Status: BLA approved in April 2008; marketed in EU

Organizations involved:

Celldex Therapeutics, Inc. – Manuf.; R&D; Tech.

AVANT Immunotherapeutics, Inc.– Former

GlaxoSmithKline Biologicals S.A. – R&D; Tech.; World mark.

GlaxoSmithKline plc (GSK) – Parent

Virus Research Institute – R&D; Tech.; Former.

Children’s Medical Center – R&D; Tech.

Universal Preservation Technologies Inc. – Tech.

Paul Capital Partners – Tech.

Cross ref.: See the entry for Rotavirus Vaccine/Wyeth (RotaShield), the first rotavirus vaccine to have received FDA approval, for general background information. See also the entry for the other rotavirus vaccine (RotaTeq).

Description: Rotarix is a lyophilized (freeze-dried) buffered formulation of a single live human reassortant (natural recombinant) rotavirus 89-12C2, a rotavirus G1P[8] strain, cultured in Vero cells, a continuous African green monkey kidney (AGMK) cell line, presumably using the microcarrier method. The vaccine is packaged as a powder for reconstitution. Each oral dose contains at least 1 x 10.sup6.0 median Cell Culture Infective Dose or CCID50 (also, before approval, reported ast 1 x 10.sup.5 pfu) of live rotavirus 89-12C2. The vaccine is packaged in a calcium carbonate buffer that protects the attenuated virus from inactivation by stomach acids.

The lyophilized vaccine contains amino acids, Dulbecco's Modified Eagle Medium (DMEM), sorbitol, and sucrose. DMEM contains sodium chloride, potassium chloride, magnesium sulfate, sodium pyruvate, D-glucose, concentrated vitamin solution, L-cystine, L-tyrosine, amino acids solution, L-glutamine, calcium chloride, sodium hydrogencarbonate, and phenol red. The liquid diluent contains calcium carbonate, sterile water and xanthan, with the antiacid component (calcium chloride) protecting the stomach and preventing viral inactivation by acid in the stomach. Rotarix Manufacturecontains no preservatives.

Rotarix is packaged powder in a glass vial, along with a prefilled oral applicator of liquid diluent (1 mL) with a plunger stopper and a transfer adapter for reconstitution.

After use, vials are disposed of as biohazards. Rotarix is stored at 2-8˚C (refrigerated).

Rotarix uses a VitriLife, a sugar-based process for the large-scale preservation of biological solutions and suspensions, to stabilize Rotarix. AVANT acquired VitriLife through its acquisition of Universal Preservation Technologies Inc. VitriLife enables vaccines to be preserved and dried in bulk as a sugar solution in only 24 hours vs. the usual four days for lyophilization, and without loss of viability due to lyophilization. The resulting powder can be stored at room temperature (without refrigeration or freezing), which reduces “cold chain” maintenance costs, and makes the product more suited for distribution in lesser-developed countries.

Nomenclature: Rotavirus Vaccine, live/GSK [BIO]; Rotarix [TR]; Rotavirus Vaccine, Live, Oral, Monovalent [FDA; likely FDA proper name upon approval]; RIX-4414 [SY]

Biological.: See the entry for RotaShield, the first approved rotavirus vaccine (subsequently withdrawn) for information about rotavirus and rotavirus vaccines.

The 89-12C2 human rotavirus used in Rotarix was originally isolated by researchers at the Cincinnati Children’s Medical Center from the stool samples of a 14-month old infant with rotavirus gastroenteritis. The human 89-12C2 strain belongs to the G1[P] type. Rotavirus strain 89-12C2 was cultured-adapted (attenuated) by two passages in primary African green monkey kidney (AGMK) cells and four passages in MA-104 cells (see J. Clin. Microbiol., 19:748-753, 1984). It was then plaque purified three times in MA-104 cells and cultured for two additional passages in these cells. The 89-12C2 human rotavirus strain has been through at least 11 tissue culture passages. One additional passage was made for deposition with the American Type Culture Collection (deposited as ATCC VR-2272). Although adapted for cell culture, rotavirus 89-12C2 does not replicate in humans any better after oral demonstration than animal rotaviruses.

