NIAID Rotavirus Vaccine Licensed for Commercialization The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), announced today a new license agreement aimed at helping to prevent hundreds of thousands of deaths annually from rotavirus diarrhea in children living in developing countries. An effective oral rotavirus vaccine — created by NIAID scientists in the mid- to late 1980s and developed further through a Cooperative Research and Development Agreement with an industry partner — has now been licensed by the NIH Office of Technology Transfer to BIOVIRx, Inc., of Minneapolis, MN. BIOVIRx, which is responsible for obtaining requisite marketing approvals for this product, plans global commercialization of the oral vaccine (RotaShield®).
Rotaviruses are consistently shown to be the leading cause of severe diarrhea in infants and young children. Worldwide, the wheel-shaped viruses are estimated to cause more than 135 million episodes of diarrhea each year in infants and children younger than 5 years old, resulting in up to 592,000 deaths annually.
Rotaviruses are egalitarian viruses: they readily infect and cause illness in infants and young children in both developed and developing countries. The overall consequences of these illnesses, however, are quite different. Approximately 1,600 rotavirus-related deaths each day occur predominantly in the developing countries, notes Albert Z. Kapikian, M.D., who led the NIAID team that developed the vaccine and serves as head of the epidemiology section in the Institute's Laboratory of Infectious Diseases.
Symptoms of rotavirus infection develop quickly and in addition to diarrhea, may include vomiting, fever and dehydration. The resulting dehydration can be reversed through oral rehydration therapy or, in more serious cases, through hospitalization and intravenous fluids. Although effective, these therapies are not readily available or used in many parts of the developing world. Children in developing countries are more vulnerable to severe and fatal illness.
Dr. Kapikian has devoted most of his career to working on viruses that cause gastroenteritis. He and his colleagues discovered the Norwalk virus, the first virus to be established as an important cause of diarrhea. Later, he and his colleagues in NIAID developed the rotavirus vaccine that was tested in the United States and abroad in collaborative studies.
Wyeth Laboratories, Inc., manufactured the vaccine and carried out extensive field trials that led to its licensure. In 1998, the Food and Drug Administration (FDA) approved the vaccine under the trade name of RotaShield®. Subsequently, it was added to the pediatric immunization schedule and given to young infants in the United States.
More than 1 million doses were administered before the vaccine was withdrawn from the market in 1999 because of a link with an intestinal blockage known as intussusception. After continuing debate and controversy, the risk of this adverse event was estimated to be about 1 excess case per 10,000 vaccinated infants and young children. A recent scientific perspective published by NIH scientists in the Journal of Infectious Diseases, however, estimated the risk to be 1 excess case per 32,000 vaccinated infants in the target population for the vaccine, infants 45 to 210 days old. Moreover, this perspective 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 United States is estimated to be 1 case per 3,000 infants during the first year of life.
NIAID is a component of the National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on transplantation and immune-related illnesses, including autoimmune disorders, asthma and allergies. Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.
Reference: BR Murphy et al. Reappraisal of the association of intussusception with the licensed live rotavirus vaccine challenges initial conclusions. Journal of Infectious Diseases 187:1301-08 (2003).
New Rotavirus Vaccine Close to Launch in Mexico
By Lorraine Orlandi
MEXICO CITY (Reuters) - A new vaccine against rotavirus, one of the world's chief killers of children, is due to be launched in Mexico as soon as this year and will mark a sea change in how major companies market drugs worldwide. GlaxoSmithKline submitted its oral vaccine Rotarix to Mexican authorities for approval and conducted clinical trials with more than 60,000 children in
one of the largest such studies ever, Dr. Bruce Innis, vice president for Latin America research and development at GSK, said in a telephone interview on Monday.
In launching the vaccine in Mexico, the company "reverses the history of vaccine development in the last 50 years, in which new products are introduced in the United States and Europe and then to the developing world," Innis said. "For the first time a manufacturer has made an effort to make a new vaccine available in the countries where the disease burden is the greatest," he said.
