Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates

Ault, Alida; Tennant, Sharon M.; Gorres, J. Patrick; Eckhaus, Michael; Sandler, Netanya G.; Roque, Annelys; Livio, Sofie; Bao, Saran; Foulds, Kathryn E.; Kao, Shing Fen; Schmidlein, Patrick; Boyd, Mary Adetinuke; Pasetti, Marcela F.; Douek, Daniel C.; Estes, Jacob D.; Nabel, Gary J.; Levine, Myron M.; Rao, Srinivas S.

doi:10.1016/j.vaccine.2013.09.041

Cited by 20 publications

(22 citation statements)

References 36 publications

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“…This novel strain was shown to be significantly attenuated, with decreased systemic spread, shedding, and clinical disease manifestations (116). Preliminary analysis of the humoral immune response to vaccination showed seroconversion for both anti-LPS and anti-FliC (flagellin) serum IgG in three (out of three) immunized rhesus macaques.…”

Section: Gastroenteritis Modelsmentioning

confidence: 97%

“…Due to the close genetic relationship with humans, nonhuman primates provide the most relevant model for determination of vaccine efficacy. Salmonella Typhimurium has been evaluated in rhesus macaques (98,115,116), while Salmonella Typhi has been tested in chimpanzees (117)(118)(119). In both models, animals are infected via the oral route and show symptoms similar to those in humans, such as diarrhea, weight loss, and fever.…”

Section: Gastroenteritis Modelsmentioning

confidence: 99%

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Animal Models for Salmonellosis: Applications in Vaccine Research

Higginson

Simon

Tennant

2016

Clin Vaccine Immunol

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Salmonellosis remains an important cause of human disease worldwide. While there are several licensed vaccines for Salmonella enterica serovar Typhi, these vaccines are generally ineffective against other Salmonella serovars. Vaccines that target paratyphoid and nontyphoidal Salmonella serovars are very much in need. Preclinical evaluation of candidate vaccines is highly dependent on the availability of appropriate scientific tools, particularly animal models. Many different animal models exist for various Salmonella serovars, from whole-animal models to smaller models, such as those recently established in insects. Here, we discuss various mouse, rat, rabbit, calf, primate, and insect models for Salmonella infection, all of which have their place in research. However, choosing the right model is imperative in selecting the best vaccine candidates for further clinical testing. In this minireview, we summarize the various animal models that are used to assess salmonellosis, highlight some of the advantages and disadvantages of each, and discuss their value in vaccine development.A nimal models are indispensable tools for assessing candidate vaccines, with preclinical animal safety, immunogenicity, and efficacy data being prerequisite for regulatory agencies such as the U.S. Food and Drug Administration (FDA) prior to undertaking early-stage clinical trials. However, not all animal models are created equal. While some models are highly robust and closely mimic clinical infection, others are contrived and far removed from clinical relevance. Choosing the right animal model for the vaccine under investigation is imperative in determining its safety and/or effectiveness.Salmonella spp. are often used as model organisms to study bacterial pathogenesis and host-microbe interactions, due to the ability of certain Salmonella serovars to readily infect animals. As such, there are a myriad of animal models available to vaccine developers. These range from colonization or lethality models to those involving complex surgical techniques (Table 1). The choice of model is often related not only to relevance but also cost, ethics, housing requirements, and the availability of appropriate technical expertise. While most researchers utilize one model or another, integration of data from multiple animal models can provide a more complete understanding of the safety of a candidate vaccine and/or predict how a potential vaccine may perform in humans. In this minireview, we provide background on Salmonella clinical syndromes and pathogenesis and then summarize the various animal models that have been used for Salmonella vaccine research. We include a brief discussion of the technical aspects, advantages, and limitations of each model, followed by a review of the literature surrounding its use in vaccine evaluation. While there has been considerable development for veterinary Salmonella vaccines, here we will focus solely on vaccines and models for human salmonellosis.