Rotarix is much different from RotaShield. As discussed in the RotaShield entry, intussusception (twisting of the lower intestines) is a major potential serious adverse effect from rotavirus vaccination of infants. Apparent increases in the incidence of intussusception in RotaShield-vaccinated infants caused withdrawal of the vaccine (although more recent analyses suggest this may have been premature). Because there is no link between intussusception and natural human rotavirus infection, it is generally presumed that an attenuated human virus, such as used in Rotarix, should not provoke this unusual side effect. In contrast, RotaShield contained four live viruses—a naturally attenuated rhesus rotavirus (serotype 3) and three rhesus-human reassortant viruses (serotypes 1, 2 and 4). Another major difference between the two vaccines is that Rotarix involves two oral doses while RotaShield involved three. Also, in trials, Rotarix provided ~89% efficacy compared to 49-68% for RotaShield.

Human rotaviruses may be divided into six serotypes, i.e., serotypes 1-4 and 8-9, based upon differences in the VP4 and VP7 proteins. Human rotaviruses are also divided into two subgroups, i.e., subgroups I and II, based on antigenic differences in the inner capsid VP6 protein. Serotype 2 and 8 strains of human rotavirus usually belong to subgroup I, and serotypes 1, 3, 4 and 9 of human rotavirus strains usually belong to subgroup II. Most rotavirus disease is believed to be caused by rotaviruses belonging to serotypes 1-4 strains. Serotype 1 strains have been found to predominate in many geographic regions. The HRV 89-12C2 rotavirus belongs to rotavirus subgroup II on the basis of gel electrophoresis of its RNA genome, and is serotype 1 on the basis of its reactions to serotyping monoclonal antibodies.

There has been controversy among investigators regarding the importance and extent of serotype-specific antibodies in rotavirus vaccine-induced prophylaxis. Studies indicate that immunity induced by Rotarix is at least partially due to factors other than induction of humoral IgG antibodies (e.g., see Viral Immunology, 16(1), p. 17-24, 2003). Cellular immunity, particularly CD8+ and CD4+ cytotoxic T-lymphocytes (T-cells) and mucosal IgA immunity apparently are involved in disease prophylaxis. Those emphasizing the importance of outer rotavirus capsid VP4 and/or VP7 epitopes as essential vaccine immunogens assert that multivalent vaccines, e.g., RotaTeq from Merck (see related entry), will be more effective than monovalent vaccines. Those emphasizing the importance of cellular immunity assert that monovalent vaccines with proven induction of cellular immunity, e.g., Rotarix, will provide better prophylactic efficacy.

In most of Rotarix’s clinical trials, particularly earlier trials in the U.S. and Finland, the locally predominant rotavirus strains belonged to the G1 serotype, the same type as Rotarix (89-12C). However, in reported Phase II trials in Mexico, Brazil and Venezuela, there was nearly equal distribution of rotavirus serotypes between G1 and G2 among infants developing rotavirus disease, with Rotarix having efficacy of 76.5% against G1 and 76.6% against G2 epitopes. This demonstrated that Rotarix, despite being a monovalent vaccine, can provide protection against heterologous strains. But the extent of protection conferred by serotype cross-reactive antibodies vs. cellular immunity remains undetermined, so the rotavirus vaccine antigen-related controversy has not been fully resolved.

Other monovalent vaccines have shown cross-serotype immunity. This includes an early monovalent bovine rotavirus G1 reassortant vaccine, RIT 4237, from SmithKline Beecham, for which development was abandoned after inadequate efficacy in a Rwandan clinical trial. Another monovalent bovine reassortant vaccine, WC3, provided efficacy in one U.S. trial but not in another trial in another city, although the predominant circulating strains in both locales were of type G1.

Cross-strain immunity from Rotarix (and other rotavirus vaccines) is further supported by substantial heterotypic protection observed in immunized children aged 2-4 months with less-developed immune systems. It is presumed that the majority of the efficacy of Rotarix is due to cross strain-reactive neutralizing antibodies induced against common VP4 epitopes.

