Escherichia coli Nissle 1917 Enhances Efficacy of Oral Attenuated Human Rotavirus Vaccine in a Gnotobiotic Piglet Model

Human rotavirus (HRV) infection is a major cause of viral gastroenteritis in young children worldwide. Current oral vaccines perform poorly in developing countries where efficacious vaccines are needed the most. Therefore, an alternative affordable strategy to enhance efficacy of the current RV vaccines is necessary. This study evaluated the effects of colonization of neonatal gnotobiotic (Gn) pigs with Escherichia coli Nissle (EcN) 1917 and Lacticaseibacillus rhamnosus GG (LGG) probiotics on immunogenicity and protective efficacy of oral attenuated (Att) HRV vaccine. EcN-colonized pigs had reduced virulent HRV (VirHRV) shedding and decreased diarrhea severity compared with the LGG-colonized group. They also had enhanced HRV-specific IgA antibody titers in serum and antibody secreting cell numbers in tissues pre/post VirHRV challenge, HRV-specific IgA antibody titers in intestinal contents, and B-cell subpopulations in tissues post VirHRV challenge. EcN colonization also enhanced T-cell immune response, promoted dendritic cells and NK cell function, reduced production of proinflammatory cytokines/Toll like receptor (TLR), and increased production of immunoregulatory cytokines/TLR expression in various tissues pre/post VirHRV challenge. Thus, EcN probiotic adjuvant with AttHRV vaccine enhances the immunogenicity and protective efficacy of AttHRV to a greater extent than LGG and it can be used as a safe and economical oral vaccine adjuvant.

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Identification of Three Highly Attenuated Salmonella typhimurium Mutants That Are More Immunogenic and Protective in Mice than a Prototypical aroA Mutant

Infection and Immunity ◽

10.1128/iai.66.7.3378-3383.1998 ◽

1998 ◽

Vol 66 (7) ◽

pp. 3378-3383 ◽

Cited By ~ 46

Author(s):

Peter J. Valentine ◽

Brian P. Devore ◽

Fred Heffron

Keyword(s):

Salmonella Typhimurium ◽

Oral Vaccine ◽

Secretory Iga ◽

Control Strain ◽

Vaccine Candidates ◽

Specific Serum ◽

Antibody Titers ◽

Aroa Mutant ◽

Iga Antibody ◽

Mouse Model Of Infection

ABSTRACT A panel of Salmonella typhimurium 14028s mutants, which were previously shown to be highly attenuated in the BALB/c mouse model of infection, were analyzed for their potential as liveSalmonella oral-vaccine candidates. A prototypicalaroA mutant was chosen as a basis of comparison. From the panel of mutants initially chosen for this study, three mutants with comparable levels of attenuation elicited higherSalmonella-specific serum immunoglobulin G (IgG) and/or mucosal secretory-IgA antibody titers than the aroA vaccine strain. The three mutants, CL288, CL401, and CL554, also elicited a better protective immune response than the aroA control strain, after a single oral dose of 1 × 109 to 2 × 109 bacteria.

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Sterilizing immunity against SARS-CoV-2 in hamsters conferred by a novel recombinant subunit vaccine

10.1101/2020.12.18.423552 ◽

2020 ◽

Author(s):

Yangtao Wu ◽

Xiaofen Huang ◽

Lunzhi Yuan ◽

Shaojuan Wang ◽

Yali Zhang ◽

...

Keyword(s):

T Cell ◽

Subunit Vaccine ◽

Vaccine Candidate ◽

Protective Efficacy ◽

Humoral Response ◽

Neutralizing Antibody ◽

Cell Immune Response ◽

Antibody Titers ◽

A Subunit ◽

Sterilizing Immunity

AbstractA safe and effective SARS-CoV-2 vaccine is essential to avert the on-going COVID-19 pandemic. Here, we developed a subunit vaccine, which is comprised of CHO-expressed spike ectodomain protein (StriFK) and nitrogen bisphosphonates-modified zinc-aluminum hybrid adjuvant (FH002C). This vaccine candidate rapidly elicited the robust humoral response, Th1/Th2 balanced helper CD4 T cell and CD8 T cell immune response in animal models. In mice, hamsters, and non-human primates, 2-shot and 3-shot immunization of StriFK-FH002C generated 28- to 38-fold and 47- to 269-fold higher neutralizing antibody titers than the human COVID-19 convalescent plasmas, respectively. More importantly, the StriFK-FH002C immunization conferred sterilizing immunity to prevent SARS-CoV-2 infection and transmission, which also protected animals from virus-induced weight loss, COVID-19-like symptoms, and pneumonia in hamsters. Vaccine-induced neutralizing and cell-based receptor-blocking antibody titers correlated well with protective efficacy in hamsters, suggesting vaccine-elicited protection is immune-associated. The StriFK-FH002C provided a promising SARS-CoV-2 vaccine candidate for further clinical evaluation.

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Clinical, Laboratory, and Epidemiologic Features of a Viral Gastroenteritis in Infants and Children

PEDIATRICS ◽

10.1542/peds.60.2.217 ◽

1977 ◽

Vol 60 (2) ◽

pp. 217-222

Author(s):

Susan Tallett ◽

Carrie MacKenzie ◽

Peter Middleton ◽

Benny Kerzner ◽

Richard Hamilton

Keyword(s):

Additional Data ◽

Clinical Laboratory ◽

Fecal Excretion ◽

Watery Diarrhea ◽

Viral Gastroenteritis ◽

Low Concentrations ◽

Human Rotavirus ◽

Antibody Titers ◽

Available Information ◽

Epidemiologic Features

We studied 27 infants admitted to the hospital with acute diarrhea caused by human rotavirus (HRV) and obtained additional data on fecal excretion from ten outpatients with the same infection. The disease was characterized by watery diarrhea with fever and vomiting at the onset, isotonic dehydration, compensated metabolic acidosis, and increased concentrations of sodium and chloride but low concentrations of sugar in stools. Diarrhea usually ceased in three to four days when oral feedings were reduced or stopped but recurred mildly in four patients. Of 57 household contacts, 12 were symptomatic, 6 had HRV in their stools, and 19 had significantly increased serum HRV antibody titers. These features of the disease accord with available information on the pathogenesis of HRV infection. Knowledge of the clinical pattern of this newly diagnosable infection should help physicians to recognize and treat quickly this highly infectious, potentially dangerous illness.

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Escherichia coli Nissle 1917 administered as a dextranomar microsphere biofilm enhances immune responses against human rotavirus in a neonatal malnourished pig model colonized with human infant fecal microbiota

PLoS ONE ◽

10.1371/journal.pone.0246193 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0246193

Author(s):

Husheem Michael ◽

Francine C. Paim ◽

Ayako Miyazaki ◽

Stephanie N. Langel ◽

David D. Fischer ◽

...

Keyword(s):

Escherichia Coli ◽

Dendritic Cells ◽

B Cells ◽

Immune Responses ◽

Killer Cell ◽

Fecal Microbiota ◽

Pig Model ◽

Human Infant ◽

Human Rotavirus ◽

Iga Antibody

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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Salmonella Vaccine Vectors Displaying Delayed Antigen Synthesis InVivo To Enhance Immunogenicity

Infection and Immunity ◽

10.1128/iai.00444-10 ◽

2010 ◽

Vol 78 (9) ◽

pp. 3969-3980 ◽

Cited By ~ 47

Author(s):

Shifeng Wang ◽

Yuhua Li ◽

Giorgio Scarpellini ◽

Wei Kong ◽

HuoYing Shi ◽

...

Keyword(s):

Immune Responses ◽

Fluorescent Protein ◽

Protective Efficacy ◽

Start Codon ◽

Antibody Titers ◽

Iga Antibody ◽

Green Fluorescent ◽

High Level

ABSTRACTWe have developed a regulated delayed antigen synthesis (RDAS) system for use in recombinant attenuatedSalmonellavaccine (RASV) strains to enhance immune responses by reducing the adverse effects of high-level antigen synthesis. This system includes a chromosomal repressor gene,lacI, expressed from the arabinose-regulatedaraCPBADpromoter. LacI serves to regulate expression from a plasmid promoter, Ptrc, that directs antigen synthesis. In the presence of arabinose LacI is produced, which binds to Ptrc, blocking antigen synthesis.In vivo, an arabinose-poor environment, the concentration of LacI decreases with each cell division, allowing increased antigen synthesis. To optimize the system and for comparison, we altered thelacIribosome-binding site, start codon, and/or codon content to construct RDAS strains χ9095, χ9959, and χ9241, synthesizing from low to high levels of LacI, respectively, and non-RDAS strain χ9555 as a control. We evaluated this system with two test antigens, the green fluorescent protein for initialin vitroassessment and theStreptococcus pneumoniaePspA protein for validation of our system in mice. All RASV strains expressing PspA generated high antilipopolysaccharide antibody titers, indicating that expression oflacIdid not interfere with the capacity to induce an immune response. Strain χ9241 induced significantly higher anti-PspA IgG and IgA antibody titers than strain χ9555, which expressed PspA constitutively. Anti-PspA antibody titers were inversely correlated to the level of LacI synthesis. Strain χ9241 also induced significantly greater protective efficacy against challenge with virulentS. pneumoniae. These results suggest that regulated delayed antigen synthesis is useful for improving immunogenicity of RASV strains.

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