- Email: [email protected]
The rotavirus vaccine
Journal of Clinical Virology 11 (1998) 155 – 159
The rotavirus vaccine Paul A. Offit * Section of Infectious Diseases, The Children’s Hospital of Philadelphia The Uni6ersity of Pennsyl6ania School of Medicine, 34th Street and Ci6ic Centre Bl6d., Philadelphia, PA, USA Received 18 September 1998; received in revised form 25 September 1998; accepted 29 September 1998
Abstract Background: Rotavirus gastroenteritis is an important cause of morbidity and mortality worldwide. Objectives: To review the biology, immunology, and virology of rotavirus infections and describe the efforts towards the construction of vaccines using human and animal rotaviruses. Study design: A review of the literature and provision of the author’s understanding and speculation of vaccination of infants against rotavirus disease. Results: In August 1998 the Food and Drug Administration in the United States approved the licensure of a rotavirus vaccine. Both the Advisory Committee of Immunization Practices and the American Academy of Pediatrics are likely to recommend that the vaccine be given to all children by mouth as a series of three doses at 2, 4, and 6 months of age. The vaccine is made by combining a simian rotavirus strain (RRV) with several human strains representing different rotavirus serotypes. An understanding of the biology, immunology, and virology of rotavirus will help to explain the strengths and limitations of the rotavirus vaccine. Conclusion: If used as recommended, the rotavirus vaccine should cause a significant decrease in the number of deaths, hospitalizations, and office visits of children infected with rotavirus. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Rotavirus vaccine; Rotavirus gastroenteritis; Literature review
1. Introduction On 31 August 1998 the Food and Drug Administration (FDA) licensed a rotavirus vaccine. Both * Tel.: + 1 215 5902020; fax: + 1 215 5902025; e-mail: [email protected]
the Advisory Committee on Immunization Practices (ACIP) and the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) are likely to recommend use of the rotavirus vaccine for all infants. The strengths and limitations of the rotavirus vaccine are best realized by understanding se-
1386-6532/98/$ - see front matter © 1998 Elsevier Science B.V. All rights reserved. PII S0928-0197(98)00063-4
156
P.A. Offit / Clinical and Diagnostic Virology 11 (1998) 155–159
lected aspects of rotavirus biology, immunology, and virology.
2. Burden of disease Rotavirus is an important cause of gastroenteritis both in the United States and in developing countries. Every year in the United States, rotavirus infection accounts for approximately 2 – 3 million cases of gastroenteritis, 500000 visits to the doctor, 50000 hospitalizations, and 20 – 40 deaths (Kilgore et al., 1995; Glass et al., 1996a). About $1.5 billion are spent both directly (health care costs) and indirectly (time lost from work by parents) on children with rotavirus infection (Glass et al., 1996b). In developing countries, rotavirus infections kill about 500000 children each year (Walsh and Warren, 1979; Snyder and Merson, 1982; Bern et al., 1992; Murray and Lopez, 1997). Indeed, as a single infectious agent, rotaviruses are the most common killer of infants and young children throughout the world. The devastating impact of this infection has spurred an intense effort over the past two decades to develop a rotavirus vaccine.
3. Epidemiology Rotavirus infections are primarily a disease of children 6–24 months of age (Brandt et al., 1979). In temperate climates, rotavirus is a disease with a peak occurrence in winter (Ho et al., 1988). Therefore, for a rotavirus vaccine to be effective in the United States, infants must be fully immunized by 6 months of age, and have an immune response that lasts throughout the winter months.