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Section: Gastroenteritis Modelsmentioning

confidence: 97%

Section: Gastroenteritis Modelsmentioning

confidence: 99%

Animal Models for Salmonellosis: Applications in Vaccine Research

Higginson

Simon

Tennant

2016

Clin Vaccine Immunol

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“…Our prototypic S. Typhimurium and S. Enteritidis vaccine strains, CVD 1921 and CVD 1941, with mutations in guaBA and clpP, were immunogenic in BALB/c mice and protected the mice against homologous oral challenge with 100 LD 50 of wild-type S. Typhimurium or S. Enteritidis, respectively (26). Importantly, the S. Typhimurium vaccine CVD 1921 was well tolerated by orally immunized, simian immunodeficiency virus (SIV)-infected rhesus macaques (29). Murine and macaque antibodies induced by these vaccine strains were functional in vitro, mediating bactericidal and opsonophagocytic activities (26,29).…”

mentioning

confidence: 98%

“…Importantly, the S. Typhimurium vaccine CVD 1921 was well tolerated by orally immunized, simian immunodeficiency virus (SIV)-infected rhesus macaques (29). Murine and macaque antibodies induced by these vaccine strains were functional in vitro, mediating bactericidal and opsonophagocytic activities (26,29). Robust enhancement of opsonophagocytic uptake was noted for other invasive serovars of homologous serogroups, but the uptake was variable and generally less robust for strains from heterologous serogroups (26).…”

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confidence: 99%

Refined Live Attenuated Salmonella enterica Serovar Typhimurium and Enteritidis Vaccines Mediate Homologous and Heterologous Serogroup Protection in Mice

et al. 2015

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Invasive nontyphoidal Salmonella (NTS) infections constitute a major health problem among infants and toddlers in sub-Saharan Africa; these infections also occur in infants and the elderly in developed countries. We genetically engineered a Salmonella enterica serovar Typhimurium strain of multilocus sequence type 313, the predominant genotype circulating in sub-Saharan Africa. We evaluated the capacities of S. Typhimurium and Salmonella enterica serovar Enteritidis ⌬guaBA ⌬clpX live oral vaccines to protect mice against a highly lethal challenge dose of the homologous serovar and determined protection against other group B and D serovars circulating in sub-Saharan Africa. The vaccines S. Typhimurium CVD 1931 and S. Enteritidis CVD 1944 were immunogenic and protected BALB/c mice against 10,000 50% lethal doses (LD 50 ) of S. Typhimurium or S. Enteritidis, respectively. S. Typhimurium CVD 1931 protected mice against the group B serovar Salmonella enterica serovar Stanleyville (91% vaccine efficacy), and S. Enteritidis CVD 1944 protected mice against the group D serovar Salmonella enterica serovar Dublin (85% vaccine efficacy). High rates of survival were observed when mice were infected 12 weeks postimmunization, indicating that the vaccines elicited long-lived protective immunity. Whereas CVD 1931 did not protect against S. Enteritidis R11, CVD 1944 did mediate protection against S. Typhimurium D65 (81% efficacy). These findings suggest that a bivalent (S. Typhimurium and S. Enteritidis) vaccine would provide broad protection against the majority of invasive NTS infections in sub-Saharan Africa. N on-typhoidal Salmonella (NTS) is a leading cause of bacterial bloodstream infections in febrile children and immunocompromised individuals in sub-Saharan Africa and has been associated with a high case fatality rate of 20 to 25% (1). Although severe malarial anemia and human immunodeficiency virus (HIV) are important risk factors for invasive NTS infection, the disease is also common in low-HIV-prevalence areas (1-4).There are Ͼ2,500 Salmonella serovars that can be differentiated on the basis of the O polysaccharide (OPS) antigens of their lipopolysaccharide (LPS) and their H flagellum antigens, using the Kauffman-White typing scheme (5). For example, Salmonella enterica serovar Typhimurium has O antigens 1, 4, 12, and occasionally 5. Epitope 12 is formed by trisaccharide repeats of mannose, rhamnose, and galactose; glucosylation of the galactose residue forms epitope 1. An abequose linked to each mannose defines it as a serovar within group B and constitutes the immunodominant O4 epitope; epitope 5 results from a phage conversion that introduces an O-acetyl moiety on the abequose. S. Typhimurium also has separate H antigens, i (phase 1) and 1 and 2 (phase 2), expressed alternatively via a process called phase variation. In contrast, Salmonella enterica serovar Enteritidis has O antigen epitope 9, which identifies it as a member of group D. Epitope 9 is formed by a tyvelose residue that is linked to the mannose of the ...

