaccine/Wyeth (RotaShield), the first rotavirus vaccine to have received FDA approval, for further background information. See also the entry for Rotarix from GlaxoSmithKline.
Description: RotaTeq is a oral formulation of five live bovine/human reassortant (natural recombinant) rotavirus strains cultured in VERO cells, a continuous African green monkey kidney (AGMK) cell line, used as an oral vaccine for prevention of pediatric rotavirus disease. The five strains are based on a bovine rotavirus G6 strain WC-3 [WC3; P7G6] backbone. Each of the five reassortants consists of the RNA backbone of the bovine rotavirus WC-3 (WC3) strain with a single inserted portion of a human rotavirus gene coding for a different human rotavirus surface protein – either the VP7 gene from a G1, G2, G3 or G4 human rotavirus or the VP4 gene from a P1A human rotavirus. Four reassortant rotaviruses express one of the outer capsid proteins (G1, G2, G3, or G4) from the human rotavirus parent strain, and the attachment protein (P8) from the bovine rotavirus parent strain. The fifth reassortant virus expresses the attachment protein, P1A (genotype P; P1) from the human rotavirus parent strain and the outer capsid protein G6 from the bovine rotavirus parent strain. These five viral serotypes/genotypes account for at least 80% of rotavirus gastroenteritis strains worldwide, although the prevalence of each serotype varies from one geographic area to another.
The G1 reassortant contains G1 and P1[8] outer capsid surface proteins from human rotavirus stain W179, along with the G6 and P7[5] outer capsid proteins from bovine rotavirus strain WC-3, presenting G1 and P7[5] on its outer surface capsid membrane. The G2 reassortant contains G2 and P2[8] capsid proteins from human rotavirus stain SC2, along with the G6 and P7[5] outer capsid proteins from WC-3, presenting G2 and P7[5] on its outer surface membrane. The G3 reassortant contains G3 and P1[8] capsid proteins from human rotavirus stain W178, along with the G6 and P7[5] outer capsid proteins from WC-3, presenting G3 and P7[5] on its outer surface membrane. The G4 reassortant contains G4 and P2[6] capsid proteins from human rotavirus stain BrB, along with the G6 and P7[5] outer capsid proteins from WC-3, presenting G4 and P7[5] on its outer surface membrane. The P1[8] reassortant contains G1 and P1[8] from human rotavirus strain W179, along with the G6 and P7[5] outer capsid proteins from WC-3, presenting G8 and P1[8] on its outer surface membrane. Only the outer surface exposed capsid proteins induce prophylactic immune responses.
Rotateq is supplied is individually pouched single-dose tubes in packages of one or ten tubes, each containing a 2 mL a suspension for oral administration. A tube with a screw-off cap containing the liquid is packaged within a pouch that is ripped to remove the tube prior to dosing. The dating period for Rotateq is 24 months from the date of manufacture when stored at 2-8 oC. The date of manufacture is defined as the date of the final fill. The shelf life includes the time that the product is held at 2-8 oC prior to packaging. A single dose of vaccine, including at end-of-expiry (end of dating period), contains no less than 2.2 x 106 (2.2 million) infectious units for the G1 serotype, 2.8 x 106 (2.8 million) infectious units for the G2 serotype, 2.2 x 106 (2.2 million) infectious units for the G3 serotype, 2.0 x 106 (2.0 million) infectious units for the G4 serotype, and 2.3 x 106 (2.3 million) infectious units for the P1[8] serotype. The reassortant viruses are suspended in a buffered stabilizer solution containing sodium citrate, sodium phosphate monobasic monohydrate and trace amounts of fetal bovine serum from the culture media. Rotateq contains no preservatives, including thimerosal. Rotateq is stored at 2-8°C (36-46°F; refrigerated).