4. Clinical features The classic triad of rotavirus infection is fever, vomiting, and diarrhea. The child usually first develops fever and vomiting followed by diarrhea: vomiting lasts 2–3 days and diarrhea lasts 4 – 5 days (Tallett et al., 1977; Carr et al., 1978; Kovacs
et al., 1987). Among the multiple infectious causes of diarrhea, rotavirus infection is most likely to be accompanied by vomiting (Rodriguez et al., 1977). Because diarrhea and fever cause water loss, and vomiting makes it difficult to replace water, rotaviruses are more likely to be a cause of dehydration than any other cause of gastroenteritis. 5. Protection after natural infection Rotaviruses infect mature villous epithelial cells of the small intestine (Starkey et al., 1986). Virus does not enter the blood stream or replicate at sites distant to the intestine. Therefore, protection against rotavirus infection is mediated by an immune response active at the small intestinal mucosal surface. The first evidence that a rotavirus vaccine may be effective in prevention of rotavirus disease was that of Ruth Bishop and coworkers (Bishop et al., 1983). These investigators studied infants who either did or did not have a rotavirus infection within the first month of life. They followed these children prospectively for more than 1 year and found that infants infected with rotavirus in the first month of life were less likely than those who were not infected to have moderate-to-severe disease associated with reinfection. However, rotavirus infection did not prevent reinfection. So natural infection with rotavirus modified disease associated with reinfection but did not prevent reinfection. The immunologic correlate of protection against rotavirus disease following natural infection is the presence of rotavirus-specific, secretory immunoglobulin A (sIgA) at the intestinal mucosal surface as reflected in the feces (Coulson et al., 1992; Matson et al., 1993). However, following natural infection, rotavirus-specific sIgA at the intestinal mucosal surface is short-lived—usually lasting only several months (Coulson et al., 1992). Therefore, whereas it is common for a child to be infected twice with the same rotavirus serotype within a 1-year period, it is extremely uncommon for a child to be infected twice with the same serotype within a perioed of several months (Matson et al., 1993).
P.A. Offit / Clinical and Diagnostic Virology 11 (1998) 155–159
The inability of natural infection with rotavirus to afford complete and life-long protection is best explained by the manner in which rotavirus infects the host. Rotavirus, like influenza and respiratory syncytial viruses, is a true ‘mucosal pathogen’; replication is limited to the site of entry in the host (for rotavirus, the intestinal mucosal surface). Therefore, incubation periods are short, usually 1 – 2 days. This contrasts with ‘systemic pathogens’ such as measles, mumps, rubella, or varicella. Although these viruses also initially replicate at the mucosal surface associated with the site of entry, viremia and replication of virus at sites distant to the mucosal surface is an important part of pathogenesis. As a result, incubation periods are longer, often 8 – 14 days. Both ‘mucosal’ and ‘systemic’ pathogens induce high frequencies of virus-specific memory B and T cells. However, it often takes 3 – 5 days for effector cells (such as antibody-secreting B cells or virus-specific cytotoxic T cells) to be generated from memory cells. Therefore, for ‘mucosal’ infections, generation of effector cells from memory cells (3–5 days) may take longer than the incubation period of the disease (1 – 2 days). The result is that natural infection with ‘mucosal’ pathogens causes a modification of disease associated with reinfection (i.e. protection against moderate-tosevere disease). On the other hand, because generation of effector cells from memory cells occurs within the incubation period for ‘systemic’ pathogens, protection afforded by natural infection is usually complete (i.e. protection against mild, moderate and severe disease).