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“…As these vaccines enter clinical development, it is important to establish their immunogenicity through relevant, well-characterized immunological assays. There is a growing realization within the vaccinology community that in addition to determining antibody levels through binding assays, it is important to determine the functional, antimicrobial capacity of these antibodies.Although many studies have evaluated anti-Salmonella serum bactericidal and opsonophagocytic antibody activity (2,(8)(9)(10)(11)(12)(13)(14)(15), there is a need for reproducible assays that can be used routinely to characterize functional antibody responses to Salmonella in a standardized manner. We previously developed a complementdependent serum bactericidal antibody (SBA) activity assay that quantifies serum antibody responses to typhoidal (S. Typhi and S. Paratyphi A) and nontyphoidal (S. Typhimurium and S. Enteritidis) Salmonella (16).…”

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confidence: 99%

Opsonophagocytic Assay To Evaluate Immunogenicity of Nontyphoidal Salmonella Vaccines

Ramachandran

Boyd

MacSwords

et al. 2016

Clin Vaccine Immunol

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Nontyphoidal Salmonella (NTS) invasive infections are an important cause of morbidity and mortality in sub-Saharan Africa. Several vaccines are in development to prevent these infections. We describe an NTS opsonophagocytic killing assay that uses HL-60 cells and baby rabbit complement to quantify functional antibodies elicited by candidate NTS vaccines. Invasive nontyphoidal Salmonella (NTS) infections are increasingly being recognized as an important cause of morbidity and mortality in infants and HIV-infected adults and children in subSaharan Africa (1). Multiple vaccines are currently in development, including live-attenuated vaccines, conjugate vaccines, and generalized modules for membrane antigens against invasive S. Typhimurium and S. Enteritidis (2-7). As these vaccines enter clinical development, it is important to establish their immunogenicity through relevant, well-characterized immunological assays. There is a growing realization within the vaccinology community that in addition to determining antibody levels through binding assays, it is important to determine the functional, antimicrobial capacity of these antibodies.Although many studies have evaluated anti-Salmonella serum bactericidal and opsonophagocytic antibody activity (2,(8)(9)(10)(11)(12)(13)(14)(15), there is a need for reproducible assays that can be used routinely to characterize functional antibody responses to Salmonella in a standardized manner. We previously developed a complementdependent serum bactericidal antibody (SBA) activity assay that quantifies serum antibody responses to typhoidal (S. Typhi and S. Paratyphi A) and nontyphoidal (S. Typhimurium and S. Enteritidis) Salmonella (16). Here, we describe an assay that measures the opsonophagocytic capacity of NTS antibodies based on the wellcharacterized pneumococcus opsonophagocytic activity (OPA), which employs HL-60 phagocytic cells and a standardized source of complement, i.e., baby rabbit complement (BRC) (17,18).The Salmonella OPA assay was evaluated using serum samples from mice that had been vaccinated with live-attenuated NTS vaccines (7). BALB/c mice were orally immunized with 10 9 CFU of S. Typhimurium CVD 1931 or S. Enteritidis CVD 1944 suspended in phosphate-buffered saline (PBS) or given PBS alone on days 0, 28, and 56, as previously described (7) [19]) from overnight cultures were diluted 1 in 1,000 in Hy-Soy medium (0.5% sodium chloride, 1% Hy-Soy [Kerry, Clackmannshire, United Kingdom], and 0.5% Hy-Yest [Kerry]), grown at 37°C to an optical density at 600 nm (OD 600 ) of 0.3, and then diluted to 3 ϫ 10 4 CFU/ml in OPB. Immune and nonimmune sera were heat-inactivated at 56°C for 20 min, and 2-fold serial dilutions in OPB (25 l/well final volume) were performed in a Ubottomed 96-well microplate (Sigma-Aldrich, St. Louis, MO). The bottom row was left without sera to act as a negative control. To each well, 3 ϫ 10 2 CFU of bacterial suspension in 10 l OPB was added. Opsonization of bacteria was allowed to occur for 15 min at 37°C with 5% CO 2 . After incubation, 25 ...

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Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates

Cited by 20 publications

References 36 publications

Animal Models for Salmonellosis: Applications in Vaccine Research

Animal Models for Salmonellosis: Applications in Vaccine Research

Refined Live Attenuated Salmonella enterica Serovar Typhimurium and Enteritidis Vaccines Mediate Homologous and Heterologous Serogroup Protection in Mice

Opsonophagocytic Assay To Evaluate Immunogenicity of Nontyphoidal Salmonella Vaccines

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