The role of vaccination route with an adenovirus-vectored vaccine in protection, viral control, and transmission in the SARS-CoV-2/K18-hACE2 mouse infection model

IntroductionVaccination is the most effective mechanism to prevent severe COVID-19. However, breakthrough infections and subsequent transmission of SARS-CoV-2 remain a significant problem. Intranasal vaccination has the potential to be more effective in preventing disease and limiting transmission between individuals as it induces potent responses at mucosal sites.MethodsUtilizing a replication-deficient adenovirus serotype 5-vectored vaccine expressing the SARS-CoV-2 RBD (AdCOVID) in homozygous and heterozygous transgenic K18-hACE2, we investigated the impact of the route of administration on vaccine immunogenicity, SARS-CoV-2 transmission, and survival.ResultsMice vaccinated with AdCOVID via the intramuscular or intranasal route and subsequently challenged with SARS-CoV-2 showed that animals vaccinated intranasally had improved cellular and mucosal antibody responses. Additionally, intranasally vaccinated animals had significantly better viremic control, and protection from lethal infection compared to intramuscularly vaccinated animals. Notably, in a novel transmission model, intranasal vaccination reduced viral transmission to naïve co-housed mice compared to intramuscular vaccination.DiscussionOur data provide convincing evidence for the use of intranasal vaccination in protecting against SARS-CoV-2 infection and transmission

Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population

The SARS CoV-2 antibody and CD4+ T cell responses induced by natural infection and/or vaccination decline over time and cross-recognize other viral variants at different levels. However, there are few studies evaluating the levels and durability of the SARS CoV-2-specific antibody and CD4+ T cell response against the Mu, Gamma, and Delta variants. Here, we examined, in two ambispective cohorts of naturally-infected and/or vaccinated individuals, the titers of anti-RBD antibodies and the frequency of SARS-CoV-2-specific CD4+ T cells up to 6 months after the last antigen exposure. In naturally-infected individuals, the SARS-CoV-2 antibody response declined 6 months post-symptoms onset. However, the kinetic observed depended on the severity of the disease, since individuals who developed severe COVID-19 maintained the binding antibody titers. Also, there was detectable binding antibody cross-recognition for the Gamma, Mu, and Delta variants, but antibodies poorly neutralized Mu. COVID-19 vaccines induced an increase in antibody titers 15-30 days after receiving the second dose, but these levels decreased at 6 months. However, as expected, a third dose of the vaccine caused a rise in antibody titers. The dynamics of the antibody response upon vaccination depended on the previous SARS-CoV-2 exposure. Lower levels of vaccine-induced antibodies were associated with the development of breakthrough infections. Vaccination resulted in central memory spike-specific CD4+ T cell responses that cross-recognized peptides from the Gamma and Mu variants, and their duration also depended on previous SARS-CoV-2 exposure. In addition, we found cross-reactive CD4+ T cell responses in unexposed and unvaccinated individuals. These results have important implications for vaccine design for new SARS-CoV-2 variants of interest and concern

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

mRNA induced expression of human angiotensin-converting enzyme 2 in mice for the study of the adaptive immune response to severe acute respiratory syndrome coronavirus 2.

The novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic. Critical to the rapid evaluation of vaccines and antivirals against SARS-CoV-2 is the development of tractable animal models to understand the adaptive immune response to the virus. To this end, the use of common laboratory strains of mice is hindered by significant divergence of the angiotensin-converting enzyme 2 (ACE2), which is the receptor required for entry of SARS-CoV-2. In the current study, we designed and utilized an mRNA-based transfection system to induce expression of the hACE2 receptor in order to confer entry of SARS-CoV-2 in otherwise non-permissive cells. By employing this expression system in an in vivo setting, we were able to interrogate the adaptive immune response to SARS-CoV-2 in type 1 interferon receptor deficient mice. In doing so, we showed that the T cell response to SARS-CoV-2 is enhanced when hACE2 is expressed during infection. Moreover, we demonstrated that these responses are preserved in memory and are boosted upon secondary infection. Importantly, using this system, we functionally identified the CD4+ and CD8+ structural peptide epitopes targeted during SARS-CoV-2 infection in H2b restricted mice and confirmed their existence in an established model of SARS-CoV-2 pathogenesis. We demonstrated that, identical to what has been seen in humans, the antigen-specific CD8+ T cells in mice primarily target peptides of the spike and membrane proteins, while the antigen-specific CD4+ T cells target peptides of the nucleocapsid, membrane, and spike proteins. As the focus of the immune response in mice is highly similar to that of the humans, the identification of functional murine SARS-CoV-2-specific T cell epitopes provided in this study will be critical for evaluation of vaccine efficacy in murine models of SARS-CoV-2 infection

Cross-reactive humoral and CD4+ T cell responses to Mu and Gamma SARS-CoV-2 variants in a Colombian population

Las respuestas del anticuerpo SARS CoV-2 y de las células T CD4 + inducidas por la infección natural y/o la vacunación disminuyen con el tiempo y reconocen de forma cruzada otras variantes virales en diferentes niveles. Sin embargo, existen pocos estudios que evalúen los niveles y la durabilidad del anticuerpo específico del SARS CoV-2 y la respuesta de las células T CD4 + contra las variantes Mu, Gamma y Delta. Aquí, examinamos, en dos cohortes ambispectivas de individuos infectados naturalmente y/o vacunados, los títulos de anticuerpos anti-RBD y la frecuencia de células T CD4+ específicas del SARS-CoV-2 hasta 6 meses después de la última exposición al antígeno . . En personas infectadas de forma natural, la respuesta de anticuerpos contra el SARS-CoV-2 disminuyó 6 meses después de la aparición de los síntomas. Sin embargo, la cinética observada dependió de la gravedad de la enfermedad, ya que los individuos que desarrollaron COVID-19 grave mantuvieron los títulos de anticuerpos vinculantes. Además, hubo reconocimiento cruzado de anticuerpos de unión detectables para las variantes Gamma, Mu y Delta, pero los anticuerpos neutralizaron mal a Mu. Las vacunas COVID-19 indujeron un aumento en los títulos de anticuerpos entre 15 y 30 días después de recibir la segunda dosis, pero estos niveles disminuyeron a los 6 meses. Sin embargo, como se esperaba, una tercera dosis de la vacuna provocó un aumento en los títulos de anticuerpos. La dinámica de la respuesta de anticuerpos tras la vacunación dependió de la exposición previa al SARS-CoV-2. Los niveles más bajos de anticuerpos inducidos por la vacuna se asociaron con el desarrollo de infecciones irruptivas. La vacunación dio lugar a respuestas de células T CD4 + específicas de picos de memoria central que reconocían de forma cruzada péptidos de las variantes Gamma y Mu, y su duración también dependía de la exposición previa al SARS-CoV-2. Además, encontramos respuestas de células T CD4 + con reactividad cruzada en individuos no expuestos y no vacunados. Estos resultados tienen implicaciones importantes para el diseño de vacunas para las nuevas variantes de interés y preocupación del SARS-CoV-2.Q1Q1The SARS CoV-2 antibody and CD4+ T cell responses induced by natural infection and/or vaccination decline over time and cross-recognize other viral variants at different levels. However, there are few studies evaluating the levels and durability of the SARS CoV-2-specific antibody and CD4+ T cell response against the Mu, Gamma, and Delta variants. Here, we examined, in two ambispective cohorts of naturally-infected and/or vaccinated individuals, the titers of anti-RBD antibodies and the frequency of SARS-CoV-2-specific CD4+ T cells up to 6 months after the last antigen exposure. In naturally-infected individuals, the SARS-CoV-2 antibody response declined 6 months post-symptoms onset. However, the kinetic observed depended on the severity of the disease, since individuals who developed severe COVID-19 maintained the binding antibody titers. Also, there was detectable binding antibody cross-recognition for the Gamma, Mu, and Delta variants, but antibodies poorly neutralized Mu. COVID-19 vaccines induced an increase in antibody titers 15-30 days after receiving the second dose, but these levels decreased at 6 months. However, as expected, a third dose of the vaccine caused a rise in antibody titers. The dynamics of the antibody response upon vaccination depended on the previous SARS-CoV-2 exposure. Lower levels of vaccine-induced antibodies were associated with the development of breakthrough infections. Vaccination resulted in central memory spike-specific CD4+ T cell responses that cross-recognized peptides from the Gamma and Mu variants, and their duration also depended on previous SARS-CoV-2 exposure. In addition, we found cross-reactive CD4+ T cell responses in unexposed and unvaccinated individuals. These results have important implications for vaccine design for new SARS-CoV-2 variants of interest and concern.Revista Internacional - IndexadaS

Proposed Revision of the Esophageal Cancer Staging System to Accommodate Pathologic Response (pP) Following Preoperative Chemoradiation (CRT)

OBJECTIVE: To determine the impact of pathologic response following preoperative chemoradiation (CRT) on the AJCC esophageal cancer staging system. SUMMARY BACKGROUND DATA: Increasing numbers of locoregionally advanced esophageal cancer patients are treated with preoperative CRT prior to surgical resection. METHODS: Five hundred ninety-three pts from 1985 to 2003 with esophageal cancer who underwent surgery with (n = 239) or without CRT (n = 354) were reviewed. Resected esophageal tumors were assessed for pathologic response by determining extent of residual tumor following CRT (P0, 0% residual; P1, 1%–50% residual; P2, >50% residual). RESULTS: After CRT down-staging, pTNM specific survival was similar, irrespective of treatment group (P = 0.98). The pTNM stage distribution was more favorable in the CRT group (P < 0.001) despite a more advanced initial cTNM stage distribution (P < 0.001). Following CRT, the pathologic response (pP) at the primary tumor as defined by extent of residual tumor predicted overall survival (3 years: P0, 0% residual = 74%; P1, 1%–50% residual = 54%; P2, >50% residual = 24%, P < 0.001) and stage specific survival with greater accuracy than pTNM stage alone. CONCLUSIONS: Our analyses demonstrate that following CRT, pTNM continues to predict survival. The extent of pathologic response following CRT is an independent risk factor for survival (pP) and should be incorporated in the pTNM esophageal cancer staging system to better predict patient outcome in esophageal cancer