Publications by authors named "Fabián E Díaz"

8 Publications

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A Recombinant BCG Vaccine Is Safe and Immunogenic in Neonatal Calves and Reduces the Clinical Disease Caused by the Respiratory Syncytial Virus.

Front Immunol 2021 26;12:664212. Epub 2021 Apr 26.

Department of Veterinary Microbiology and Preventative Medicine, Iowa State University, Ames, IA, United States.

The human respiratory syncytial virus (hRSV) constitutes a major health burden, causing millions of hospitalizations in children under five years old worldwide due to acute lower respiratory tract infections. Despite decades of research, licensed vaccines to prevent hRSV are not available. Development of vaccines against hRSV targeting young infants requires ruling out potential vaccine-enhanced disease presentations. To achieve this goal, vaccine testing in proper animal models is essential. A recombinant BCG vaccine that expresses the Nucleoprotein of hRSV (rBCG-N-hRSV) protects mice against hRSV infection, eliciting humoral and cellular immune protection. Further, this vaccine was shown to be safe and immunogenic in human adult volunteers. Here, we evaluated the safety, immunogenicity, and protective efficacy of the rBCG-N-hRSV vaccine in a neonatal bovine RSV calf infection model. Newborn, colostrum-replete Holstein calves were either vaccinated with rBCG-N-hRSV, WT-BCG, or left unvaccinated, and then inoculated aerosol challenge with bRSV strain 375. Vaccination with rBCG-N-hRSV was safe and well-tolerated, with no systemic adverse effects. There was no evidence of vaccine-enhanced disease following bRSV challenge of rBCG-N-hRSV vaccinated animals, suggesting that the vaccine is safe for use in neonates. Vaccination increased virus-specific IgA and virus-neutralization activity in nasal fluid and increased the proliferation of virus- and BCG-specific CD4+ and CD8+ T cells in PBMCs and lymph nodes at 7dpi. Furthermore, rBCG-N-hRSV vaccinated calves developed reduced clinical disease as compared to unvaccinated control calves, although neither pathology nor viral burden were significantly reduced in the lungs. These results suggest that the rBCG-N-hRSV vaccine is safe in neonatal calves and induces protective humoral and cellular immunity against this respiratory virus. These data from a newborn animal model provide further support to the notion that this vaccine approach could be considered as a candidate for infant immunization against RSV.
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http://dx.doi.org/10.3389/fimmu.2021.664212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108697PMC
April 2021

Immune response during hantavirus diseases: implications for immunotherapies and vaccine design.

Immunology 2021 Jul 18;163(3):262-277. Epub 2021 Mar 18.

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

Orthohantaviruses, previously named hantaviruses, cause two emerging zoonotic diseases: haemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. Overall, over 200 000 cases are registered every year worldwide, with a fatality rate ranging between 0·1% and 15% for HFRS and between 20% and 40% for HCPS. No specific treatment or vaccines have been approved by the U.S. Food and Drug Administration (FDA) to treat or prevent hantavirus-caused syndromes. Currently, little is known about the mechanisms at the basis of hantavirus-induced disease. However, it has been hypothesized that an excessive inflammatory response plays an essential role in the course of the disease. Furthermore, the contributions of the cellular immune response to either viral clearance or pathology have not been fully elucidated. This article discusses recent findings relative to the immune responses elicited to hantaviruses in subjects suffering HFRS or HCPS, highlighting the similarities and differences between these two clinical diseases. Also, we summarize the most recent data about the cellular immune response that could be important for designing new vaccines to prevent this global public health problem.
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http://dx.doi.org/10.1111/imm.13322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207335PMC
July 2021

BCG-Induced Cross-Protection and Development of Trained Immunity: Implication for Vaccine Design.

Front Immunol 2019 29;10:2806. Epub 2019 Nov 29.

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

The Bacillus Calmette-Guérin (BCG) is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Vaccination with BCG reduces mortality in newborns and induces an improved innate immune response against microorganisms other than , such as and . Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. This phenomenon associated with a memory-like response in innate immune cells is known as "trained immunity." Epigenetic reprogramming through histone modification in the regulatory elements of particular genes has been reported as one of the mechanisms associated with the induction of trained immunity in both, humans and mice. Indeed, it has been shown that BCG vaccination induces changes in the methylation pattern of histones associated with specific genes in circulating monocytes leading to a "trained" state. Importantly, these modifications can lead to the expression and/or repression of genes that are related to increased protection against secondary infections after vaccination, with improved pathogen recognition and faster inflammatory responses. In this review, we discuss BCG-induced cross-protection and acquisition of trained immunity and potential heterologous effects of recombinant BCG vaccines.
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http://dx.doi.org/10.3389/fimmu.2019.02806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896902PMC
November 2020

Current Animal Models for Understanding the Pathology Caused by the Respiratory Syncytial Virus.

Front Microbiol 2019 3;10:873. Epub 2019 May 3.

Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Millennium Institute on Immunology and Immunotherapy, Pontificia Universidad Católica de Chile, Santiago, Chile.

The human respiratory syncytial virus (hRSV) is the main etiologic agent of severe lower respiratory tract infections that affect young children throughout the world, associated with significant morbidity and mortality, becoming a serious public health problem globally. Up to date, no licensed vaccines are available to prevent severe hRSV-induced disease, and the generation of safe-effective vaccines has been a challenging task, requiring constant biomedical research aimed to overcome this ailment. Among the difficulties presented by the study of this pathogen, it arises the fact that there is no single animal model that resembles all aspects of the human pathology, which is due to the specificity that this pathogen has for the human host. Thus, for the study of hRSV, different animal models might be employed, depending on the goal of the study. Of all the existing models, the murine model has been the most frequent model of choice for biomedical studies worldwide and has been of great importance at contributing to the development and understanding of vaccines and therapies against hRSV. The most notable use of the murine model is that it is very useful as a first approach in the development of vaccines or therapies such as monoclonal antibodies, suggesting in this way the direction that research could have in other preclinical models that have higher maintenance costs and more complex requirements in its management. However, several additional different models for studying hRSV, such as other rodents, mustelids, ruminants, and non-human primates, have been explored, offering advantages over the murine model. In this review, we discuss the various applications of animal models to the study of hRSV-induced disease and the advantages and disadvantages of each model, highlighting the potential of each model to elucidate different features of the pathology caused by the hRSV infection.
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http://dx.doi.org/10.3389/fmicb.2019.00873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510261PMC
May 2019

Contribution of Fcγ Receptor-Mediated Immunity to the Pathogenesis Caused by the Human Respiratory Syncytial Virus.

Front Cell Infect Microbiol 2019 29;9:75. Epub 2019 Mar 29.

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.

The human Respiratory Syncytial Virus (hRSV) is the leading cause of severe acute lower respiratory tract infections (ALRTIs) in humans at all ages and is the main cause of hospitalization due to pneumonia, asthma, and bronchiolitis in infants. hRSV symptoms mainly develop due to an excessive host immune and inflammatory response in the respiratory tissue. hRSV infection during life is frequent and likely because of non-optimal immunological memory is developed against this virus. Vaccine development against this pathogen has been delayed after the detrimental effects produced in children by vaccination with a formalin-inactivated hRSV preparation (FI-hRSV), which caused enhanced disease upon natural viral infection. Since then, several studies have focused on understanding the mechanisms underlying such disease exacerbation. Along these lines, several studies have suggested that antibodies elicited by immunization with FI-hRSV show low neutralizing capacity and promote the formation of immune complexes containing hRSV (hRSV-ICs), which contribute to hRSV pathogenesis through the engagement of Fc gamma receptors (FcγRs) expressed on the surface of immune cells. Furthermore, a role for FcγRs is supported by studies evaluating the contribution of these molecules to hRSV-induced disease. These studies have shown that FcγRs can modulate viral clearance by the host and the inflammatory response triggered by hRSV infection. In addition, ICs can facilitate viral entry into host cells expressing FcγRs, thus extending hRSV infectivity. In this article, we discuss current knowledge relative to the contribution of hRSV-ICs and FcγRs to the pathogenesis caused by hRSV and their putative role in the exacerbation of the disease caused by this virus after FI-hRSV vaccination. A better understanding FcγRs involvement in the immune response against hRSV will contribute to the development of new prophylactic or therapeutic tools to promote virus clearance with limited inflammatory damage to the airways.
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http://dx.doi.org/10.3389/fcimb.2019.00075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450440PMC
December 2019

Patterns of antibody response during natural hRSV infection: insights for the development of new antibody-based therapies.

Expert Opin Investig Drugs 2018 09 23;27(9):721-731. Epub 2018 Aug 23.

a Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas , Pontificia Universidad Católica de Chile , Santiago , Chile.

Introduction: The human respiratory syncytial virus (hRSV) is the main cause of acute lower respiratory tract infection in susceptible population worldwide, such as young children and the elderly. Although hRSV is a major public health burden, there are no licensed vaccines and the only available therapy is palivizumab. During life, reinfections with hRSV are common, suggesting that the virus can impair the development of an efficient host immune response. This feature has hindered the development of efficient therapies.

Areas Covered: This article focuses on research about the natural development of antibodies in humans after the exposure to hRSV. The difficulties of developing anti-hRSV therapies based on monoclonal antibodies have been recently associated to the relationship between the disease outcome and the pattern of antibody response.

Expert Opinion: Development of monoclonal antibodies is a potentially successful approach to prevent the population from suffering severe respiratory diseases caused by hRSV infection, for which there are no available vaccines. Although the use of palivizumab is safe, its effectiveness is controversial. Recent data have prompted research to develop therapies targeting alternative viral antigens, rather than focusing only on the F protein, as well as the development of antibodies with a cell-mediated function.
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http://dx.doi.org/10.1080/13543784.2018.1511699DOI Listing
September 2018

Geographical distribution and phylogenetic analysis of Rhipicephalus sanguineus sensu lato in northern and central Chile.

Ticks Tick Borne Dis 2018 05 5;9(4):792-797. Epub 2018 Mar 5.

Departamento de Enfermedades Infecciosas e Inmunología Pediátricas, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Laboratorio de Infectología y Virología Molecular, Red Salud UC, Santiago, Chile; Millennium Institute on Immunology and Immunotherapy, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address:

The presented study analyzed the presence and geographical distribution of the tropical and temperate lineages of Rhipicephalus sanguineus sensu lato in Chile. R. sanguineus s.l. ticks were collected from dogs at 14 sites in northern and central Chile for morphological and genetic analysis based on the 16S rDNA gene. Phylogenetic studies proved the existence of both, the tropical and the temperate lineages. The former was represented by a single haplotype and occurred in the far north; the latter included four haplotypes and was observed from the Tarapacá Region southwards. In four sites at latitudes from 20°S to 22°S, both lineages were found to coexist. Our study discovered for the first time the existence of the tropical lineage in Chile and demonstrated that distributions of the tropical and temperate lineages overlap, forming a transitional zone of approximately 200 km in northern coastal Chile.
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http://dx.doi.org/10.1016/j.ttbdis.2018.03.004DOI Listing
May 2018

An Update on Host-Pathogen Interplay and Modulation of Immune Responses during Orientia tsutsugamushi Infection.

Clin Microbiol Rev 2018 04 31;31(2). Epub 2018 Jan 31.

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

The obligate intracellular bacterium is the causative agent of scrub typhus in humans, a serious mite-borne disease present in a widespread area of endemicity, which affects an estimated 1 million people every year. This disease may exhibit a broad range of presentations, ranging from asymptomatic to fatal conditions, with the latter being due to disseminated endothelial infection and organ injury. Unique characteristics of the biology and host-pathogen interactions of , including the high antigenic diversity among strains and the highly variable, short-lived memory responses developed by the host, underlie difficulties faced in the pursuit of an effective vaccine, which is an imperative need. Other factors that have hindered scientific progress relative to the infectious mechanisms of and the immune response triggered by this bacterium in vertebrate hosts include the limited number of mechanistic studies performed on animal models and the lack of genetic tools currently available for this pathogen. However, recent advances in animal model development are promising to improve our understanding of host-pathogen interactions. Here, we comprehensively discuss the recent advances in and future perspectives on host-pathogen interactions and the modulation of immune responses related to this reemerging disease, highlighting the role of animal models.
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http://dx.doi.org/10.1128/CMR.00076-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967693PMC
April 2018