Nomenclature: Rotavirus Vaccine, live/Merck [BIO]; Rotateq [TR]; Rotavirus Vaccine, Live, Oral, Pentavalent [FDA]; Rotavirus Vaccine, Quintavalent [FDA, used prior to approval]; WC3 vaccine, pentavalent [SY]; WC3-PV [SY]; NDC 0006-4047-31; NDC 0006-4047-41 [NDC]
Biological.: As discussed in the entry for RotaShield (another reassortant rotavirus vaccine), rotaviruses, like influenza viruses, naturally undergo reassortment, with segments of the viral RNA genome readily exchanged between viruses. The resulting reassortant viruses may be thought of a natural recombinant viruses.
A number of animal rotaviruses are attenuated in humans, i.e., have reduced or lack pathogenicity, and have been evaluated as potential live rotavirus vaccines, including the bovine serotype G6 WC3 rotavirus.
As with other reassortant viruses, whether rotavirus or influenza virus, the method for producing novel reassortants involves co-culture of heterologous viruses of the same species. The parent virus, e.g., bovine rotavirus strain WC3, is used along with another virus(es), e.g., a P1A human rotavirus, to co-infect a host cell line by conventional techniques. Progeny viruses are identified by running each parent and the progeny on conventional gel electrophoresis. Each gene segment runs with a characteristic mobility. The makeup of the reassortant is readily identified by comparison of its electrophoresis-based profile with that of the parent.
Aiming to avoid the adverse affects that RotaShield was associated with in infants, particularly intussusception (twisting of the lower intestines), the vaccine is based on a bovine strain of rotavirus. This bovine strain was chosen because it replicates less prolifically in the human gastrointestinal tract, e.g., than the simian strain used for RotaShield, a tetravalent rhesus reassortant vaccine. Each of the five reassortants in RotaTeq consists of the genetic backbone of the bovine virus with an inserted gene coding from a different human rotavirus surface protein (VP7 or VP4). The inserted genes were selected to represent a broad range of serotypes in order to elicit protection against a wide variety of strains.
Initially, a reassortant virus (W179-9) with a bovine rotavirus strain WC3 backbone and human rotavirus G1 VP7 (from strain W179) was developed and tested by Dr. Paul A. Offit, et al., at the Children’s Hospital of Philadelphia. This was well tolerated and induced 64% protection against all rotavirus disease and 87% protection against severe disease in a study in 325 infants. Since immunity was primarily WC3-specific, it was eventually decided to include four other reassortants to extend immunity to other rotavirus serotypes and strains. Because the human rotavirus VP4 gene of genotype P[8], is shared by most G1, G3, G4 and G9 human rotavirus strains, it was selected for inclusion in the vaccine. The reassortant rotaviruses in RotaTeq replicate more slowly than RRV (RotaShield), a factor thought to reduce the risk for intussusception. In general, such bovine-based rotavirus vaccines have shown the fewest adverse effects in clinical trials, and do not induce low-grade fever as seen with RRV (RotaShield). This is one reason why Merck based its vaccine on bovine rotavirus reassortants.
As part of the development of RotaTeq, Merck developed a new polymerase chain reaction (PCR)-based method to quantitate rotavirus infectivity.
Companies.: Merck & Co., Inc., CBER/FDA est. no. 0002, developed and manufactures Rotateq. The vaccine is manufactured and packaged at West Point, PA, facilities. RotaTeq development has been reported to have cost Merck about $800 million.
Merck licensed rotavirus reassortant viruses from the Children’s Hospital of Philadelphia and the Wistar Institute (both in Philadelphia, PA). The vaccine was invented by Drs. H. Fred Clark; Paul A. Offit; and Stanley A. Plotkin, who led laboratory studies of the vaccine at The Children’s Hospital of Philadelphia (CHOP) and the Wistar Institute between 1980 and 1991. Dr. Clark isolated from a calf the Wistar Calf-3 (WC3) strain of rotavirus in 1981. Early studies with the WC-3 strain indicated that while it was safe for use as a vaccine, it did not provide sufficiently effective protection. During the 1980s, the team turned to reassortants. Over 10 years ago, researchers from Children’s Hospital demonstrated efficacy with a quadravalent (4-strain) vaccine (lacking one of the strains added later to RotaTeq).