6. Development of a vaccine The initial strategy to develop a rotavirus vaccine was the same as that used by Edward Jenner 200 years earlier—namely, to identify a non-human rotavirus strain that induces a protective immune response but not disease in humans. The first virus tested was a bovine rotavirus strain isolated from a calf in Nebraska. The strain was termed Nebraska Calf Diarrhea Virus or NCDV. Initial studies showed promise. Studies done in Finland found that about 80% of infants
157
and young children orally inoculated with one or two doses of NCDV were protected against moderate-to-severe rotavirus disease following natural challenge (Vesikari et al., 1983). However, the early successes in Finland were not repeated in developing countries such as Rwanda and Gambia (DeMol et al., 1986; Hanlon et al., 1987), and this strain was not tested further. The next vaccine candidate tested was a simian rotavirus strain first isolated from a rhesus monkey termed rhesus rotavirus or RRV. Again initial studies of infants orally inoculated with one dose of RRV were successful in Finland and Sweden (Gothefors et al., 1990; Vesikari et al., 1990), but this success was not matched in a trial in Rochester, New York (Christy et al., 1988). Because of the inconsistent performance of this vaccine candidate, it was not pursued further. The last non-human rotavirus strain tested for efficacy in infants and young children was one isolated from a calf in southeastern Pennsylvania and adapted to growth in cell culture at the Wistar Institute (termed Wistar calf 3 or WC3). Preliminary trails in Philadelphia showed that one dose of WC3 given orally to infants afforded 100% protection against moderate-to-severe disease (Clark et al., 1988). However, subsequent trials in Cincinnati, Ohio, and the Central African Republic were unsuccessful (Bernstein et al., 1990; Georges-Courbot et al., 1991) and again a nonhuman rotavirus strain was not tested further. Because non-human vaccine candidates were not consistently effective in protecting infants from rotavirus disease, researchers focused on trying to make non-human rotavirus strains more ‘human-like’. The goal was to retain the attenuated virulence characteristics of the non-human viruses (all trials with NCDV, RRV, and WC3 showed that non-human rotaviruses were tolerated well), but include human rotavirus proteins that evoked virus-neutralizing and, presumably, protective antibodies. To best understand how animal rotavirus strains were made more ‘human-like’ one must first understand selected aspects of rotavirus structure and function (reviewed in Estes and Cohen, 1989). Rotaviruses are a genus within the family Reo6iridae. The virus has an outer capsid
158
P.A. Offit / Clinical and Diagnostic Virology 11 (1998) 155–159
but no envelope. Two proteins comprise the outer capsid: viral protein 4 or vp4 and viral protein 7 or vp7. Both vp4 and vp7 evoke antibodies that neutralize virus infectivity (i.e. determine neutralization phenotype or serotype). Rotavirus is, therefore, similar to influenza A virus, which also contains two surface proteins that determine serotype (the hemagglutinin and neuraminidase). Because vp4 is activated by the protease trypsin, vp4 proteins are referred to as P (protease) types. Because vp7 is a glycoprotein, vp7 proteins are referred to as G (glycoprotein) types. The most common P serotype in the United States is P1. The most common G serotypes in the United States are G1, G2, G3, G4, and G9. The most common rotavirus strain circulating in the United States is P1G1. Neither NCDV nor WC3 share P or G types with human strains. RRV, on the other hand, is similar to human G type 3. Now the task was to make rotavirus strains that retained the attenuated virulence characteristics of the animal rotavirus strains and included human rotavirus genes responsible for determining serotype. The rotavirus genome consists of 11 separate segments of double-stranded RNA. When two different rotavirus strains infect the same cell at the same time, these gene segments reassort. Therefore, it is relatively easy to make rotavirus strains that contain some gene segments from one rotavirus parent and others from another parent. A series of rotavirus strains were made that contained all rotavirus genes from the animal strain and one of the genes that determined serotype from human rotavirus strains. Researchers at the National Institutes of Health constructed reassortant rotavirus strains that contained all genes from the primate strain RRV except for the gene that encoded vp7. The vp7 genes were obtained from human rotavirus strains representing G types 1, 2, and 4 (vp7 from RRV is similar to human G3). Because studies in animal models found that rotavirus virulence was determined by four genes (Hoshino et al., 1993), these single gene reassortants were unlikely to be pathogenic in humans. Two large multicenter trails of RRV (representing G type 3) plus RRV× human reassortant rotaviruses containing human G types 1, 2 and 4 were performed (Bern-
stein et al. 1995; Kapikian et al. 1996). Infants were orally inoculated with RRV plus RRV× human reassortants G1, G2, and G4 at a dose of 1× 105 plaque-forming units (pfu) per strain (total of 4× 105 pfu per dose). Similar to protection observed following natural infection, the vaccine was found to be about 50% effective in protecting against all rotavirus disease and about 80% effective in protecting against moderate-to-severe rotavirus disease. The RRV× human reassortant vaccine was found to have some adverse events associated with receipt of the first dose. Children receiving vaccine were more likely than those receiving placebo to have a the following symptoms: fevers greater than 38°C (21% vs. 6%), fevers greater than 39°C (2% vs. 1%), decreased appetite (17% vs. 11%), irritability (42% vs. 31%), and decreased activity (20% vs. 13%). These adverse events were not observed after receipt of the second or third doses of vaccine. Researchers at The Children’s Hospital of Philadelphia have also constructed reassortant rotavirus strains composed of the bovine strain WC3 and human genes encoding G types 1–4 (Clark et al., 1996) or P type 1. Clinical trials of these reassortants in infants are in progress. Bovine strain WC3 is less well adapted to growth in the infant intestine than primate strain RRV. Therefore, the WC3× human reassortant rotavirus vaccine may have less adverse effects associated with the first dose than RRV×human reassortant viruses. 7. Summary and recommendations The rotavirus vaccine containing simian strain RRV (representing human G type 3) and three other strains containing all genes from simian strain RRV and genes encoding G types 1, 2, and 4 from human rotavirus strains has now been licensed by the FDA. Because the vaccine has been found to be both safe and effective, the Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) are likely to recommend it for universal use in children. The vaccine will be given by mouth at 2, 4, and 6 months of age.