Introduction of the vaccine, five years after another was withdrawn due to health concerns, would be a major step toward saving hundreds of thousands of lives, experts say. "If we have a vaccine this will be a major breakthrough," said Dr. Ciro de Quadros, an authority on rotavirus at the nonprofit Sabin Vaccine Institute in Washington. The highly infectious disease can cause severe vomiting and diarrhea leading to dehydration. It kills 400,000-600,000 children a year worldwide, mainly in developing countries. Some 15,000 children die from it in Latin America every year.
Almost every child is exposed to rotavirus by age five. But 82 percent of rotavirus deaths occur in less developed countries, where children have limited access to health care and often arrive at the clinic too late. GSK has spent some $500 million to develop Rotarix. Landmark research on rotavirus by Mexican investigators helped inspire the manufacturer to launch the vaccine here. GSK will present results of its Rotarix trials at a forum this week in Mexico City, when some 300 health ministers, public health workers, scientists and pharmaceutical companies meet to review progress in the fight against rotavirus.
PROTECTING POOR CHILDREN
Mexico and other nations have battled deadly diarrhea with hygiene and sanitation programs. But such measures are less successful against rotavirus. "If sanitary measures are not sufficient, the most important way to control it is the vaccine," said Romeo Rodriguez, head of Mexico's child health office. In 1998 a rotavirus vaccine marketed in the United States by Wyeth was withdrawn for fears it could cause a sometimes deadly bowel obstruction.
That caused governments worldwide to reject a remedy that might have saved many lives, experts say. And manufacturers now had to conduct much larger safety trials for new vaccines. Besides GSK, today Merck and Co. is also testing a new vaccine and will report at the Mexico forum. Any new vaccine will be relatively expensive, but international health leaders like De Quadros hope to bring it to poor people around the world, the populations most at risk.
Mexico will study the cost-effectiveness of including it in routine child immunization while it enters the private sector. Honduras, one of the poorest countries in the hemisphere, and other Latin American nations are working to make the vaccine part of public health systems. "The major challenge is how the vaccine could be introduced in the public sector, and that's one of the things we hope will come out of this meeting ... so that the majority of children will benefit," De Quadros said.
HYPING VACCINES: AN INVESTIGATION
Chickenpox, Lyme, Rotavirus, And A Highly Revealing Analysis Of Flu Statistics
By RFD Columnist, Dr. F. Edward Yazbak
TL Autism Research
Years ago, the description of diseases used to be accurate. Smallpox was a very dreaded, serious, and often fatal illness. Certainly, no parent wished smallpox on his children. Chickenpox on the other hand was a relatively benign illness: a low-grade fever, an itchy rash and a week out of school. Like all childhood illnesses, it was worse in adults and parents were actually hoping that their children could “catch chickenpox” and be finished with it for the future.
In 1995, chickenpox suddenly became a major health problem. Six children were reported to have died from chickenpox; frequent and repeated TV coverage lasted for weeks without anyone mentioning that two of the six children had leukemia and the others were on cortico-steroids. Concurrently, chickenpox became a major economical disaster that was gravely impacting the United States economy, as working mothers stayed home to give their children Aveeno baths and syrup to relieve itching. A short time later, the chickenpox vaccine was cheerfully and successfully launched.
Historically, epidemics have occurred in cycles. Experts in infectious diseases could often predict them. The number of unvaccinated children increased during several successive years of low spread and when the reservoir was full, an outbreak, an epidemic or a pandemic occurred. Children then developed a solid immunity that was boosted successfully during subsequent outbreaks. Recently, in the United States, a new epidemiological trend has become very evident: MBAs and Marketing Directors predict epidemics that are then orchestrated to occur, on cue, when a new vaccine is due to be launched.
A flurry of interest about Lyme disease started in the Northeast and Upper Midwest in 1996-97. It promptly snowballed into a major news campaign in the targeted areas, where indeed there were increasing numbers of cases, many with serious long-term complications. In 1998, the LYMErix vaccine received conditional approval by the FDA and was welcome in the geographical locations where the disease was common and often devastating. Unfortunately, it was soon discovered that the vaccine itself had major side effects and doctors became disenchanted with its use. Since the manufacturer discontinued production of the vaccine, the newspaper articles, experts’ interviews and television “health minutes” on Lyme disease have completely stopped. It is almost as if the disease has totally disappeared, when it obviously has not.