Merck assumed financial support of CHOP’s and the Wistar Institute’s rotavirus vaccine R&D in 1991, and after licensing the technology from Wistar and CHOP in 1992, the company moved toward clinical development and testing. From 1993 to 2005, Merck conducted studies to determine the safety, efficacy, dose, buffer combinations, and serotype composition of the vaccine. Between 2001 and 2004, the company conducted one of the largest clinical trials of a vaccine ever performed by a pharmaceutical company, involving 70,301 infants in 11 countries.
In Dec. 2005, Paul Royalty Fund, Paul Capital Partners, purchased from the Wistar Institute a portion of its royalties from worldwide sales of Rotateq. Wistar Inst. received a $1 million upfront payment and another $44 million payment upon launch in the U.S., and will receive unspecified royalties on sales. Wistar Inst. will retain all worldwide royalties in excess of ~$300 million annually. These funds will be used to increase the organization’s endowment and support Wistar Inst. activities and expansion. Note, Paul Capital also has a royalty interest in Rotarix from GlaxoSmithKline (GSK).
In April 2008, Royalty Pharma paid the Children's Hospital Foundation, the parent company of The Children's Hospital of Philadelphia, $182 million for its worldwide royalty interest in sales of RotaTeq starting Oct. 1, 2007.
Manufacture: The reassortant viruses are individually cultured in Vero cells using standard cell culture techniques in the absence of antifungal agents.
For a general reference concerning rotavirus vaccine manufacture, see "The Development of Live, Attenuated Rotavirus Vaccines: A manufacturer's Resourc Guide," issued by PATH.
FDA class: Biologic BLA
Approvals: Date = 20060203; first approval, BLA (STN BL 125122/0)
Date = 20070212; BLA supplement; Indication = changes to the insert/labeling to including reports of cases of intussusception and hematochezia seen post-marketing
Date = 20070615; BLA supplement; Indication = revised insert/labeling to include information on Kawasaki disease as a rare adverse effect
Date = 20070928; BLA supplement; Indication = revised insert/labeling to include G9 P1A[8] Serotype case reduction in the "Clinical Studies" section of the package insert, and revisions of the label in the Physician's Labeling Rule format
Date = 20080430; BLA supplement; Indication = labeling changes to the post-marketing experience section of the insert/label to include a post-marketing report of a death due to intussusception that occurred after vaccination with RotaTeq
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:
RotaTeq is indicated for the prevention of rotavirus gastroenteritis in infants and children caused by the serotypes G1, G2, G3, and G4 when administered as a 3-dose series to infants between the ages of 6 to 32 weeks. The first dose of RotaTeq should be administered between 6 and 12 weeks of age (see DOSAGE AND ADMINISTRATION).
Status: Merck’s submitted a BLA for RotaTeq on April 5, 2005, and it was accepted for review in July 2005. This was earlier than many had expected, perhaps by up to several years. Interim Phase III trial results supported filing for approval before planned end-of-trial analyses, with this enabled by the vaccine’s very high efficacy in trials. In Jan. 2006, the Vaccines and Related Biological Products Advisory Committee, FDA, unanimously recommended that the FDA approve Rotateq. The BLA was approved on Feb. 3, 2006; approval time = 9+ months. The vaccine was available for purchase from Merck (launched in the U.S.) upon approval.
Merck reports having filed for RotaTeq approval in 50 countries in 2005, including the European Union, Australia, Mexico, Asian and Latin American countries. Many countries will likely follow the lead of FDA and grant approval to RotaTeq.