Companies.: The rotavirus 89-12 strain used was originally developed at the James N. Gamble Institute of Medical Research, Children’s Hospital Medical Center (Cincinnati, OH), by Drs. David Bernstein, Richard Ward, and coworkers. The Children’s Hospital Medical Center exclusively licensed the vaccine to Virus Research Institute (formed in 1998 from the merger of the Virus Research Institute and T Cell Sciences, Inc.), later AVANT Immunotherapeutics (became Celldex Therapeutics, Inc. in Oct. 2008). AVANT (sub)licensed exclusive worldwide rights to SmithKline Beecham Biologicals (SKB; now GlaxoSmithKline) in Dec. 1997. SKB/GSK assumed clinical and manufacturing process development of the vaccine in 1999 after successful completion of a Phase II trial in infants by AVANT. AVANT received licensing payments, continues to receive milestone payments, and receives unspecified royalties on sales.

AVANT, now Celldex Therapeutics, has reported that it manufactures Rotarix at a new facility in Fall River, MA. [However, the product insert attributes manufacture to GlaxoSmithKline Biologicals (Rixensart, Belgium), CBER/FDA est. no. 1617. Most likely, Celldex manufactures it under contract for GSK, with FDA ofter attributing manufacture to the applicant or contractee vs. the manufacturing contractor].

GSK has invested $500 million in the development of Rotarix and has conducted some of the largest ever clinical trials for the product. Royalty revenues to AVANT/Celldex began in the first half of 2005 (with sales in Mexico), with royalties of about $1-2 million expected in 2005 and increasing as more countries approve the vaccine.

In May 2005, Paul Capital’s Paul Royalty Fund II, Paul Capital Partners, entered into an agreement with AVANT to provide total financing of up to $61 million in exchange for a portion of AVANT’s royalties on Rotarix from GSK. AVANT received an initial milestone payment of $5 million upon execution of agreement and a second milestone of $5 million in Dec. 2005. AVANT will receive a further $40 million upon launch in the European Union and $9-11 million upon launch in the U.S. Paul Royalty receives 100% of the first $27.5 million of AVANT’s Rotarix royalties each year, with AVANT retaining 92.5% above $27.5 million. AVANT will also receive a share of royalties if Paul Royalty annually receives a return of 2.45 times the cash payments it makes to AVANT. AVANT was expected to receive royalties of $5-$8 million in 2006.

In Jan. 2006, Paul Capital Partners similarly purchased an undisclosed interest in Rotarix’s royalties from three researchers (inventors) at the Cincinnati Children’s Hospital Medical Center, presumably including Drs. Bernstein and Ward. Note, Paul Capital also has a royalty interest in RotaTeq from Merck.

Among the factors influencing Paul Capital to invest in rotavirus vaccines were the “high price of admission,” e.g., the history with Rotashield forcing trials in 60-70,000 infants and the major investments in manufacturing required, with these costs likely to prevent any additional companies from developing a rotavirus vaccine for use in Western countries.

In March 2006, AVANT Immunotherapeutics amended its agreement with Paul Royalty Fund II, L.P. to accelerate receipt of a $40 million milestone payment (received on March 17, 2006). The payment had previously been due upon the first sale of Rotarix in the European Union (with approval granted in late Feb.). Other terms were not changed. Also, in March 2006, AVANT received a $4 million milestone payment from GSK related to European Union approval of Rotarix.

In Oct. 2008, with the merger of Celldex Therapeutics, Inc. (a spin-off from Medarex) with AVANT Immunotherapeutics, Avant became Celldex Therapeutics.

In Jan. 2008, Paul Capital purchased an additional interest (royalty stream) in Rotarix, acquiring from Cincinnati Children's Medical Center all of its royalties on worldwide sales of Rotarix. This was the third investment that the Fund has completed related to Rotarix royalties, having previously acquired AVANT's and inventors' royalties. Note, Paul Capital also has an interest in RotaTeq.

Manufacture: For a general reference concerning rotavirus vaccine manufacture, see "The Development of Live, Attenuated Rotavirus Vaccines: A manufacturer's Resource Guide," issued by PATH.

FDA class: Biologic BLA

Approvals: Date = 20080403; BLA

20090212; BLA supplement; Indications: include changes to package insert and container/carton labels to move the phrase "Do not freeze; discard if frozen".

Indications: [Full text of the "Indications and USAGE" section of the product insert/labeling]:

Rotarix is a vaccine indicated for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4 and G9) when administered as a 2-dose series in infants and children.

Status: On June 27, 2007, GSK filed a BLA seeking FDA approval of Rotarix as a two-dose rotavirus vaccine administered to children for the prevention of gastroenteritis caused by rotavirus.

