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El. knyga: Vaccine Efficacy Evaluation: The Gnotobiotic Pig Model

(Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA)
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Testing the immunogenicity, protective efficacy and safety in animal models is a crucial step in vaccine development. Pigs raised in germ-free environments, called gnotobiotic (Gn) pigs, are one of the most useful animal models for testing vaccines. The Gn pig model is a widely accepted model for studying pathogenesis and immunity and an ideal model for pre-clinical testing for the safety and efficacy of enteric viral vaccines. Through these studies and others, the Gn pig model has been established as the most reliable animal model for pre-clinical evaluation of human rotavirus and norovirus vaccines. This book provides detailed information on establishing Gn pig models, determining a proper virus inoculum pool and challenge dose, measuring protection and calculating efficacy, and delineating intestinal and systemic immune responses associated with the protection.

Key Features











Provides a natural history of human rotavirus and norovirus infection in Gn pigs Establishes the optimal virus challenge doses in Gn pigs for vaccine evaluation Evaluates various candidate rotavirus and norovirus vaccines Discusses human gut microbiota transplanted Gn pig models Documents the role of probiotics and rice bran as prophylactics and vaccine adjuvants
Preface xii
Acknowledgments xiii
About the Author xv
1 Introduction
1(3)
1.1 Importance of pig models in human vaccine development
1(1)
1.2 Definition of gnotobiotic pigs
2(1)
1.3 Brief history of the first studies of HRV and HuNoV infection in Gn pigs
2(2)
2 Establishment of Gn Pig Model of HRV Infection and Diarrhea: Infectivity and Pathogenesis of HRV in Gn Pigs
4(5)
2.1 Origin of the virulent Wa HRV inoculum
4(1)
2.2 Determination of infectious dose of virulent Wa HRV inoculums in Gn pigs
4(1)
2.3 VirHRV fecal shedding pattern in Gn pigs
5(2)
2.4 Pathogenesis and distribution of HRV antigens in tissues of VirHRV infected Gn pigs
7(1)
2.5 Attenuated Wa HRV as a prototype HRV vaccine in Gn pigs
8(1)
3 Establishment of Gn Pig Model of HuNoV Infection and Diarrhea
9(5)
3.1 Median infectious dose of HuNoV Gll.4/2006b in two different age groups of Gn pigs
9(1)
3.2 Median infectious dose and median diarrhea dose of HuNoV Gil.4/2003 in Gn pigs and dose-response models
10(4)
4 Evaluation of Live Oral and Inactivated Intramuscular HRV Vaccines in Gn Pigs
14(7)
4.1 Protective efficacy conferred by natural infection versus live attenuated HRV vaccines and correlates of protective immunity
14(3)
4.2 Evaluation of immunogenicity and protective efficacy of inactivated HRV vaccines
17(4)
5 Virus-like Particles Given Intranasally or DNA Plasmids Given Intramuscularly Failed to Induce Any Protection in Gn Pigs
21(2)
5.1 The 2/6-VLP vaccine with mLT or ISCOM mucosal adjuvant failed in Gn pigs
21(1)
5.2 VP6 DNA vaccine failed in Gn pigs
22(1)
6 Prime-Boost Rotavirus Vaccine Regimens Are Highly Effective
23(5)
6.1 VLPs serve as effective booster doses in prime-boost regimens
23(2)
6.2 DNA plasmids serve as effective booster doses in prime-boost regimens
25(3)
7 Rotavirus P2-VP8* and P24-VP8* Intramuscular Vaccines Evaluated in Gn Pigs
28(8)
7.1 Highly immunogenic P2-VP8* subunit rotavirus vaccine demonstrated protective effects against diarrhea and virus shedding in Gn pigs
28(2)
7.2 P24-VP8* nanoparticle vaccine conferred strong protection against rotavirus diarrhea and virus shedding in Gn pigs
30(6)
8 Norovirus P Particle and VLP Vaccines Evaluated in Gn Pig Model of Gil.4 HuNoV Infection and Diarrhea
36(10)
8.1 Introduction
36(1)
8.2 Intranasal P particle and VLP vaccine provided partial protection against Gil.4 HuNoV diarrhea and shedding in Gn pigs
36(1)
8.3 Higher dose of P particle vaccine induced stronger T cell responses
37(5)
8.3.1 High dose P particle (HiPP) primed for increased Th and CTL in intestine and blood
37(1)
8.3.2 HiPP primed for increased activated T cells post-challenge
37(4)
8.3.3 HiPP primed for increased IFN-y producing effector T cells
41(1)
8.3.4 HiPP down-regulated systemic regulator T cell (Treg) responses
42(1)
8.3.5 Correlations between protection rate against diarrhea and Treg expansion
42(1)
8.4 Summary
42(4)
9 Simvastatin Reduces Protection and Intestinal T cell Responses Induced by a Norovirus P Particle Vaccine in Gnotobiotic Pigs
46(13)
9.1 Introduction
46(1)
9.2 Simvastatin feeding significantly reduced serum cholesterol in Gn pigs
47(1)
9.3 Protective efficacy conferred by the P particle vaccine in simvastatin-fed pigs
48(1)
9.4 Simvastatin decreases frequencies of proliferating intestinal CD8+ T cells after infection
48(1)
9.5 Simvastatin feeding decreased total MNCs isolated from duodenum pre-challenge and PBL post-challenge
48(2)
9.6 Simvastatin decreased total number and frequency of CTLs in duodenum of vaccinated pigs pre-challenge but increased Th cells in PBL post-challenge
50(1)
9.7 Simvastatin reduced numbers and/or frequencies of activated CD4+ and CD8+ T cells in the intestinal tissues and blood pre-challenge and CD8+ T cells in spleen and blood post-challenge
51(1)
9.8 Simvastatin feeding reduced numbers of CD8+IFN-y+ T cells in duodenum and PBL at PID 28
52(1)
9.9 Simvastatin-fed pigs had reduced CD25-FoxP3+ and CD25+FoxP3+ Tregs in duodenum
53(1)
9.10 Summary
54(5)
10 Dissecting Importance of B Cells versus T Cells in Rotavirus Vaccine-Induced Immunity Using Gene Knockout Gn Pigs
59(16)
10.1 Introduction
59(1)
10.2 Immunophenotyping of B cell-deficient and CD8 T cell-depleted Gn pigs
60(9)
10.2.1 HCKO pigs lack immature B cells and Ig secreting cells (IgSC) and are totally incapable of producing antibodies
60(2)
10.2.2 Efficiency of CD8 T cell depletion by a single injection of anti-pig CD8 antibody
62(1)
10.2.3 HCKO pigs had increased CD4 and CD8 T cell population but decreased Treg cell population
62(1)
10.2.4 CD8 depletion in B cell-deficient pigs significantly decreased CD8 T cells and NK cells
62(4)
10.2.5 CD8 depletion in B cell-deficient pigs further increased CD4 T cells but restored the level of Treg cell population
66(1)
10.2.6 B cell-deficient pigs had higher frequencies of IFN-y producing CD4 and CD8 T cells and NK cells
66(1)
10.2.7 CD8 depletion in B cell-deficient pigs significantly decreased the IFN-y producing CD4 and CD8 T cells in most tissues
66(1)
10.2.8 CD8 depletion in B cell-deficient pigs further enhanced IFN-y producing NK cells in all tissues and IFN-y producing CD4 and CD8 T cells in ileum at PCD 7
66(1)
10.2.9 CD8 depletion in B cell-deficient pigs reduced IFN-y producing CD8+ y8 T cells but enhanced IFN-y producing CD8- y5 T cells
67(2)
10.3 Cellular immune responses to AttHRV vaccine and protection against VirHRV challenge in HCKO pigs
69(4)
10.3.1 AttHRV vaccination increased CD4 and CD8 T cell and NK cells population and decreased Treg cell population in HCKO pigs
69(1)
10.3.2 B cells contribute to protective immunity against rotavirus infection and diarrhea
69(1)
10.3.3 In the absence of B cells, vaccine-induced adaptive immune responses still provided partial protection
69(1)
10.3.4 AttHRV vaccine-induced CD8 T cells played a role in shortening the duration of diarrhea and decreasing virus shedding titers
69(3)
10.3.5 Vaccine-induced other lymphocytes may have contributed to resolving rotavirus shedding
72(1)
10.4 Summary
73(2)
11 Human Gut Microbiota-Transplanted Gn Pig Models for HRV Infection
75(20)
11.1 HRV infection changes the microbial community structures and probiotics prevent the change in HGM Gn pigs
75(8)
11.1.1 Establish the HGM Gn pig model of HRV infection and analysis of microbiome
76(1)
11.1.1.1 Transplantation of HGM into Gn pigs
76(1)
11.1.1.2 Inoculation of Gn pigs with attenuated HRV vaccine, virulent HRV, and probiotic LGG
76(1)
11.1.1.3 Microbial community analysis
76(1)
