Skip to main content Accessibility help

Rotavirus vaccines: how they work or don't work

  • Richard L. Ward (a1)


In 2004 and 2006, two new rotavirus vaccines – Rotarix and RotaTeq – were licensed worldwide. Both are live virus vaccines and are composed of either a monovalent attenuated human rotavirus or five bovine–human reassortant rotaviruses, respectively. Studies in humans and animals have reported correlations between rotavirus antibody levels and protection, the most consistent of which has been with rotavirus IgA. Cellular immunity was also found to have a role in protection after live rotavirus immunisation, particularly in mice. However, the primary importance of CD8+ T cells may be in resolution of infection and that of CD4+ T cells may be their helper function, particularly for antibody production. CD4+ T cells have been reported to have a more direct role in protection after mucosal immunisation with non-living rotavirus vaccines, possibly because of direct or indirect effects of the cytokines they generate. Immune effectors have overlapping functions, and protection against rotavirus by either live or non-living vaccines is probably enhanced by this redundancy.



Hide All
1Parashar, U.D. et al. (2006) Rotavirus and severe childhood diarrhea. Emerg Infect Dis 12, 304-306
2Ruiz-Palacios, G.M. et al. (2006) Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med 354, 11-22
3Vesikari, T. et al. (2006) Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 354, 23-33
4Shaw, A.L. et al. (1993) Three-dimensional visualization of the rotavirus hemagglutinin structure. Cell 74, 693-701
5Prasad, B.V. and Chiu, W. (1994) Structure of rotavirus. Curr Top Microbiol Immunol 185, 9-29
6Yoder, J.D. and Dormitzer, P.R. (2006) Alternative intermolecular contacts underlie the rotavirus VP5* two- to three-fold rearrangement. EMBO J 25, 1559-1568
7Yeager, M. et al. (1994) Three-dimensional structure of the rotavirus haemagglutinin VP4 by cryo-electron microscopy and difference map analysis. EMBO J 13, 1011-1018
8Wyatt, R.G. et al. (1982) Definition of human rotavirus serotypes by plaque reduction assay. Infect Immun 37, 110-115
9Hoshino, Y. et al. (1984) Serotypic similarity and diversity of rotaviruses of mammalian and avian origin as studied by plaque-reduction neutralization. J Infect Dis 149, 694-702
10Ward, R.L. et al. (1988) Relative concentrations of serum neutralizing antibody to VP3 and VP7 proteins in adults infected with a human rotavirus. J Virol 62, 1543-1549
11Ward, R.L. et al. (1993) Immunodominance of the VP4 neutralization protein of rotavirus in protective natural infections of young children. J Virol 67, 464-468
12Davidson, G.P. et al. (1977) Human rotavirus enteritis induced in conventional piglets. Intestinal structure and transport. J Clin Invest 60, 1402-1409
13Graham, D.Y., SackmanJ,W J,W, and Estes, M.K. (1984) Pathogenesis of rotavirus-induced diarrhea. Preliminary studies in miniature swine piglet. Dig Dis Sci 29, 1028-1035
14Ball, J.M. et al. (1996) Age-dependent diarrhea induced by a rotaviral nonstructural glycoprotein. Science 272, 101-104
15Morris, A.P. et al. (1999) NSP4 elicits age-dependent diarrhea and Ca++ mediated I influx into intestinal crypts of CF mice. Am J Physiol 277, G431-G444
16Dong, Y. et al. (1997) The rotavirus enterotoxin NSP4 mobilizes intracellular calcium in human intestinal cells by stimulating phospholipase C-mediated inositol 1,4,5-trisphosphate production. Proc Natl Acad Sci U S A 94, 3960-3965
17Tian, P. et al. (1995) The rotavirus nonstructural glycoprotein NSP4 mobilizes Ca2+ from the endoplasmic reticulum. J Virol 69, 5763-5772
18Lundgren, O. et al. (2000) Role of the enteric nervous system in the fluid and electrolyte secretion of rotavirus diarrhea. Science 287, 491-495
