Chapter 17 : Rotavirus

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Rotavirus, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817411/9781555817350_Chap17-1.gif /docserver/preview/fulltext/10.1128/9781555817411/9781555817350_Chap17-2.gif


Rotaviruses (RV) are ubiquitous highly infectious double-stranded RNA viruses of importance in public health because of the severe acute gastroenteritis (GE) they cause in young children and many other animal species. They are very well adapted to their host, causing frequent symptomatic and asymptomatic reinfections. Antibodies are the major component of the immune system that protects infants against RV reinfection. The relationship between the virus and the B cells (Bc) that produce these antibodies is complex and incompletely understood ( ). In this review, the following basic aspects of RV-specific Bc (RV-Bc) will be addressed: (i) ontogeny; (ii) use of immunoglobulin (Ig) genes; (iii) differential distribution (compartmentalization) in the intestinal and systemic immune systems; (iv) specificity of RV-Ig produced and the mechanisms by which it mediates protection; and finally, (v) practical applications for the use of RV-Ig, including RV-Ig as a prophylactic or therapeutic agent and as a correlate of protection. The immune response generated against RV vaccines has been recently reviewed ( ) and will only be briefly discussed. The focus of this review is antibodies induced by natural RV infection in humans, but reference to studies of the murine and porcine animal models of RV infection will be made when necessary.

Citation: Franco M, Greenberg H. 2015. Rotavirus, p 289-301. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0011-2013
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

Flow cytometry experiment to characterize and compare RV-Bc to total Bc subsets (from reference with modifications). Top row plots illustrate the Bc subsets considered. Middle row dot plots are gated on total CD20 Bc. Bottom row plots are gated on CD20 Bc that bind fluorescent RV VLPs (RV-Bc). As a first step in this analysis, Bc are evaluated for the expression of IgD and CD27 (left dot plots). IgD CD27 Bc are naive cells, and IgD CD27 (IgM, IgG, or IgA) are a low-frequency subset of mBc. The CD27 Bc of the left panels are further analyzed for the expression of IgD and IgM (right dot plots). IgM IgD cells are classical switched mBc; IgM IgD cells are called IgM-only mBc and resemble in many ways the switched mBc. IgD IgM cells are a poorly characterized subset of mBc. Double-positive IgM IgD mBc are a heterogeneous population of mBc; in the present experiment, they are further subdivided into IgM IgD (a phenotype that resembles marginal zone Bc) and IgM IgD.

Citation: Franco M, Greenberg H. 2015. Rotavirus, p 289-301. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0011-2013
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Distribution of RV-Bc 9 months after primary oral infection of mice in selected organs (data from experiments reported in reference ). The top panel shows numbers of IgG and IgA RV ASC per mouse, in different organs, evaluated by enzyme-linked immunospot assay. The middle panel shows numbers of RV-mBc (small IgD Bc) that bind RV VLPs per mouse, in different organs, evaluated by flow cytometry. The bottom panel shows the same data as the second panel but expressed as RV-mBc per 10 cells of the respective organ. LN, lymph node; LP, lamina propria.

Citation: Franco M, Greenberg H. 2015. Rotavirus, p 289-301. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0011-2013
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

Expression of the integrin α4β7 (the intestinal homing receptor) and CCR9 (chemokine receptor 9 whose ligand, TECK or CCL25, is selectively expressed in the small intestine) on RV-Bc (Bc that bind fluorescent RV VLPs) in children with acute (left dot plot)- or convalescent (right dot plot)-phase RV infection. The figure is from reference , with modifications.