P.A. Offit / Clinical and Diagnostic Virology 11 (1998) 155–159
If used as recommended, the vaccine will cause a significant decrease in the number of deaths, hospitalizations, and office visits of children infected with rotavirus.
References Bern C, Martines J, deZoysa I, Glass RI. The magnitude of the global problem of diarrhoeal disease: a ten-year update. Bull WHO 1992;70:705–14. Bernstein D, Smith V, Sander D, et al. Evaluation of WC3 rotavirus vaccine and correlates of protection in healthy infants. J Infect Dis 1990;162:1055–62. Bernstein DI, Glass RI, Rogers G, et al. Evaluation of rhesus rotavirus monovalent and tetravalent reassortant vaccines in US children. J Am Med Assoc 1995;273:1191–6. Bishop R, Barnes G, Cipriani E, et al. Clinical immunity after neonatal rotavirus infection: a prospective longitudinal study in children. New Engl J Med 1983;309:72–6. Brandt CD, Kim HW, Yolken RH, et al. Comparative epidemiology of two rotavirus serotypes and other viral agents associated with pediatric gastroenteritis. Am J Epidemiol 1979;110:243 –54. Carr M, McKendrick D, Spyridakis T. The clinical features of infantile gastroenteritis due to rotavirus. Scand J Infect Dis 1978;8:241 – 3. Christy C, Madore P, Pichichero M, et al. Field trials of rhesus rotavirus vaccine in infants. Pediatr Infect Dis J 1988;7:645 – 50. Clark H, Borian F, Bell L, et al. Protective effect of WC3 vaccine against rotavirus diarrhea in infants during a predominantly serotype 1 rotavirus season. J Infect Dis 1988;158:570 – 87. Clark HF, Offit PA, Ellis RW, et al., WC3 reassortant vaccines in children. Arch Virol 1996;12(Suppl):187–98. Coulson B, Grimwood K, Hudson I, et al. Role of coproantibody in clinical protection of children during infection with rotavirus. J Clin Microbiol 1992;30:1678–84. DeMol P, Zissis G, Butzler J et al. Failure of live attenuated oral rotavirus vaccine. Lancet 1986:I;108. Estes M, Cohen J. Rotavirus gene structure and function. Microbiol Rev 1989;53:410–49. Georges-Courbot M, Monges J, Siopathis M, et al. Evaluation of the efficacy of a low-passage bovine rotavirus (strain WC3) vaccine in children in Central Africa. Res Virol 1991;142:405 – 11. Glass RI, Kilgore PE, Holman RC, et al. The epidemiology of rotavirus diarrhea in the United States: surveillance and estimates of disease burden. J Infect Dis 1996a;174(Suppl 1):5 – 11. Glass RI, Kilgore PE, Holman RC, et al. The epidemiology of rotavirus diarrhea in the United States: surveillance and
.