As part of the BLA approval, Merck made a commitment to conduct a large-scale observational post-licensure safety study to evaluate the incidence of intussusception and other safety parameters in recipients of Rotateq in ~44,000 subjects (with adjustments to sample size based on background rate of intussusception). The study will be designed to detect an increased risk of intussusception due to vaccine of 2.5% or greater with 80% probability. The study protocol is to be submitted by May 5, 2006, and the study initiated no later than the 3rd quarter of 2006. The study will be completed by the 4th quarter of 2008. Merck also agreed to conduct an adequately powered non-inferiority study of the concomitant administration of Rotateq with acellular pertussis vaccine sufficiently to detect a 1.5-fold difference in antibody titers (GMTs) (whether the vaccines interfere with each other). A final protocol concept sheet is to be submitted no later than May 5, 2006. Merck must file annual progress reports for its post-marketing studies. Also, for the first three years of licensure, Merck must report cases of intussusception and all serious and unexpected adverse events to FDA within 15 days of receiving them, and all other side effects on a monthly basis,
FDA approval included exemption from performing the General Safety Test on this product..
The Centers for Disease Control and Prevention (CDC) will conduct a large post-approval study designed to rapidly detect any association of intussusception with RotaTeq through its Vaccine Safety Datalink Program, which evaluates vaccine safety in ~80,000 U.S. infants every year. FDA and CDC will also closely monitor the Vaccine Adverse Event Reporting System (VAERS) for reports of intussusception.
Merck started applications for RotaTeq in Europe and Latin America in 2005. Unlike GlaxoSmithKline with Rotarix, Merck is following a more traditional development and approval route with RotaTeq, with its emphasis on regulatory submissions, approvals and marketing expected first in the U.S. and other developed countries, after which the company will pursue approvals and marketing in lesser-developed countries. Upon Rotateq approval, Merck officials restated their commitment to make RotaTeq available at a substantial discount in the developing world, but noted that this was years away. Several years of testing in various lesser-developed countries will be required to confirm the safety and efficacy observed in trials in affluent, developed countries. Questions remain whether an oral vaccine that works in the Western world will be as effective in children raised in poor countries with different diets and substandard health care systems.
On July 5, 2006, Sanofi-Pasteur MSD received European Union (EU) approval for Rotateq.
In Aug. 2006, Merck Frosst Canada Ltd. received approval for Rotateq in Canada.
In Feb. 2007, the Advisory Committee on Immunization RotaTeq (ACIP), CDC, reconfirmed its initial support of RotaTeq after reviewing data on rotavirus hospitalizations and intussusception. In May 2007, FDA sent a letter to U.S. health care providers reporting that since its approval to Jan. 31, 2007, 28 cases of intussusception had been reported in U.S. in infants who received RotaTeq. The FDA notification was issued to encourage reporting of any additional cases of intussusception that may have occurred or that occur in the future after administration of RotaTeq. The number of cases reported did not exceed the number expected based on background rates of 18–43 per 100 000 per year for an unvaccinated population of children 6 to 35 weeks. A related article, “ Postmarketing Monitoring of Intussusception After RotaTeq Vaccination --- United States, February 1, 2006--February 15, 2007,” was published in Morbidity and Mortality Weekly Report (MMWR), March 16, 2007. CDC noted, “The data we have reviewed are reassuring, and we continue to recommend the RotaTeq vaccine.”
In June 2007, after eight reports of infants receiving Rotateq developing Kawasaki disease, including five in clinical trials, Merck added a warning to the product insert/labeling about this. At the time, about six million doses of the vaccine had been administered in the U.S., and FDA noted that “there is not a known cause and effect relationship between receiving RotaTeq, or any other vaccine, and the occurrence of Kawasaki disease. The cases reported to date are not more frequent than what could be expected to occur by coincidence.” The FDA added that doctors and parents “should remain confident in using RotaTeq.”
In Oct. 2008, RotaTeq was added by WHO to its list of prequalified vaccines for purchase by UN agencies.
