Rotavirus Vaccines, Take Two

Image: Courtesy of Umesh D. Parashar and Roger I. Glass HOMING IN ON THE TARGET: Rotavirus particles visualized by immune electron microscopy in stool filtrate from a child with acute gastroenteritis. The 70-nm particles possess a distinctive double-walled outer capsid. Ridding the world of smallpox was a triumph of 20th century medical science: Mass vaccinations directly averted some 350 million cases and saved 40 million lives. So, humanitarian hopes were similarly high when a rotavirus vaccine was developed in the 1990s with comparable potential to save young children from severe gastroenteritis.1-5 But that vaccine's controversial withdrawal from use ultimately put those hopes into limbo for years. The optimism however, has reemerged with new vaccines that are in the pipeline. And perhaps within the next five years, the battle against rotavirus can be rejoined. Although public awareness is low, rotavirus is one of the world's worst infectious disease agents, killing up to 2,000 children a day. Known as the democratic virus, rotavirus is highly contagious and can infect virtually everyone, regardless of their wealth, health, or hygiene standards. According to the National Institute of Allergy and Infectious Diseases (NIAID), the primary mode of transmission is fecal-oral, although standard hygiene practices have little impact on its incidence. Stanford University researchers recently reported that rotavirus infection not only involves multiple interactions with the hosts' gut-cell surfaces, but also alters the activity of more than 500 host cell genes within 16 hours of exposure.6 The virus itself is a relatively simple organism, in which 11 genes code three layers of proteins, notes Australian bacteriologist Ruth Bishop, whose team identified rotaviruses in 1973.7 (See related Profile on page 64.) Those genes can be experimentally shuffled like a deck of cards and vaccine researchers can insert genes from animal rotaviruses to create reassorted strains that are nonvirulent to humans, she says. Roger I. Glass, head of the viral gastroenteritis section at the Centers for Disease Control and Prevention (CDC), likens the process to "creating a sheep in wolf's clothing" whereby selected genes can be included on the virus' outer coat to provoke a protective immune response in the host, but not cause serious illness. Both Merck & Co., and GlaxoSmithKline Biologicals now have candidate vaccines of that type in clinical trials. Merck has announced plans to begin Phase III clinical trials this year for its candidate--a three-dose vaccine derived from a reassortment of a bovine rotavirus strain.8 GlaxoSmithKline is currently conducting Phase II trials in Latin America for its candidate, a two-dose vaccine derived from a human rotavirus. "So far the data we have in terms of safety and efficacy is already encouraging," says spokeswoman Anne Walsh. The company plans to progress next year to Phase III trials, also in Latin America, which should involve up to 60,000 children, according to Walsh. DEMOCRACY AT WORK Children from 1 to 2-years-old are most vulnerable to developing severe gastroenteritis from rotaviral infections. When a person is first infected, the virus takes hold in the small intestine and replicates rapidly there over the next 18 to 36 hours, often causing vomiting and low-grade fever. Diarrhea lasting between three and seven days usually follows. If the symptoms are severe, an infant can become dehydrated quickly from prolonged loss of fluids and electrolytes. Left untreated, the child can progress into shock, abnormal heart rhythms and death. Although the first infection is often relatively serious, survivors develop an immune response and repeated infections can occur with few or no symptoms--an effect that live oral vaccines can simulate. Image: Courtesy of Massimo Battaglia, Consiglio Nazionale Delle Richerche DEADLY IMAGE: CV-1 cells infected with AmC-1 group C rotavirus obtained by indirect immuno-fluorescence. Developed nations are not immune to this malady. In the US, some 2.7 million children under age 5 are affected yearly, resulting in 500,000 physician visits, 50,000 hospitalizations and up to 40 deaths.2,3 The toll is higher still in the developing world: between 20% and 70% of hospitalizations and about 600,000 of the three million annual deaths from diarrhea are caused by rotaviruses.4 On humanitarian grounds alone, the potential benefits of mass immunization programs are obvious. Economic arguments are also strong. In the US, for example, rotavirus disease costs an estimated $274 million (US) in medical care and more than $1 billion in societal costs.2 Since the viruses' discovery in 1973 research teams worldwide have struggled to understand and fight them. The breakthrough came from Al Kapikian and colleagues at the NIAID who developed a live oral vaccine based on a nonvirulent rotavirus strain from rhesus monkeys, known as RRV-TV. It sailed through all the necessary clinical trials and approval processes in the US. Under Wyeth Laboratories' commercial name, Rotashield, it was licensed for use in August 1998, and soon after added to the list of recommended immunizations for healthy infants. Rotashield was put into use. After approximately 800,000 US children received 1.5 million doses, surveillance measures detected a statistical link with a rare bowel ailment known as intussusception (a telescoping of a section of bowel).1 Although the condition is readily treatable surgically and only one in 11,000 of vaccinated children were potentially affected, the vaccine's license was suspended and Wyeth withdrew it from the market in 1999, reportedly incurring costs of some $80 million. COSTS OF DEMOCRACY Ethical and statistical debates ensued regarding how applicable US public health standards are to the developing world and whether Rotashield's life-saving potential would far outweigh any adverse effects. "As it seems to have turned out, the first effective vaccine against rotavirus will become of historical interest only," says Bishop. "In the end, I don't think it will be used anywhere. It's one of those tragic situations where the heart tells you one thing and the mind tells you another and there's just no reconciling the two." A subsequent study suggested the vaccine might simply compress the usual risk period of intussusception in infancy into a shorter time frame involving the few weeks after the vaccine was given.9 Alternately, others questioned whether any intussusception risk can be deemed acceptable in developed nations, where even the most severe diarrhea is treatable. Alexandre C. Linhares, of the Fundação Nacional de Saúde, Instituto Evandro Chagas, Brazil and Joseph Bresee of the CDC reported: "Each year there may be only 20 to 40 deaths from rotavirus gastroenteritis in the US, but 15,000 to 30,000 in Bangladesh."10 Preliminary data from Latin America also suggest that the potential benefit of RRV-TV vaccine far outweighs the risk of intussusception. In Venezuela, the rate of rotavirus hospitalization was found to be 158 times the rate of hospitalization for naturally occurring intussusception. A risk-benefit study conducted in Peru indicated that a rotavirus vaccine would prevent 1,440 deaths and 23,000 hospitalizations, as compared to an estimated 78 cases of intussusception that might be related to the vaccine." The Rotashield experience means that other candidates will have to undergo far more rigorous testing. Clinical trials will require 60,000 to 70,000 subjects (as compared to the 10,000 tested for Rotashield) at a cost of $200-400 million. Bishop points out: "That's a huge undertaking. It's not just the expense but the fact that it's very difficult to conduct such a large trial and recruit so many subjects." Future options may speculatively include a genetically engineered vaccine or a DNA vaccine, but such an approach is unlikely to bear fruit for another 15 to 20 years, Bishop believes. CDC's Glass agrees that a live oral vaccine is currently the best bet. "The principle already has been well demonstrated. We know how it works and how to make the vaccines." Many questions remain about intussusception itself and its link with the use of Rotashield, Glass says. Even less is known about its incidence in developing nations. Physicians in India, for example, say cases of intussusception are very uncommon, Glass notes. What is painfully clear, he concedes, is that rotaviral disease continues to kill one out of every 200 to 250 Indian children before they reach age 5. "That is on the consciences of all of us who are working on it. In the US we're very aware of adverse events. But the perception of risks and benefits are clearly tremendously different in developed and developing countries." Glass argues that the Rotashield experience stimulated a string of new vaccine development programs. "We now have the potential for several other vaccines becoming available in developing nations, made by national producers in China, India, and Indonesia, and by multinational producers within the next three to five years. As a result, we may even achieve our goals faster than we would have before with just one product and one company." Bob Beale (www.bob.beale.org) is a freelance writer in Sydney, Australia. References 1. U. Parashar et al., "Rotavirus," Emerging Infectious Diseases, 4:561-70, 1998. 2. U. Parashar et al., "Hospitalizations associated with rotavirus diarrhea in the United States, 1993 through 1995: Surveillance based on the new ICD-9-CM rotavirus-specific diagnostic code," Journal of Infectious Diseases, 177:13-7, 1998. 3. A.W. Tucker et al., "Cost-effectiveness analysis of a rotavirus immunization program for the United States," Journal of the American Medical Association, 279:1371-6, 1998. 4. Institute of Medicine, "The prospects of immunizing against rotavirus," In: New Vaccine Development: Diseases of Importance in Developing Countries, Vol. 2, Washington: National Academy Press, 1986, pp. D-13-D-13-2. 5. R.I. Glass et al., "Rotavirus vaccines at the threshold," Nature Medicine, 3:1324-5, 1997. 6. M.A. Cuadras et al., "Gene expression pattern in Caco-2 cells following rotavirus infection," Journal of Virology, 76:4467-82, May 2002. 7. R.F. Bishop et al., "Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis," Lancet, 1:1281-3, 1973. 8. www.merck.com/newsroom/press_releases/121101.html 9. L. Simonsen et al., "Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception," Lancet, 358:1224-9, October 13, 2001. 10. A.C. Linhares et al., "Rotavirus vaccines and vaccination in Latin America," Pan American Journal of Public Health, 8:305-31, 2000.

Rotavirus Vaccines, Take Two

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Image: Courtesy of Umesh D. Parashar and Roger I. Glass
HOMING IN ON THE TARGET: Rotavirus particles visualized by immune electron microscopy in stool filtrate from a child with acute gastroenteritis. The 70-nm particles possess a distinctive double-walled outer capsid.