Oral Vaccine Protects Infants From Severe Rotavirus Diarrhea

October 22, 1997

An oral vaccine against rotavirus -- the most important cause of life-threatening diarrhea in children under age 2 -- reduced severe diarrheal illness by 88 percent in a study of more than 2,000 infants in Venezuela. This is the largest and most successful trial to date of a rotavirus vaccine among children in a developing country.

Worldwide, rotavirus diarrhea affects 130 million infants and children each year, some 18 million of whom have moderate to severe disease, resulting in 873,000 deaths.

The study was conducted by Albert Z. Kapikian, M.D., head of the Epidemiology Section of the Laboratory of Infectious Diseases (LID), part of the National Institute of Allergy and Infectious Diseases (NIAID); Irene Perez-Schael, M.D., chief of the Laboratory of Enteric Disease at the Instituto de Biomedicina, Universidad Central de Venezuela in Caracas; and their co-workers. Results are reported Oct. 23 in The New England Journal of Medicine.

"This is the first study designed to determine if the vaccine prevents severe illness in a developing country where rotavirus circulates year-round rather than seasonally," explains Anthony S. Fauci, M.D., NIAID director. "In this setting, the vaccine proved to be very efficacious."

Although rotavirus infection is nearly universal, "The outcome and consequences of rotavirus illness in developed countries are very different from those in developing countries," Dr. Perez-Schael says. Children in developing countries more often develop severe and fatal illness.

Symptoms develop quickly and, in addition to diarrhea, include vomiting, fever and dehydration. In severe cases, a child can experience 10 to 20 episodes of diarrhea and 10 to 15 vomiting episodes per day. Dehydration can be reversed through oral rehydration therapy or, if more serious, through hospitalization and intravenous fluids. Although effective, these therapies are not readily available or utilized in many parts of the developing world, Dr. Kapikian says. Also, Dr. Kapikian notes, "Rotaviruses are very egalitarian viruses. Practically every child in the developed and developing world will be infected with rotavirus in the first few years of life, regardless of hygienic conditions."

Dr. Kapikian has devoted a major part of his career to working on rotavirus since its discovery almost 25 years ago by Australian investigators. He and his colleagues in NIAID's LID developed and patented the vaccine, which, with assistance from many outside collaborators, has been tested in nearly 18,000 people in the United States and abroad.

"The development of the quadrivalent rotavirus vaccine evaluated in the study represents the culmination of a long and highly creative process of research and development at the National Institutes of Health," comments Gerald T. Keusch, M.D., and Richard A. Cash, M.D., M.P.H., both affiliated with the Harvard Institute for International Development, in a companion editorial in the Journal.

"To be there from the beginning has been a great privilege," Dr. Kapikian says. "But what's most exciting and gratifying to me as a physician is to see that most babies can be protected from a severe disease with a product that has been developed in our laboratory."

Dr. Fauci expresses his admiration for their achievement to date. "Dr. Kapikian and others in the Laboratory of Infectious Diseases have been at the forefront of the effort to develop a rotavirus vaccine. Their ingenuity, perseverance and leadership have contributed enormously to the development of this important vaccine."

In the United States, rotavirus causes more than 3 million cases of childhood diarrhea during the cooler months of each year, leading to an estimated 500,000 doctor visits, 55,000 to 100,000 hospitalizations and 20 to 100 deaths. Rotavirus illness costs the U.S. health care system an estimated $400 million in direct costs annually, rising to $1.4 billion when indirect costs, including lost work time for parents, are included.

The potential benefits of a licensed vaccine in developed countries such as the United States are noted by Drs. Keusch and Cash. "Studies in the United States indicate that the rhesus rotavirus-based quadrivalent vaccine is safe and can prevent nearly half of all rotavirus infections, 80 percent of severe episodes, and virtually all cases of dehydrating rotavirus illness."

The candidate vaccine is currently being reviewed by the Food and Drug Administration (FDA) for licensure in the United States. An FDA advisory committee will meet in early December to consider all the data and make their recommendation regarding licensure to the FDA.

The World Health Organization is following closely developments here and in the European Union in an effort to determine how and when the vaccine might also be made available in the developing world.

***Study Details***

The Venezuelan study, which began in March 1992, was conducted at a hospital specializing in obstetrics and pediatrics in a poor urban area southwest of Caracas. The hospital team enrolled 2,207 full-term, healthy infants, each assigned at random to receive three doses total of either the vaccine or a placebo. A small amount of reconstituted pink liquid vaccine or its look-alike was given by mouth to the infants at 2, 3 and 4 months of age. Neither the study investigators nor the infants' parents knew which product a child received until the study ended.

