ABSTRACT
Objectives To develop and probe the first computerised decision-support tool to provide antidepressant treatment guidance to GPs in UK primary care. Design A parallel group, cluster-randomised controlled feasibility trial, where individual participants were blind to treatment allocation. Setting South London NHS GP practices. Participants Ten practices and eighteen patients with treatment-resistant current major depressive disorder (MDD). Interventions Practices were randomised to two treatment arms: 1) treatment-as-usual, 2) computerised decision support tool. Results Ten GP practices participated in the trial, which was within our target range (8-20). However, practice and patient recruitment were slower than anticipated and only 18 of 86 intended patients were recruited. This was due to fewer than expected patients being eligible for the study, as well as disruption resulting from the Covid-19 pandemic. Only one patient was lost to follow-up. There were no serious or medically important adverse events during the trial. GPs in the ‘Decision tool’ arm indicated moderate support for the tool. A minority of patients fully engaged with the mobile app-based tracking of symptoms, medication adherence and side effects. Conclusions Overall, the trial is not feasible in the current form and would need to be modified as follows to overcome its limitations: 1) inclusion of patients who have only tried one SSRI, rather than two, to improve recruitment and pragmatic relevance of the study, 2) approaching community pharmacists to implement tool recommendations rather than GPs, 3) further funding to directly interface between the decision support tool and self-reported symptom app, 4) increasing the geographic reach by not requiring detailed diagnostic assessments and replacing this with supported remote self-report. Ethics and dissemination The study has received NHS ethical approval from the London - Camberwell St Giles Research Ethics Committee (ref:17/LO/2074). Trial registration number ClinicalTrials.gov Identifier: NCT03628027 Strengths and limitations of this study The Antidepressant Advisor tool was incorporated into an existing GP healthcare record system for ease of use by GPs We were unable to recruit a sufficient number of participants to estimate effect sizes for future trials The eligibility criteria for participants to have tried two antidepressants before entering the study limited the number of eligible participants
Subject(s)
COVID-19 , Depressive Disorder , Depressive Disorder, MajorABSTRACT
Omicron spike (S) encoding vaccines as boosters, are a possible strategy to improve COVID-19 vaccine efficacy against Omicron. Here, non-human primates immunized twenty months earlier with Ad26.COV2.S, were boosted with Ad26.COV2.S, Ad26.COV2.S.529 (encoding Omicron BA.1 S) or a combination of both vaccines. All vaccines elicited a rapid increase in WA1/2020 and Omicron S antibody titers; Omicron BA.1 and BA.2 antibody responses were most effectively boosted by vaccines including Ad26.COV2.S.529. Independent of vaccine used, mostly WA1/2020-reactive or WA1/2020 and Omicron BA.1 cross-reactive B cells were detected. Boosting with vaccines including Ad26.COV2.S.529 provided slightly higher protection of the lower respiratory tract against Omicron BA.1 challenge compared with Ad26.COV2.S. Antibodies and cellular immune responses were identified as complementary correlates of protection. Overall, a booster with an Omicron-spike based vaccine provided moderately improved immune responses and protection compared with the original Wuhan-spike based vaccine, which still provided robust immune responses and protection against Omicron infection.
Subject(s)
Poult Enteritis Mortality Syndrome , COVID-19ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant sparked concern due to its fast spread and the unprecedented number of mutations in the spike protein that enables it to partially evade spike-based COVID-19 vaccine-induced humoral immunity. In anticipation of a potential need for an Omicron spike-based vaccine, we generated an Ad26 vector encoding an Omicron (BA.1) spike protein (Ad26.COV2.S.529). Ad26.COV2.S.529 encodes for a prefusion stabilized spike protein, similar to the current COVID-19 vaccine Ad26.COV2.S encoding the Wuhan-Hu-1 spike protein. We verified that spike expression by Ad26.COV2.S.529 was comparable to Ad26.COV2.S. Immunogenicity of Ad26.COV2.S.529 was then evaluated in naive mice and SARS-CoV-2 Wuhan-Hu-1 spike pre-immunized hamsters. In naive mice, Ad26.COV2.S.529 elicited robust neutralizing antibodies against SARS-CoV-2 Omicron (BA.1) but not to SARS-CoV-2 Delta (B.1.617.2), while the opposite was observed for Ad26.COV2.S. In pre-immune hamsters, Ad26.COV2.S.529 vaccination resulted in robust increases in neutralizing antibody titers against both SARS-CoV-2 Omicron (BA.1) and Delta (B.1.617.2), while Ad26.COV2.S vaccination only increased neutralizing antibody titers against the Delta variant. Our data imply that Ad26.COV2.S.529 can both expand and boost a Wuhan-Hu-1 spike-primed humoral immune response to protect against distant SARS-CoV-2 variants.