Years ago, we did not talk much about the rotavirus. Most people did not even know the name and some thought that it was “RotoVirus”, because it kept spreading “around and around” nursery schools. We were happy to tell the parents the baby had “some kind of a virus”, that penicillin was not going to help, that we were seeing many children with the same symptoms, and that they improved after a few days. We then suggested liquids and a limited diet and the reassured parents left with their little ones, to stop at their neighborhood drugstore for Pampers and Pedialyte. We obviously were immensely more alarmed when a child had salmonella, shigella, cholera, pathogenic E. Coli and staphylococcus gastro-enteritis.
Rarely, the babies with rotavirus infections became dehydrated. They were then brought to a holding unit at the hospital, given intravenous fluids and discharged before 23 hours. Officially, they had not been actually “admitted” to the hospital.
Suddenly, in 1998, every newspaper and every TV news program started continuous reporting on the rotavirus. Overnight, the rotavirus became a household name and the most common cause of diarrhea. It also killed thousands of babies. The fact that the deaths occurred in Third World countries was rarely, if ever, mentioned. In addition, the news programs warned that the economy of the United States was once more in dire danger, that HMOs were almost bankrupt trying to keep up with the rising costs of hospitalizations and that millions of hours were lost in the workplace during the rotavirus season; after all, mothers of affected children had to stay out of work to care for them and could not drop them off, as usual, at schools and day-care centers. In the midst of that intense “information” campaign, the rotavirus vaccine “Rotashield” was released to the joy and relief of The Centers for Disease Control and Prevention (CDC), pediatricians and parents. Because three doses were needed, the delight of the manufacturer and stockholders was tripled. One could almost imagine them visualizing a set of gorgeous blond triplets singing “Triple the Doses, Triple the Dough” using the old and proven tune of “Double the Mint, Double the Fun”.
And then, something went wrong, very wrong. It became quickly evident that some infants who received the vaccine developed intussusception, a form of intestinal obstruction and that a few died. The CDC, to its credit, acted promptly and suspended the administration of the Rotashield in July 1999, just a few months after it was released. In October 1999, it issued a detailed statement that started with the following two paragraphs: “The Advisory Committee on Immunization Practices (ACIP) decided that Rotashield, the only U.S.-licensed rotavirus vaccine, should no longer be recommended for infants in the United States. This action was based on the results of an expedited review of scientific data presented to the ACIP by CDC in cooperation with the FDA, NIH, and Public Health Service officials, along with Wyeth-Lederle. Data from the review indicated a strong association between Rotashield and intussusception (bowel obstruction) among some infants during the first 1-2 weeks following vaccination. Use of the vaccine was suspended in July pending the data review by the ACIP. Parents should be reassured that their children who received rotavirus vaccine before July and remain well are not at increased risk for intussusception now.
Rotavirus is a severe diarrheal illness in childhood that accounts for more than 500,000 physician visits and approximately 50,000 hospitalizations each year among children less than 5 years of age. Symptoms include fever, an upset stomach and vomiting followed by diarrhea, which may lead to dehydration. This results in $264 million in direct medical costs and $1 billion in total costs to society.
The rotavirus media blitz came to a screeching halt and for four years, interest in the “designer diarrhea” has ranged between nil and minimal. Children with the disease had once again “some kind of a virus.”
However, this is due to change AGAIN. Yes indeed, very soon, we will be undoubtedly bombarded once more with a barrage of relentless rotavirus propaganda, diarrhea will become extremely serious in the United States and the cost to the National economy will become even more staggering as the launching of the “new, safe, effective and improved” rotavirus vaccine is carefully orchestrated. This second vaccine has been developed for years and has been ready to go. If rotavirus disease is so serious, the new formulation should have been released already “to save lives”. But it was probably felt that releasing it too soon after the first fiasco would not have been a good business move and as it happens sometimes, when it comes to the care of children, MBAs may overrule MDs. So everyone involved had to wait patiently for the opportune time. Indications are that 2004 will be the year.