Tech. transfer: Dr. Paul Offit, Children’s Hospital of Philadelphia, and colleagues at the hospital and the Wistar Institute worked on this vaccine for about 25 years. The vaccine was initially developed during the 1980s. RotaTeq-related patents assigned to the Children’s Hospital of Philadelphia and Wistar Institute and exclusively licensed to Merck in 1991 include, “Rotavirus Reassortant Vaccine,” U.S. 6,290,968; 6,113,910; 5,750,109; and 5,626,851. These claim reassortant rotaviruses containing the human rotavirus VP7 neutralization antigen gene, and another containing the human rotavirus VP4 neutralization antigen, with the remaining genes from the bovine rotavirus WC-3 strain.
Merck has received related patents including “Rotavirus Vaccine Formulations,” U.S. 6,403,098; 5,932,223; WO 9813065; and WO 0211540; and “Serum-Free, Low-Protein Media for Rotavirus Vaccine Production,” WO 9921969.
Trials: Researchers from the Children’s Hospital of Philadelphia over a decade ago demonstrated efficacy with a quadravalent (4-strain) predecessor version of the current quintavalent vaccine in a U.S. multi-center trial. The vaccine provided 73% protection against all rotavirus disease as well as against more severe disease. In a dose-ranging study, pentavalent vaccine, RotaTeq, demonstrated 100% efficacy against severe rotavirus gastroenteritis and 74% efficacy against rotavirus gastroenteritis of any severity in healthy infants.
In 1999, Merck’s plans to conduct final trials in about 2,000 children were put on hold after the reports of RotaShield’s association with intussusception. Merck subsequently launched the placebo-controlled Rotavirus Efficacy and Safety Trial (called REST) in about 70,000 children based in the U.S. and European countries. This was based on Merck’s decision to only enroll children in countries with the highest standards of care available (not lesser-developed countries), in order to treat any possible cases of intussusception
Overall, 72,324 infants were randomized (71,725 evaluated) in three placebo-controlled, Phase III studies conducted in 11 countries on three continents, including 36,165 infants evaluated in the group that received RotaTeq and 35,560 infants in the group that received placebo. Data demonstrating the efficacy of RotaTeq in preventing rotavirus gastroenteritis come from 6,983 of these infants from the U.S. (including infants from the Navajo and White Mountain Apache Nations) and Finland who were enrolled in two of these studies: the Rotavirus Efficacy and Safety Trial (REST) and Study 007. Results from these two pivotal trials were reported in the Jan. 4, 2006 issue of the New England Journal of Medicine. In these studies, RotaTeq prevented 74% of all rotavirus gastroenteritis cases; 98% of severe cases; and ~96% of hospitalizations due to rotavirus gastroenteritis. RotaTeq was not associated with an increased risk of intussusception when compared to placebo; and was not associated with an increased risk of other serious adverse events when compared to placebo. Within one year after the first dose, there were 13 cases of intussusception in the vaccine group and 15 in the placebo group. A third trial, Study 009, provided clinical evidence supporting the consistency of manufacture and contributed data to the overall safety evaluation.
Results from Merck’s Phase III studies show that RotaTeq is effective for prevention of severe rotavirus infections without causing serious side effects such as intussusception. The efficacy evaluations in these studies included: 1) prevention of any grade of severity of rotavirus gastroenteritis; 2) prevention of severe rotavirus gastroenteritis, as defined by a clinical scoring system; and 3) reduction in hospitalizations due to rotavirus gastroenteritis. The vaccine was given as a three-dose series to healthy infants with the first dose administered between 6 and 12 weeks of age. followed by two doses administered at 4- to 10-week intervals. The age of infants receiving the third dose was 32 weeks of age or less. Oral polio vaccine administration was not permitted; but other childhood vaccines could be concomitantly administered.
The primary efficacy analyses included cases of rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 that occurred at least 14 days after the third dose through the first rotavirus season post vaccination. Analyses also evaluated the efficacy of RotaTeq against rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 at any time following the first dose through the first rotavirus season postvaccination among infants who received at least one vaccination (Intent-to-treat, ITT, analysis). Primary efficacy against any grade of severity of rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 74.0% (95% CI: 66.8, 79.9) and the ITT efficacy was 60.0% (95% CI: 51.5, 67.1). Primary efficacy against severe rotavirus gastroenteritis caused by naturally occurring serotypes G1, G2, G3, or G4 through the first rotavirus season after vaccination was 98.0% (95% CI: 88.3, 100.0), and ITT efficacy was 96.4%, (95% CI: 86.4, 99.6).