19Bernstein, D.I. et al. (1991) Protection from rotavirus reinfection: 2-year prospective study. J Infect Dis 164, 277-283
20Velazquez, F.R. et al. (1996) Rotavirus infections in infants as protection against subsequent infections. N Engl J Med 335, 1022-1028
21Bishop, R.F. et al. (1983) Clinical immunity after neonatal rotavirus infection. A prospective longitudinal study in young children. N Engl J Med 309, 72-76
22Bhan, M.K. et al. (1993) Protection conferred by neonatal rotavirus infection against subsequent rotavirus diarrhea. J Infect Dis 168, 282-287
23Vethanayagam, R.R. et al. (2004) Possible role of neonatal infection with the asymptomatic reassortant rotavirus (RV) strain I321 in the decrease in hospital admissions for RV diarrhea, Bangalore, India, 1988-1999. J Infect Dis 189, 2282-2289
24Banerjee, I. et al. (2007) Neonatal infection with G10P[11] rotavirus did not confer protection against subsequent rotavirus infection in a community cohort in Vellore, South India. J Infect Dis 195, 625-632
25Griffin, D.D. et al. (2002) Outbreaks of adult gastroenteritis traced to a single genotype of rotavirus. J Infect Dis 185, 1502-1505
26Velazquez, F.R. et al. (2000) Serum antibody as a marker of protection against natural rotavirus infection and disease. J Infect Dis 182, 1602-1609
27Ward, R.L. et al. (1989) Effects of antibody to rotavirus on protection of adults challenged with a human rotavirus. J Infect Dis 159, 79-88
28Clemens, J.D. et al. (1992) Seroepidemiologic evaluation of antibodies to rotavirus as correlates of the risk of clinically significant rotavirus diarrhea in rural Bangladesh. J Infect Dis 165, 161-165
29O'Ryan, M.L. et al. (1994) Anti-rotavirus G type-specific and isotype-specific antibodies in children with natural rotavirus infections. J Infect Dis 169, 504-511
30Matson, D.O. et al. (1993) Fecal antibody responses to symptomatic and asymptomatic rotavirus infections. J Infect Dis 167, 577-583
31Coulson, B.S. et al. (1992) Role of coproantibody in clinical protection of children during reinfection with rotavirus. J Clin Microbiol 30, 1678-1684
32Chiba, S. et al. (1986) Protective effect of naturally acquired homotypic and heterotypic rotavirus antibodies. Lancet 2, 417-421
33Ward, R.L. et al. (1992) Evidence that protection against rotavirus diarrhea after natural infection is not dependent on serotype-specific neutralizing antibody. J Infect Dis 166, 1251-1257
34Vesikari, T. et al. (1983) Immunogenicity and safety of live oral attenuated bovine rotavirus vaccine strain RIT 4237 in adults and young children. Lancet 2, 807-811
35Vesikari, T. et al. (1985) Clinical efficacy of the RIT 4237 live attenuated bovine rotavirus vaccine in infants vaccinated before a rotavirus epidemic. J Pediatr 107, 189-194
36Flores, J. et al. (1987) Protection against severe rotavirus diarrhoea by rhesus rotavirus vaccine in Venezuelan infants. Lancet 1, 882-884
37Ward, R.L. et al. (1997) Serological correlates of immunity in a pivotal tetravalent reassortant rotavirus vaccine trial. J Infect Dis 176, 570-577
38Murphy, B.R. et al. (2003) Reappraisal of the association of intussusception with the licensed live rotavirus vaccine challenges initial conclusions. J Infect Dis 187, 1301-1308
39Clark, H.F. et al. (1988) Protective effect of WC3 vaccine against rotavirus diarrhea in infants during a predominantly serotype 1 rotavirus season. J Infect Dis 158, 570-587
40De Vos, B. et al. (2004) A rotavirus vaccine for prophylaxis of infants against rotavirus gastroenteritis. Pediatr Infect Dis J 23, S179-S182
41Salinas, B. et al. (2005) Evaluation of safety, immunogenicity and efficacy of an attenuated rotavirus vaccine, RIX4414. Pediatr Infect Dis J 24, 807-816
42Vesikari, T. et al. (2006) Human rotavirus vaccine Rotarix (RIX4414) is highly efficacious in Europe. In 24th Annual Meeting of the European Society for Pediatric Infectious Diseases, Basel, Switzerland