Since Rotarix received its first approval and was launched in Mexico in 2004 (as of 12/15/2005), it has received approvals in over 90 countries worldwide.

In Jan. 2005, EMEA/European Union (EU) -accepted for filing a MAA seeking EU-wide approval of Rotarix for rotavirus prophylaxis in infants. This triggered a $2 million milestone payment to AVANT. In Dec. 2005, the Committee for Medicinal Products for Human Use (CHMP), European Union (EU), issued a positive opinion supporting approval. On Feb. 28, 2006, the EU granted full approval to Rotarix. Based on this, AVANT received a $40 million milestone payment from GSK.

In July 2004, Rotarix received full approval in Mexico, its first approval. Rotarix was launched in Mexico in Jan. 2005. Mexico was a major participant in Rotarix Phase III clinical trials. Rotarix is being integrated into the government’s universal infant immunization programs.

First approval in Mexico set a major precedent and was a significant change from most prior patterns for approvals for pharmaceuticals meant for worldwide distribution, particularly for vaccines and those originating from large international pharmaceutical companies, such as GSK. Previously, essentially all pharmaceuticals, including vaccines, from larger companies destined for worldwide markets were tested and usually approved first in the U.S. (and/or European Union), with FDA’s (and/or EMEA/European Union) approval based on rigorous review of efficacy, safety and manufacturing aspects considered the “gold standard” for approval worldwide. This was particularly true for vaccines for childhood diseases, which have been introduced first in U.S. and/or Europe, with lesser-developed countries often having to wait about 15 years for the vaccines. Historically, many lesser-developed countries have been reticent or refused to grant approval to products not tested and approved in the U.S. and/or other developed countries.

GSK has set a major precedent, much welcome by many, of first gaining approval and launching a novel vaccine in a lesser-developed country, where it is needed most. Many hope this precedent will be successful and be applied to other vaccines and pharmaceutical products much needed in lesser-developed countries, e.g., malaria vaccines. GSK’s extensive testing of Rotarix and its approval in Mexico has, to some extent, effectively allowed the company to bypass initial FDA/EU approval and first launch Rotarix in less developed countries, where rotavirus disease is more prevalent and infection is more likely to be fatal.

Rotavirus disease and mortality is high in many lesser developed countries, e.g., 600,000 infant deaths/year are commonly attributed to rotavirus infections. This contrasts with the situation in the U.S. and other developed countries, where hospitalization and treatment, e.g., oral rehydration for the dehydration induced by rotaviral diarrhea, is ready available for infants needing this, and deaths from rotavirus are very rare. In the U.S., much of the incentive for vaccination is economic, with infant hospitalization due to rotavirus infection estimated to cost about $2 billion annually.

GSK launched Rotarix in additional Latin American countries as well as Asia Pacific countries in 2005 and 2006, focusing on countries with the most medical need for the vaccine. GSK planned to seek/gain FDA approval only after it has launched the vaccine in all Latin American countries and selected Asian markets. However, some critics will inevitably argue that by postponing approval in the U.S., GSK is dumping a possibly unsafe product and/or profiteering at the expense of lesser-developed countries.

This approval paradigm with emphasis on lesser-developed country markets is different than with RotaShield (from Wyeth), which was being developed first use for the U.S. and other affluent countries and received its first approval from FDA. RotaShield was only ever used in the U.S. Even though studies performed after U.S. withdrawal of the vaccine due to an increase in intussusception among vaccinated infant indicate that the vaccine’s withdrawal may have been premature or an error, U.S. withdrawal tainted the vaccine (and rotavirus vaccines, in general) such that it was essentially politically impossible for Wyeth to market the vaccine in lesser-developed countries. Even though desperately needed and desired by lesser-developed countries, Wyeth would surely have been accused of marketing (dumping) an unsafe product, exploiting poorer countries, etc., despite many countries and public health experts desiring to have the vaccine available. From their perspective, the minor increase in risk for intussusception observed with RotaShield was insignificant in the context of rotavirus causing much more serious disease and deaths in lesser-developed countries, e.g., it is often cited that RotaShield could have saved 100,000 lives annually.