The efficacy of RotaTeq against severe disease was also demonstrated by a reduction in hospitalizations for rotavirus gastroenteritis among all subjects enrolled in REST. RotaTeq reduced hospitalizations for rotavirus gastroenteritis caused by serotypes G1, G2, G3, and G4 through the first two years after the third dose by 95.8% (95% CI: 90.5, 98.2). The efficacy of RotaTeq in preventing cases in the REST trial occurring only during the second rotavirus season postvaccination was 62.6% (95% CI: 44.3, 75.4). The efficacy of RotaTeq beyond the second season postvaccination was not evaluated. In REST, the efficacy of RotaTeq against any grade of severity of naturally occurring rotavirus gastroenteritis regardless of serotype was 71.8% (95% CI: 64.5, 77.8) and efficacy against severe rotavirus disease was 98.0% (95% CI: 88.3, 99.9). The ITT efficacy starting at dose 1 was 51.0% (95% CI: 41.7, 58.9) for any grade of severity of rotavirus disease and was 96.4% (95% CI: 86.4, 99.6) for severe rotavirus disease. Shedding was evaluated among a subset of subjects in REST 4-6 days after each dose and among all subjects who submitted a stool antigen rotavirus positive sample at any time. RotaTeq was shed in the stools of 32 of 360 (8.9%) vaccine recipients tested after dose 1; 0 of 249 vaccine recipients tested after dose 2; and in 1 of 385 (0.3%) recipients after dose 3. Shedding was observed as early as 1 day and as late as 15 days after a dose. Transmission of the vaccine strains to nonimmunized persons has not evaluated.
Serious adverse events occurred in 2.4% of recipients of RotaTeq, compared to 2.6% of placebo recipients, within a 42-day period after a dose in the Phase III studies of RotaTeq. The most frequently reported serious adverse events for RotaTeq compared to placebo were bronchiolitis (0.6% RotaTeq vs. 0.7% Placebo); gastroenteritis (0.2% RotaTeq vs. 0.3% Placebo); pneumonia (0.2% RotaTeq vs. 0.2% Placebo); fever (0.1% RotaTeq vs. 0.1% Placebo); and urinary tract infection (0.1% RotaTeq vs. 0.1% Placebo). Note, intussusception was not even a minor adverse event. There were 25 deaths in the RotaTeq recipients compared to 27 deaths in the placebo recipients. The most commonly reported cause of death was sudden infant death syndrome, which was observed in 8 recipients of RotaTeq and 9 placebo recipients.
A relationship between antibody responses to RotaTeq and protection against rotavirus gastroenteritis has not been established. In Phase III studies, 92.9% to 100% of 439 recipients of RotaTeq achieved a 3-fold or more rise in serum anti-rotavirus IgA after a three-dose regimen, compared to 12.3%-20.0% of 397 placebo recipients. The efficacy of Rotateq beyond the second season after vaccination has not been evaluated.
Merck reported in Jan. 2006 that it plans to conduct Rotateq clinical trials in Africa and Asia. The Program for Appropriate Technology in Health (PATH) is also planning clinical trials in lesser-developed countries.
In Oct. 2007, updated data on intussusception rates in the U.S. were reported. Between March 2006 and August 2007, 9.1 million doses of RotaTeq were distributed in the U.S., and ongoing, routine surveillance confirmed 160 cases of intussusceptio, a rate below the expected background occurrence. Of these 160 cases, 47 were reported within three weeks of the infant receiving a vaccine dose. In an unvaccinated population of the same age, the number of expected cases would be ~150.
