Evaluación de la efectividad de las vacunas contra la COVID-19: orientación provisional / Evaluation of COVID-19 vaccine effectiveness

En este documento se presenta orientación provisional sobre las mejores prácticas para evaluar la efectividad de las vacunas contra la COVID-19 usando el diseño de estudio observacional. Se examinan las consideraciones esenciales del diseño, el análisis y la interpretación de las evaluaciones de la efectividad de las vacunas contra la COVID-19, dado que se pueden obtener resultados sesgados aun en entornos en los que la exhaustividad y la calidad de los datos son altas. Esta orientación se dirige principalmente a las evaluaciones realizadas en los países de ingresos bajos o medianos, pero la mayoría de los conceptos también son aplicables en entornos de ingresos altos.

Since its emergence in December 2019, SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), has taken a tremendous toll globally; by 28 February 2021, there have been over 110 million cases and 2.5 million deaths worldwide from COVID-19 (1). Although most COVID-19 deaths occur among older adults and persons with chronic comorbid medical conditions, deaths have occurred in persons of all ages. Moreover, the pandemic has caused widespread morbidity and necessitated control measures that have devastated economies worldwide. In response to the pandemic, the global efforts to develop multiple vaccines to protect against COVID-19 disease have been unrivalled in the history of public health. By the end of 2020, three COVID-19 vaccines have received Emergency Use Approval/Listing (EUA/EUL) by maturity level 4 regulatory authorities, based on reaching predefined criteria for safety and efficacy, and at least several dozen more are in clinical trials.

Role of T. cruzi exposure in the pattern of T cell cytokines among chronically infected HIV and Chagas disease patients

OBJECTIVES: The impact of Chagas disease (CD) in HIV-infected patients is relevant throughout the world. In fact, the characterization of the adaptive immune response in the context of co-infection is important for predicting the need for interventions in areas in which HIV and Chagas disease co-exist. METHODS: We described and compared the frequency of cytokine-producing T cells stimulated with soluble antigen of Trypanosoma cruzi (T. cruzi) using a cytometric assay for the following groups: individuals with chronic Chagas disease (CHR, n=10), those with Chagas disease and HIV infection (CO, n=11), those with only HIV (HIV, n=14) and healthy individuals (C, n=15). RESULTS: We found 1) a constitutively lower frequency of IL-2+ and IFN-γ+ T cells in the CHR group compared with the HIV, CO and healthy groups; 2) a suppressive activity of soluble T. cruzi antigen, which down-regulated IL-2+CD4+ and IFN-γ+CD4+ phenotypes, notably in the healthy group; 3) a down-regulation of inflammatory cytokines on CD8+ T cells in the indeterminate form of Chagas disease; and 4) a significant increase in IL-10+CD8+ cells distinguishing the indeterminate form from the cardiac/digestive form of Chagas disease, even in the presence of HIV infection. CONCLUSIONS: Taken together, our data suggest the presence of an immunoregulatory response in chronic Chagas disease, which seems to be driven by T. cruzi antigens. Our findings provide new insights into immunotherapeutic strategies for people living with HIV/AIDS and Chagas disease.

Plasticity of neutrophils reveals modulatory capacity

Neutrophils are widely known as proinflammatory cells associated with tissue damage and for their early arrival at sites of infection, where they exert their phagocytic activity, release their granule contents, and subsequently die. However, this view has been challenged by emerging evidence that neutrophils have other activities and are not so short-lived. Following activation, neutrophil effector functions include production and release of granule contents, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs). Neutrophils have also been shown to produce a wide range of cytokines that have pro- or anti-inflammatory activity, adding a modulatory role for this cell, previously known as a suicide effector. The presence of cytokines almost always implies intercellular modulation, potentially unmasking interactions of neutrophils with other immune cells. In fact, neutrophils have been found to help B cells and to modulate dendritic cell (DC), macrophage, and T-cell activities. In this review, we describe some ways in which neutrophils influence the inflammatory environment in infection, cancer, and autoimmunity, regulating both innate and adaptive immune responses. These cells can switch phenotypes and exert functions beyond cytotoxicity against invading pathogens, extending the view of neutrophils beyond suicide effectors to include functions as regulatory and suppressor cells.

Evasión de la respuesta inmune por virus herpes simplex / Immune evasion by herpes simplex viruses

Herpes simplex viruses and humans have co-existed for tens of thousands of years. This long relationship has translated into the evolution and selection of viral determinants to evade the host immune response and reciprocally the evolution and selection of host immune components for limiting virus infection and damage. Currently there are no vaccines available to avoid infection with these viruses or therapies to cure them. Herpes simplex viruses are neurotropic and reside latently in neurons at the trigeminal and dorsal root ganglia, occasionally reactivating. Most viral recurrences are subclinical and thus, unnoticed. Here, we discuss the initial steps of infection by herpes simplex viruses and the molecular mechanisms they have developed to evade innate and adaptive immunity. A better understanding of the molecular mechanisms evolved by these viruses to evade host immunity should help us envision novel vaccine strategies and therapies that limit infection and dissemination.

Los virus herpes simplex y humanos co-existen desde decenas de miles de años. Esta prolongada relación se ha traducido en la evolución y selección de determinantes virales para evadir la respuesta inmune y recíprocamente la evolución y selección de componentes inmunes del hospedero para limitar la infección viral y el daño que producen. Actualmente no existen vacunas para evitar la infección de estos virus o terapias que la curen. Los virus herpes simplex son neurotrópicos y permanecen latentes en neuronas de ganglios trigémino y dorsales, reactivándose esporádicamente. La mayoría de las recurrencias por virus herpes simplex son sub-clínicas y por tanto pasan inadvertidas. Aquí discutimos los pasos iniciales de la infección porvirus herpes simplex y los mecanismos moleculares que estos virus han desarrollado para evadir la respuesta inmune innata y adaptativa. Una mejor comprensión de los mecanismos moleculares evolucionados por estos virus para evadir la respuesta inmune del hospedero deberían ayudarnos visualizar nuevas estrategias para desarrollar vacunas y terapias que limiten su infección y diseminación.

Inmunología perinatal / Perinatal immunology

Se ha considerado que el útero gestante es un lugar inmunológicamente privilegiado, donde el feto es protegido del rechazo por el sistema inmune materno, mediante un amplio repertorio de estrategias de evasión que contribuye a la sobrevivencia del feto. La gestación en sí misma constituye un acontecimiento de equilibrio inmunológico y la tolerancia inmunológica permite la progresión del embarazo, donde participan una secuencia sincronizada de eventos que se inicia desde la concepción y fertilización para dar lugar a la implantación y progresa hasta alcanzar un embarazo a término. El sistema inmune es la principal barrera que poseemos para protegernos de las infecciones. Durante la vida intrauterina, el feto está protegido por la madre de las agresiones externas, por lo que no necesita que su sistema inmunológico sea operativo, sin embargo, al nacer, recibe una avalancha de elementos extraños, por lo que necesitará disponer de cierta protección, así como una preparación para ejecutar las defensas necesarias para su protección inmunológica. La inmunidad sérica durante la vida fetal queda limitada a la transferencia a través de la placenta de IgG materna, a pesar de que el feto tiene la facultad de sintetizar inmunoglobulinas desde las primeras etapas de la gestación. Al nacimiento, el niño tiene su sistema inmunológico completo, aunque inmaduro, pero es capaz de responder a los estímulos antigénicos. Tiene múltiples anormalidades en el desarrollo de su sistema inmune, que involucran a los anticuerpos/inmunoglobulinas, complemento y granulocitos pudiendo contribuir a la alta incidencia de sus infecciones. El recién nacido carece de memoria inmunológica debido a que, en condiciones normales, el feto está exento de estímulos producidos por antígenos extraños. Dicha memoria se va adquiriendo a medida que entra en contacto con los diferentes antígenos. Se obtendrá cierta protección a las infecciones entéricas gracias a las IgA que aporta la lactancia materna. La exposición prenatal y postnatal a productos microbianos ambientales que pueden activar la inmunidad innata, puede acelerar el proceso de maduración del sistema inmune.(AU)

It has been considered the pregnant women`s womb as an immunological exceptional place, where fetus is protected against been rejected because of maternal immune system by means of a wide groups of evasive strategies that help in its survival. Pregnancy itself is an immunological equilibrium state and the immunological tolerance allow the progression of this event, where participate a synchronized sequence of biological events started from conception and fertilization to allow the implantation, and progress until to reach the pregnancy end. The immune system is our main barrier against infections. During intrauterine life fetus is protected by the mother against external aggressions, therefore he don`t need an operative immune system, nevertheless, at birth the new organisms receive an avalanche of strange elements needing some kind of protection as well as a preparation to carry out the necessary defense for his immunological protection. Serum immunity during fetal life is limited to the transference of maternal IgG through placenta, despite fetus capability to synthesize immunoglobulins from first stages of gestation. At birth the babe has a complete immunological system although immature but capable to respond to antigenic stimulus. He has multiples abnormalities in the immune system development that take account antibodies/immunoglobulin, complement and granulocytes contributing to his high incidence of infections. Newborn lack immunological memory because in normal conditions fetus is not stimulated by odd antigens. This memory is acquired through the contact with different antigens. It will be obtained some protection against enteric infections because IgA from maternal lactation. The prenatal and postnatal exposition to environmental microbial products that activate the innate immunity can accelerate the immune system maturing process.(AU)

Modulation of cell proliferation, survival and gene expression by RAGE and TLR signaling in cells of the innate and adaptive immune response: role of p38 MAPK and NF-KB

Objective: The aim of this study was to evaluate a possible synergism between AGE-RAGE and TLR4 signaling and the role of p38 MAPK and NF-kB signaling pathways on the modulation of the expression of inflammatory cytokines and proliferation of cells from the innate and adaptive immune response. Material and Methods: T lymphocyte (JM) and monocyte (U937) cell lines were stimulated with LPS and AGE-BSA independently and associated, both in the presence and absence of p38 MAPK and NF-kB inhibitors. Proliferation was assessed by direct counting and viability was assessed by a biochemical assay of mitochondrial function. Cytokine gene expression for RAGe, CCL3, CCR5, IL-6 and TNF-α was studied by RT-PCR and RT-qPCR. Results: RAGE mRNA expression was detected in both cell lines. LPS and AGE-BSA did not influence cell proliferation and viability of either cell line up to 72 hours. LPS and LPS associated with AGE induced expression of IL-6 and TNF-α in monocytes and T cells, respectively. Conclusions: There is no synergistic effect between RAGE and TLR signaling on the expression of IL-6, TNF-α , RAGE, CCR5 and CCL3 by monocytes and lymphocytes. Activation of RAGE associated or not with TLR signaling also had no effect on cell proliferation and survival of these cell types. .

Proposed method for agglutinating antibody titer analysis and its use as indicator of acquired immunity in pacu, Piaractus mesopotamicus / Aglutinante de anticorpos como indicador de imunidade adquirida de pacu Piaractus mesopotamicus

Antibody can be assessed by agglutinating antibody titer which is a quantitative measure of circulating antibodies in serum from fish previously immunized. The antibody evaluation has been performed with different fish species, and is considered a reliable method that can be applied to confirm several hypothesis regarding acquired immunity, even in conjunction with precise methods to describe immune mechanisms. In order to provide appropriate analytical methods for future studies on the specific immune system of native fish, the present study standardized on assay to measure the serum agglutinating antibody titer produced after immunization with inactivated A. hydrophila and levamisole administration in pacu. It was possible to determine the agglutinating antibodies titer in a satisfactorily way in pacu immunized with inactive A. hydrophila, and the highest titers were observed on fish fed with levamisole.

Os anticorpos podem ser avaliados pelo título aglutinante de anticorpos, que é uma medida quantitativa de anticorpos no soro de peixe previamente imunizados. A determinação do título de anticorpos foi realizada com diversas espécies de peixes e é considerado um método confiável que pode ser aplicado para confirmar diversas hipóteses que envolvam o sistema adquirido de defesa, mesmo em conjunto com métodos precisos, para descrever mecanismos imunes. A fim de prover métodos analíticos adequados para futuros estudos sobre o sistema imune específico de peixes nativos, o presente estudo aperfeiçoou o ensaio para avaliar o título aglutinante de anticorpos em soro de pacu imunizados com A. hydrophila e alimentados com levamisol. Foi possível determinar o título aglutinante de anticorpos de forma satisfatória, em pacus imunizados com A. hydrophila inativa, e os maiores títulos foram observados em peixes alimentados com levamisol.