Taipei Times, Taiwan
Infant's death could be the result of vaccine treatment
By Wang Hsiao-wen
Thursday, Jan 13, 2005,Page 4
Advertising Doubts about vaccine safety re-emerged as a three-month-old baby died after being given an oral vaccine that is still under clinical trials in one of the nation's leading hospitals, the Center for Disease (CDC) reported yesterday. The baby was given an oral rotavirus to prevent severe diarrhea and vomiting and a licensed combo vaccine at around 5pm on Tuesday at National Taiwan University Hospital, according to Huang Li-min, chief of the infectious diseases division at the hospital.
At 7pm, the mother put her baby to sleep, placing the child chest down, local media reported. Around midnight yesterday, the mother found that the baby was not breathing, and rushed back to the hospital -- but in vain. "Doctors only told me the vaccine may bring on a fever as a side-effect. I
didn't know she would die of it," the mother said. Doctors at the hospital said that the unlicensed rotavirus vaccine should be safe, despite the fact that it is still undergoing clinical trials.
"We have recruited 2,000 subjects since last year to undergo the trials. So far we have found no vaccine-related injuries," Huang said. The hospital is still waiting for the results of an autopsy to confirm the cause of the infant's death. According to the hospital's research, about 5 percent of infants who take rotavirus vaccine develop a mild fever, whereas 60 to 90 percent of infant subjects are successfully treated for gastrointestinal infection. Thus far, no one has died as a result of the vaccine. But in 1999, the US Center for Disease Control recommended suspension of the rotavirus vaccine for infants based on a review of scientific data. Taiwan's Center for Disease Control said that if the unlicensed rotavirus vaccine leads to an infant's death, the bereaved families can appeal for insurance compensation from the hospital.
Merck Submits Biologics License Application to FDA for ROTATEQ®, an Investigational Vaccine for Rotavirus 13 Apr 2005
Merck & Co, Inc announced today that it has submitted a Biologics License Application for ROTATEQ® (rotavirus vaccine, live, oral, pentavalent) to the U.S. Food and Drug Administration (FDA). ROTATEQ is Merck's investigational vaccine to protect against rotavirus gastroenteritis. ROTATEQ is an oral, liquid vaccine that contains five human serotypes - G1, G2, G3, G4 and P1. These serotypes cause most rotavirus disease worldwide.
Merck submitted the application to the FDA on April 5 and also announced that it has plans to file for licensure of ROTATEQ in Australia, Canada, the EU and Mexico, as well as countries in Asia and Latin America in 2005. Within the next 60 days, the FDA will determine whether it will accept for review Merck's application as submitted.
About Rotavirus Gastroenteritis
Rotavirus causes approximately one-third of diarrhea-associated hospitalizations in developing countries and nearly half a million deaths worldwide every year in children under five. In the United States, rotavirus accounts for approximately 50,000 hospitalizations, 500,000 visits to primary care offices and 20-40 deaths annually. Although symptoms may vary, those typically associated with rotavirus gastroenteritis include vomiting, fever, abdominal pain and watery diarrhea which can persist for three to nine days. The severity of rotavirus gastroenteritis ranges from asymptomatic to dehydrating gastroenteritis that can be fatal. Incidence of rotavirus is similar in developed and developing countries, which suggests that differences in environment (e.g., clean water, hygiene or sanitation) do not affect incidence.
During the first few years of life, a child typically has several rotavirus infections. The highest rates of gastroenteritis are generally in children under two years of age, who are also at the greatest risk for severe disease. Nearly all children will be infected with rotavirus by age five. There are several different serotypes of rotavirus and the prevalence of these serotypes varies by geographic region and changes from season to season. Children gradually develop immunity against different strains of the virus after several infections.
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines in more than 20 therapeutic categories. The company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit http://www.merck.com.
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed, and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the cautionary statements in Item 1 of Merck's Form 10-K for the year ended Dec. 31, 2004, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.
ROTATEQ® is a registered trademark of Merck & Co., Inc.