11.1.2 HRV infection caused a phylum-level shift from Firmicutes to Proteobacteria, and LGG prevented the changes in microbial communities caused by HRV in HGM pigs
77(2)
11.1.3 Summary
79(4)
11.2 Modeling human enteric dysbiosis and rotavirus immunity in HGM Gn pigs
83(12)
11.2.1 Introduction
83(1)
11.2.2 HGM transplantation, vaccination, and challenge of Gn pigs
84(1)
11.2.2.1 Stool samples for HGM transplantation
84(1)
11.2.2.2 Selection and preparation of infant samples for HGM Gn pig transplantation
84(1)
11.2.2.3 Inoculation of Gn pigs with HGM, vaccination with AttHRV, and challenge with VirHRV
85(1)
11.2.3 Results
85(1)
11.2.3.1 Antibody response in HHGM and UHGM pigs
85(1)
11.2.3.2 Virus-specific effector T cell response
85(1)
11.2.3.3 Clinical signs and virus shedding
86(1)
11.2.3.4 Microbiome analysis
86(4)
11.2.3.5 Enteropathy biomarkers, histopathology, pig weights
90(2)
11.2.4 Summary
92(3)
12 Probiotics Modulate Adaptive Immune Responses to Oral HRV Vaccines in HGM Transplanted Gn Pigs
95(11)
12.1 Introduction
95(1)
12.2 Preparation of HGM inoculum and generation of HGM transplanted Gn pigs
95(1)
12.2.1 Human gut microbiota inoculum
95(1)
12.2.2 Treatment groups and inoculation of Gn pigs
96(1)
12.3 Results
96(6)
12.3.1 Similar clinical signs in AttHRV-vaccinated pigs with or without HGM transplantation after VirHRV challenge
96(2)
12.3.2 High dose LGG feeding significantly enhanced the fecal and intestinal LGG counts in HGM transplanted Gn pigs
98(1)
12.3.3 HGM colonization significantly promoted the development of Th1 type immune responses and down-regulated Treg cell responses
98(1)
12.3.4 High dose LGG significantly enhanced rotavirus-specific IFN-y producing T cell responses but did not affect Treg cells in AttHRV-vaccinated pigs with HGM
98(3)
12.3.5 Similar rotavirus-specific antibody responses associated with similar protection rate against rotavirus infection among all three groups of AttHRV-vaccinated HGM pigs with or without LGG feeding
101(1)
12.3.6 Safety of the HGM in newborn Gn pigs
102(1)
12.4 Summary
102(4)
13 Probiotics Modulate Cell Signaling Pathway and Innate Cytokine Responses to Oral HRV Vaccine in HGM-Transplanted Gn Pigs
106(9)
13.1 Introduction
106(1)
13.2 Bacterial communities in feces of HGM-transplanted pigs
107(1)
13.3 Probiotic LGG at nine doses significantly enhanced the innate cytokine and TLR responses at the transcriptional level in the AttHRV-vaccinated HGM pigs
108(1)
13.4 The signal pathway molecule expression in the ileal MNCs
108(1)
13.5 Immunohistochemistry for detection of signaling pathway molecules in ileal tissue
109(1)
13.6 Summary
110(5)
14 Probiotics as HRV Vaccine Adjuvants in Gn Pigs
115(21)
14.1 Introduction
115(1)
14.2 Probiotic Lactobacillus acidophilus enhances the immunogenicity and protective efficacy of the AttHRV vaccine in Gn pigs
116(8)
14.2.1 Probiotic LA dosing, AttHRV vaccination, and VirHRV challenge
116(1)
14.2.2 LA reduced AttHRV vaccine-associated diarrhea and substantially improved the protection against virus shedding conferred by the AttHRV vaccine against VirHRV challenge
117(1)
14.2.3 LA significantly enhanced the T cell, B cell, and antibody responses induced by the AttHRV vaccine
117(1)
14.2.3.1 LA significantly enhanced HRV-specific IFN-y producing CD8+ T cell responses induced by the AttH RV vaccine
117(1)
14.2.3.2 LA significantly enhanced intestinal HRV-specific IgA and IgG ASC responses induced by the AttHRV vaccine as well as the total intestinal IgA and IgG immunoglobulin-secreting cells (IgSC)
117(4)
14.2.3.3 LA significantly enhanced serum IgM, IgA, IgG, and VN antibody responses induced by the AttHRV vaccine
121(1)
14.2.4 Summary
121(3)
14.3 Dose effects of LAB on modulation of rotavirus vaccine-induced immune responses
124(12)
14.3.1 Introduction
124(1)
14.3.2 Dose effects of LA on T cell responses
125(1)
14.3.3 Low dose LA, but not high dose LA, enhanced HRV-specific IFN-y producing T cell responses
125(1)
