scholarly journals Extended Safety and Efficacy Studies of the Attenuated Brucella Vaccine Candidates 16MΔvjbRand S19ΔvjbRin the Immunocompromised IRF-1−/−Mouse Model

2011 ◽  
Vol 19 (2) ◽  
pp. 249-260 ◽  
Author(s):  
A. M. Arenas-Gamboa ◽  
A. C. Rice-Ficht ◽  
Y. Fan ◽  
M. M. Kahl-McDonagh ◽  
T. A. Ficht
Keyword(s):  
Mouse Model ◽  
Brucella Melitensis ◽  
Protective Efficacy ◽  
Pathological Changes ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Content Type ◽  
Vaccine Candidates ◽  
Multiple Organs ◽  
Efficacious Vaccine

ABSTRACTThe global distribution of brucellosis and high incidence in certain areas of the world warrant the development of a safer and efficacious vaccine. For the past 10 years, we have focused our attention on the development of a safer, but still highly protective, live attenuated vaccine for human and animal use. We have demonstrated the safety and protective efficacy of the vaccine candidates 16MΔvjbRand S19ΔvjbRagainst homologous and heterologous challenge in multiple immunocompetent animal models, including mice and deer. In the present study, we conducted a series of experiments to determine the safety of the vaccine candidates in interferon regulatory factor-1-knockout (IRF-1−/−) mice. IRF-1−/−mice infected with either wild-typeBrucella melitensis16M or the vaccine strainBrucella abortusS19 succumb to the disease within the first 3 weeks of infection, which is characterized by a marked granulomatous and neutrophilic inflammatory response that principally targets the spleen and liver. In contrast, IRF-1−/−mice inoculated with either the 16MΔvjbRor S19ΔvjbRvaccine do not show any clinical or major pathological changes associated with vaccination. Additionally, when 16MΔvjbR- or S19ΔvjbR-vaccinated mice are challenged with wild-typeBrucella melitensis16M, the degree of colonization in multiple organs, along with associated pathological changes, is significantly reduced. These findings not only demonstrate the safety and protective efficacy of thevjbRmutant in an immunocompromised mouse model but also suggest the participation of lesser-known mechanisms in protective immunity against brucellosis.

scholarly journals Abrogation of Neuraminidase Reduces Biofilm Formation, Capsule Biosynthesis, and Virulence of Porphyromonas gingivalis

2011 ◽  
Vol 80 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Chen Li ◽  
Kurniyati ◽  
Bo Hu ◽  
Jiang Bian ◽  
Jianlan Sun ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Biofilm Formation ◽  
Adult Population ◽  
Transcriptional Analysis ◽  
Wild Type ◽  
Content Type ◽  
Multiple Organs ◽  
Biochemical Analyses

ABSTRACTThe oral bacteriumPorphyromonas gingivalisis a key etiological agent of human periodontitis, a prevalent chronic disease that affects up to 80% of the adult population worldwide.P. gingivalisexhibits neuraminidase activity. However, the enzyme responsible for this activity, its biochemical features, and its role in the physiology and virulence ofP. gingivalisremain elusive. In this report, we found thatP. gingivalisencodes a neuraminidase, PG0352 (SiaPg). Transcriptional analysis showed thatPG0352is monocistronic and is regulated by a sigma70-like promoter. Biochemical analyses demonstrated that SiaPgis an exo-α-neuraminidase that cleaves glycosidic-linked sialic acids. Cryoelectron microscopy and tomography analyses revealed that thePG0352deletion mutant (ΔPG352) failed to produce an intact capsule layer. Compared to the wild type,in vitrostudies showed that ΔPG352 formed less biofilm and was less resistant to killing by the host complement.In vivostudies showed that while the wild type caused a spreading type of infection that affected multiple organs and all infected mice were killed, ΔPG352 only caused localized infection and all animals survived. Taken together, these results demonstrate that SiaPgis an important virulence factor that contributes to the biofilm formation, capsule biosynthesis, and pathogenicity ofP. gingivalis, and it can potentially serve as a new target for developing therapeutic agents againstP. gingivalisinfection.