Citation: Franco M, Greenberg H. 2015. Rotavirus, p 289-301. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0011-2013
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Franco MA,, Angel J,, Greenberg HB . 2006. Immunity and correlates of protection for rotavirus vaccines. Vaccine 24 : 2718 2731. [PubMed] [CrossRef]
2. Angel J,, Franco MA,, Greenberg HB . 2007. Rotavirus vaccines: recent developments and future considerations. Nat Rev Microbiol 5 : 529 539. [PubMed] [CrossRef]
3. Angel J,, Franco MA,, Greenberg HB . 2012. Rotavirus immune responses and correlates of protection. Curr Opin Virol 2 : 419 425. [PubMed] [CrossRef]
4. Ray PG,, Kelkar SD,, Walimbe AM,, Biniwale V,, Mehendale S . 2007. Rotavirus immunoglobulin levels among Indian mothers of two socio-economic groups and occurrence of rotavirus infections among their infants up to six months. J Med Virol 79 : 341 349. [PubMed] [CrossRef]
5. Ogra SS,, Weintraub D,, Ogra PL . 1977. Immunologic aspects of human colostrum and milk. III. Fate and absorption of cellular and soluble components in the gastrointestinal tract of the newborn. J Immunol 119 : 245 248. [PubMed]
6. Nguyen TV,, Yuan L,, Azevedo MS,, Jeong KI,, Gonzalez AM,, Iosef C,, Lovgren-Bengtsson K,, Morein B,, Lewis P,, Saif LJ . 2006. High titers of circulating maternal antibodies suppress effector and memory B-cell responses induced by an attenuated rotavirus priming and rotavirus-like particle-immunostimulating complex boosting vaccine regimen. Clin Vaccine Immunol 13 : 475 485. [PubMed] [CrossRef]
7. Nguyen TV,, Yuan L,, Azevedo MS,, Jeong KI,, Gonzalez AM,, Iosef C,, Lovgren-Bengtsson K,, Morein B,, Lewis P,, Saif LJ . 2006. Low titer maternal antibodies can both enhance and suppress B cell responses to a combined live attenuated human rotavirus and VLP-ISCOM vaccine. Vaccine 24 : 2302 2316. [PubMed] [CrossRef]
8. Parez N,, Garbarg-Chenon A,, Fourgeux C,, Le Deist F,, Servant-Delmas A,, Charpilienne A,, Cohen J,, Schwartz-Cornil I . 2004. The VP6 protein of rotavirus interacts with a large fraction of human naive B cells via surface immunoglobulins. J Virol 78 : 12489 12496. [PubMed] [CrossRef]
9. Kallewaard NL,, McKinney BA,, Gu Y,, Chen A,, Prasad BV,, Crowe JE, Jr . 2008. Functional maturation of the human antibody response to rotavirus. J Immunol 180 : 3980 3989. [PubMed]
10. Rojas OL,, Caicedo L,, Guzman C,, Rodriguez LS,, Castaneda J,, Uribe L,, Andrade Y,, Pinzon R,, Narvaez CF,, Lozano JM,, De Vos B,, Franco MA,, Angel J . 2007. Evaluation of circulating intestinally committed memory B cells in children vaccinated with attenuated human rotavirus vaccine. Viral Immunol 20 : 300 311. [PubMed] [CrossRef]
11. Narvaez CF,, Feng N,, Vasquez C,, Sen A,, Angel J,, Greenberg HB,, Franco MA . 2012. Human rotavirus-specific IgM memory B cells have differential cloning efficiencies and switch capacities and play a role in antiviral immunity in vivo. J Virol 86 : 10829 10840. [PubMed] [CrossRef]
12. Reynaud CA,, Descatoire M,, Dogan I,, Huetz F,, Weller S,, Weill JC . 2012. IgM memory B cells: a mouse/human paradox. Cell Mol Life Sci 69 : 1625 1634. [PubMed] [CrossRef]
13. Gonzalez AM,, Jaimes MC,, Cajiao I,, Rojas OL,, Cohen J,, Pothier P,, Kohli E,, Butcher EC,, Greenberg HB,, Angel J,, Franco MA . 2003. Rotavirus-specific B cells induced by recent infection in adults and children predominantly express the intestinal homing receptor α4β7. Virology 305 : 93 105. [PubMed]
14. Jaimes MC,, Rojas OL,, Kunkel EJ,, Lazarus NH,, Soler D,, Butcher EC,, Bass D,, Angel J,, Franco MA,, Greenberg HB . 2004. Maturation and trafficking markers on rotavirus-specific B cells during acute infection and convalescence in children. J Virol 78 : 10967 10976. [PubMed] [CrossRef]
15. Ray PG,, Kelkar SD . 2004. Measurement of antirotavirus IgM/IgA/IgG responses in the serum samples of Indian children following rotavirus diarrhoea and their mothers. J Med Virol 72 : 416 423. [PubMed] [CrossRef]
16. Coulson BS,, Grimwood K,, Hudson IL,, Barnes GL,, Bishop RF . 1992. Role of coproantibody in clinical protection of children during reinfection with rotavirus. J Clin Microbiol 30 : 1678 1684. [PubMed]
17. Hjelt K,, Grauballe PC,, Andersen L,, Schiotz PO,, Howitz P,, Krasilnikoff PA . 1986. Antibody response in serum and intestine in children up to six months after a naturally acquired rotavirus gastroenteritis. J Pediatr Gastroenterol Nutr 5 : 74 80. [PubMed]
18. Mantis NJ,, Forbes SJ . 2010. Secretory IgA: arresting microbial pathogens at epithelial borders. Immunol Investig 39 : 383 406. [PubMed] [CrossRef]
19. Bernstein DI,, McNeal MM,, Schiff GM,, Ward RL . 1989. Induction and persistence of local rotavirus antibodies in relation to serum antibodies. J Med Virol 28 : 90 95. [PubMed]
20. Tian C,, Luskin GK,, Dischert KM,, Higginbotham JN,, Shepherd BE,, Crowe JE, Jr . 2008. Immunodominance of the VH1-46 antibody gene segment in the primary repertoire of human rotavirus-specific B cells is reduced in the memory compartment through somatic mutation of nondominant clones. J Immunol 180 : 3279 3288. [PubMed]
21. Weitkamp JH,, Kallewaard N,, Kusuhara K,, Bures E,, Williams JV,, LaFleur B,, Greenberg HB,, Crowe JE, Jr . 2003. Infant and adult human B cell responses to rotavirus share common immunodominant variable gene repertoires. J Immunol 171 : 4680 4688. [PubMed]
22. Weitkamp JH,, Lafleur BJ,, Greenberg HB,, Crowe JE Jr . 2005. Natural evolution of a human virus-specific antibody gene repertoire by somatic hypermutation requires both hotspot-directed and randomly-directed processes. Hum Immunol 66 : 666 676. [PubMed] [CrossRef]
23. Di Niro R,, Mesin L,, Raki M,, Zheng NY,, Lund-Johansen F,, Lundin KE,, Charpilienne A,, Poncet D,, Wilson PC,, Sollid LM . 2010. Rapid generation of rotavirus-specific human monoclonal antibodies from small-intestinal mucosa. J Immunol 185 : 5377 5383. [PubMed] [CrossRef]
24. Benckert J,, Schmolka N,, Kreschel C,, Zoller MJ,, Sturm A,, Wiedenmann B,, Wardemann H . 2011. The majority of intestinal IgA + and IgG + plasmablasts in the human gut are antigen-specific. J Clin Investig 121 : 1946 1955. [PubMed] [CrossRef]
25. Youngman KR,, Franco MA,, Kuklin NA,, Rott LS,, Butcher EC,, Greenberg HB . 2002. Correlation of tissue distribution, developmental phenotype, and intestinal homing receptor expression of antigen-specific B cells during the murine anti-rotavirus immune response. J Immunol 168 : 2173 2181. [PubMed]
26. Bowman EP,, Kuklin NA,, Youngman KR,, Lazarus NH,, Kunkel EJ,, Pan J,, Greenberg HB,, Butcher EC . 2002. The intestinal chemokine thymus-expressed chemokine (CCL25) attracts IgA antibody-secreting cells. J Exp Med 195 : 269 275. [PubMed]
27. Brown KA,, Kriss JA,, Moser CA,, Wenner WJ,, Offit PA . 2000. Circulating rotavirus-specific antibody-secreting cells (ASCs) predict the presence of rotavirus-specific ASCs in the human small intestinal lamina propria. J Infect Dis 182 : 1039 1043. [PubMed] [CrossRef]
28. VanCott JL,, McNeal MM,, Flint J,, Bailey SA,, Choi AH,, Ward RL . 2001. Role for T cell-independent B cell activity in the resolution of primary rotavirus infection in mice. Eur J Immunol 31 : 3380 3387. [PubMed] [CrossRef]
29. Franco MA,, Greenberg HB . 1995. Role of B cells and cytotoxic T lymphocytes in clearance of and immunity to rotavirus infection in mice. J Virol 69 : 7800 7806. [PubMed]
30. Williams MB,, Rose JR,, Rott LS,, Franco MA,, Greenberg HB,, Butcher EC . 1998. The memory B cell subset responsible for the secretory IgA response and protective humoral immunity to rotavirus expresses the intestinal homing receptor, alpha4beta7. J Immunol 161 : 4227 4235. [PubMed]
31. Kuklin NA,, Rott L,, Feng N,, Conner ME,, Wagner N,, Muller W,, Greenberg HB . 2001. Protective intestinal anti-rotavirus B cell immunity is dependent on alpha 4 beta 7 integrin expression but does not require IgA antibody production. J Immunol 166 : 1894 1902. [PubMed]
32. VanCott JL,, Prada AE,, McNeal MM,, Stone SC,, Basu M,, Huffer B, Jr,, Smiley KL,, Shao M,, Bean JA,, Clements JD,, Choi AH,, Ward RL . 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. [PubMed] [CrossRef]
33. Blutt SE,, Warfield KL,, Lewis DE,, Conner ME . 2002. Early response to rotavirus infection involves massive B cell activation. J Immunol 168 : 5716 5721. [PubMed]
34. Blutt SE,, Crawford SE,, Warfield KL,, Lewis DE,, Estes MK,, Conner ME . 2004. The VP7 outer capsid protein of rotavirus induces polyclonal B-cell activation. J Virol 78 : 6974 6981. [PubMed] [CrossRef]
35. Narvaez CF,, Franco MA,, Angel J,, Morton JM,, Greenberg HB . 2010. Rotavirus differentially infects and polyclonally stimulates human B cells depending on their differentiation state and tissue of origin. J Virol 84 : 4543 4555. [PubMed] [CrossRef]
36. Ishida SI,, Feng N,, Gilbert JM,, Tang B,, Greenberg HB . 1997. Immune responses to individual rotavirus proteins following heterologous and homologous rotavirus infection in mice. J Infect Dis 175 : 1317 1323. [PubMed]
37. Burns JW,, Siadat-Pajouh M,, Krishnaney AA,, Greenberg HB . 1996. Protective effect of rotavirus VP6-specific IgA monoclonal antibodies that lack neutralizing activity. Science 272 : 104 107. [PubMed]
38. Feng N,, Lawton JA,, Gilbert J,, Kuklin N,, Vo P,, Prasad BV,, Greenberg HB . 2002. Inhibition of rotavirus replication by a non-neutralizing, rotavirus VP6-specific IgA mAb. J Clin Investig 109 : 1203 1213. [PubMed] [CrossRef]
39. Schwartz-Cornil I,, Benureau Y,, Greenberg H,, Hendrickson BA,, Cohen J . 2002. Heterologous protection induced by the inner capsid proteins of rotavirus requires transcytosis of mucosal immunoglobulins. J Virol 76 : 8110 8117. [PubMed]
40. Corthesy B,, Benureau Y,, Perrier C,, Fourgeux C,, Parez N,, Greenberg H,, Schwartz-Cornil I . 2006. Rotavirus anti-VP6 secretory immunoglobulin A contributes to protection via intracellular neutralization but not via immune exclusion. J Virol 80 : 10692 10699. [PubMed] [CrossRef]
41. Aladin F,, Einerhand AW,, Bouma J,, Bezemer S,, Hermans P,, Wolvers D,, Bellamy K,, Frenken LG,, Gray J,, Iturriza-Gomara M . 2012. In vitro neutralisation of rotavirus infection by two broadly specific recombinant monovalent llama-derived antibody fragments. PLoS One 7 : e32949. [PubMed] [CrossRef]
42. Garaicoechea L,, Olichon A,, Marcoppido G,, Wigdorovitz A,, Mozgovoj M,, Saif L,, Surrey T,, Parreno V . 2008. Llama-derived single-chain antibody fragments directed to rotavirus VP6 protein possess broad neutralizing activity in vitro and confer protection against diarrhea in mice. J Virol 82 : 9753 9764. [PubMed] [CrossRef]
43. Aoki ST,, Settembre EC,, Trask SD,, Greenberg HB,, Harrison SC,, Dormitzer PR . 2009. Structure of rotavirus outer-layer protein VP7 bound with a neutralizing Fab. Science 324 : 1444 1447. [PubMed] [CrossRef]
44. Trask SD,, McDonald SM,, Patton JT . 2012. Structural insights into the coupling of virion assembly and rotavirus replication. Nat Rev Microbiol 10 : 165 177. [PubMed] [CrossRef]
45. Guarino A,, Canani RB,, Russo S,, Albano F,, Canani MB,, Ruggeri FM,, Donelli G,, Rubino A . 1994. Oral immunoglobulins for treatment of acute rotaviral gastroenteritis. Pediatrics 93 : 12 16. [PubMed]
46. Losonsky GA,, Johnson JP,, Winkelstein JA,, Yolken RH . 1985. Oral administration of human serum immunoglobulin in immunodeficient patients with viral gastroenteritis. A pharmacokinetic and functional analysis. J Clin Investig 76 : 2362 2367. [PubMed] [CrossRef]
47. Sarker SA,, Casswall TH,, Mahalanabis D,, Alam NH,, Albert MJ,, Brussow H,, Fuchs GJ,, Hammerstrom L . 1998. Successful treatment of rotavirus diarrhea in children with immunoglobulin from immunized bovine colostrum. Pediatr Infect Dis J 17 : 1149 1154. [PubMed]
48. Sarker SA,, Casswall TH,, Juneja LR,, Hoq E,, Hossain I,, Fuchs GJ,, Hammarstrom L . 2001. Randomized, placebo-controlled, clinical trial of hyperimmunized chicken egg yolk immunoglobulin in children with rotavirus diarrhea. J Pediatr Gastroenterol Nutr 32 : 19 25. [PubMed]
49. Pant N,, Hultberg A,, Zhao Y,, Svensson L,, Pan-Hammarstrom Q,, Johansen K,, Pouwels PH,, Ruggeri FM,, Hermans P,, Frenken L,, Boren T,, Marcotte H,, Hammarstrom L . 2006. Lactobacilli expressing variable domain of llama heavy-chain antibody fragments (lactobodies) confer protection against rotavirus-induced diarrhea. J Infect Dis 194 : 1580 1588. [PubMed] [CrossRef]
50. Pammi M,, Haque KN . 2011. Oral immunoglobulin for the treatment of rotavirus diarrhea in low birth weight infants. Cochrane Database Syst Rev 2011 : CD003742. [PubMed] [CrossRef]
51. Yuan L,, Ward LA,, Rosen BI,, To TL,, Saif LJ . 1996. Systematic 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. [PubMed]
52. Amar CF,, East CL,, Gray J,, Iturriza-Gomara M,, Maclure EA,, McLauchlin J . 2007. Detection by PCR of eight groups of enteric pathogens in 4,627 faecal samples: re-examination of the English case-control Infectious Intestinal Disease Study (1993–1996). Eur J Clin Microbiol Infect Dis 26 : 311 323. [PubMed] [CrossRef]
53. Rojas OL,, Narvaez CF,, Greenberg HB,, Angel J,, Franco MA . 2008. Characterization of rotavirus specific B cells and their relation with serological memory. Virology 380 : 234 242. [PubMed] [CrossRef]
54. Ward RL,, Kirkwood CD,, Sander DS,, Smith VE,, Shao M,, Bean JA,, Sack DA,, Bernstein DI . 2006. Reductions in cross-neutralizing antibody responses in infants after attenuation of the human rotavirus vaccine candidate 89-12. J Infect Dis 194 : 1729 1736. [PubMed] [CrossRef]


Generic image for table

Blood-circulating Bc subsets in healthy adults and their enrichment or not in RV-Bc

Citation: Franco M, Greenberg H. 2015. Rotavirus, p 289-301. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0011-2013

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error