In review documents prepared for the public Vaccines and Related Biological Products Advisory Committee that considered approval of Rotarix, FDA staff noted that analysis of 11 studies revealed that in the largest trial there was a statistically significant increase in deaths related to pneumonia compared with placebo. That study, which enrolled ~63,000 children, also found an increase in convulsions in children receiving Rotarix. Another study found an increased rate of bronchitis compared with placebo. In a conclusion section, FDA documents noted the pneumonia-related deaths and convulsions, but did not make specific recommendations to the advisory panel. GSK, in documents provided ahead of the committee meeting, noted that respiratory infections like pneumonia account for "dramatically greater numbers and proportions of infant deaths in Latin America, compared to the USA."”

On Feb. 21, 2008, the Vaccines and Related Biological Products Advisory Committee provided a favorable recommendation for approval of Rotarix. At that time, Rotarix had already been approved in over 100 countries worldwide, including the European Union. The Vaccines and Related Biological Products Advisory Committee voted unanimously (12-0) in favor of GSK's data being adequate to support the efficacy of Rotarix in preventing rotavirus gastroenteritis in infants and 11-1 concerning the safety of the product.

Regarding post-approval studies, although the FDA concluded that the available data do not establish that intussusception events are related to the vaccine, FDA requested GSK conduct post-marketing safety studies involving more than 40,000 infants to provide additional safety information.

In Jan. 2007, RotaTeq was added by WHO to its list of prequalified vaccines for purchase by UN agencies..

Tech. transfer: Relevant patents include U.S. 5,474,773 and 5,695,767 (a div. of 5,474,773) both entitled “Human Rotaviruses, Vaccines and Methods,” with Dr. R Ward as the sole inventor, assigned to the Children’s Hospital Medical Center (5,695,767) and the affiliated James N. Gamble Institute of Medical Research (5,474,773). These patents include claims for rotavirus 89-12C2, deposited as ATCC VR 2272, and its use for prophylactic vaccines.

In Sept. 2006, AVANT Immunotherapeutics (now Celldex Therapeutics) went public with a dispute with GlaxoSmithKline (GSK) concerning royalties for Rotarix. GSK had paid royalties for sales in Australia and certain European countries at the lower of two royalty rates (70% of the full rate) under the companies’ 1997 licence agreement. GSK asserted that Rotarix is not covered by the patents GSK licensed from AVANT in Australia and certain European countries. AVANT questioned the underlying assertion that GSK’s development of Rotarix took the vaccine outside the scope of the claims of these licensed patents. If AVANT is unable to reverse GSK’s assertion that royalties are payable at the lower rate, the value of AVANT’s residual interest in Rotarix royalties under its agreement with Paul Royalty would be adversely affected, along with Paul’s royalties. Also, the royalties to which Paul Royalty is entitled would no longer be limited by a $27.5 million annual threshold, which AVANT projected may be reached in later years as sales of Rotarix increase. Irrespective of GSK’s position, AVANT/Celldex will still retain essentially all of the royalties on worldwide sales of Rotarix once Paul Royalty receives 2.45-times the aggregate cash payments it made to AVANT, though the amount of such residual royalties will be lower if GSK’s position stands.

Trials: AVANT conducted a Phase II study in 215 infants at four U.S. centers with Rotarix protecting ~90% of vaccinated infants from rotavirus disease. The vaccine was helpful in preventing rotavirus disease in young children for at least two years following administration. Examination of the safety data revealed only mild transient symptoms of rotavirus disease (from the live virus in the vaccin) in a small number of infants. Results of the first year of a Phase II study performed by AVANT were published in Lancet, July 24, 1999.

In 1999, Glaxo (now GSK) assumed development of the vaccine from AVANT. Glaxo/GSK has since completed clinical studies in over 85,000 subjects in Europe, Latin America and Southeast Asia. Glaxo/GSK performed Phase I/II bridging studies in Europe and Phase II studies in over 6,500 subjects in Europe, Latin America and Southeast Asia. Glaxo/GSK may have initially avoided U.S. trials out of concerns that the FDA, having withdrawn RotaShield, would request excessively large clinical trials, or that FDA’s high level of caution, fully appropriate for a country with few rotavirus-associated deaths (U.S.), would unduly influence the decisions of countries with a very different balance of risks and benefits.

Glaxo/GSK tested the vaccine in over 9,400 subjects in Phase I and Phase II clinical trials, primarily in the U.S., Latin America, and Europe, following the timing of local routine childhood vaccination schedules.

