Origins and diversity of pan-isotype human bone marrow plasma cells.

Bone marrow plasma cells (BMPCs) produce durable, protective IgM, IgG, and IgA antibodies, and in some cases, pro-allergic IgE antibodies, but their properties and sources are unclear. We charted single BMPC transcriptional and clonal heterogeneity in food-allergic and non-allergic individuals across CD19 protein expression given its inverse correlation to BMPC longevity. Transcriptional and clonal diversity revealed distinct functional profiles. Additionally, distribution of somatic hypermutation and intraclonal antibody sequence variance suggest that CD19low and CD19high BMPCs arise from recalled memory and germinal center B cells, respectively. Most IgE BMPCs were from peanut-allergic individuals; two out of 32 from independent donors bound peanut antigens in vitro and in vivo. These findings shed light on BMPC origins and highlight the bone marrow as a source of pathogenic IgE in peanut allergy.

Characterization of the humoral and cellular immunity induced by a recombinant BCG vaccine for the respiratory syncytial virus in healthy adults.

Introduction: The human respiratory syncytial virus (hRSV) is responsible for most respiratory tract infections in infants. Even though currently there are no approved hRSV vaccines for newborns or infants, several candidates are being developed. rBCG-N-hRSV is a vaccine candidate previously shown to be safe in a phase I clinical trial in adults (clinicaltrials.gov identifier #NCT03213405). Here, secondary immunogenicity analyses were performed on these samples. Methods: PBMCs isolated from immunized volunteers were stimulated with hRSV or mycobacterial antigens to evaluate cytokines and cytotoxic T cell-derived molecules and the expansion of memory T cell subsets. Complement C1q binding and IgG subclass composition of serum antibodies were assessed. Results: Compared to levels detected prior to vaccination, perforin-, granzyme B-, and IFN-γ-producing PBMCs responding to stimulus increased after immunization, along with their effector memory response. N-hRSV- and mycobacterial-specific antibodies from rBCG-N-hRSV-immunized subjects bound C1q. Conclusion: Immunization with rBCG-N-hRSV induces cellular and humoral immune responses, supporting that rBCG-N-hRSV is immunogenic and safe in healthy individuals. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/, identifier NCT03213405.

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.

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.

A booster dose of an inactivated SARS-CoV-2 vaccine increases neutralizing antibodies and T cells that recognize Delta and Omicron variants of concern.

Background: CoronaVac ® is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization. Previous studies reported increased levels of neutralizing antibodies and specific T cells two- and four-weeks after two doses of CoronaVac ® , but the levels of neutralizing antibodies are reduced at six to eight months after two doses. Here we report the effect of a booster dose of CoronaVac ® on the anti-SARS-CoV-2 immune response generated against variants of concern (VOC) Delta and Omicron in adults participating in a phase 3 clinical trial in Chile. Methods: Volunteers immunized with two doses of CoronaVac ® in a four-week interval received a booster dose of the same vaccine between twenty-four and thirty weeks after the 2nd dose. Four weeks after the booster dose, neutralizing antibodies and T cell responses were measured. Neutralization capacities and T cell activation against VOC Delta and Omicron were detected at four weeks after the booster dose. Findings: We observed a significant increase in neutralizing antibodies at four weeks after the booster dose. We also observed an increase in CD4 + T cells numbers over time, reaching a peak at four weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2 specific T cells induced by the booster showed activity against VOC Delta and Omicron. Interpretation: Our results show that a booster dose of CoronaVac ® increases the anti-SARS-CoV-2 humoral and cellular immune responses in adults. Immunity induced by a booster dose of CoronaVac ® is active against VOC, suggesting an effective protection.

Safety and Immunogenicity of an Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Subgroup of Healthy Adults in Chile.

BACKGROUND: The development of effective vaccines against coronavirus disease 2019 is a global priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 years in a phase 3 clinical trial. METHODS: Volunteers randomly received 2 doses of CoronaVac or placebo, separated by 2 weeks. A total of 434 volunteers were enrolled, 397 aged 18-59 years and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity. RESULTS: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22% and 84.44% in the 18-59 year age group and 62.69% and 70.37% in the ≥60 year age group, 2 and 4 weeks after the second dose, respectively. A significant increase in circulating neutralizing antibodies was detected 2 and 4 weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T-cell responses characterized by the secretion of interferon-γ (IFN-γ) upon stimulation with Mega Pools of peptides from SARS-CoV-2. CONCLUSIONS: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 years is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γ upon stimulation with SARS-CoV-2 antigens.

Recognition of Variants of Concern by Antibodies and T Cells Induced by a SARS-CoV-2 Inactivated Vaccine.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible of the current pandemic ongoing all around the world. Since its discovery in 2019, several circulating variants have emerged and some of them are associated with increased infections and death rate. Despite the genetic differences among these variants, vaccines approved for human use have shown a good immunogenic and protective response against them. In Chile, over 70% of the vaccinated population is immunized with CoronaVac, an inactivated SARS-CoV-2 vaccine. The immune response elicited by this vaccine has been described against the first SARS-CoV-2 strain isolated from Wuhan, China and the D614G strain (lineage B). To date, four SARS-CoV-2 variants of concern described have circulated worldwide. Here, we describe the neutralizing capacities of antibodies secreted by volunteers in the Chilean population immunized with CoronaVac against variants of concern Alpha (B.1.1.7), Beta (B.1.351) Gamma (P.1) and Delta (B.617.2). Methods: Volunteers enrolled in a phase 3 clinical trial were vaccinated with two doses of CoronaVac in 0-14 or 0-28 immunization schedules. Sera samples were used to evaluate the capacity of antibodies induced by the vaccine to block the binding between Receptor Binding Domain (RBD) from variants of concern and the human ACE2 receptor by an in-house ELISA. Further, conventional microneutralization assays were used to test neutralization of SARS-CoV-2 infection. Moreover, interferon-γ-secreting T cells against Spike from variants of concern were evaluated in PBMCs from vaccinated subjects using ELISPOT. Results: CoronaVac promotes the secretion of antibodies able to block the RBD of all the SARS-CoV-2 variants studied. Seropositivity rates of neutralizing antibodies in the population evaluated were over 97% for the lineage B strain, over 80% for Alpha and Gamma variants, over 75% for Delta variant and over 60% for the Beta variant. Geometric means titers of blocking antibodies were reduced when tested against SARS-CoV-2 variants as compared to ancestral strain. We also observed that antibodies from vaccinated subjects were able to neutralize the infection of variants D614G, Alpha, Gamma and Delta in a conventional microneutralization assay. Importantly, after SARS-CoV-2 infection, we observed that the blocking capacity of antibodies from vaccinated volunteers increased up to ten times for all the variants tested. We compared the number of interferon-γ-secreting T cells specific for SARS-CoV-2 Spike WT and variants of concern from vaccinated subjects and we did not detect significant differences. Conclusion: Immunization with CoronaVac in either immunization schedule promotes the secretion of antibodies able to block SARS-CoV-2 variants of concern and partially neutralizes SARS-CoV-2 infection. In addition, it stimulates cellular responses against all variants of concern.

Immune Profile and Clinical Outcome of Breakthrough Cases After Vaccination With an Inactivated SARS-CoV-2 Vaccine.

