Malnutrition Decreases Antibody Secreting Cell Numbers Induced by an Oral Attenuated Human Rotavirus Vaccine in a Human Infant Fecal Microbiota Transplanted Gnotobiotic Pig Model

Human rotavirus (HRV) is a leading cause of diarrhea in children. It causes significant morbidity and mortality, especially in low- and middle-income countries (LMICs), where HRV vaccine efficacy is low. The probiotic Escherichia coli Nissle (EcN) 1917 has been widely used in the treatment of enteric diseases in humans. However, repeated doses of EcN are required to achieve maximum beneficial effects. Administration of EcN on a microsphere biofilm could increase probiotic stability and persistence, thus maximizing health benefits without repeated administrations. Our aim was to investigate immune enhancement by the probiotic EcN adhered to a dextranomar microsphere biofilm (EcN biofilm) in a neonatal, malnourished piglet model transplanted with human infant fecal microbiota (HIFM) and infected with rotavirus. To create malnourishment, pigs were fed a reduced amount of bovine milk. Decreased HRV fecal shedding and protection from diarrhea were evident in the EcN biofilm treated piglets compared with EcN suspension and control groups. Moreover, EcN biofilm treatment enhanced natural killer cell activity in blood mononuclear cells (MNCs). Increased frequencies of activated plasmacytoid dendritic cells (pDC) in systemic and intestinal tissues and activated conventional dendritic cells (cDC) in blood and duodenum were also observed in EcN biofilm as compared with EcN suspension treated pigs. Furthermore, EcN biofilm treated pigs had increased frequencies of systemic activated and resting/memory antibody forming B cells and IgA+ B cells in the systemic tissues. Similarly, the mean numbers of systemic and intestinal HRV-specific IgA antibody secreting cells (ASCs), as well as HRV-specific IgA antibody titers in serum and small intestinal contents, were increased in the EcN biofilm treated group. In summary EcN biofilm enhanced innate and B cell immune responses after HRV infection and ameliorated diarrhea following HRV challenge in a malnourished, HIFM pig model.

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An Oral versus Intranasal Prime/Boost Regimen Using Attenuated Human Rotavirus or VP2 and VP6 Virus-Like Particles with Immunostimulating Complexes Influences Protection and Antibody-Secreting Cell Responses to Rotavirus in a Neonatal Gnotobiotic Pig Model

Clinical and Vaccine Immunology ◽

10.1128/cvi.00395-09 ◽

2010 ◽

Vol 17 (3) ◽

pp. 420-428 ◽

Cited By ~ 24

Author(s):

Marli S. P. Azevedo ◽

Ana Maria Gonzalez ◽

Lijuan Yuan ◽

Kwang-il Jeong ◽

Cristiana Iosef ◽

...

Keyword(s):

Effective Vaccine ◽

Lymphoid Tissues ◽

Secreting Cell ◽

Virus Shedding ◽

Antibody Secreting Cell ◽

Human Rotavirus ◽

Vaccine Type ◽

Gnotobiotic Pig ◽

The Impact ◽

Immunostimulating Complexes

ABSTRACT We determined the impact of mucosal prime/boost regimens and vaccine type (attenuated Wa human rotavirus [AttHRV] or nonreplicating Wa 2/6 rotavirus-like particles [VLP]) on protection and antibody-secreting cell (ASC) responses to HRV in a neonatal gnotobiotic pig disease model. Comparisons of delivery routes for AttHRV and evaluation of nonreplicating VLP vaccines are important as alternative vaccine approaches to overcome risks associated with live oral vaccines. Groups of neonatal gnotobiotic pigs were vaccinated using combinations of oral (PO) and intranasal (IN) inoculation routes as follows: (i) 3 oral doses of AttHRV (AttHRV3×PO); (ii) AttHRV3×IN; (iii) AttHRVPO, then 2/6VLP2×IN; (iv) AttHRVIN, then 2/6VLP2×IN; and (v) mock-inoculated controls. Subsets of pigs from each group were challenged with virulent Wa HRV [P1A(8) G1] (4 weeks post-primary inoculation) to assess protection. The AttHRVPO+2/6VLP2×IN pigs had the highest protection rates against virus shedding and diarrhea (71% each); however, these rates did not differ statistically among the vaccine groups, except for the AttHRVIN+2/6VLPIN group, which had a significantly lower protection rate (17%) against diarrhea. The isotype, magnitude, and tissue distribution of ASCs were analyzed by enzyme-linked immunospot assay. The highest mean numbers of virus-specific IgG and IgA ASCs were observed pre- and postchallenge in both intestinal and systemic lymphoid tissues of the AttHRVPO+2/6VLPIN group. Thus, the AttHRVPO+2/6VLPIN vaccine regimen using immunostimulating complexes (ISCOM) and multiple mucosal inductive sites, followed by AttHRV3×PO or IN regimens, were the most effective vaccine regimens, suggesting that either AttHRVPO+2/6VLPIN or AttHRV3×IN may be an alternative approach to AttHRV3×PO for inducing protective immunity against rotavirus diarrhea.

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Influence of probiotic Lactobacilli colonization on neonatal B cell responses in a gnotobiotic pig model of human rotavirus infection and disease

Veterinary Immunology and Immunopathology ◽

10.1016/j.vetimm.2007.10.003 ◽

2008 ◽

Vol 122 (1-2) ◽

pp. 175-181 ◽

Cited By ~ 45

Author(s):

Wei Zhang ◽

Marli S.P. Azevedo ◽

Ana M. Gonzalez ◽

Linda J. Saif ◽

Trang Van Nguyen ◽

...

Keyword(s):

B Cell ◽

Pig Model ◽

Rotavirus Infection ◽

Cell Responses ◽

Human Rotavirus ◽

B Cell Responses ◽

Probiotic Lactobacilli ◽

Gnotobiotic Pig

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Systemic and intestinal antibody responses to NSP4 enterotoxin of Wa human rotavirus in a gnotobiotic pig model of human rotavirus disease

Journal of Medical Virology ◽

10.1002/jmv.10178 ◽

2002 ◽

Vol 68 (1) ◽

pp. 119-128 ◽

Cited By ~ 14

Author(s):

Cristiana Iosef ◽

Kyeong-Ok Chang ◽

Marli S.P. Azevedo ◽

Linda J. Saif

Keyword(s):

Antibody Responses ◽

Pig Model ◽

Human Rotavirus ◽

Gnotobiotic Pig

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Systemic and intestinal antibody secreting cell responses and protection in gnotobiotic pigs immunized orally with attenuated Wa human rotavirus and Wa 2/6-rotavirus-like-particles associated with immunostimulating complexes

Vaccine ◽

10.1016/s0264-410x(02)00031-2 ◽

2002 ◽

Vol 20 (13-14) ◽

pp. 1741-1753 ◽

Cited By ~ 37

Author(s):

Cristiana Iosef ◽

Trang Van Nguyen ◽

Kwang-il Jeong ◽

Karin Bengtsson ◽

Bror Morein ◽

...

Keyword(s):

Secreting Cell ◽

Antibody Secreting Cell ◽

Cell Responses ◽

Human Rotavirus ◽

Gnotobiotic Pigs ◽

Immunostimulating Complexes

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Human rotavirus virus-like particle vaccines evaluated in a neonatal gnotobiotic pig model of human rotavirus disease

Expert Review of Vaccines ◽

10.1586/erv.13.3 ◽

2013 ◽

Vol 12 (2) ◽

pp. 169-181 ◽

Cited By ~ 24

Author(s):

Marli P Azevedo ◽

Anastasia N Vlasova ◽

Linda J Saif

Keyword(s):

Pig Model ◽

Virus Like Particle ◽

Human Rotavirus ◽

Gnotobiotic Pig

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Effect of antibiotic, probiotic, and human rotavirus infection on colonisation dynamics of defined commensal microbiota in a gnotobiotic pig model

Beneficial Microbes ◽

10.3920/bm2016.0225 ◽

2018 ◽

Vol 9 (1) ◽

pp. 71-86 ◽

Cited By ~ 10

Author(s):

H.-C. Huang ◽

A.N. Vlasova ◽

A. Kumar ◽

S. Kandasamy ◽

D.D. Fischer ◽

...

Keyword(s):

Bifidobacterium Longum ◽

Anaerobic Bacteria ◽

Antibiotic Use ◽

Pig Model ◽

Bifidobacterium Adolescentis ◽

Commensal Microbiota ◽

Human Rotavirus ◽

Escherichia Coli Nissle 1917 ◽

Colonisation Dynamics ◽

Gnotobiotic Pig

We developed a gnotobiotic (Gn) pig model colonised with defined commensal microbiota (DMF) to provide a simplified and controlled system to study the interactions between intestinal commensals, antibiotics (ciprofloxacin, CIP), probiotics (Escherichia coli Nissle 1917, EcN) and virulent human rotavirus (VirHRV). The DMF included seven gut commensal species of porcine origin that mimic the predominant species in the infant gut. Gn piglets were divided into four groups: DMF control (non-treated), DMF+CIP (CIP treated), DMF+CIP+EcN (CIP/EcN treated), DMF+EcN (EcN treated) and inoculated orally with 105 cfu of each DMF strain. The pig gut was successfully colonised by all DMF species and established a simplified bacterial community by post-bacteria colonisation day (PBCD) 14/post-VirHRV challenge day (PCD) 0. Overall, Bifidobacterium adolescentis was commonly observed in faeces in all groups and time points. At PCD0, after six days of CIP treatment (DMF+CIP), we observed significantly decreased aerobic and anaerobic bacteria counts especially in jejunum (P<0.001), where no DMF species were detected in jejunum by T-RFLP. Following HRV challenge, 100% of pigs in DMF+CIP group developed diarrhoea with higher diarrhoea scores and duration as compared to all other groups. However, only 33% of pigs treated with EcN plus CIP developed diarrhoea. EcN treatment also enhanced the bacterial diversity and all seven DMF species were detected with a higher proportion of Bifidobacterium longum in jejunum in the DMF+CIP+EcN group on PBCD14/PCD0. Our results suggest that EcN increased the proportion of B. longum especially in jejunum and mitigated adverse impacts of antibiotic use during acute-infectious diarrhoea. The DMF model with a simplified gut commensal community can further our knowledge of how commensals and probiotics promote intestinal homeostasis and contribute to host health.

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