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estimates of disease burden. J Infect Dis 1996b;174(Suppl 1):5 – 11. Gothefors L, Wadell G, Juto P, et al. Prolonged efficacy of rhesus rotavirus vaccine in Swedish children. J Infect Dis 1990;159:753 – 7. Hanlon P, Marsh V, Shenton F, et al. Trial of an attenuated bovine rotavirus vaccine (RIT 4237) in Gambian infants. Lancet 1987;I:1342 – 5. Ho M, Glass R, Pinsky P, et al. Rotavirus as a cause of diarrheal morbidity and mortality in the U.S. J Infect Dis 1988;158:1112– 6. Hoshino Y, Sereno MM, Kapikian, AZ et al. Genetic determinants of rotavirus virulence studied in gnotobiotic piglets. In: Vaccines ’93, Cold Spring Harbor, NY. New York: Cold Spring Harbor Laboratory Press, 1993:277 – 282. Kapikian AZ, Hoshino Y, Chanock RM, et al. Efficacy of a quadrivalent rhesus rotavirus-based human rotavirus vaccine aimed at preventing severe rotavirus diarrhea in infants and young children. J Infect Dis 1996;1:65 – 72. Kilgore P E, Holman RC, Clarke MJ, Glass R I. Trends of diarrheal disease-associated mortality in U.S. children, 1968 through 1991. J Am Med Assoc 1995;274:1143– 8. Kovacs A, Chan L, Hotrakitya C, et al. Rotavirus gastroenteritis: clinical and laboratory features and use of the rotazyme test. Am J Dis Child 1987;141:161 – 6. Matson DO, O’Ryan ML, Herrera I, et al. Fecal antibody responses to symptomatic and asymptomatic rotavirus infections. J Infect Dis 1993;167:577 – 83. Murray C J, Lopez A D. Global mortality, disability, and the contribution of risk factors: global burden of disease study. Lancet 1997;349:1436– 42. Rodriguez W, Kim H, Arrobio J, et al. Clinical features of acute gastroenteritis associated with human reovirus-like agent in infants and young children. J Pediatr 1977;91:188 – 93. Snyder JD, Merson MH. The magnitude of the global problem of acute diarrhoeal disease: a review of active surveillance data. Bull WHO 1982;60:605 – 13. Starkey W, Collins J, Wallis T, et al. Kinetics, tissue specificity, and pathological changes in murine rotavirus infection of mice. J Gen Virol 1986;67:2625 – 34. Tallett S, MacKenzie C, Middleton P, et al. Clinical, laboratory, and epidemiologic features of a viral gastroenteritis in infants and children. Pediatrics 1977;60:217 – 22. Vesikari T, Isolauri E, Delem A, et al. Immunogenicity and safety of live oral attenuated bovine rotavirus vaccine strain RIT 4237 in adults and young children. Lancet 1983;II:807 – 11. Vesikari T, Rautanen T, Varis T, et al. Rhesus rotavirus candidate vaccine: clinical trial in children vaccinated between 2 and 5 months of age. Am J Dis Child 1990;144:285 – 9. Walsh JA, Warren KS. Selective primary health care. An interim strategy for disease control in developing countries. New Engl J Med 1979;301:967 – 74.
The rotavirus vaccine Paul A. Offit * Section of Infectious Diseases, The Children’s Hospital of Philadelphia The Uni6ersity of Pennsyl6ania School of Medicine, 34th Street and Ci6ic Centre Bl6d., Philadelphia, PA, USA Received 18 September 1998; received in revised form 25 September 1998; accepted 29 September 1998
Abstract Background: Rotavirus gastroenteritis is an important cause of morbidity and mortality worldwide. Objectives: To review the biology, immunology, and virology of rotavirus infections and describe the efforts towards the construction of vaccines using human and animal rotaviruses. Study design: A review of the literature and provision of the author’s understanding and speculation of vaccination of infants against rotavirus disease. Results: In August 1998 the Food and Drug Administration in the United States approved the licensure of a rotavirus vaccine. Both the Advisory Committee of Immunization Practices and the American Academy of Pediatrics are likely to recommend that the vaccine be given to all children by mouth as a series of three doses at 2, 4, and 6 months of age. The vaccine is made by combining a simian rotavirus strain (RRV) with several human strains representing different rotavirus serotypes. An understanding of the biology, immunology, and virology of rotavirus will help to explain the strengths and limitations of the rotavirus vaccine. Conclusion: If used as recommended, the rotavirus vaccine should cause a significant decrease in the number of deaths, hospitalizations, and office visits of children infected with rotavirus. © 1998 Elsevier Science B.V. All rights reserved. Keywords: Rotavirus vaccine; Rotavirus gastroenteritis; Literature review
1. Introduction On 31 August 1998 the Food and Drug Administration (FDA) licensed a rotavirus vaccine. Both * Tel.: + 1 215 5902020; fax: + 1 215 5902025; e-mail: [email protected]
the Advisory Committee on Immunization Practices (ACIP) and the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) are likely to recommend use of the rotavirus vaccine for all infants. The strengths and limitations of the rotavirus vaccine are best realized by understanding se-
1386-6532/98/$ - see front matter © 1998 Elsevier Science B.V. All rights reserved. PII S0928-0197(98)00063-4
156
P.A. Offit / Clinical and Diagnostic Virology 11 (1998) 155–159
lected aspects of rotavirus biology, immunology, and virology.
2. Burden of disease Rotavirus is an important cause of gastroenteritis both in the United States and in developing countries. Every year in the United States, rotavirus infection accounts for approximately 2 – 3 million cases of gastroenteritis, 500000 visits to the doctor, 50000 hospitalizations, and 20 – 40 deaths (Kilgore et al., 1995; Glass et al., 1996a). About $1.5 billion are spent both directly (health care costs) and indirectly (time lost from work by parents) on children with rotavirus infection (Glass et al., 1996b). In developing countries, rotavirus infections kill about 500000 children each year (Walsh and Warren, 1979; Snyder and Merson, 1982; Bern et al., 1992; Murray and Lopez, 1997). Indeed, as a single infectious agent, rotaviruses are the most common killer of infants and young children throughout the world. The devastating impact of this infection has spurred an intense effort over the past two decades to develop a rotavirus vaccine.
3. Epidemiology Rotavirus infections are primarily a disease of children 6–24 months of age (Brandt et al., 1979). In temperate climates, rotavirus is a disease with a peak occurrence in winter (Ho et al., 1988). Therefore, for a rotavirus vaccine to be effective in the United States, infants must be fully immunized by 6 months of age, and have an immune response that lasts throughout the winter months.
4. Clinical features The classic triad of rotavirus infection is fever, vomiting, and diarrhea. The child usually first develops fever and vomiting followed by diarrhea: vomiting lasts 2–3 days and diarrhea lasts 4 – 5 days (Tallett et al., 1977; Carr et al., 1978; Kovacs
et al., 1987). Among the multiple infectious causes of diarrhea, rotavirus infection is most likely to be accompanied by vomiting (Rodriguez et al., 1977). Because diarrhea and fever cause water loss, and vomiting makes it difficult to replace water, rotaviruses are more likely to be a cause of dehydration than any other cause of gastroenteritis. 5. Protection after natural infection Rotaviruses infect mature villous epithelial cells of the small intestine (Starkey et al., 1986). Virus does not enter the blood stream or replicate at sites distant to the intestine. Therefore, protection against rotavirus infection is mediated by an immune response active at the small intestinal mucosal surface. The first evidence that a rotavirus vaccine may be effective in prevention of rotavirus disease was that of Ruth Bishop and coworkers (Bishop et al., 1983). These investigators studied infants who either did or did not have a rotavirus infection within the first month of life. They followed these children prospectively for more than 1 year and found that infants infected with rotavirus in the first month of life were less likely than those who were not infected to have moderate-to-severe disease associated with reinfection. However, rotavirus infection did not prevent reinfection. So natural infection with rotavirus modified disease associated with reinfection but did not prevent reinfection. The immunologic correlate of protection against rotavirus disease following natural infection is the presence of rotavirus-specific, secretory immunoglobulin A (sIgA) at the intestinal mucosal surface as reflected in the feces (Coulson et al., 1992; Matson et al., 1993). However, following natural infection, rotavirus-specific sIgA at the intestinal mucosal surface is short-lived—usually lasting only several months (Coulson et al., 1992). Therefore, whereas it is common for a child to be infected twice with the same rotavirus serotype within a 1-year period, it is extremely uncommon for a child to be infected twice with the same serotype within a perioed of several months (Matson et al., 1993).
