Rotavirus Vaccine
Special Report
The approval of rotavirus vaccine in august 1998 and the subsequent inclusion of this vaccine for universal pediatric immunization1,2 capped nearly three decades of research.3 Vaccine approval brought with it the expectation that the leading etiologic agent for severe dehydrating diarrhea could be controlled in the United States and, perhaps, throughout the world.4 However, the finding of increased numbers of cases of intussusception associated with vaccination initially put vaccine implementation on hold until further study could be completed5 and, at the end of October, led to removal of the vaccine from the market and the recommendation from the Centers for Disease Control that the vaccine no longer be given to infants in the United States.6
Rotavirus is the most common cause of severe diarrhea throughout the world. In the United States, about 70% of children will become ill from rotavirus sometime in their first 5 years of life (2.7 million children per year), resulting in approximately 500,000 physician visits and 50,000 hospitalizations per year.1,3,7 On a global basis, it may cause 125 million cases of diarrhea annually, account for 25% of deaths due to diarrhea, and 6% of all deaths in children younger than the age of 5.4 The impact of infection in a developing world setting is illustrated in a recent paper from Lima, Peru. Rotavirus was detected in 52% of children hospitalized with diarrhea, and was particularly associated with those who had severe diarrhea (O.R. = 2.3, 95% C.I. = 1.6-3.2).8 In adults, rotavirus is an infrequent cause of diarrhea, affecting travelers,9,10 caregivers of children with rotavirus, and the elderly.
Because the incidence of rotavirus is equally high in both developed and developing countries, it was felt that vaccination would be an important mode in control of infection, rather than just improved sanitation. Also, natural immunity was observed following an episode of rotavirus infection, and subsequent episodes were less severe.11
The recently licensed vaccine in the United States was RotaShield (Wyeth-Lederle). It is a live, attenuated, oral, human-rhesus reassortant vaccine, and expresses four rotavirus serotypes, which, based on epidemiologic surveys, are the most common globally. The vaccine is engineered by starting with a rhesus monkey rotavirus strain that has antigenic similarity to human rotavirus serotype G3. By gene reassortment during co-culture with human strains, the monkey virus acquires three human-rhesus reassortants with serotype specificity for human rotavirus surface glycoproteins G1, G2, and G4.1,3
Using three doses of 4 ´ 105 plaque-forming units of vaccine virus per dose, trials in the United States,12,13 Finland,14 and Venezuela15 demonstrated 48% to 68% efficacy in preventing all cases of rotavirus diarrhea, and 69% to 91% efficacy in preventing severe diarrhea. These trials showing efficacy in developed countries led to inclusion of the vaccine for routine childhood immunization in the United States. It was scheduled to be given to infants at age 2, 4, and 6 months. A cost-efficacy analysis projects that with universal childhood vaccination, 1.08 million cases of diarrhea, 34,000 hospitalizations, and 227,000 physician visits would be avoided in the first 5 years of life.7 Vaccination would result in net savings to society and cost about $100 to prevent each case of rotavirus diarrhea. These projections improve as vaccine cost declines.
The one study from Venezuela demonstrated efficacy in children living in poor sanitary conditions. However, the World Health Organization (WHO), in its position paper on rotavirus vaccine (one of a new series by WHO on vaccines), has reserved judgment about inclusion of the vaccine in programs of developing nations until more studies have been carried out in developing world settings.4 In addition, the cost of the vaccine would need to be lowered.
The enthusiasm for the vaccine was well founded based on efficacy studies and its projected role in preventing dehydrating diarrhea in children. In addition, prelicensure studies found the vaccine to be well tolerated with few side effects, further raising hopes of wide acceptance. The most common side effect was fever, which usually occurred 3-5 days following the first dose in about 20% of vaccine recipients.
During these prelicensure studies, however, five cases (among 10,054 doses of vaccine) of intussusception occurred. This was not statistically more frequent than in placebo recipients. Following licensure in the United States, 15 cases of intussusception among 1.5 million doses of vaccine administered were passively reported between September 1998 and the first week of July 1999 to the Vaccine Adverse Experience Reporting System (VAERS, 800-822-7967).5 Although this number may not be more than expected (there is a normal frequency of about 15 cases/100,000 children), when active surveillance for intussusception was undertaken in California and Minnesota, there was a vaccine-associated frequency of 314 cases/100,000 infant years and 292/100,000 infant years, respectively.