Innate and adaptive immunity gene expression of human keratinocytes cultured of severe burn injury

PURPOSE: Evaluate the expression profile of genes related to Innate and Adaptive Immune System (IAIS) of human Primary Epidermal keratinocytes (hPEKP) of patients with severe burns. METHODS: After obtaining viable fragments of skin with and without burning, culture hKEP was initiated by the enzymatic method using Dispase (Sigma-Aldrich). These cells were treated with Trizol(r) (Life Technologies) for extraction of total RNA. This was quantified and analyzed for purity for obtaining cDNA for the analysis of gene expression using specific IAIS PCR Arrays plates (SA Biosciences). RESULTS: After the analysis of gene expression we found that 63% of these genes were differentially expressed, of which 77% were repressed and 23% were hyper-regulated. Among these, the following genes (fold increase or decrease): IL8 (41), IL6 (32), TNF (-92), HLA-E (-86), LYS (-74), CCR6 (- 73), CD86 (-41) and HLA-A (-35). CONCLUSIONS: This study contributes to the understanding of the molecular mechanisms underlying wound infection caused by the burn. Furthermore, it may provide new strategies to restore normal expression of these genes and thereby change the healing process and improve clinical outcome. .

Immune Response and the Tumor Microenvironment: How They Communicate to Regulate Gastric Cancer

Gastric cancer is the second most common cause of cancer-related death in the world. A growing body of evidence indicates that inflammation is closely associated with the initiation, progression, and metastasis of many tumors, including those of gastric cancer. In addition, approximately 60% of the world's population is colonized by Helicobacter pylori, which accounts for more than 50% of gastric cancers. While the role of inflammation in intestinal and colonic cancers is relatively well defined, its role in stomach neoplasia is still unclear because of the limited access of pathogens to the acidic environment and the technical difficulties isolating and characterizing immune cells in the stomach, especially in animal models. In this review, we will provide recent updates addressing how inflammation is involved in gastric malignancies, and what immune characteristics regulate the pathogenesis of stomach cancer. Also, we will discuss potential therapeutics that target the immune system for the efficient treatment of gastric cancer.

Autophagy in Innate Recognition of Pathogens and Adaptive Immunity

Autophagy is a specialized cellular pathway involved in maintaining homeostasis by degrading long-lived cellular proteins and organelles. Recent studies have demonstrated that autophagy is utilized by immune systems to protect host cells from invading pathogens and regulate uncontrolled immune responses. During pathogen recognition, induction of autophagy by pattern recognition receptors leads to the promotion or inhibition of consequent signaling pathways. Furthermore, autophagy plays a role in the delivery of pathogen signatures in order to promote the recognition thereof by pattern recognition receptors. In addition to innate recognition, autophagy has been shown to facilitate MHC class II presentation of intracellular antigens to activate CD4 T cells. In this review, we describe the roles of autophagy in innate recognition of pathogens and adaptive immunity, such as antigen presentation, as well as the clinical relevance of autophagy in the treatment of human diseases.

Trends in adjuvant development for vaccines: DAMPs and PAMPs as potential new adjuvants

Aluminum salts have been widely used in vaccine formulations and, after their introduction more than 80 years ago, only few vaccine formulations using new adjuvants were developed in the last two decades. Recent advances in the understanding of how innate mechanisms influence the adaptive immunity opened up the possibility for the development of new adjuvants in a more rational design. The purpose of this review is to discuss the recent advances in this field regarding the attempts to determine the molecular basis and the general mechanisms underlying the development of new adjuvants, with particular emphasis on the activation of receptors of innate immune recognition. One can anticipate that the use of these novel adjuvants will also provide a window of opportunities for the development of new vaccines.

Immune response to Leishmania (Leishmania) chagasi infection is reduced in malnourished BALB/c mice

Protein-energy malnutrition and micronutrient deficiencies may down-regulate immune response and increase morbidity and mortality due to infection. In this study, a murine model was used to study the effects of protein, iron and zinc deficiencies on the immune response to Leishmania (Leishmania) chagasi infection. Mice were initially fed a standard diet or with a diet containing 3 percent casein but deficient in zinc and iron. After malnutrition was established, mice were inoculated with L. chagasiand sacrificed four weeks later in order to evaluate liver and spleen parasite loads and serum biochemical parameters. Significant decreases in liver and spleen weight, an increase in the parasite loads in these organs and decreases in serum protein and glucose concentrations in malnourished animals were observed. Furthermore, the production of interferon-gamma by spleen cells from infected malnourished mice stimulated by Leishmaniaantigen was significantly lower compared with that in control diet mice. These data suggest that malnutrition alters the immune response to L. chagasiinfection in the BALB/c model and, in association with the effects on biochemical and anatomical parameters of the host, favored increases in the parasite loads in the spleens and livers of these animals.