P.A. Offit / Clinical and Diagnostic Virology 11 (1998) 155–159
The inability of natural infection with rotavirus to afford complete and life-long protection is best explained by the manner in which rotavirus infects the host. Rotavirus, like influenza and respiratory syncytial viruses, is a true ‘mucosal pathogen’; replication is limited to the site of entry in the host (for rotavirus, the intestinal mucosal surface). Therefore, incubation periods are short, usually 1 – 2 days. This contrasts with ‘systemic pathogens’ such as measles, mumps, rubella, or varicella. Although these viruses also initially replicate at the mucosal surface associated with the site of entry, viremia and replication of virus at sites distant to the mucosal surface is an important part of pathogenesis. As a result, incubation periods are longer, often 8 – 14 days. Both ‘mucosal’ and ‘systemic’ pathogens induce high frequencies of virus-specific memory B and T cells. However, it often takes 3 – 5 days for effector cells (such as antibody-secreting B cells or virus-specific cytotoxic T cells) to be generated from memory cells. Therefore, for ‘mucosal’ infections, generation of effector cells from memory cells (3–5 days) may take longer than the incubation period of the disease (1 – 2 days). The result is that natural infection with ‘mucosal’ pathogens causes a modification of disease associated with reinfection (i.e. protection against moderate-tosevere disease). On the other hand, because generation of effector cells from memory cells occurs within the incubation period for ‘systemic’ pathogens, protection afforded by natural infection is usually complete (i.e. protection against mild, moderate and severe disease).
6. Development of a vaccine The initial strategy to develop a rotavirus vaccine was the same as that used by Edward Jenner 200 years earlier—namely, to identify a non-human rotavirus strain that induces a protective immune response but not disease in humans. The first virus tested was a bovine rotavirus strain isolated from a calf in Nebraska. The strain was termed Nebraska Calf Diarrhea Virus or NCDV. Initial studies showed promise. Studies done in Finland found that about 80% of infants
157
and young children orally inoculated with one or two doses of NCDV were protected against moderate-to-severe rotavirus disease following natural challenge (Vesikari et al., 1983). However, the early successes in Finland were not repeated in developing countries such as Rwanda and Gambia (DeMol et al., 1986; Hanlon et al., 1987), and this strain was not tested further. The next vaccine candidate tested was a simian rotavirus strain first isolated from a rhesus monkey termed rhesus rotavirus or RRV. Again initial studies of infants orally inoculated with one dose of RRV were successful in Finland and Sweden (Gothefors et al., 1990; Vesikari et al., 1990), but this success was not matched in a trial in Rochester, New York (Christy et al., 1988). Because of the inconsistent performance of this vaccine candidate, it was not pursued further. The last non-human rotavirus strain tested for efficacy in infants and young children was one isolated from a calf in southeastern Pennsylvania and adapted to growth in cell culture at the Wistar Institute (termed Wistar calf 3 or WC3). Preliminary trails in Philadelphia showed that one dose of WC3 given orally to infants afforded 100% protection against moderate-to-severe disease (Clark et al., 1988). However, subsequent trials in Cincinnati, Ohio, and the Central African Republic were unsuccessful (Bernstein et al., 1990; Georges-Courbot et al., 1991) and again a nonhuman rotavirus strain was not tested further. Because non-human vaccine candidates were not consistently effective in protecting infants from rotavirus disease, researchers focused on trying to make non-human rotavirus strains more ‘human-like’. The goal was to retain the attenuated virulence characteristics of the non-human viruses (all trials with NCDV, RRV, and WC3 showed that non-human rotaviruses were tolerated well), but include human rotavirus proteins that evoked virus-neutralizing and, presumably, protective antibodies. To best understand how animal rotavirus strains were made more ‘human-like’ one must first understand selected aspects of rotavirus structure and function (reviewed in Estes and Cohen, 1989). Rotaviruses are a genus within the family Reo6iridae. The virus has an outer capsid
158
P.A. Offit / Clinical and Diagnostic Virology 11 (1998) 155–159