Based on this preliminary analysis, in July 1999 the CDC recommended that all children scheduled to receive vaccine, including those who had started the series, postpone receipt until November 1999. Since this recommendation, the CDC undertook complete analysis of reported cases of intussusception and carried out additional epidemiologic studies attempting to establish a causal relationship between vaccination and this complication. As of Oct. 15, 1999, 57 confirmed and presumptive cases of intussusception with onset within seven days of receipt of vaccine were reported to VAERS (Wharton M., personal communication). Of these cases, 29 (51%) underwent surgery. Based on this information and the strong association of receipt of rotavirus vaccine and the development of intussusception within 1-2 weeks, the CDC recommended on Oct. 22, 1999, that vaccination no longer be given to infants in the United States. In the wake of these findings, the manufacturer removed the vaccine from the market.
The unfortunate loss of RotaShield in the effort to prevent severe diarrhea brings to an end one part of the immense amount of work over 30 years to understand and prevent rotavirus infections. Hopefully, efforts to develop a safer vaccine will proceed using the knowledge generated by experience with RotaShield. For its part, the CDC has initiated a national campaign to educate parents in the management of severe diarrhea. For our part, we should continue to stress the importance of vaccination in the safe and effective prevention of illness.
References
1. CDC. Rotavirus vaccine for the prevention of rotavirus gastroenteritis among children: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 1999;48(No. RR-2):1-20.
2. CDC. Recommended childhood immunization schedule—United States, 1999. MMWR Morb Mortal Wkly Rep 1999;48:12-16.
3. Parashar UD, et al. Rotavirus. Emerg Infect Dis 1998;4. (www.cdc.gov/ncidod/EID/vol4no4/ parashar.htm)
4. World Health Organization. Rotavirus vaccines. WHO position paper. Wkly Epidemiol Rec 1999;74:33-38.
5. CDC. Intussusception among recipients of rotavirus vaccine—United States, 1998-1999. MMWR Morb Mortal Wkly Rep 1999;48:577-581.
6. CDC. Press release. Oct. 22, 1999. http://www.cdc.gov/ nip/news/rotavirus-pr.htm.
7. Tucker AW, et al. Cost-effectiveness analysis of a rotavirus immunization program for the United States. JAMA 1998;279:1371-1376.
8. Cama RI, et al. Enteropathogens and other factors associated with severe disease in children with acute watery diarrhea in Lima, Peru. J Infect Dis 1999; 179:1139-1144.
9. Keswick BH, et al. Norwalk virus and rotavirus in travellers’ diarrhoea in Mexico. Lancet 1982;1:109-110.
10. Bourgeois AL, et al. Etiology of acute diarrhea among United States military personnel deployed to South America and West Africa. Am J Trop Med Hyg 1993; 48:243-248.
11. Velazquez FR, et al. Rotavirus infection in infants as protection against subsequent infections. N Engl J Med 1996;335:1022-1028.
12. Rennels MB, et al. Safety and efficacy of high-dose rhesus-human reassortment rotavirus vaccine—report of the National Multicenter Trial. Pediatrics 1996;97:7-13.
13. Santosham M, et al. Efficacy and safety of high-dose rhesus-human reassortant rotavirus vaccine in Native American populations. J Pediatr 1997;131:632-638.
14. Joensuu J, et al. Randomised placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for the prevention of severe rotavirus gastroenteritis. Lancet 1997;350:1205-1209.
15. Pérez-Schael I, et al. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. N Engl J Med 1997;337:1181-1187.
Rotavirus vaccine is:
a. indicated for all children aged 2 months to 12 years.
b. accepted by WHO for universal childhood vaccination.
c. temporally associated with intussusception.
d. an oral, whole-cell, killed human vaccine.
e. administered to overseas travelers.
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