GSK initiated global Phase III clinical trials in 3rd quarter 2003. These were then the largest vaccine clinical trials to date. More than 70,000 infants were enrolled, with studies conducted in Europe, the U.S., Latin America, and Asia. Results from this pivotal, double-blind, placebo-controlled, international Phase III study in 63,225 infants from 12 countries who received rotavirus vaccine at 2 and 4 months of age were reported in Jan. 2006 issue of the New England Journal of Medicine. From administration of the first dose until one to three months after administration of the second dose, the entire study population was followed for the assessment of intussusception and serious adverse events. A subgroup of 20,169 was followed up to one year of age for the assessment of efficacy.

Rotarix provided 85% protection against severe rotavirus disease and 100% protection against more severe disease. This protection was proven against the most common circulating strains: G1P[8], G3P[8], G4P[8] and the globally emerging G9P[8] strain. A meta-analysis considering data from this trial and other efficacy studies conducted with similar methods showed 67% protection against G2P[4] rotavirus disease. Children receiving the vaccine had an overall lower incidence of serious adverse events compared to placebo; and there was no increased risk for intussusception in vaccine recipients compared to placebo. There was a lower incidence of serious adverse events in children receiving the rotavirus vaccine candidate compared to children receiving placebo, with this primarily attributable to the lower number of serious gastrointestinal disease-related adverse events in those receiving the vaccine. The most common adverse events were reported with similar frequency in both study arms. These included irritability and loss of appetite, fever, fatigue, diarrhea, vomiting, flatulence, abdominal pain, and regurgitation of food.

Rotarix has not caused intussusception in its clinical trials. The vaccine has been shown to be effective, safe and well-tolerated. GSK will continue monitoring the vaccine’s safety. GSK has conducted intussusception surveillance in many Latin American countries to provide a baseline against which to interpret Phase III trial results. GSK has largely basing its assessment of vaccine safety on the occurrence of intussusception during the 31 days after each vaccine dose. Children in GSK’s Phase III studies are being followed for two years.

Rotarix is the only approved or near-term rotavirus vaccine with a 2-dose regimen (RotaTeq involves 3 doses) that allows for early protection, an important consideration since very young infants are particularly vulnerable to more severe complications (dehydration) that lead to high mortality. Clinical data support the broad protection of Rotarix against moderate and severe disease, which will lead to substantial reduction in hospitalization and death.

Analyses of efficacy data from Rotarix trials show that the vaccine reduces the risk of rotaviral gastroenteritis and hospitalizations for rotaviral diarrhoea by 85%, with efficacy against the common G1 strain, which accounts for around 50% of all cases worldwide, as well as the rapidly-emerging G9 strain which was first discovered in the mid-1990s and has reached levels of around 20% in some countries. This cross-protection is a crucial finding, since Rotarix contains only antigens from the G1 strain, unlike Merck’s Rotateq which contains five rotavirus antigens. In Brazil, where the G9 rotavirus serotype is common, Rotarix elicited cross-protective efficacy of up to 83% against severe rotavirus due to non-G1 serotypes.

In May 2006, results from the European, multi-center, pivotal, double-blind, placebo-controlled REVEAL trial used to support European Union approval were reported. Rotarix provided protection against 96% of severe rotavirus gastroenteritis cases of any cause and prevented 100% of hospitalizations due to rotavirus-induced gastroenteritis independent of the rotavirus strain.

In Sept. 2007, GSK reported that studies showed Rotarix could be safely co-administered along with other pediatric vaccines recommended in the U.S. at the two and four month old immunization visit.

In Nov. 23, 2007 issue of The Lancet, GSK reported results showing that Rotarix prevents rotavirus gastroenteritis and provides protection against the five most commonly circulating rotavirus types around the world and in the U.S. This multi-center, randomized, double-blind, placebo- controlled Phase IIIb clinical trial performed by researchers at the University of Tampere in Finland involved almost 4,000 European infants (vaccine n=2,572; placebo n=1,302). The trial showed that two doses of Rotarix provided highly effective and sustained protection through two consecutive rotavirus seasons (at ~2 years of age). Efficacy after two doses over two consecutive rotavirus seasons was 90.4% against severe rotavirus gastroenteritis and 83.8% for rotavirus-related medical attention. The data showed that, through two rotavirus seasons, the vaccine was highly efficacious against rotavirus hospitalizations (96%), severe rotavirus gastroenteritis (90%) and against rotavirus gastroenteritis of any severity (79%). Significant protection was shown against severe rotavirus gastroenteritis caused by types G1 (96%), G2 (86%), G3 (94%), G4 (95%), and G9 (85%), the most commonly circulating rotavirus types around the world and in the U.S. These data onfirmed that immunization with two doses of the vaccine could provide broad protection against rotavirus gastroenteritis caused by emerging types in addition to those that are already commonly circulating.

Medical: Rotarix is administered as a series of two injections at months 2 and 4 (unlike RotaTeq, which is administered as three doses at 2, 4, and 6 months of age). This is unlike RotaTeq, which involves three injections.

With its European Union approval, it was reported that about 87,000 babies in the EU are hospitalized and there are over 700,000 physician visits each year related to rotavirus infection.

Market: GSK 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. Some analysts have predicted that Rotateq sales could top $500 million a year at peak. The 2010 market potential (by sales) is projected to be U.S., 25%; Europe, 20%; GAVI, 15%, and diverse international sales, 40%

In the U.S., according to the CDC, the typical cost for Rotarix is $38/dose or $114 for a full course.

The main competition for Rotarix is RotaTeq (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).

GSK will be targeting marketing of the vaccine to the U.S., EU, and also the growing sector of middle class citizens in the many developing countries, besides the vaccination programs of governments and international organizations (the major market, particularly in terms of number of doses). With U.S. and other developed countries likely being among the last where the vaccine is approved, the usual pattern of the U.S. (and other developed countries) subsidizing vaccine or pharmaceutical costs for the rest of the world is not being followed. With individual purchasers expected to pay much more than government and other vaccination programs, middle class purchasers in lesser-developed countries will provide much of the cost recovery and, eventually, profit from RotaTeq (and other vaccines following its approval/marketing paradigm), until the vaccine is launched and adopted in the U.S. and other developed countries.

Brazil and Panama have already included for the first time the rotavirus vaccine in their national official vaccination calendars. As part of these governments’ pediatric immunization programs, vaccination with Rotarix is available free at public health clinics.

A factor potentially affecting public acceptance of rotavirus vaccines in lesser-developed countries involves perception of their efficacy. In many of these countries, children experience as many as 5-10 episodes of diarrhea annually in their first 3-5 years of life. Only 1, or possibly 2, of these 15-35 total episodes is likely due to rotavirus infection. Thus, besides ignorance about viral diseases, the efficacy of even a 100% effective rotavirus vaccine may not be perceived in these countries. However, even a partially effective vaccine would have a discernible impact on public health, e.g., a decline in infant diarrhea-associated hospitalizations and mortality. Vaccination in lesser-developed countries will depend primarily or heavily on government vaccination programs.

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. At the time, this recommended universal vaccinatin using Rotashield (later withdrawn). ACIP has subsequently included Rotarix and Rotateq as vaccines for universal pediatric use.

Much, if not most, of the production of Rotarix will likely be purchased by the World Health Organization (WHO), United Nations; Global Alliance for Vaccines and Immunization (GAVI; funded by the Gates Foundation); Pan American Health Organization (PAHO); United Nations Children’s Fund (UNICEF), Rotavirus Vaccine Program (RVP); the Albert B. Sabin Vaccine Institute (SVI); and other non-governmental, public sector bodies supporting or conducting vaccination programs in lesser-developed countries. If Rotarix follows the pattern of many other universal pediatric vaccines, it may be sold to or by these purchasers for less than $1 dose or other relatively low price, perhaps, even below cost.

In Jan. 2007, Rotarix received prequalification status from the World Health Organization (WHO). This designation of “acceptability in principle” allows for purchase of the vaccine by United Nations agencies, and is also recognized by other organizations and governments. This facilitates WHO, PAHO, other organizations and governments purchasing the vaccine in large quantities for public health programs. GSK will be the first company to be able to sell its rotavirus to this market. The WHO endorsement complements a recent decision by GAVI to finance rotavirus vaccines for use in developing countries.

R&D: In India and other Asian markets, Rotarix and Rotateq in coming years will have serious competition from rotavirus vaccines being developed by Bharat Biotech and other Indian companies, which with government support, plan to price their vaccine at $1 or less per dose (for government and other large purchasers).