The babies were monitored at home by their parents and caretakers for episodes of diarrhea, defined as the presence of three or more liquid or semiliquid stools, or a single stool with blood, during a period of 24 hours, with or without vomiting. Those who had significant illness were brought to the hospital for treatment, evaluation and data collection. Follow-up continued until age 2.

Although the vaccine was only 48 percent efficacious against a first episode of rotavirus diarrhea of any severity, the vaccine reduced the incidence of severe rotavirus diarrhea by 88 percent and the most life-threatening symptom, dehydration, by 75 percent, and decreased hospital admissions by 70 percent.

These findings, says Dr. Kapikian, are consistent with observations of natural infection, which confers better protection against severe disease than against mild illness. "We would not anticipate that a live, attenuated vaccine would do better than wild-type virus," notes Dr. Kapikian. "The concept of eliminating the virus, like smallpox, will not occur with rotavirus," he says, "because reinfections are very common. The purpose of this vaccine is to prevent the more severe illness."

Aside from significantly greater incidence of fever in the vaccine group after the first dose only (15 percent in vaccinees versus 7 percent in controls), the two study groups experienced no differences in side effects, and the vaccine was safe and well-tolerated.

***The Vaccine***

The vaccine consists of a mixture of four viruses (hence the name tetravalent or quadrivalent) that together protect against the four most important clinical strains of rotavirus. The NIAID team designed the vaccine by substituting a gene from a human rotavirus strain for one in a weakened rotavirus that infects rhesus monkeys.

The gene contains instructions to make a protein on the virus' surface, where the immune system can easily recognize it and then tailor-make antibodies to fight that viral strain.

When making the rhesus rotavirus-tetravalent (RRV-TV) vaccine, the NIAID researchers used this substitution strategy to create weakened forms of three of the four clinically important human rotaviruses. The fourth human strain was represented by a weakened but unaltered rhesus rotavirus, which has a similar surface protein. The vaccine was licensed to Wyeth-Ayerst Laboratories (St. Davids, Pa.), a division of American Home Products Corp., and is now manufactured by Wyeth-Lederle Vaccines and Pediatrics, a unit of Wyeth-Ayerst Laboratories.

***Background***

NIAID's Laboratory of Infectious Diseases has been involved in studies of gastroenteritis since the late 1960s. "It's very exciting to see something from the beginning," says Dr. Kapikian. "When we first started out, there was little or nothing written about viruses that cause gastrointestinal diseases."

Dr. Kapikian, newly trained in electron microscopy, used this technique in 1972 to discover Norwalk virus, the first virus associated with gastroenteritis. "Since then," he notes, "there have been thousands of papers about gastrointestinal viruses."

Rotavirus was discovered by Australian scientists in 1973. Dr. Kapikian and his collaborators first identified it in the United States one year later in stool samples taken from patients at Children's Hospital in Washington, D.C.

Not only have these investigators been behind many key scientific discoveries, they also have been intimately involved with the many clinical trials done to test several rotavirus vaccine candidates.

Initially, Dr. Kapikian, Robert Chanock, M.D., chief of LID, and their colleagues developed a monovalent vaccine against rotavirus in 1984. Two years later, when it was considered that a monovalent vaccine might not protect against the four clinically important strains of the virus, the LID group developed the additional individual components of RRV-TV.

Through a cooperative research agreement with Wyeth-Ayerst Inc. in 1987, commercial development of the RRV-TV vaccine began. "This vaccine didn't happen because of one person, it happened because of a lot of dedicated people," comments Dr. Kapikian. "It's really been a fine effort around the world."

NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as AIDS and other sexually transmitted diseases, malaria, tuberculosis, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.

###





References: Perez-Schael I, Guntias MJ, Perez M, Pagone V, Rojas AM, Gonz lez R, Cunto W, Hoshino Y and Kapikian AZ. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. New Engl J Med 1997;337(17):1181-87.

Keusch GT and Cash RA. A vaccine against rotavirus -- when is too much too much? New Engl J Med 1997;337(17):1228-29.

Press releases, fact sheets and other NIAID-related materials are available on the Internet via the NIAID home page at http://www.niaid.nih.gov.

***TV Producers and Reporters: A video B-roll, including soundbites of Drs. Kapikian and Fauci, is available. For more information, call the NIAID Office of Communications at 301-402-1663.

***Print Reporters: Black-and-white photos and a color map showing the annual pattern of rotavirus illness across the United States are available. For more information, call the NIAID Office of Communications at 301-402-1663.

NIH/National Institute of Allergy and Infectious Diseases

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