but no envelope. Two proteins comprise the outer capsid: viral protein 4 or vp4 and viral protein 7 or vp7. Both vp4 and vp7 evoke antibodies that neutralize virus infectivity (i.e. determine neutralization phenotype or serotype). Rotavirus is, therefore, similar to influenza A virus, which also contains two surface proteins that determine serotype (the hemagglutinin and neuraminidase). Because vp4 is activated by the protease trypsin, vp4 proteins are referred to as P (protease) types. Because vp7 is a glycoprotein, vp7 proteins are referred to as G (glycoprotein) types. The most common P serotype in the United States is P1. The most common G serotypes in the United States are G1, G2, G3, G4, and G9. The most common rotavirus strain circulating in the United States is P1G1. Neither NCDV nor WC3 share P or G types with human strains. RRV, on the other hand, is similar to human G type 3. Now the task was to make rotavirus strains that retained the attenuated virulence characteristics of the animal rotavirus strains and included human rotavirus genes responsible for determining serotype. The rotavirus genome consists of 11 separate segments of double-stranded RNA. When two different rotavirus strains infect the same cell at the same time, these gene segments reassort. Therefore, it is relatively easy to make rotavirus strains that contain some gene segments from one rotavirus parent and others from another parent. A series of rotavirus strains were made that contained all rotavirus genes from the animal strain and one of the genes that determined serotype from human rotavirus strains. Researchers at the National Institutes of Health constructed reassortant rotavirus strains that contained all genes from the primate strain RRV except for the gene that encoded vp7. The vp7 genes were obtained from human rotavirus strains representing G types 1, 2, and 4 (vp7 from RRV is similar to human G3). Because studies in animal models found that rotavirus virulence was determined by four genes (Hoshino et al., 1993), these single gene reassortants were unlikely to be pathogenic in humans. Two large multicenter trails of RRV (representing G type 3) plus RRV× human reassortant rotaviruses containing human G types 1, 2 and 4 were performed (Bern-
stein et al. 1995; Kapikian et al. 1996). Infants were orally inoculated with RRV plus RRV× human reassortants G1, G2, and G4 at a dose of 1× 105 plaque-forming units (pfu) per strain (total of 4× 105 pfu per dose). Similar to protection observed following natural infection, the vaccine was found to be about 50% effective in protecting against all rotavirus disease and about 80% effective in protecting against moderate-to-severe rotavirus disease. The RRV× human reassortant vaccine was found to have some adverse events associated with receipt of the first dose. Children receiving vaccine were more likely than those receiving placebo to have a the following symptoms: fevers greater than 38°C (21% vs. 6%), fevers greater than 39°C (2% vs. 1%), decreased appetite (17% vs. 11%), irritability (42% vs. 31%), and decreased activity (20% vs. 13%). These adverse events were not observed after receipt of the second or third doses of vaccine. Researchers at The Children’s Hospital of Philadelphia have also constructed reassortant rotavirus strains composed of the bovine strain WC3 and human genes encoding G types 1–4 (Clark et al., 1996) or P type 1. Clinical trials of these reassortants in infants are in progress. Bovine strain WC3 is less well adapted to growth in the infant intestine than primate strain RRV. Therefore, the WC3× human reassortant rotavirus vaccine may have less adverse effects associated with the first dose than RRV×human reassortant viruses. 7. Summary and recommendations The rotavirus vaccine containing simian strain RRV (representing human G type 3) and three other strains containing all genes from simian strain RRV and genes encoding G types 1, 2, and 4 from human rotavirus strains has now been licensed by the FDA. Because the vaccine has been found to be both safe and effective, the Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) are likely to recommend it for universal use in children. The vaccine will be given by mouth at 2, 4, and 6 months of age.
P.A. Offit / Clinical and Diagnostic Virology 11 (1998) 155–159
If used as recommended, the vaccine will cause a significant decrease in the number of deaths, hospitalizations, and office visits of children infected with rotavirus.
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