43Kapikian, A.Z. et al. (2001) Rotaviruses. In Fields Virology (4th edn) (Knipe, D.M. et al. , eds), pp. 1787-1833, Lippincott, Williams & Wilkins
44Ward, R.L. et al. (2004) Rotavirus IgA responses stimulated by each of three doses of a quadrivalent human/bovine reassortant rotavirus vaccine. J Infect Dis 189, 2290-2293
45Cebra, J.J. (1999) Influences of microbiota on intestinal immune system development. Am J Clin Nutr 69, 1046S-1051S
46Umesaki, Y. and Setoyama, H. (2000) Structure of the intestinal flora responsible for development of the gut immune system in a rodent model. Microbes Infect 2, 1343-1351
47Savage, D.C. (2005) Mucosal microbiota. In Mucosal Immunology (3rd edn) (Mestecky, J. et al. , eds), pp. 19-33, Elsevier Academic Press
48Yuan, L. et al. (1996) Systemic and intestinal antibody-secreting cell responses and correlates of protective immunity to human rotavirus in a gnotobiotic pig model of disease. J Virol 70, 3075-3083
49Ward, L.A. et al. (1996) Development of mucosal and systemic lymphoproliferative responses and protective immunity to human group A rotaviruses in a gnotobiotic pig model. Clin Diag Lab Immunol 3, 342-350
50Feng, N. et al. (1994) Comparison of mucosal and systemic humoral immune responses and subsequent protection in mice orally inoculated with a homologous or a heterologous rotavirus. J Virol 68, 7766-7773
51McNeal, M.M., Broome, R.L. and Ward, R.L. (1994) Active immunity against rotavirus infection in mice is correlated with viral replication and titers of serum rotavirus IgA following vaccination. Virology 204, 642-650
52Burns, J.W. et al. (1996) Protective effect of rotavirus VP6-specific IgA monoclonal antibodies that lack neutralizing activity. Science 272, 104-107
53Feng, N. et al. (2002) Inhibition of rotavirus replication by a non-neutralizing, rotavirus VP6-specific IgA mAb. J Clin Invest 109, 1203-1213
54Schwartz-Cornil, I. et al. (2002) Heterologous protection induced by the inner capsid proteins of rotavirus requires transcytosis of mucosal immunoglobulins. J Virol 76, 8110-8117
55O'Neal, C.M. et al. (2000) Protection of the villus epthelial cells of the small intestine from rotavirus infection does not require immunoglobulin A. J Virol 74, 4102-4109
56Besser, T.E. et al. (1988) Passive immunity to bovine rotavirus infection associated with transfer of serum antibody into the intestinal lumen. J Virol 62, 2238-2242
57Westerman, L.E. et al. (2005) Serum IgG mediates mucosal immunity against rotavirus infection. Proc Natl Acad Sci U S A 102, 7268-7273
58Losonsky, G.A., et al. (1985) Oral administration of human serum immunoglobulin in immunodeficient patients with viral gastroenteritis. J Clin Invest 76, 2362-2367
59Offit, P.A. and Dudzik, K.I. (1988) Rotavirus-specific cytotoxic T lymphocytes cross-react with target cells infected with different rotavirus serotypes. J Virol 62, 127-131
60Offit, P.A. et al. (1991) Outer capsid glycoprotein vp7 is recognized by cross-reactive, rotavirus-specific, cytotoxic T lymphocytes. Virology 184, 563-568
61Franco, M.A. et al. (1994) Identification of cytotoxic T cell epitopes on the VP3 and VP6 rotavirus proteins. J Gen Virol 75, 589-596
62Offit, P.A. and Dudzik, K.I. (1990) Rotavirus-specific cytotoxic T lymphocytes passively protect against gastroenteritis in suckling mice. J Virol 64, 6325-6328
63Dharakul, T., Rott, L. and Greenberg, H.B. (1990) Recovery from chronic rotavirus infection in mice with severe combined immunodeficiency: virus clearance mediated by adoptive transfer of immune CD8+ T lymphocytes. J Virol 64, 4375-4382
64McNeal, M.M.VanCott, J.L.Choi, A.H. et al. 2002. CD4 T cells are the only lymphocytes needed to protect mice against rotavirus shedding after intranasal immunization with a chimeric VP6 protein and the adjuvant LT(R192G). J Virol 76, 560-568