In the Jan. 5, 2007, issue of the New England Journal of Medicine, an article, “Safety and Efficacy of a Pentavalent Human–Bovine (WC3) Reassortant Rotavirus Vaccine,” reviewed results of administering Rotateq to 34,035 infants and concluded the vaccine “ was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients.”
A study by researchers at Quest Diagnostics Inc., of Madison, N.J., has shown that 26% of 27,625 rotavirus tests done at company labs around the country were positive for rotavirus in the three years Rotateq was licensed. In the most recent peak season, which ran from Dec. 2007 to June 2008, only 8% of 21,873 tests were positive.
In Oct. 2008, Merck reported results from a study of more than 61,000 infants showing that RotaTeq provided complete (100%) protection against hospitalizations and emergency room visits because of strains of rotavirus targeted by the vaccine.
Medical: RotaTeq is given by mouth, with the entire contents of the vial swallowed. The first dose is given between 6-12 weeks of age and two additional doses are administered at 4- to 10-week intervals. All three doses should be completed before a child reaches 32-weeks of age. RotaTeq may be given to pre-term infants according to their age in weeks since birth. This regimen is unlike Rotarix, which is administered as two doses, e.g., 2 and 4 months.
As with other live vaccines, caution is advised when considering whether to administer RotaTeq to individuals with close contacts with immune deficiencies, including HIV-infected patients and patients receiving.
Market: The total potential market for rotavirus vaccines, including universal or at least broad use in the U.S. and use internationally, including by public health programs in lesser-developed countries, is projected to be well over $1 billion a year. RotaTeq was the first approved in the U.S., where most of its sales, particularly in dollar terms, are expected.
Total sales were $648 million in 2012 (Merck reported $601 million with $47 million reported by Sanofi Pasteur MSD); $695 million in 2011 (Merck reported $651 million with $44 million reported by Sanofi Pasteur MSD); $519 million in 2010, and $522 million in 2009.
GSK, marketer of Rotarix, has estimated that the global market for rotavirus vaccines could achieve a value of £1-1.3 billion ($1.8-2.4 billion) by 2010. Rotarix sales could peak at $500 million/year or more. Its primary competition is Rotarix.
Merck upon approval set the U.S. wholesale price at $62.50 per dose when purchased as a pack of 10 single-dose tubes. With each infant requiring three required doses, the cost per infant is $187.50 (at wholesale).
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 $66.94 for package of 10 single-dose 2 mL tubes. The CDC Cost/Dose, the cost negotiated by NIP, CDC, for bulk contract purchase for public-sector state and local immunization programs, is $55.05 for package of 10 single-dose 2 mL tubes. 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 $85.25/vial, with a Direct Price (Manufacturer’s discount price) of $71.17; and $801.76/10 vials, with a Direct Price of $669.38 (Red Book, 2007).
In March 2006, the Advisory Committee on Immunization Practices (ACIP), CDC, unanimously voted to recommend that infants 6-12 weeks of age be vaccinated with Rotateq to prevent rotavirus gastroenteritis as part of the current baby immunization schedule. Thus, the vaccine was recommended for use as a universal pediatric vaccine. However, particularly due to its cost, it will likely take some time for public health programs to adopt the vaccine, if they can afford it (which remains to be seen). The three-dose regimen of RotaTeq vs. the 2-dose regimen for Rotarix, may put RotaTeq at a disadvantage for use by public health programs, where compliance (requiring 3 vs. 2 visits to a clinic) is always a problem. On Aug. 11, 2006, the “Prevention of Rotavirus Gastroenteritis Among Infants and Children: Recommendations of the Advisory Committee on Immunization Practices (ACIP)” was published in the Morbidity and Mortality Weekly Report (MMWR) from CDC.