Two regulatory factors of Vibrio cholerae activating the mannose-sensitive haemagglutinin pilus expression is important for biofilm formation and colonization in mice

Microbiology ◽  
2021 ◽  
Vol 167 (10) ◽  
Author(s):  
Mengting Shi ◽  
Yue Zheng ◽  
Xianghong Wang ◽  
Zhengjia Wang ◽  
Menghua Yang
Keyword(s):  
Mouse Model ◽  
Vibrio Cholerae ◽  
Biofilm Formation ◽  
Type Species ◽  
Wild Type ◽  
Expression Library ◽  
Content Type ◽  
Genomic Expression ◽  
Infant Mouse ◽  
Link Type

Vibrio cholerae the causative agent of cholera, uses a large number of coordinated transcriptional regulatory events to transition from its environmental reservoir to the host intestine, which is its preferred colonization site. Transcription of the mannose-sensitive haemagglutinin pilus (MSHA), which aids the persistence of V. cholerae in aquatic environments, but causes its clearance by host immune defenses, was found to be regulated by a yet unknown mechanism during the infection cycle of V. cholerae . In this study, genomic expression library screening revealed that two regulators, VC1371 and VcRfaH, are able to positively activate the transcription of MSHA operon. VC1371 is localized and active in the cell membrane. Deletion of vc1371 or VcrfaH genes in V. cholerae resulted in less MshA protein production and less efficiency of biofilm formation compared to that in the wild-type strain. An adult mouse model showed that the mutants with vc1371 or VcrfaH deletion colonized less efficiently than the wild-type; the VcrfaH deletion mutant showed less colonization efficiency in the infant mouse model. The findings strongly suggested that the two regulators, namely VC1371 and VcRfaH, which are involved in the regulation of MSHA expression, play an important role in V. cholerae biofilm formation and colonization in mice.

scholarly journals A Host-Restricted Self-Attenuated Influenza Virus Provides Broad Pan-Influenza A Protection in a Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Minjin Kim ◽  
Yucheol Cheong ◽  
Jinhee Lee ◽  
Jongkwan Lim ◽  
Sanguine Byun ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Viruses ◽  
Cross Protection ◽  
Infection Model ◽  
Wild Type ◽  
Group 1

Influenza virus infections can cause a broad range of symptoms, form mild respiratory problems to severe and fatal complications. While influenza virus poses a global health threat, the frequent antigenic change often significantly compromises the protective efficacy of seasonal vaccines, further increasing the vulnerability to viral infection. Therefore, it is in great need to employ strategies for the development of universal influenza vaccines (UIVs) which can elicit broad protection against diverse influenza viruses. Using a mouse infection model, we examined the breadth of protection of the caspase-triggered live attenuated influenza vaccine (ctLAIV), which was self-attenuated by the host caspase-dependent cleavage of internal viral proteins. A single vaccination in mice induced a broad reactive antibody response against four different influenza viruses, H1 and rH5 (HA group 1) and H3 and rH7 subtypes (HA group 2). Notably, despite the lack of detectable neutralizing antibodies, the vaccination provided heterosubtypic protection against the lethal challenge with the viruses. Sterile protection was confirmed by the complete absence of viral titers in the lungs and nasal turbinates after the challenge. Antibody-dependent cellular cytotoxicity (ADCC) activities of non-neutralizing antibodies contributed to cross-protection. The cross-protection remained robust even after in vivo depletion of T cells or NK cells, reflecting the strength and breadth of the antibody-dependent effector function. The robust mucosal secretion of sIgA reflects an additional level of cross-protection. Our data show that the host-restricted designer vaccine serves an option for developing a UIV, providing pan-influenza A protection against both group 1 and 2 influenza viruses. The present results of potency and breadth of protection from wild type and reassortant viruses addressed in the mouse model by single immunization merits further confirmation and validation, preferably in clinically relevant ferret models with wild type challenges.

scholarly journals Complete Genome Sequence of the Live Attenuated Vaccine StrainBrucella melitensisRev.1

2018 ◽  
Vol 6 (12) ◽  
pp. e00175-18 ◽  
Author(s):  
Mali Salmon-Divon ◽  
Menachem Banai ◽  
Svetlana Bardenstein ◽  
Shlomo E. Blum ◽  
David Kornspan
Keyword(s):  
Genome Sequence ◽  
Brucella Melitensis ◽  
Small Ruminants ◽  
Essential Elements ◽  
Whole Genome Sequence ◽  
Original Strain ◽  
Live Attenuated Vaccine ◽  
Content Type ◽  
Live Attenuated Vaccines ◽  
Control Programs

ABSTRACTLive attenuated vaccines are essential elements in control programs for the prevention of brucellosis. Here, we report the whole-genome sequence of the original ElbergBrucella melitensisRev.1 vaccine strain, passage 101 (1970). Commercial lines of the original strain have been successfully used in small ruminants worldwide.

scholarly journals Protective efficacy of rhesus adenovirus COVID-19 vaccines against mouse-adapted SARS-CoV-2

2021 ◽  
Author(s):  
Lisa H. Tostanoski ◽  
Lisa E. Gralinski ◽  
David R. Martinez ◽  
Alexandra Schaefer ◽  
Shant H. Mahrokhian ◽  
...  
Keyword(s):  
Viral Replication ◽  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
Wild Type ◽  
Adenovirus Serotype ◽  
Vaccine Candidates ◽  
Correlates Of Protection ◽  
Immune Correlates ◽  
Antibody Titers ◽  
Adenovirus Vectors

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. Importance We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibits a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative Ad vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to i) evaluate the protective efficacy of RhAd52 vaccines and ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.

scholarly journals The Burkholderia pseudomallei ΔasdMutant Exhibits Attenuated Intracellular Infectivity and Imparts Protection against Acute Inhalation Melioidosis in Mice

2011 ◽  
Vol 79 (10) ◽  
pp. 4010-4018 ◽  
Author(s):  
Michael H. Norris ◽  
Katie L. Propst ◽  
Yun Kang ◽  
Steven W. Dow ◽  
Herbert P. Schweizer ◽  
...  
Keyword(s):  
Burkholderia Pseudomallei ◽  
Cell Model ◽  
Single Copy ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Content Type ◽  
Life Threatening ◽  
A Cell ◽  
Bioterrorism Agent

ABSTRACTBurkholderia pseudomallei, the cause of serious and life-threatening diseases in humans, is of national biodefense concern because of its potential use as a bioterrorism agent. This microbe is listed as a select agent by the CDC; therefore, development of vaccines is of significant importance. Here, we further investigated the growth characteristics of a recently createdB. pseudomallei1026b Δasdmutantin vitro, in a cell model, and in an animal model of infection. The mutant was typified by an inability to grow in the absence of exogenous diaminopimelate (DAP); upon single-copy complementation with a wild-type copy of theasdgene, growth was restored to wild-type levels. Further characterization of theB. pseudomalleiΔasdmutant revealed a marked decrease in RAW264.7 murine macrophage cytotoxicity compared to the wild type and the complemented Δasdmutant. RAW264.7 cells infected by the Δasdmutant did not exhibit signs of cytopathology or multinucleated giant cell (MNGC) formation, which were observed in wild-typeB. pseudomalleicell infections. The Δasdmutant was found to be avirulent in BALB/c mice, and mice vaccinated with the mutant were protected against acute inhalation melioidosis. Thus, theB. pseudomalleiΔasdmutant may be a promising live attenuated vaccine strain and a biosafe strain for consideration of exclusion from the select agent list.

scholarly journals Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus

2016 ◽  
Vol 85 (2) ◽  
Author(s):  
Liana C. Chan ◽  
Siyang Chaili ◽  
Scott G. Filler ◽  
Lloyd S. Miller ◽  
Norma V. Solis ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Host Defense ◽  
Protective Efficacy ◽  
Innate Immune ◽  
Immune Memory ◽  
Wild Type ◽  
Methicillin Resistant ◽  
Content Type ◽  
Skin Structure ◽  
Mrsa Infection

ABSTRACT Staphylococcus aureus is the leading cause of skin and skin structure infections (SSSI). The high frequency of recurring SSSI due to S. aureus, including methicillin-resistant S. aureus (MRSA) strains, despite high titers of specific antibodies and circulating T cells, implies that traditional adaptive immunity imparts incomplete protection. We hypothesized that innate immune memory contributes to the protective host defense against recurring MRSA infection. To test this hypothesis, SSSI was induced in wild-type and rag1 −/− mice in the BALB/c and C57BL/6 backgrounds. Prior infection (priming) of wild-type and rag1 −/− mice of either background afforded protection against repeat infection, as evidenced by reduced abscess severities and decreased CFU densities compared to those in naive controls. Interestingly, protection was greater on the previously infected flank than on the naive flank for wild-type and rag1 −/− mice. For wild-type mice, protective efficacy corresponded to increased infiltration of neutrophils (polymorphonuclear leukocytes [PMN]), macrophages (MΦ), Langerin+ dendritic cells (LDC), and natural killer (NK) cells. Protection was associated with the induction of interleukin-17A (IL-17A), IL-22, and gamma interferon (IFN-γ) as well as the antimicrobial peptides CRAMP and mβD-3. Priming also protected rag1 −/− mice against recurring SSSI, with increased MΦ and LDC infiltration and induction of IL-22, CRAMP, and mβD-3. These findings suggest that innate immune memory, mediated by specific cellular and molecular programs, likely contributes to the localized host defense in recurrent MRSA SSSI. These insights support the development of targeted immunotherapeutic strategies to address the challenge of MRSA infection.

scholarly journals African Green Monkeys Recapitulate the Clinical Experience with Replication of Live Attenuated Pandemic Influenza Virus Vaccine Candidates

2014 ◽  
Vol 88 (14) ◽  
pp. 8139-8152 ◽  
Author(s):  
Yumiko Matsuoka ◽  
Amorsolo Suguitan ◽  
Marlene Orandle ◽  
Myeisha Paskel ◽  
Kobporn Boonnak ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Animal Models ◽  
Avian Influenza ◽  
Immune Responses ◽  
Respiratory Tract ◽  
Nonhuman Primate ◽  
Protective Efficacy ◽  
Wild Type ◽  
Vaccine Candidates ◽  
Green Monkeys

ABSTRACTLive attenuated cold-adapted (ca) H5N1, H7N3, H6N1, and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets, and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild-type (wt) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in phase I clinical trials, there were inconsistencies between the observations in animal models and in humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative with respect to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a nonhuman primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to that in humans. We evaluated the replication ofwtandcaviruses of avian influenza (AI) virus subtypes H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of thewtviruses replicated efficiently, while replication of thecavaccine viruses was restricted to the upper respiratory tract. Interestingly, the patterns and sites of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3, and H9N2cavaccines. Protection fromwtvirus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than when it was delivered intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects and that AGMs may be a useful model to evaluate the replication ofcavaccine candidates.IMPORTANCEFerrets and mice are commonly used for preclinical evaluation of influenza vaccines. However, we observed significant inconsistencies between observations in humans and in these animal models. We used African green monkeys (AGMs) as a nonhuman primate (NHP) model for a comprehensive and comparative evaluation of pairs of wild-type and pandemic live attenuated influenza virus vaccines (pLAIV) representing four subtypes of avian influenza viruses and found that pLAIVs replicate similarly in AGMs and humans and that AGMs can be useful for evaluation of the protective efficacy of pLAIV.

scholarly journals Protective Efficacy and Safety of Brucella melitensis 16MΔmucRagainst Intraperitoneal and Aerosol Challenge in BALB/c Mice

2011 ◽  
Vol 79 (9) ◽  
pp. 3653-3658 ◽  
Author(s):  
A. M. Arenas-Gamboa ◽  
A. C. Rice-Ficht ◽  
M. M. Kahl-McDonagh ◽  
T. A. Ficht
Keyword(s):  
Vaccine Candidate ◽  
Brucella Melitensis ◽  
Protective Efficacy ◽  
Significant Degree ◽  
Content Type ◽  
Degree Of Protection ◽  
Worldwide Distribution ◽  
Human Use ◽  
Identification And Characterization

ABSTRACTBrucellosis is a zoonosis of nearly worldwide distribution. Vaccination against this pathogen is an important control strategy to prevent the disease. Currently licensed vaccine strains used in animals are unacceptable for human use due to undesirable side effects and modest protection. Substantial progress has been made during the past 10 years toward the development of improved vaccines for brucellosis. In part, this has been achieved by the identification and characterization of live attenuated mutants that are safer in the host but still can stimulate an adequate immune response. In the present study, the identification and characterization of themucRmutant (BMEI 1364) as a vaccine candidate for brucellosis was conducted. BALB/c mice were vaccinated intraperitoneally at a dose of 105CFU with the mutant to evaluate safety and protective efficacy against intraperitoneal and aerosol challenge. All animals vaccinated with the vaccine candidate demonstrated a statistically significant degree of protection against both intraperitoneal and aerosol challenge. Safety was revealed by the absence ofBrucellaassociated pathological changes, including splenomegaly, hepatomegaly, or granulomatous disease. These results suggest that the 16MΔmucRvaccine is safe, elicits a strong protective immunity, and should be considered as a promising vaccine candidate for human use.

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