Dataset Information

Design of live attenuated bacterial vaccines based on D-glutamate auxotrophy.

ABSTRACT: Vaccine development is a priority for global health due to the growing multidrug resistance in bacteria. D-glutamate synthesis is essential for bacterial cell wall formation. Here we present a strategy for generating effective bacterial whole-cell vaccines auxotrophic for D-glutamate. We apply this strategy to generate D-glutamate auxotrophic vaccines for three major pathogens, Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus. These bacterial vaccines show virulence attenuation and self-limited growth in mice, and elicit functional and cross-reactive antibodies, and cellular immunity. These responses correlate with protection against acute lethal infection with other strains of the same species, including multidrug resistant, virulent and/or high-risk clones such as A. baumannii AbH12O-A2 and Ab307-0294, P. aeruginosa PA14, and community-acquired methicillin-resistant S. aureus USA300LAC. This approach can potentially be applied for the development of live-attenuated vaccines for virtually any other bacterial pathogens, and does not require the identification of virulence determinants, which are often pathogen-specific.

SUBMITTER: Cabral MP

PROVIDER: S-EPMC5458566 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Design of live attenuated bacterial vaccines based on D-glutamate auxotrophy.

Cabral Maria P MP García Patricia P Beceiro Alejandro A Rumbo Carlos C Pérez Astrid A Moscoso Miriam M Bou Germán G

Nature communications 20170526

Vaccine development is a priority for global health due to the growing multidrug resistance in bacteria. D-glutamate synthesis is essential for bacterial cell wall formation. Here we present a strategy for generating effective bacterial whole-cell vaccines auxotrophic for D-glutamate. We apply this strategy to generate D-glutamate auxotrophic vaccines for three major pathogens, Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus. These bacterial vaccines show virulence atte ...[more]

PMID: 28548079

Similar Datasets

Project description:Diseases caused by human herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) affect millions of people worldwide and range from fatal encephalitis in neonates and herpes keratitis to orofacial and genital herpes, among other manifestations. The viruses can be shed efficiently by asymptomatic carriers, causing increased rates of infection. Viral transmission occurs through direct contact of mucosal surfaces followed by initial replication of the incoming virus in skin tissues. Subsequently, the viruses infect sensory neurons in the trigeminal and lumbosacral dorsal root ganglia, where they are primarily maintained in a transcriptionally repressed state termed "latency", which persists for the lifetime of the host. HSV DNA has also been detected in other sympathetic ganglia. Periodically, latent viruses can reactivate, causing ulcerative and often painful lesions primarily at the site of primary infection and proximal sites. In the United States, recurrent genital herpes alone accounts for more than a billion dollars in direct medical costs per year, while there are much higher costs associated with the socio-economic aspects of diseased patients, such as loss of productivity due to mental anguish. Currently, there are no effective FDA-approved vaccines for either prophylactic or therapeutic treatment of human herpes simplex infections, while several recent clinical trials have failed to achieve their endpoint goals. Historically, live-attenuated vaccines have successfully combated viral diseases, including polio, influenza, measles, and smallpox. Vaccines aimed to protect against the devastation of smallpox led to the most significant achievement in medical history: the eradication of human disease by vaccination. Recently, novel approaches toward developing safe and effective live-attenuated vaccines have demonstrated high efficacy in various preclinical models of herpetic disease. This next generation of live-attenuated vaccines has been tailored to minimize vaccine-associated side effects and promote effective and long-lasting immune responses. The ultimate goal is to prevent or reduce primary infections (prophylactic vaccines) or reduce the frequency and severity of disease associated with reactivation events (therapeutic vaccines). These vaccines' "rational" design is based on our current understanding of the immunopathogenesis of herpesviral infections that guide the development of vaccines that generate robust and protective immune responses. This review covers recent advances in the development of herpes simplex vaccines and the current state of ongoing clinical trials in pursuit of an effective vaccine against herpes simplex virus infections and associated diseases.

Project description:Arenaviruses have a significant impact on public health and pose a credible biodefense threat, but the development of safe and effective arenavirus vaccines has remained elusive, and currently, no Food and Drug Administration (FDA)-licensed arenavirus vaccines are available. Here, we explored the use of a codon deoptimization (CD)-based approach as a novel strategy to develop live-attenuated arenavirus vaccines. We recoded the nucleoprotein (NP) of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) with the least frequently used codons in mammalian cells, which caused lower LCMV NP expression levels in transfected cells that correlated with decreased NP activity in cell-based functional assays. We used reverse-genetics approaches to rescue a battery of recombinant LCMVs (rLCMVs) encoding CD NPs (rLCMV/NP(CD)) that showed attenuated growth kinetics in vitro. Moreover, experiments using the well-characterized mouse model of LCMV infection revealed that rLCMV/NP(CD1) and rLCMV/NP(CD2) were highly attenuated in vivo but, upon a single immunization, conferred complete protection against a subsequent lethal challenge with wild-type (WT) recombinant LCMV (rLCMV/WT). Both rLCMV/NP(CD1) and rLCMV/NP(CD2) were genetically and phenotypically stable during serial passages in FDA vaccine-approved Vero cells. These results provide proof of concept of the safety, efficacy, and stability of a CD-based approach for developing live-attenuated vaccine candidates against human-pathogenic arenaviruses.Several arenaviruses cause severe hemorrhagic fever in humans and pose a credible bioterrorism threat. Currently, no FDA-licensed vaccines are available to combat arenavirus infections, while antiarenaviral therapy is limited to the off-label use of ribavirin, which is only partially effective and is associated with side effects. Here, we describe the generation of recombinant versions of the prototypic arenavirus LCMV encoding codon-deoptimized viral nucleoproteins (rLCMV/NP(CD)). We identified rLCMV/NP(CD1) and rLCMV/NP(CD2) to be highly attenuated in vivo but able to confer protection against a subsequent lethal challenge with wild-type LCMV. These viruses displayed an attenuated phenotype during serial amplification passages in cultured cells. Our findings support the use of this approach for the development of safe, stable, and protective live-attenuated arenavirus vaccines.

Project description:With an ongoing threat posed by circulating zoonotic strains, new strategies are required to prepare for the next emergent coronavirus (CoV). Previously, groups had targeted conserved coronavirus proteins as a strategy to generate live attenuated vaccine strains against current and future CoVs. With this in mind, we explored whether manipulation of CoV NSP16, a conserved 2'O methyltransferase (MTase), could provide a broad attenuation platform against future emergent strains. Using the severe acute respiratory syndrome-CoV mouse model, an NSP16 mutant vaccine was evaluated for protection from heterologous challenge, efficacy in the aging host, and potential for reversion to pathogenesis. Despite some success, concerns for virulence in the aged and potential for reversion makes targeting NSP16 alone an untenable approach. However, combining a 2'O MTase mutation with a previously described CoV fidelity mutant produced a vaccine strain capable of protection from heterologous virus challenge, efficacy in aged mice, and no evidence for reversion. Together, the results indicate that targeting the CoV 2'O MTase in parallel with other conserved attenuating mutations may provide a platform strategy for rapidly generating live attenuated coronavirus vaccines.IMPORTANCE Emergent coronaviruses remain a significant threat to global public health and rapid response vaccine platforms are needed to stem future outbreaks. However, failure of many previous CoV vaccine formulations has clearly highlighted the need to test efficacy under different conditions and especially in vulnerable populations such as the aged and immunocompromised. This study illustrates that despite success in young models, the 2'O methyltransferase mutant carries too much risk for pathogenesis and reversion in vulnerable models to be used as a stand-alone vaccine strategy. Importantly, the 2'O methyltransferase mutation can be paired with other attenuating approaches to provide robust protection from heterologous challenge and in vulnerable populations. Coupled with increased safety and reduced pathogenesis, the study highlights the potential for 2'O methyltransferase attenuation as a major component of future live attenuated coronavirus vaccines.

Dataset Information

Design of live attenuated bacterial vaccines based on D-glutamate auxotrophy.

Publications

Design of live attenuated bacterial vaccines based on D-glutamate auxotrophy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets