Brucellosis: The case for live, attenuated vaccines

Ficht, Thomas A.; Kahl-McDonagh, Melissa; Arenas-Gamboa, Ángela M.; Rice‐Ficht, Allison C.

doi:10.1016/j.vaccine.2009.08.058

Cited by 78 publications

(75 citation statements)

References 71 publications

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“…Historically, the most efficacious vaccines against brucellosis have been live attenuated vaccines, as is the case for multiple currently licensed vaccine strains for animal use, including S19, Rev1, and RB51 (15,37). Unfortunately, both S19 and Rev1 vaccines, which have been highly efficacious in controlling the disease in cattle and goats, respectively, have proven to be unsafe or have the capacity to cause adverse reactions in humans due to local and systemic reactions that in some cases resulted in the development of the disease (3,38).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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Brucellosis 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 the mucR mutant (BMEI 1364) as a vaccine candidate for brucellosis was conducted. BALB/c mice were vaccinated intraperitoneally at a dose of 10 5 CFU 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 of Brucella associated pathological changes, including splenomegaly, hepatomegaly, or granulomatous disease. These results suggest that the 16M⌬mucR vaccine is safe, elicits a strong protective immunity, and should be considered as a promising vaccine candidate for human use.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2011

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“…Because complete eradication of Brucella is unpractical because of its presence in a wide range of wild mammals (7,8), antibiotic treatment is costly, and patients frequently suffer from resurgence of the bacteria (9), vaccination remains the most rational strategy to confer durable protection on populations living in endemic countries and professionals who are frequently exposed to Brucella. Unfortunately, there is no available human brucellosis vaccine; all commercially available animal vaccines are live vaccines that would cause disease in humans (10,11).…”

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confidence: 99%

Identification of Immune Effectors Essential to the Control of Primary and Secondary Intranasal Infection with Brucella melitensis in Mice

Mambres

Machelart

Potemberg

et al. 2016

The Journal of Immunology

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The mucosal immune system represents the first line of defense against Brucella infection in nature. We used genetically deficient mice to identify the lymphocytes and signaling pathways implicated in the control of primary and secondary intranasal infection with B. melitensis. Our analysis of primary infection demonstrated that the effectors implicated differ at the early and late stages and are dependent on the organ. TCR-δ, TAP1, and IL-17RA deficiency specifically affects early control of Brucella in the lungs, whereas MHC class II (MHCII) and IFN-γR deficiency impairs late control in the lungs, spleen, and liver. Interestingly, IL-12p35−/− mice display enhanced Brucella growth in the spleen but not in the lungs or liver. Secondary intranasal infections are efficiently contained in the lung. In contrast to an i.p. infectious model, in which IL-12p35, MHCII, and B cells are strictly required for the control of secondary infection, we observed that only TCR-β deficiency or simultaneous neutralization of IL-12p35– and IL-17A–dependent pathways impairs the memory protective response against a secondary intranasal infection. Protection is not affected by TCR-δ, MHCII, TAP1, B cell, IL-17RA, or IL-12p35 deficiency, suggesting that CD4+ and CD8+ α/β+ T cells are sufficient to mount a protective immune response and that an IL-17A–mediated response can compensate for the partial deficiency of an IFN-γ–mediated response to control a Brucella challenge. These findings demonstrate that the nature of the protective memory response depends closely on the route of infection and highlights the role of IFN-γ–and IL-17RA–mediated responses in the control of mucosal infection by Brucella.

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“…Unfortunately, there is currently no available vaccine against human brucellosis, as all commercially available animal vaccines are based on live attenuated strains of Brucella (B. melitensis Rev.1, B. abortus S19, and B. abortus RB51) (12,13) that cause disease in humans. Little real progress in the field of Brucella vaccination has been recently reported.…”

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confidence: 99%

Humoral Immunity and CD4+ Th1 Cells Are Both Necessary for a Fully Protective Immune Response upon Secondary Infection with Brucella melitensis

Vitry

Mambres

Trez

et al. 2014

The Journal of Immunology

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Brucella spp are intracellular bacteria that cause brucellosis, one of the most common zoonoses in the world. Given the serious medical consequences of this disease, a safe and effective human vaccine is urgently needed. Efforts to develop this vaccine have been hampered by our lack of understanding of what constitutes a protective memory response against Brucella. In this study, we characterize the cells and signaling pathways implicated in the generation of a protective immune memory response following priming by the injection of heat-killed or live Brucella melitensis 16M. Using a panel of gene-deficient mice, we demonstrated that during a secondary recall response, both the Brucella-specific humoral response and CD4+ Th1 cells must act together to confer protective immunity in the spleen to B. melitensis infection. Humoral protective immunity is induced by the inoculation of both heat-killed and live bacteria, and its development does not require T cells, MyD88/IL-12p35 signaling pathways, or an activation-induced deaminase–mediated isotype switch. In striking contrast, the presence of memory IFN-γ–producing CD4+ Th1 cells requires the administration of live bacteria and functional MyD88/IL-12p35 pathways. In summary, our work identifies several immune markers closely associated with protective immune memory and could help to define a rational strategy to obtain an effective human vaccine against brucellosis.

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Brucellosis: The case for live, attenuated vaccines

Cited by 78 publications

References 71 publications

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

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

Identification of Immune Effectors Essential to the Control of Primary and Secondary Intranasal Infection with Brucella melitensis in Mice

Humoral Immunity and CD4+ Th1 Cells Are Both Necessary for a Fully Protective Immune Response upon Secondary Infection with Brucella melitensis

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