The Role of Imaging for GI Bleeding: ACG and SAR Consensus Recommendations.

Gastrointestinal (GI) bleeding is the most common GI diagnosis leading to hospitalization within the United States. Prompt diagnosis and treatment of GI bleeding is critical to improving patient outcomes and reducing high health care utilization and costs. Radiologic techniques including CT angiography, catheter angiography, CT enterography, MR enterography, nuclear medicine red blood cell scan, and technetium-99m pertechnetate scintigraphy (Meckel scan) are frequently used to evaluate patients with GI bleeding and are complementary to GI endoscopy. However, multiple management guidelines exist, which differ in the recommended utilization of these radiologic examinations. This variability can lead to confusion as to how these tests should be used in the evaluation of GI bleeding. In this document, a panel of experts from the American College of Gastroenterology and Society of Abdominal Radiology provide a review of the radiologic examinations used to evaluate for GI bleeding including nomenclature, technique, performance, advantages, and limitations. A comparison of advantages and limitations relative to endoscopic examinations is also included. Finally, consensus statements and recommendations on technical parameters and utilization of radiologic techniques for GI bleeding are provided. © Radiological Society of North America and the American College of Gastroenterology, 2024. Supplemental material is available for this article. This article is being published concurrently in American Journal of Gastroenterology and Radiology. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. Citations from either journal can be used when citing this article. See also the editorial by Lockhart in this issue.

Human metapneumovirus respiratory infection affects both innate and adaptive intestinal immunity.

Introduction: Respiratory infections are one of the leading causes of morbidity and mortality worldwide, mainly in children, immunocompromised people, and the elderly. Several respiratory viruses can induce intestinal inflammation and alterations in intestinal microbiota composition. Human metapneumovirus (HMPV) is one of the major respiratory viruses contributing to infant mortality in children under 5 years of age worldwide, and the effect of this infection at the gut level has not been studied. Methods: Here, we evaluated the distal effects of HMPV infection on intestinal microbiota and inflammation in a murine model, analyzing several post-infection times (days 1, 3, and 5). Six to eight-week-old C57BL/6 mice were infected intranasally with HMPV, and mice inoculated with a non-infectious supernatant (Mock) were used as a control group. Results: We did not detect HMPV viral load in the intestine, but we observed significant changes in the transcription of IFN-γ in the colon, analyzed by qPCR, at day 1 post-infection as compared to the control group. Furthermore, we analyzed the frequencies of different innate and adaptive immune cells in the colonic lamina propria, using flow cytometry. The frequency of monocyte populations was altered in the colon of HMPV -infected mice at days 1 and 3, with no significant difference from control mice at day 5 post-infection. Moreover, colonic CD8+ T cells and memory precursor effector CD8+ T cells were significantly increased in HMPV-infected mice at day 5, suggesting that HMPV may also alter intestinal adaptive immunity. Additionally, we did not find alterations in antimicrobial peptide expression, the frequency of colonic IgA+ plasma cells, and levels of fecal IgA. Some minor alterations in the fecal microbiota composition of HMPV -infected mice were detected using 16s rRNA sequencing. However, no significant differences were found in ß-diversity and relative abundance at the genus level. Discussion: To our knowledge, this is the first report describing the alterations in intestinal immunity following respiratory infection with HMPV infection. These effects do not seem to be mediated by direct viral infection in the intestinal tract. Our results indicate that HMPV can affect colonic innate and adaptive immunity but does not significantly alter the microbiota composition, and further research is required to understand the mechanisms inducing these distal effects in the intestine.

Understanding the Neurotrophic Virus Mechanisms and Their Potential Effect on Systemic Lupus Erythematosus Development.

Central nervous system (CNS) pathologies are a public health concern, with viral infections one of their principal causes. These viruses are known as neurotropic pathogens, characterized by their ability to infiltrate the CNS and thus interact with various cell populations, inducing several diseases. The immune response elicited by neurotropic viruses in the CNS is commanded mainly by microglia, which, together with other local cells, can secrete inflammatory cytokines to fight the infection. The most relevant neurotropic viruses are adenovirus (AdV), cytomegalovirus (CMV), enterovirus (EV), Epstein-Barr Virus (EBV), herpes simplex virus type 1 (HSV-1), and herpes simplex virus type 2 (HSV-2), lymphocytic choriomeningitis virus (LCMV), and the newly discovered SARS-CoV-2. Several studies have associated a viral infection with systemic lupus erythematosus (SLE) and neuropsychiatric lupus (NPSLE) manifestations. This article will review the knowledge about viral infections, CNS pathologies, and the immune response against them. Also, it allows us to understand the relevance of the different viral proteins in developing neuronal pathologies, SLE and NPSLE.

A molecular perspective for the development of antibodies against the human respiratory syncytial virus.

The human respiratory syncytial virus (hRSV) is the leading etiologic agent causing respiratory infections in infants, children, older adults, and patients with comorbidities. Sixty-seven years have passed since the discovery of hRSV, and only a few successful mitigation or treatment tools have been developed against this virus. One of these is immunotherapy with monoclonal antibodies against structural proteins of the virus, such as Palivizumab, the first prophylactic approach approved by the Food and Drug Administration (FDA) of the USA. In this article, we discuss different strategies for the prevention and treatment of hRSV infection, focusing on the molecular mechanisms against each target that underly the rational design of antibodies against hRSV. At the same time, we describe the latest results regarding currently approved therapies against hRSV and the challenges associated with developing new candidates.

Different Safety Pattern of an Inactivated SARS-CoV-2 Vaccine (CoronaVac®) According to Age Group in a Pediatric Population from 3 to 17 Years Old, in an Open-Label Study in Chile.

During the COVID-19 pandemic, the importance of vaccinating children against SARS-CoV-2 was rapidly established. This study describes the safety of CoronaVac® in children and adolescents between 3- and 17-years-old in a multicenter study in Chile with two vaccine doses in a 4-week interval. For all participants, immediate adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs) were registered throughout the study. In the safety subgroup, AEs were recorded 28 days after each dose. COVID-19 surveillance was performed throughout the study. A total of 1139 individuals received the first and 1102 the second dose of CoronaVac®; 835 were in the safety subgroup. The first dose showed the highest number of AEs: up to 22.2% of participants reported any local and 17.1% systemic AE. AEs were more frequent in adolescents after the first dose, were transient, and mainly mild. Pain at the inoculation site was the most frequent AE for all ages. Fever was the most frequent systemic AE for 3-5 years old and headache in 6-17 years old. No SAEs or AESIs related to vaccination occurred. Most of the COVID-19 cases were mild and managed as outpatients. CoronaVac® was safe and well tolerated in children and adolescents, with different safety patterns according to age.

Dual-Energy CT Evaluation of Gastrointestinal Bleeding.

Gastrointestinal (GI) bleeding is a potentially life-threatening condition accounting for more than 300 000 annual hospitalizations. Multidetector abdominopelvic CT angiography is commonly used in the evaluation of patients with GI bleeding. Given that many patients with severe overt GI bleeding are unlikely to tolerate bowel preparation, and inpatient colonoscopy is frequently limited by suboptimal preparation obscuring mucosal visibility, CT angiography is recommended as a first-line diagnostic test in patients with severe hematochezia to localize a source of bleeding. Assessment of these patients with conventional single-energy CT systems typically requires the performance of a noncontrast series followed by imaging during multiple postcontrast phases. Dual-energy CT (DECT) offers several potential advantages for performing these examinations. DECT may eliminate the need for a noncontrast acquisition by allowing the creation of virtual noncontrast (VNC) images from contrast-enhanced data, affording significant radiation dose reduction while maintaining diagnostic accuracy. VNC images can help radiologists to differentiate active bleeding, hyperattenuating enteric contents, hematomas, and enhancing masses. Additional postprocessing techniques such as low-kiloelectron voltage virtual monoenergetic images, iodine maps, and iodine overlay images can increase the conspicuity of contrast material extravasation and improve the visibility of subtle causes of GI bleeding, thereby increasing diagnostic confidence and assisting with problem solving. GI bleeding can also be diagnosed with routine single-phase DECT scans by constructing VNC images and iodine maps. Radiologists should also be aware of the potential pitfalls and limitations of DECT. ©RSNA, 2023 Quiz questions for this article are available through the Online Learning Center.

Current and emerging pharmacological treatments for respiratory syncytial virus infection in high-risk infants.

INTRODUCTION: The human respiratory syncytial virus (hRSV) is the leading cause of respiratory infections in children, older adults, and patients with comorbidities. Since the hRSV discovery, multiple efforts have been made to generate therapies that control the devastating effects on the population at risk in winter. AREAS COVERED: This article describes the development of different drugs and treatments approved for use in the risk-population against hRSV infection. In addition, an exhaustive bibliographical review is presented here describing new candidate molecules under evaluation and showing promising results in different assays in animal models and clinical studies. Additionally, we highlight antiviral molecules, monoclonal antibodies, and nanobodies among the new candidate treatments. EXPERT OPINION: hRSV is a major burden for the health systems, promoting their collapse worldwide. Therefore, developing new therapies is an essential goal to decrease hospitalization rates caused by hRSV infection in high-risk populations. For this, injecting resources and exploring new targets in addition to the F protein is an interesting alternative to achieve this goal.

Humoral and cellular response induced by a second booster of an inactivated SARS-CoV-2 vaccine in adults.

BACKGROUND: The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster. METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT. FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4+ T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4+ T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found. INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4+T cell response may confer protection against the Omicron variant. FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.

Immune Responses at Host Barriers and Their Importance in Systemic Autoimmune Diseases.

Host barriers such as the skin, the lung mucosa, the intestinal mucosa and the oral cavity are crucial at preventing contact with potential threats and are populated by a diverse population of innate and adaptive immune cells. Alterations in antigen recognition driven by genetic and environmental factors can lead to autoimmune systemic diseases such rheumatoid arthritis, systemic lupus erythematosus and food allergy. Here we review how different immune cells residing at epithelial barriers, host-derived signals and environmental signals are involved in the initiation and progression of autoimmune responses in these diseases. We discuss how regulation of innate responses at these barriers and the influence of environmental factors such as the microbiota can affect the susceptibility to develop local and systemic autoimmune responses particularly in the cases of food allergy, systemic lupus erythematosus and rheumatoid arthritis. Induction of pathogenic autoreactive immune responses at host barriers in these diseases can contribute to the initiation and progression of their pathogenesis.

New Developments and Challenges in Antibody-Based Therapies for the Respiratory Syncytial Virus.

Since the discovery of the human respiratory syncytial virus (hRSV), multiple research efforts have been conducted to develop vaccines and treatments capable of reducing the risk of severe disease, hospitalization, long-term sequelae, and death from this pathogen in susceptible populations. In this sense, therapies specifically directed against hRSV are mainly based on monoclonal and polyclonal antibodies such as intravenous IgG (IVIG)-RSV and the monoclonal antibody palivizumab. However, these therapies are associated with significant limitations, including the need for the recruitment of a high number of convalescent volunteers who donate blood to procure IVIG-RSV and the costs associated with the need for repeated administrations of palivizumab. These limitations render this product not cost-effective for populations other than high-risk patients. These problems have underscored that it is still necessary to identify new safe and effective therapies for human use. However, these new therapies must benefit from a comparatively cheap production cost and the opportunity to be available to the high-risk population and anyone who requires treatment. Here, we review the different antibodies used to prevent the pathology caused by hRSV infection, highlighting therapies currently approved for human use and their clinical value. Also, the new, most promising candidates based on preclinical studies and clinical trial results are revised.

Gadolinium Deposition in the Rat Brain Measured with Quantitative MRI versus Elemental Mass Spectrometry.

Background T1-weighted MRI and quantitative longitudinal relaxation rate (R1) mapping have been used to evaluate gadolinium retention in the brain after gadolinium-based contrast agent (GBCA) administration. Whether MRI measures accurately reflect gadolinium regional distribution and concentration in the brain remains unclear. Purpose To compare gadolinium retention in rat forebrain measured with in vivo quantitative MRI R1 and ex vivo laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) mapping after gadobenate, gadopentetate, gadodiamide, or gadobutrol administration. Materials and Methods Adult female Sprague-Dawley rats were randomly assigned to one of five groups (eight per group) and administered gadobenate, gadopentetate, gadodiamide, gadobutrol (2.4 mmol/kg per week for 5 weeks), or saline (4.8 mL/kg per week for 5 weeks). MRI R1 mapping was performed at baseline and 1 week after the final injection to determine R1 and ΔR1. Postmortem brains from the same rats were analyzed with LA-ICP-MS elemental mapping to determine regional gadolinium concentrations. Student t tests were performed to compare results between GBCA and saline groups. Results Rats that were administered gadobenate showed gadolinium-related MRI ΔR1 in 39.5% of brain volume (ΔR1 = 0.087 second-1 ± 0.051); gadopentetate, 20.6% (ΔR1 = 0.069 second-1 ± 0.018); gadodiamide, 5.4% (ΔR1 = 0.055 second-1 ± 0.019); and gadobutrol, 2.2% (ΔR1 = 0.052 second-1 ± 0.041). Agent-specific gadolinium-related ΔR1 was detected in multiple forebrain regions (neocortex, hippocampus, dentate gyrus, thalamus, and caudate-putamen) in rats treated with gadobenate or gadopentetate, whereas rats treated with gadodiamide showed gadolinium-related ΔR1 in caudate-putamen. By contrast, LA-ICP-MS elemental mapping showed a similar regional distribution pattern of heterogeneous retained gadolinium in the forebrain of rats treated with gadobenate, gadopentetate, or gadodiamide, with the average gadolinium concentration of 0.45 µg · g-1 ± 0.07, 0.50 µg · g-1 ± 0.10, and 0.60 µg · g-1 ± 0.11, respectively. Low levels (0.01 µg · g-1 ± 0.00) of retained gadolinium were detected in the forebrain of gadobutrol-treated rats. Conclusion Differences in in vivo MRI longitudinal relaxation rate versus ex vivo elemental mass spectrometry measures of retained gadolinium in rat forebrains suggest that some forms of retained gadolinium may escape detection with MRI. © RSNA, 2022 Online supplemental material is available for this article.

Involvement of trained immunity during autoimmune responses.

Recently, it has been described that innate immune cells such as monocytes, macrophages, and natural killer cells can develop a non-specific immune response induced by different stimuli, including lipopolysaccharides, Mycobacterium bovis Bacillus Calmette-Guérin, and oxidized low-density lipoprotein. This non-specific immune response has been named "trained immunity," whose mechanism is essential for host defense and vaccine response, promoting better infection control. However, limited information about trained immunity in other non-infectious diseases, such as autoimmune illness, has been reported. The complexity of autoimmune pathology arises from dysfunctions in the innate and adaptive immune systems, triggering different clinical outcomes depending on the disease. Nevertheless, T and B cell function dysregulation is the most common characteristic associated with autoimmunity by promoting the escape from central and peripheral tolerance. Despite the importance of adaptative immunity to autoimmune diseases, the innate immune system also plays a prominent and understudied role in these pathologies. Accordingly, epigenetic and metabolic changes associated with innate immune cells that undergo a trained process are possible new therapeutic targets for autoimmune diseases. Even so, trained immunity can be beneficial or harmful in autoimmune diseases depending on several factors associated with the stimuli. Here, we reviewed the role of trained immunity over the innate immune system and the possible role of these changes in common autoimmune diseases, including Systemic Lupus Erythematosus, Rheumatoid Arthritis, Multiple Sclerosis, and Type 1 Diabetes.

Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children.

Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4+ T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4+ T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4+ T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) IMPORTANCE This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4+ T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.

Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial.

Background: The development of vaccines to control the coronavirus disease 2019 (COVID-19) pandemic progression is a worldwide priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile. Methods: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac separated by 2 (0-14 schedule) or 4 weeks (0-28 schedule); 2302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured. Results: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4+ T cells for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion. Conclusions: Immunization with CoronaVac in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule. Funding: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile. Clinical trial number: NCT04651790.

SARS-CoV-2 vaccine booster in solid organ transplant recipients previously immunised with inactivated versus mRNA vaccines: A prospective cohort study.

Background: Solid-organ transplant (SOT) recipients have worse COVID-19 outcomes than general population and effective immunisation in these patients is essential but more difficult to reach. We aimed to determine the immunogenicity of an mRNA SARS-CoV-2 vaccine booster in SOT recipients previously immunised with either inactivated or homologous SARS-CoV-2 mRNA vaccine. Methods: Prospective cohort study of SOT recipients under medical care at Red de Salud UC-CHRISTUS, Chile, previously vaccinated with either CoronaVac or BNT162b2. All participants received a BNT162b2 vaccine booster. The primary study end point was anti-SARS-CoV-2 total IgG antibodies (TAb) seropositivity at 8-12 weeks (56-84 days) post booster. Secondary end points included neutralising antibodies (NAb) and specific T-cell responses. Findings: A total of 140 (50% kidney, 38% liver, 6% heart) SOT recipients (mean age 54 [13.6] years; 64 [46%] women) were included. Of them, 62 had homologous (three doses of BNT162b2) and 78 heterologous vaccine schedules (two doses of CoronaVac followed by BNT162b2 booster). Boosters were received at a median of 21.3 weeks after primary vaccination. The proportion achieving TAb seropositivity (82.3% vs 65.4%, P = 0.035) and NAb positivity (77.4% vs 55.1%, P = 0.007) were higher for the homologous versus the heterologous group. On the other hand, the number of IFN-γ and IL-2 secreting SARS-CoV-2-specific T-cells did not differ significantly between groups. Interpretation: This cohort study shows that homologous mRNA vaccine priming plus boosting in SOT recipients, reaches a significantly higher humoral immune response than inactivated SARS-CoV-2 vaccine priming followed by heterologous mRNA booster. Funding: School of Medicine, UC-Chile and ANID.ClinicalTrials.gov ID: NCT05124509.

Female offspring gestated in hypothyroxinemia and infected with human Metapneumovirus (hMPV) suffer a more severe infection and have a higher number of activated CD8+ T lymphocytes.

Maternal thyroid hormones (THs) are essential for the appropriate development of the fetus and especially for the brain. Recently, some studies have shown that THs deficiency can also alter the immune system development of the progeny and their ability to mount an appropriate response against infectious agents. In this study, we evaluated whether adult mice gestated under hypothyroxinemia (Hpx) showed an altered immune response against infection with human metapneumovirus (hMPV). We observed that female mice gestated under Hpx showed higher clinical scores after seven days of hMPV infection. Besides, males gestated under Hpx have higher lung viral loads at day seven post-infection. Furthermore, the female offspring gestated in Hpx have already reduced the viral load at day seven and accordingly showed an increased proportion of activated (CD71+ and FasL+) CD8+ T cells in the lungs, which correlated with a trend for a higher histopathological clinical score. These results support that T4 deficiency during gestation might condition the offspring differently in males and females, enhancing their ability to respond to hMPV.

Modulation of Immune Cells as a Therapy for Cutaneous Lupus Erythematosus.

Cutaneous lupus erythematosus (CLE) is an autoimmune disorder like systemic lupus erythematosus (SLE). Both SLE and CLE characterize autoantibody secretion and immune cell recruitment. In particular, CLE can be divided into three more frequent types, varying in the severity of the skin lesions they present. The role of type I IFN was shown to be one of the leading causes of the development of this pathology in the skin. Different treatments have been developed and tested against these different variants of CLE to decrease the increasing levels of CLE in humans. In this article, a literature revision discussing the similarities between SLE and CLE is carried out. In addition, new advances in understanding the development of CLE and the leading treatments being evaluated in animal models and clinical trials are reviewed.

A Booster Dose of CoronaVac Increases Neutralizing Antibodies and T Cells that Recognize Delta and Omicron Variants of Concern.

CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4+ T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. IMPORTANCE CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4+ T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers.

Increased Heme Oxygenase 1 Expression upon a Primary Exposure to the Respiratory Syncytial Virus and a Secondary Mycobacterium bovis Infection.

The human respiratory syncytial virus (hRSV) is the leading cause of severe lower respiratory tract infections in infants. Because recurrent epidemics based on reinfection occur in children and adults, hRSV has gained interest as a potential primary pathogen favoring secondary opportunistic infections. Several infection models have shown different mechanisms by which hRSV promotes immunopathology to prevent the development of adaptive protective immunity. However, little is known about the long-lasting effects of viral infection on pulmonary immune surveillance mechanisms. As a first approach, here we evaluated whether a primary infection by hRSV, once resolved, dampens the host immune response to a secondary infection with an attenuated strain of Mycobacterium bovis (M. Bovis) strain referred as to Bacillus Calmette-Guerin (BCG). We analyzed leukocyte dynamics and immunomodulatory molecules in the lungs after eleven- and twenty-one-days post-infection with Mycobacterium, using previous hRSV infected mice, by flow cytometry and the expression of critical genes involved in the immune response by real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR). Among the latter, we analyzed the expression of Heme Oxygenase (HO)-1 in an immunization scheme in mice. Our data suggest that a pre-infection with hRSV has a conditioning effect promoting lung pathology during a subsequent mycobacterial challenge, characterized by increased infiltration of innate immune cells, including interstitial and alveolar macrophages. Our data also suggest that hRSV impairs pulmonary immune responses, promoting secondary mycobacterial colonization and lung survival, which could be associated with an increase in the expression of HO-1. Additionally, BCG is a commonly used vaccine that can be used as a platform for the generation of new recombinant vaccines, such as a recombinant BCG strain expressing the nucleoprotein of hRSV (rBCG-N-hRSV). Therefore, we evaluated if the immunization with rBCG-N-hRSV could modulate the expression of HO-1. We found a differential expression pattern for HO-1, where a higher induction of HO-1 was detected on epithelial cells compared to dendritic cells during late infection times. This is the first study to demonstrate that infection with hRSV produces damage in the lung epithelium, promoting subsequent mycobacterial colonization, characterized by an increase in the neutrophils and alveolar macrophages recruitment. Moreover, we determined that immunization with rBCG-N-hRSV modulates differentially the expression of HO-1 on immune and epithelial cells, which could be involved in the repair of pulmonary tissue.