Constant efforts to prevent infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are actively carried out around the world. Several vaccines are currently approved for emergency use in the population, while ongoing studies continue to provide information on their safety and effectiveness. CoronaVac is an inactivated SARS-CoV-2 vaccine with a good safety and immunogenicity profile as seen in phase 1, 2, and 3 clinical trials around the world, with an effectiveness of 65.9% for symptomatic cases. Although vaccination reduces the risk of disease, infections can still occur during or after completion of the vaccination schedule (breakthrough cases). This report describes the clinical and immunological profile of vaccine breakthrough cases reported in a clinical trial in progress in Chile that is evaluating the safety, immunogenicity, and efficacy of two vaccination schedules of CoronaVac (clinicaltrials.gov NCT04651790). Out of the 2,263 fully vaccinated subjects, at end of June 2021, 45 have reported symptomatic SARS-CoV-2 infection 14 or more days after the second dose (1.99% of fully vaccinated subjects). Of the 45 breakthrough cases, 96% developed mild disease; one case developed a moderate disease; and one developed a severe disease and required mechanical ventilation. Both cases that developed moderate and severe disease were adults over 60 years old and presented comorbidities. The immune response before and after SARS-CoV-2 infection was analyzed in nine vaccine breakthrough cases, revealing that six of them exhibited circulating anti-S1-RBD IgG antibodies with neutralizing capacities after immunization, which showed a significant increase 2 and 4 weeks after symptoms onset. Two cases exhibited low circulating anti-S1-RBD IgG and almost non-existing neutralizing capacity after either vaccination or infection, although they developed a mild disease. An increase in the number of interferon-γ-secreting T cells specific for SARS-CoV-2 was detected 2 weeks after the second dose in seven cases and after symptoms onset. In conclusion, breakthrough cases were mostly mild and did not necessarily correlate with a lack of vaccine-induced immunity, suggesting that other factors, to be defined in future studies, could lead to symptomatic infection after vaccination with CoronaVac.

Induction of Protective Immunity by a Single Low Dose of a Master Cell Bank cGMP-rBCG-P Vaccine Against the Human Metapneumovirus in Mice.

Human metapneumovirus (hMPV) is an emergent virus, which mainly infects the upper and lower respiratory tract epithelium. This pathogen is responsible for a significant portion of hospitalizations due to bronchitis and pneumonia in infants and the elderly worldwide. hMPV infection induces a pro-inflammatory immune response upon infection of the host, which is not adequate for the clearance of this pathogen. The lack of knowledge regarding the different molecular mechanisms of infection of this virus has delayed the licensing of effective treatments or vaccines. As part of this work, we evaluated whether a single and low dose of a recombinant Mycobacterium bovis Bacillus Calmette-Guérin (BCG) expressing the phosphoprotein of hMPV (rBCG-P) can induce a protective immune response in mice. Immunization with the rBCG-P significantly decreased neutrophil counts and viral loads in the lungs of infected mice at different time points. This immune response was also associated with a modulated infiltration of innate cells into the lungs, such as interstitial macrophages (IM) and alveolar macrophages (AM), activated CD4+ and CD8+ T cells, and changes in the population of differentiated subsets of B cells, such as marginal zone B cells and plasma cells. The humoral immune response induced by the rBCG-P led to an early and robust IgA response and a late and constant IgG response. Finally, we determined that the transfer of cells or sera from immunized and infected mice to naïve mice promoted an efficient viral clearance. Therefore, a single and low dose of rBCG-P can protect mice from the disease caused by hMPV, and this vaccine could be a promising candidate for future clinical trials.

Bacterial and Viral Coinfections with the Human Respiratory Syncytial Virus.

The human respiratory syncytial virus (hRSV) is one of the leading causes of acute lower respiratory tract infections in children under five years old. Notably, hRSV infections can give way to pneumonia and predispose to other respiratory complications later in life, such as asthma. Even though the social and economic burden associated with hRSV infections is tremendous, there are no approved vaccines to date to prevent the disease caused by this pathogen. Recently, coinfections and superinfections have turned into an active field of study, and interactions between many viral and bacterial pathogens have been studied. hRSV is not an exception since polymicrobial infections involving this virus are common, especially when illness has evolved into pneumonia. Here, we review the epidemiology and recent findings regarding the main polymicrobial infections involving hRSV and several prevalent bacterial and viral respiratory pathogens, such as Staphylococcus aureus, Pseudomonas aeruginosa, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, human rhinoviruses, influenza A virus, human metapneumovirus, and human parainfluenza viruses. As reports of most polymicrobial infections involving hRSV lack a molecular basis explaining the interaction between hRSV and these pathogens, we believe this review article can serve as a starting point to interesting and very much needed research in this area.

Host Components That Modulate the Disease Caused by hMPV.

Human metapneumovirus (hMPV) is one of the main pathogens responsible for acute respiratory infections in children up to 5 years of age, contributing substantially to health burden. The worldwide economic and social impact of this virus is significant and must be addressed. The structural components of hMPV (either proteins or genetic material) can be detected by several receptors expressed by host cells through the engagement of pattern recognition receptors. The recognition of the structural components of hMPV can promote the signaling of the immune response to clear the infection, leading to the activation of several pathways, such as those related to the interferon response. Even so, several intrinsic factors are capable of modulating the immune response or directly inhibiting the replication of hMPV. This article will discuss the current knowledge regarding the innate and adaptive immune response during hMPV infections. Accordingly, the host intrinsic components capable of modulating the immune response and the elements capable of restricting viral replication during hMPV infections will be examined.

Type I Natural Killer T Cells as Key Regulators of the Immune Response to Infectious Diseases.

The immune system must work in an orchestrated way to achieve an optimal response upon detection of antigens. The cells comprising the immune response are traditionally divided into two major subsets, innate and adaptive, with particular characteristics for each type. Type I natural killer T (iNKT) cells are defined as innate-like T cells sharing features with both traditional adaptive and innate cells, such as the expression of an invariant T cell receptor (TCR) and several NK receptors. The invariant TCR in iNKT cells interacts with CD1d, a major histocompatibility complex class I (MHC-I)-like molecule. CD1d can bind and present antigens of lipid nature and induce the activation of iNKT cells, leading to the secretion of various cytokines, such as gamma interferon (IFN-γ) and interleukin 4 (IL-4). These cytokines will aid in the activation of other immune cells following stimulation of iNKT cells. Several molecules with the capacity to bind to CD1d have been discovered, including α-galactosylceramide. Likewise, several molecules have been synthesized that are capable of polarizing iNKT cells into different profiles, either pro- or anti-inflammatory. This versatility allows NKT cells to either aid or impair the clearance of pathogens or to even control or increase the symptoms associated with pathogenic infections. Such diverse contributions of NKT cells to infectious diseases are supported by several publications showing either a beneficial or detrimental role of these cells during diseases. In this article, we discuss current data relative to iNKT cells and their features, with an emphasis on their driving role in diseases produced by pathogenic agents in an organ-oriented fashion.

Interim report: Safety and immunogenicity of an inactivated vaccine against SARS-CoV-2 in healthy chilean adults in a phase 3 clinical trial.

Background: The ongoing COVID-19 pandemic has had a significant impact worldwide, with an incommensurable social and economic burden. The rapid development of safe and protective vaccines against this disease is a global priority. CoronaVac is a vaccine prototype based on inactivated SARS-CoV-2, which has shown promising safety and immunogenicity profiles in pre-clinical studies and phase 1/2 trials in China. To this day, four phase 3 clinical trials are ongoing with CoronaVac in Brazil, Indonesia, Turkey, and Chile. This article reports the safety and immunogenicity results obtained in a subgroup of participants aged 18 years and older enrolled in the phase 3 Clinical Trial held in Chile. Methods: This is a multicenter phase 3 clinical trial. Healthcare workers aged 18 years and older were randomly assigned to receive two doses of CoronaVac or placebo separated by two weeks (0-14). We report preliminary safety results obtained for a subset of 434 participants, and antibody and cell-mediated immunity results obtained in a subset of participants assigned to the immunogenicity arm. The primary and secondary aims of the study include the evaluation of safety parameters and immunogenicity against SARS-CoV-2 after immunization, respectively. This trial is registered at clinicaltrials.gov ( NCT04651790 ). Findings: The recruitment of participants occurred between November 27 th , 2020, until January 9 th , 2021. 434 participants were enrolled, 397 were 18-59 years old, and 37 were ≥60 years old. Of these, 270 were immunized with CoronaVac, and the remaining 164 participants were inoculated with the corresponding placebo. The primary adverse reaction was pain at the injection site, with a higher incidence in the vaccine arm (55.6%) than in the placebo arm (40.0%). Moreover, the incidence of pain at the injection site in the 18-59 years old group was 58.4% as compared to 32.0% in the ≥60 years old group. The seroconversion rate for specific anti-S1-RBD IgG was 47.8% for the 18-59 years old group 14 days post immunization (p.i.) and 95.6% 28 and 42 days p.i. For the ≥60 years old group, the seroconversion rate was 18.1%, 100%, and 87.5% at 14, 28, and 42 days p.i., respectively. Importantly, we observed a 95.7% seroconversion rate in neutralizing antibodies for the 18-59 years old group 28 and 42 days p.i. The ≥60 years old group exhibited seroconversion rates of 90.0% and 100% at 28 and 42 days p.i. Interestingly, we did not observe a significant seroconversion rate of anti-N-SARS-CoV-2 IgG for the 18-59 years old group. For the participants ≥60 years old, a modest rate of seroconversion at 42 days p.i. was observed (37.5%). We observed a significant induction of a T cell response characterized by the secretion of IFN-γ upon stimulation with Mega Pools of peptides derived from SARS-CoV-2 proteins. No significant differences between the two age groups were observed for cell-mediated immunity. Interpretation: Immunization with CoronaVac in a 0-14 schedule in adults of 18 years and older in the Chilean population is safe and induces specific IgG production against the S1-RBD with neutralizing capacity, as well as the activation of T cells secreting IFN-γ, upon recognition of SARS-CoV-2 antigens. Funding: Ministry of Health of the Chilean Government; Confederation of Production and Commerce, Chile; Consortium of Universities for Vaccines and Therapies against COVID-19, Chile; Millennium Institute on Immunology and Immunotherapy.

The Role of Dendritic Cells During Infections Caused by Highly Prevalent Viruses.

Dendritic cells (DCs) are a type of innate immune cells with major relevance in the establishment of an adaptive response, as they are responsible for the activation of lymphocytes. Since their discovery, several reports of their role during infectious diseases have been performed, highlighting their functions and their mechanisms of action. DCs can be categorized into different subsets, and each of these subsets expresses a wide arrange of receptors and molecules that aid them in the clearance of invading pathogens. Interferon (IFN) is a cytokine -a molecule of protein origin- strongly associated with antiviral immune responses. This cytokine is secreted by different cell types and is fundamental in the modulation of both innate and adaptive immune responses against viral infections. Particularly, DCs are one of the most important immune cells that produce IFN, with type I IFNs (α and ß) highlighting as the most important, as they are associated with viral clearance. Type I IFN secretion can be induced via different pathways, activated by various components of the virus, such as surface proteins or genetic material. These molecules can trigger the activation of the IFN pathway trough surface receptors, including IFNAR, TLR4, or some intracellular receptors, such as TLR7, TLR9, and TLR3. Here, we discuss various types of dendritic cells found in humans and mice; their contribution to the activation of the antiviral response triggered by the secretion of IFN, through different routes of the induction for this important antiviral cytokine; and as to how DCs are involved in human infections that are considered highly frequent nowadays.

Innate Immune Components that Regulate the Pathogenesis and Resolution of hRSV and hMPV Infections.

The human respiratory syncytial virus (hRSV) and human Metapneumovirus (hMPV) are two of the leading etiological agents of acute lower respiratory tract infections, which constitute the main cause of mortality in infants. However, there are currently approved vaccines for neither hRSV nor hMPV. Moreover, despite the similarity between the pathology caused by both viruses, the immune response elicited by the host is different in each case. In this review, we discuss how dendritic cells, alveolar macrophages, neutrophils, eosinophils, natural killer cells, innate lymphoid cells, and the complement system regulate both pathogenesis and the resolution of hRSV and hMPV infections. The roles that these cells play during infections by either of these viruses will help us to better understand the illnesses they cause. We also discuss several controversial findings, relative to some of these innate immune components. To better understand the inflammation in the lungs, the role of the respiratory epithelium in the recruitment of innate immune cells is briefly discussed. Finally, we review the main prophylactic strategies and current vaccine candidates against both hRSV and hMPV.

Antibody development for preventing the human respiratory syncytial virus pathology.

Human respiratory syncytial virus (hRSV) is the most important etiological agent causing hospitalizations associated with respiratory diseases in children under 5 years of age as well as the elderly, newborns and premature children are the most affected populations. This viral infection can be associated with various symptoms, such as fever, coughing, wheezing, and even pneumonia and bronchiolitis. Due to its severe symptoms, the need for mechanical ventilation is not uncommon in clinical practice. Additionally, alterations in the central nervous system -such as seizures, encephalopathy and encephalitis- have been associated with cases of hRSV-infections. Furthermore, the absence of effective vaccines or therapies against hRSV leads to elevated expenditures by the public health system and increased mortality rates for the high-risk population. Along these lines, vaccines and therapies can elicit different responses to this virus. While hRSV vaccine candidates seek to promote an active immune response associated with the achievement of immunological memory, other therapies -such as the administration of antibodies- provide a protective environment, although they do not trigger the activation of the immune system and therefore do not promote an immunological memory. An interesting approach to vaccination is the use of virus-neutralizing antibodies, which inhibit the entry of the pathogen into the host cells, therefore impairing the capacity of the virus to replicate. Currently, the most common molecule targeted for antibody design against hRSV is the F protein of this virus. However, other molecular components of the virus -such as the G or the N hRSV proteins- have also been explored as potential targets for the control of this disease. Currently, palivizumab is the only monoclonal antibody approved for human use. However, studies in humans have shown a protective effect only after the administration of at least 3 to 5 doses, due to the stability of this vaccine. Furthermore, other studies suggest that palivizumab only has an effectiveness close to 50% in high-risk infants. In this work, we will review different strategies addressed for the use of antibodies in a prophylactic or therapeutic context and their ability to prevent the symptoms caused by hRSV infection of the airways, as well as in other tissues such as the CNS.

Contribution of Resident Memory CD8+ T Cells to Protective Immunity Against Respiratory Syncytial Virus and Their Impact on Vaccine Design.

Worldwide, human respiratory syncytial virus (RSV) is the most common etiological agent for acute lower respiratory tract infections (ALRI). RSV-ALRI is the major cause of hospital admissions in young children, and it can cause in-hospital deaths in children younger than six months old. Therefore, RSV remains one of the pathogens deemed most important for the generation of a vaccine. On the other hand, the effectiveness of a vaccine depends on the development of immunological memory against the pathogenic agent of interest. This memory is achieved by long-lived memory T cells, based on the establishment of an effective immune response to viral infections when subsequent exposures to the pathogen take place. Memory T cells can be classified into three subsets according to their expression of lymphoid homing receptors: central memory cells (TCM), effector memory cells (TEM) and resident memory T cells (TRM). The latter subset consists of cells that are permanently found in non-lymphoid tissues and are capable of recognizing antigens and mounting an effective immune response at those sites. TRM cells activate both innate and adaptive immune responses, thus establishing a robust and rapid response characterized by the production of large amounts of effector molecules. TRM cells can also recognize antigenically unrelated pathogens and trigger an innate-like alarm with the recruitment of other immune cells. It is noteworthy that this rapid and effective immune response induced by TRM cells make these cells an interesting aim in the design of vaccination strategies in order to establish TRM cell populations to prevent respiratory infectious diseases. Here, we discuss the biogenesis of TRM cells, their contribution to the resolution of respiratory viral infections and the induction of TRM cells, which should be considered for the rational design of new vaccines against RSV.