scholarly journals Intranasal Vaccination Induces Protective Immunity against Intranasal Infection with Virulent Francisella tularensis Biovar A

2005 ◽  
Vol 73 (5) ◽  
pp. 2644-2654 ◽  
Author(s):  
Terry H. Wu ◽  
Julie A. Hutt ◽  
Kristin A. Garrison ◽  
Lyudmila S. Berliba ◽  
Yan Zhou ◽  
...  
Keyword(s):  
Francisella Tularensis ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Inbred Mice ◽  
High Morbidity ◽  
Live Vaccine Strain ◽  
Protective Response ◽  
Protective Mechanisms ◽  
Intranasal Infection ◽  
Lack Of Information

ABSTRACT The inhalation of Francisella tularensis biovar A causes pneumonic tularemia associated with high morbidity and mortality rates in humans. Exposure to F. tularensis usually occurs by accident, but there is increasing awareness that F. tularensis may be deliberately released in an act of bioterrorism or war. The development of a vaccine against pneumonic tularemia has been limited by a lack of information regarding the mechanisms required to protect against this disease. Vaccine models for F. tularensis in inbred mice would facilitate investigations of the protective mechanisms and significantly enhance vaccine development. Intranasal vaccination with the attenuated live vaccine strain (LVS) of F. tularensis reproducibly protected BALB/c mice, but not C57BL/6 mice, against intranasal and subcutaneous challenges with a virulent clinical isolate of F. tularensis biovar A (NMFTA1). The resistance of LVS-vaccinated BALB/c mice to intranasal NMFTA1 challenge was increased 100-fold by boosting with live NMFTA1 but not with LVS. The protective response was specific for F. tularensis and required both CD4 and CD8 T cells. The vaccinated mice appeared outwardly healthy for more than 2 months after NMFTA1 challenge, even though NMFTA1 was recovered from more than half of the vaccinated mice. These results show that intranasal vaccination induces immunity that protects BALB/c mice from intranasal infection by F. tularensis biovar A.

scholarly journals Intranasal Interleukin-12 Treatment for Protection against Respiratory Infection with the Francisella tularensis Live Vaccine Strain

2005 ◽  
Vol 73 (4) ◽  
pp. 2306-2311 ◽  
Author(s):  
Nathalie S. Duckett ◽  
Sofia Olmos ◽  
Douglas M. Durrant ◽  
Dennis W. Metzger
Keyword(s):  
Respiratory Infection ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Live Vaccine ◽  
Interleukin 12 ◽  
Live Vaccine Strain ◽  
Wild Type ◽  
Intranasal Infection ◽  
Ifn Γ

ABSTRACT Francisella tularensis is a gram-negative intracellular bacterium that can induce lethal respiratory infection in humans and rodents. However, little is known about the role of innate or adaptive immunity in protection from respiratory tularemia. In the present study, the role of interleukin-12 (IL-12) in inducing protective immunity in the lungs against intranasal infection of mice with the live vaccine strain (LVS) of F. tularensis was investigated. It was found that gamma interferon (IFN-γ) and IL-12 were strictly required for protection, since mice deficient in IFN-γ, IL-12 p35, or IL-12 p40 all succumbed to LVS doses that were sublethal for wild-type mice. Furthermore, exogenous IL-12 treatment 24 h before intranasal infection with a lethal dose of LVS (10,000 CFU) significantly decreased bacterial loads in the lungs, livers, and spleens of wild-type BALB/c and C57BL/6 mice and allowed the animals to survive infection; such protection was not observed in IFN-γ-deficient mice. The resistance induced by IL-12 to LVS infection was still observed in NK cell-deficient beige mice but not in CD8−/− mice. These results demonstrate that exogenous IL-12 delivered intranasally can prevent respiratory tularemia through a mechanism that is at least partially dependent upon the expression of IFN-γ and CD8 T cells.

Lipopolysaccharide: a tool and target in enterobacterial vaccine development

2008 ◽  
Vol 389 (5) ◽  
Author(s):  
Gábor Nagy ◽  
Tibor Pál
Keyword(s):  
Immune Response ◽  
Protective Immunity ◽  
Vaccine Development ◽  
The Other ◽  
Live Vaccine Strain ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Vaccination Strategies ◽  
Optimal Balance ◽  
Alternative Approaches

AbstractLipopolysaccharide (LPS) is an essential component of Gram-negative bacteria. While mutants exhibiting truncated LPS molecules are usually over-attenuated, alternative approaches that affect the extent or timing of LPS expression, as well as its modification may establish the optimal balance for a live vaccine strain of sufficient attenuation and retained immunogenicity. On the other hand, a specific immune response to LPS molecules in itself is capable of conferring protective immunity to certain enterobacterial pathogens. Therefore, purified LPS derivatives could be used as parenteral vaccines. This review summarizes various LPS-based vaccination strategies, as well as approaches that utilize LPS mutants as whole-cell vaccines.

scholarly journals A Francisella tularensis Live Vaccine Strain (LVS) Mutant with a Deletion in capB, Encoding a Putative Capsular Biosynthesis Protein, Is Significantly More Attenuated than LVS yet Induces Potent Protective Immunity in Mice against F. tularensis Challenge

2010 ◽  
Vol 78 (10) ◽  
pp. 4341-4355 ◽  
Author(s):  
Qingmei Jia ◽  
Bai-Yu Lee ◽  
Richard Bowen ◽  
Barbara Jane Dillon ◽  
Susan M. Som ◽  
...  
Keyword(s):  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Protective Immunity ◽  
Lethal Dose ◽  
Live Vaccine ◽  
Human Macrophage ◽  
Live Vaccine Strain ◽  
Virulent Type ◽  
Marker Free ◽  
Cellular Immune

ABSTRACT Francisella tularensis, the causative agent of tularemia, is in the top category (category A) of potential agents of bioterrorism. The F. tularensis live vaccine strain (LVS) is the only vaccine currently available to protect against tularemia; however, this unlicensed vaccine is relatively toxic and provides incomplete protection against aerosolized F. tularensis, the most dangerous mode of transmission. Hence, a safer and more potent vaccine is needed. As a first step toward addressing this need, we have constructed and characterized an attenuated version of LVS, LVS ΔcapB, both as a safer vaccine and as a vector for the expression of recombinant F. tularensis proteins. LVS ΔcapB, with a targeted deletion in a putative capsule synthesis gene (capB), is antibiotic resistance marker free. LVS ΔcapB retains the immunoprotective O antigen, is serum resistant, and is outgrown by parental LVS in human macrophage-like THP-1 cells in a competition assay. LVS ΔcapB is significantly attenuated in mice; the 50% lethal dose (LD50) intranasally (i.n.) is >10,000-fold that of LVS. Providing CapB in trans to LVS ΔcapB partially restores its virulence in mice. Mice immunized with LVS ΔcapB i.n. or intradermally (i.d.) developed humoral and cellular immune responses comparable to those of mice immunized with LVS, and when challenged 4 or 8 weeks later with a lethal dose of LVS i.n., they were 100% protected from illness and death and had significantly lower levels (3 to 5 logs) of LVS in the lung, liver, and spleen than sham-immunized mice. Most importantly, mice immunized with LVS ΔcapB i.n. or i.d. and then challenged 6 weeks later by aerosol with 10× the LD50 of the highly virulent type A F. tularensis strain SchuS4 were significantly protected (100% survival after i.n. immunization). These results show that LVS ΔcapB is significantly safer than LVS and yet provides potent protective immunity against virulent F. tularensis SchuS4 challenge.

scholarly journals Purified Lipopolysaccharide from Francisella tularensis Live Vaccine Strain (LVS) Induces Protective Immunity against LVS Infection That Requires B Cells and Gamma Interferon

2000 ◽  
Vol 68 (4) ◽  
pp. 1988-1996 ◽  
Author(s):  
Valley C. Dreisbach ◽  
Siobhan Cowley ◽  
Karen L. Elkins
Keyword(s):  
B Cells ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Protective Immunity ◽  
Gamma Interferon ◽  
Live Vaccine ◽  
Immunoglobulin M ◽  
Live Vaccine Strain ◽  
Murine Splenocytes ◽  
Ifn Γ

ABSTRACT Previous results have demonstrated that nonspecific protective immunity against lethal Francisella tularensis live vaccine strain (LVS) or Listeria monocytogenes infection can be stimulated either by sublethal infection with bacteria or by treatment with bacterial DNA given 3 days before lethal challenge. Here we characterize the ability of purified lipopolysaccharide (LPS) fromF. tularensis LVS to stimulate similar early protective immunity. Treatment of mice with surprisingly small amounts of LVS LPS resulted in very strong and long-lived protection against lethal LVS challenge within 2 to 3 days. Despite this strong protective response, LPS purified from F. tularensis LVS did not activate murine B cells for proliferation or polyclonal immunoglobulin secretion, nor did it activate murine splenocytes for secretion of interleukin-4 (IL-4), IL-6, IL-12, or gamma interferon (IFN-γ). Immunization of mice with purified LVS LPS induced a weak specific anti-LPS immunoglobulin M (IgM) response and very little IgG; however, infection of mice with LVS bacteria resulted in vigorous IgM and IgG, particularly IgG2a, anti-LPS antibody responses. Studies using various immunodeficient mouse strains, including LPS-hyporesponsive C3H/HeJ mice, μMT− (B-cell-deficient) knockout mice, and IFN-γ-deficient mice, demonstrated that the mechanism of protection does not involve recognition through the Lpsn gene product; nonetheless, protection was dependent on B cells as well as IFN-γ.

scholarly journals Protective characteristics of COVID-19 convalescent and post-vaccination IgG antibodies

2021 ◽  
Author(s):  
Melvin E Klegerman ◽  
Tao Peng ◽  
Ira Seferovich ◽  
Mohammad H. Rahbar ◽  
Manouchehr Hessabi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Critical Element ◽  
Receptor Binding Domain ◽  
Igg Antibodies ◽  
Igg Antibody ◽  
Post Vaccination ◽  
Lack Of Information

Soon after commencement of the SARS-CoV-2 disease outbreak of 2019 (COVID-19), it became evident that the receptor-binding domain of the viral spike protein is the target of neutralizing antibodies that comprise a critical element of protective immunity to the virus. This study addresses the relative lack of information regarding actual antibody concentrations in convalescent plasma samples from COVID-19 patients and extends these analyses to post-vaccination samples to estimate protective IgG antibody (Ab) levels. Both sample populations were similar and a protective Ab level of 7.5 μg/ml was determined, based on 95% of the normal distribution of the post-vaccination population. The results of this study have implications for future vaccine development, projection of protective efficacy duration, and understanding of the immune response to SARS-CoV-2 infection.

scholarly journals Oral Live Vaccine Strain-Induced Protective Immunity against Pulmonary Francisella tularensis Challenge Is Mediated by CD4+ T Cells and Antibodies, Including Immunoglobulin A

2009 ◽  
Vol 16 (4) ◽  
pp. 444-452 ◽  
Author(s):  
Heather J. Ray ◽  
Yu Cong ◽  
Ashlesh K. Murthy ◽  
Dale M. Selby ◽  
Karl E. Klose ◽  
...  
Keyword(s):  
T Cells ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Protective Immunity ◽  
Immunoglobulin A ◽  
Live Vaccine ◽  
Live Vaccine Strain ◽  
Oral Vaccination ◽  
Enhanced Production ◽  
Schu S4

ABSTRACT Francisella tularensis is an intracellular gram-negative bacterium and the etiological agent of pulmonary tularemia. Given the high degrees of infectivity in the host and of dissemination of bacteria following respiratory infection, immunization strategies that target mucosal surfaces are critical for the development of effective vaccines against this organism. In this study, we have characterized the efficacy of protective immunity against pneumonic tularemia following oral vaccination with F. tularensis LVS (live vaccine strain). Mice vaccinated orally with LVS displayed colocalization of LVS with intestinal M cells, with subsequent enhanced production of splenic antigen-specific gamma interferon and of systemic and mucosal antibodies, including immunoglobulin A (IgA). LVS-vaccinated BALB/c mice were highly protected against intranasal (i.n.) SCHU S4 challenge and exhibited significantly less bacterial replication in the lungs, liver, and spleen than mock-immunized animals. Depletion of CD4+ T cells significantly abrogated the protective immunity, and mice deficient in B cells or IgA displayed partial protection against SCHU S4 challenge. These results suggest that oral vaccination with LVS induces protective immunity against i.n. challenge with F. tularensis SCHU S4 by a process mediated cooperatively by CD4+ T cells and antibodies, including IgA.

scholarly journals Additional evidence on the efficacy of different Akirin vaccines assessed on Anopheles arabiensis (Diptera: Culicidae)

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Blaženka D. Letinić ◽  
Marinela Contreras ◽  
Yael Dahan-Moss ◽  
Ingrid Linnekugel ◽  
José de la Fuente ◽  
...  
Keyword(s):  
Vector Control ◽  
Aedes Albopictus ◽  
Malaria Vector ◽  
Vaccine Efficacy ◽  
Anopheles Arabiensis ◽  
Vaccine Development ◽  
Target Antigen ◽  
Control Methods ◽  
Protective Response ◽  
Current Vector

Abstract Background Anopheles arabiensis is an opportunistic malaria vector that rests and feeds outdoors, circumventing current indoor vector control methods. Furthermore, this vector will readily feed on both animals and humans. Targeting this vector while feeding on animals can provide an additional intervention for the current vector control activities. Previous results have displayed the efficacy of using Subolesin/Akirin ortholog vaccines for the control of multiple ectoparasite infestations. This made Akirin a potential antigen for vaccine development against An. arabiensis. Methods The efficacy of three antigens, namely recombinant Akirin from An. arabiensis, recombinant Akirin from Aedes albopictus, and recombinant Q38 (Akirin/Subolesin chimera) were evaluated as novel interventions for An. arabiensis vector control. Immunisation trials were conducted based on the concept that mosquitoes feeding on vaccinated balb/c mice would ingest antibodies specific to the target antigen. The antibodies would interact with the target antigen in the arthropod vector, subsequently disrupting its function. Results All three antigens successfully reduced An. arabiensis survival and reproductive capacities, with a vaccine efficacy of 68–73%. Conclusions These results were the first to show that hosts vaccinated with recombinant Akirin vaccines could develop a protective response against this outdoor malaria transmission vector, thus providing a step towards the development of a novel intervention for An. arabiensis vector control. Graphic Abstract

scholarly journals TolC-Dependent Modulation of Host Cell Death by the Francisella tularensis Live Vaccine Strain

2014 ◽  
Vol 82 (5) ◽  
pp. 2068-2078 ◽  
Author(s):  
Christopher R. Doyle ◽  
Ji-An Pan ◽  
Patricio Mena ◽  
Wei-Xing Zong ◽  
David G. Thanassi
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Host Cell ◽  
Francisella Tularensis ◽  
Vaccine Strain ◽  
Live Vaccine ◽  
Live Vaccine Strain ◽  
Type I ◽  
Content Type ◽  
Host Cell Death

ABSTRACTFrancisella tularensisis a facultative intracellular, Gram-negative pathogen and the causative agent of tularemia. We previously identified TolC as a virulence factor of theF. tularensislive vaccine strain (LVS) and demonstrated that a ΔtolCmutant exhibits increased cytotoxicity toward host cells and elicits increased proinflammatory responses compared to those of the wild-type (WT) strain. TolC is the outer membrane channel component used by the type I secretion pathway to export toxins and other bacterial virulence factors. Here, we show that the LVS delays activation of the intrinsic apoptotic pathway in a TolC-dependent manner, both during infection of primary macrophages and during organ colonization in mice. The TolC-dependent delay in host cell death is required forF. tularensisto preserve its intracellular replicative niche. We demonstrate that TolC-mediated inhibition of apoptosis is an active process and not due to defects in the structural integrity of the ΔtolCmutant. These findings support a model wherein the immunomodulatory capacity ofF. tularensisrelies, at least in part, on TolC-secreted effectors. Finally, mice vaccinated with the ΔtolCLVS are protected from lethal challenge and clear challenge doses faster than WT-vaccinated mice, demonstrating that the altered host responses to primary infection with the ΔtolCmutant led to altered adaptive immune responses. Taken together, our data demonstrate that TolC is required for temporal modulation of host cell death during infection byF. tularensisand highlight how shifts in the magnitude and timing of host innate immune responses may lead to dramatic changes in the outcome of infection.

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