14.3.4 High dose LA significantly increased frequencies of intestinal and systemic CD4+CD25-FoxP3+ Treg cells whereas low dose LA decreased TGF-p and IL-10 producing Treg cell responses
126(1)
14.3.5 Dose effects of LA on antibody and B cell responses
127(1)
14.3.6 High dose LA did not significantly alter the HRV-specific antibody responses whereas low dose LA had negative effects on the antibody responses
128(1)
14.3.7 Dose effects of LA on DC responses
129(3)
14.3.8 Dose effects of LA on protection conferred by the oral AttHRV vaccine against virulent HRV challenge
132(3)
14.3.9 Summary
135(1)
15 Rice Bran as a Vaccine Adjuvant and as Prebiotics in Reducing Viral Diarrhea
136(8)
15.1 Rice bran as a vaccine adjuvant for AttHRV vaccines in Gn pigs
136(8)
15.1.1 Introduction
136(1)
15.1.2 Rice bran feeding, AttHRV inoculation, and VirHRV challenge of Gn pigs
136(1)
15.1.3 Rice bran reduced HRV diarrhea but not virus shedding
137(1)
15.1.4 Rice bran enhanced IFN-y+ CD4+ and CD8+ Tcell responses to AttHRV vaccine
137(1)
15.1.5 Rice bran promoted the development of intestinal and systemic IgSC
137(3)
15.1.6 Rice bran stimulated the production of total IgM, IgA, and IgG in serum
140(1)
15.1.7 Rice bran decreased the intestinal and systemic HRV-specific IgA and IgG ASC responses to AttHRV vaccination but not VirHRV challenge
140(1)
15.1.8 Rice bran reduced serum HRV-specific IgA and IgG antibody responses to AttHRV
141(1)
15.1.9 Rice bran increased HRV-specific IgA titer in the intestinal contents
141(1)
15.1.10 Summary
141(3)
15.2 Combination of probiotics and rice bran is highly effective in preventing HRV diarrhea in Gn pigs
144(1)
1 5.2.1 Introduction: probiotics and RB in HRV diarrhea
144(17)
15.2.2 RB feeding, probiotic colonization, and VirHRV challenge of Gn pigs
145(1)
15.2.3 RB completely protected against rotavirus diarrhea in LGG and EcN colonized Gn pigs
145(1)
15.2.4 RB significantly enhanced the growth and colonization of LGG and EcN and increased pig body weight gain in LGG+EcN colonized pigs
145(2)
15.2.5 The combination of RB and LGG+EcN prevented epithelial damage from HRV challenge
147(1)
15.2.6 RB enhanced the innate immune response during HRV infection
148(2)
15.2.7 Summary
150(2)
15.3 Combination of probiotics and rice bran is highly effective in preventing HuNoV diarrhea in Gn pigs
152(6)
15.3.1 Gnotobiotic pig treatment groups
152(1)
15.3.2 LGG+EcN inhibited HuNoV shedding and RB reduced diarrhea in Gn pigs
153(1)
15.3.3 LGG+EcN and RB stimulated the production of total IFN-y+ T cells
153(1)
15.3.4 Probiotics plus RB cocktail regimens enhanced gut immunity
154(1)
15.3.5 Probiotics plus RB cocktail regimens increased jejuna villi length
154(2)
15.3.6 Summary
156(2)
15.4 Impacts of studies of RB in Gn pigs
158(1)
15.5 Closing remarks
159(2)
References 161(24)
Index 185
Lijuan Yuan is a Professor of Virology and Immunology in the Virginia-Maryland Vet Meds Department of Biomedical Sciences & Pathobiology. Dr. Yuan studies the interactions between enteric viruses and the host immune system. Her lab's research interests are focused on the pathogenesis and innate and adaptive immune responses induced by enteric viruses, especially noroviruses and rotaviruses, and on the development of safer and more effective vaccines as well as passive immune prophylaxis and therapeutics against viral gastroenteritis. These studies utilize wild-type, gene knock-out, and human gut microbiota transplanted gnotobiotic pig models of human rotavirus and norovirus infection and diseases and cell culture model of rotavirus infection. Currently, the Yuan lab is evaluating the immunogenicity and protective efficacy of several candidate novel rotavirus and norovirus vaccines and engineered probiotic yeast Saccharomyces boulardii secreting multi-specific single-domain antibodies as novel prophylaxis against both noroviruses and Clostridioides difficile toxins. See: https://vetmed.vt.edu/people/faculty/yuan-lijuan.html
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