The relatively high cost of Rotateq may limit acceptance in the U.S., and suggests that the vaccine may be too expensive for use in many lesser-developed countries, where rotavirus morbidity and mortality are much higher than in the U.S. and other developed countries. On the other hand, one thing the 11 month marketing of RotaShield demonstrated was that healthcare providers, insurers and parents in the U.S. (and, presumably, other affluent countries) are willing to adopt and purchase an expensive vaccine to protect children against a disease that few will likely ever contract (in a serious form) and for which fewer would ever even be diagnosed or treated. But, on the other hand, the failure of FluMist, an intranasal influenza vaccine (see related entry), to gain market share shows that the U.S. market can be highly sensitive to the prices of vaccines.
The relatively high price for Rotateq (and also probably Rotarix, upon its launch) will likely cause problems. The CDC and other authorities have recommended universal vaccination of infants against rotavirus disease. However, with half or more pediatric vaccinations in the U.S. paid for by the federal government (mostly through funding provided to states) and with these programs already financially stressed, the extent to which federal funds will be available for rotavirus vaccines is uncertain. States may be forced to abandon traditional practices of vaccinating all children from qualifying families. Already, as of Feb. 2006, at least 19 states no longer guarantee recommended immunizations to all children who need them.
The main competition for RotaTeq is Rotarix (see related entry). Rotarix has an advantage with only two inoculations required, while RotaTeq involves three. Otherwise, the two will compete on price and any perceived differences in efficacy (which may arise after both are on the market long enough or otherwise shown by further studies).
Merck, much like GSK with Rotarix, is collaborating with a coalition of public health advocates, including the international Program for Appropriate Technology in Health (PATH; primarily funded by Bill Gates and family), to develop a means to distribute the vaccine to children in lesser-developed countries. PATH estimates that an effective rotavirus vaccine could save the lives of 1,400 children per day. However, the efficacy of Rotateq has not yet been demonstrated in children in poorer countries.
See the other rotavirus entries for further discussions about the market for rotavirus vaccines.
Competition: A rotavirus vaccine is being developed with funding from various public and private philanthropic sources (e.g., PATH, GAVI). Partners in the rotavirus vaccine project are: the National Institutes of Health; various nonprofit organizations [Fundação Butantan (Sao Paulo, Brazil), Chengdu Institute of Biological Products (Chengdu, China), and Wuhan Institute of Biological Products (Wuhan, China]; and for-profit companies [Aridis Pharmaceuticals (United States), Bharat Biotech International, Ltd. (Hyderabad, India), Biological E., Ltd. (Hyderabad, India), Shanta Biotechnics, Ltd. (Hyderabad, India), and Serum Institute of India, Ltd. (Pune, India)]. The vaccine uses human-bovine reassortant rotavirus strains from NIH (apparently the the same or much the same as RotaShield).
Companies involvement:
Full monograph
531 Rotavirus Vaccine, live/Merck
Nomenclature:
Rotavirus Vaccine, live/Merck [BIO]
Rotateq [TR]
Rotavirus Vaccine, Live, Oral, Pentavalent [FDA]
Rotavirus Vaccine, Quintavalent [FDA prior to approval]
NDC 0006-4047-31; NDC 0006-4047-41 [NDC]
WC3 vaccine, pentavalent [SY]
WC3-PV [SY]
FDA Class: Biologic BLA
Year of approval (FDA) = 2006
Date of 1st FDA approval = 20060203
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
bovine materials used<!-- bovinesource -->
bovine materials used<!-- bovinesource -->
monkey source materials
rattlesnakes
vaccines, live
vaccines, oral
vaccines, viral
African green monkey kidney cells
bovine prothrombin
bovine serum
bovine transferrin
Branhamella catarrhalis
human Rho(D) cells
human Rho(D) cells
human transferrin
kidney cells, human neonatal
mammalian cell culture
p-nitrophenyl-beta-D-glucopyranoside
rotavirus prophylaxis
Vero cells
VP7, rotavirus capsid protein
Watson Scherp media
Watson Scherp media
Wiskott-Aldrich syndrome
bovine serum, fetal (FBS)
bovine serum, fetal (FBS)
sodium citrate
sodium phosphate, monobasic
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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