65Franco, M.A. and Greenberg, H.B. (1995) Role of B cells and cytotoxic T lymphocytes in clearance of and immunity to rotavirus infection in mice. J Virol 69, 7800-7806
66McNeal, M.M. et al. (1995) Effector functions of antibody and CD8+ cells in resolution of rotavirus infection and protection against reinfection in mice. Virology 214, 387-397
67VanCott, J.L. et al. (2006) Mice develop effective but delayed protective immune responses when immunized as neonates either intranasally with nonliving VP6/LT(R192G) or orally with live rhesus rotavirus vaccine candidates. J Virol 80, 4949-4961
68Yuan, L. et al. (1998) Antibody-secreting cell responses and protective immunity assesses in gnotobiotic pigs inoculated orally or intramuscularly with inactivated human rotavirus. J Virol 72, 330-338
69To, T.L. et al. (1998) Serum and intestinal isotype antibody responses and correlates of protective immunity to human rotavirus in a gnotobiotic pig model of disease. J Gen Virol 79, 2661-2672
70Yuan, L. et al. (2000) Intranasal administration of 2/6-rotavirus-like particles with mutant Escherichia coli heat-labile toxin (LT-R192G) induces antibody-secreting cell responses but not protective immunity in gnotobiotic pigs. J Virol 74, 8843-8853
71Yuan, L. et al. (2001) Protective immunity and antibody-secreting cell responses elicited by combined oral attenuated Wa human rotavirus and intransal Wa 2/6-VLPs with mutant Escherichia coli heat-labile toxin in gnotobiotic pigs. J Virol 75, 9229-9238
72Azevedo, M.S.P. et al. (2004) Magnitude of serum and intestinal antibody responses induced by sequential replicating and nonreplicating rotavirus vaccines in gnotobiotic pigs and correlation with protection. Clin Diag Lab Immunol 11, 12-20
73Yuan, L. and Saif, L.J. (2002) Induction of mucosal immune responses and protection against enteric viruses: rotavirus infection or gnotobiotic pigs as a model. Vet Immunol Immunopath 87, 147-160
74McNeal, M.M. et al. (1998) Stimulation of local immunity and protection in mice by intramuscular immunization with triple- or double-layered rotavirus particles and QS-21. Virology 243, 158-166
75McNeal, M.M. et al. (1999) Antibody-dependent and -independent protection following intranasal immunization of mice with rotavirus particles. J Virol 73, 7565-7573
76Choi, A.H. et al. (1999) Antibody-independent protection against rotavirus infection of mice stimulated by intranasal immunization with chimeric VP4 or VP6 protein. J Virol 73, 7574-7581
77Choi, A.H. et al. (2002) Intranasal or oral immunization of inbred and outbred mice with murine or human rotavirus VP6 proteins protects against viral shedding after challenge with murine rotaviruses. Vaccine 20, 3310-3321
78Smiley, K.L. et al. (2007) Association of IFNγ and IL-17 production in intestinal CD4+ T cells with protection against rotavirus shedding in mice intranasally immunized with VP6 and the adjuvant LT(R192G). J Virol 81, 3740-3748
79Blutt, S.E. et al. (2006) Immunity to rotavirus requires CD4+ T cells. In Programme and Abstracts of the 9th dsRNA Virus Symposium (21–26 October; Cape Town, South Africa), Poster No. PW5.18, p. 93.
80Parez, N. et al. (2006) Rectal immunization with rotavirus virus-like particles induces systemic and mucosal humoral immune responses and protects mice against rotavirus infection. J Virol 80, 1752-1761
81Bernstein, D.I. and Ward, R.L. (1997) Rotaviruses. In Textbook of Pediatric Infectious Diseases (Vol. 2) (4th edn) (Feigin, R.D. and Cherry, J.D., eds), pp. 1901-1922, W.B. Saunders Company, Philadelphia, PA, USA
Estes, M.E. and Kapikian, A.Z. (2007) Rotaviruses. In Fields Virology (5th edn) (Knipe, D.M. et al. , eds), pp. 1917-1974, Williams & Wilkins

Rotavirus vaccines: how they work or don't work

  • Richard L. Ward (a1)


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed