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 Mycobacterium tuberculosis, such as Candida albicans and Staphylococcus aureus. 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.

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.

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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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 0Á1% 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.

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.

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 via 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.

Background:Mycobacterium bovis Bacillus Calmette-Guérin (BCG) is a live attenuated vaccine mainly administered to newborns and used for over 100 years to prevent the disease caused by Mycobacterium tuberculosis (M. tb). This vaccine can induce immune response polarization towards a Th1 profile, which is desired for counteracting M. tb, other mycobacteria, and unrelated intracellular pathogens. The vaccine BCG has been used as a vector to express recombinant proteins and has been shown to protect against several diseases, particularly respiratory viruses. Methods: BCG was used to develop recombinant vaccines expressing either the Nucleoprotein from SARS-CoV-2 or Andes orthohantavirus. Mice were immunized with these vaccines with the aim of evaluating the safety and immunogenicity parameters. Results: Immunization with two doses of 1 × 108 CFU or one dose of 1 × 105 CFU of these BCGs was safe in mice. A statistically significant cellular immune response was induced by both formulations, characterized as the activation of CD4+ and CD8+ T cells. Stimulation with unrelated antigens resulted in increased expression of activation markers by T cells and secretion of IL-2 and IFN-γ, while increased secretion of IL-6 was found for both recombinant vaccines; all of these parameters related to a trained immunity profile. The humoral immune response elicited by both vaccines was modest, but further exposure to antigens could increase this response. Conclusions: The BCG vaccine is a promising platform for developing vaccines against different pathogens, inducing a marked antigen-specific immune response.