Subject(s)
Coronavirus Infections , Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
Background: The potentially devastating impact of novel coronavirus disease 2019 (COVID-19) has led to wide-spread concern about how individuals’ mental health will be affected. Evidence suggests that mental health in the general population has worsened due to enforced isolation during this pandemic, but it remains unknown how lockdown measures have specifically affected the wellbeing of children and adolescents.Methods: This longitudinal study investigated the psychological impact and mental health status of 1349 adolescents before, during and after the Chinese lockdown from 21 January 2020 to 13 April 2020 and identified risk and protective factors.Outcomes: Counter to our expectations, during the lockdown, school closures had a beneficial effect by reducing depression and anxiety symptoms, whereas the lockdown itself, online learning, and tracking of health information worsened these outcomes as expected. Compared with before the pandemic, unexpectedly, an overall decrease in depressive and anxiety symptoms, state anhedonia, and bullying victimization were found before, during and after lockdown. Protective factors included positive attributional style, whereas COVID-19-related stressors, anhedonia, negative attributional style, bullying, bullying victimization and schizotypal personality traits were potential risk factors.Interpretation: The decrease in emotional and behavioural problems relative to previous trends indicated that school closures may have improved the mental health of adolescents in China overall. The results investigated risk and protective factors related to COVID-19 that may better protect children and adolescents. Funding: Social Science Foundation of Hunan ProvinceDeclaration of Interests: There are no conflicts of interest specifically related to this work.Ethics Approval Statement: The study was approved by the Wenzhou Medical University ethics committee (2020-131).
Subject(s)
COVID-19 , Anxiety Disorders , Intellectual Disability , AnhedoniaABSTRACT
The first COVID-19 vaccines have recently gained authorization for emergency use.1,2 At this moment, limited knowledge on duration of immunity and efficacy of these vaccines is available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short lived,3,4 and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection.5 Here we model the relationship between immunogenicity and protective efficacy of a series of Ad26 vectors encoding stabilized variants of the SARS-CoV-2 Spike (S) protein in rhesus macaques6,7,8 and validate the analyses by challenging macaques 6 months after immunization with the Ad26.COV2.S vaccine candidate that has been selected for clinical development. We find that Ad26.COV2.S confers durable protection against replication of SARS-CoV-2 in the lungs that is predicted by the levels of S-binding and neutralizing antibodies. These results suggest that Ad26.COV2.S could confer durable protection in humans and that immunological correlates of protection may enable the prediction of durability of protection.
Subject(s)
COVID-19 , Severe Acute Respiratory SyndromeABSTRACT
The development of effective countermeasures against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the agent responsible for the COVID-19 pandemic, is a priority. We designed and produced ConVac, a replication-competent vesicular stomatitis virus (VSV) vaccine vector that expresses the S1 subunit of SARS-CoV-2 spike protein. We used golden Syrian hamsters as animal model of severe COVID-19 to test the efficacy of the ConVac vaccine. A single vaccine dose elicited high levels of SARS-CoV-2 specific binding and neutralizing antibodies; following intranasal challenge with SARS-CoV-2, animals were protected from weight loss and viral replication in the lungs. No enhanced pathology was observed in vaccinated animals upon challenge, but some inflammation was still detected. The data indicate rapid control of SARS-CoV-2 replication by the S1-based VSV-vectored SARS-CoV-2 ConVac vaccine.
Subject(s)
Coronavirus Infections , Severe Acute Respiratory Syndrome , Vesicular Stomatitis , Weight Loss , COVID-19 , InflammationABSTRACT
We previously reported that a single immunization with an adenovirus serotype 26 (Ad26) vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge. In this study, we evaluated the immunogenicity and protective efficacy of reduced doses of Ad26.COV2.S. 30 rhesus macaques were immunized once with 1×10 11 , 5×10 10 , 1.125×10 10 , or 2×10 9 vp Ad26.COV2.S or sham and were challenged with SARS-CoV-2 by the intranasal and intratracheal routes. Vaccine doses as low as 2×10 9 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125×10 10 vp were required for protection in nasal swabs. Activated memory B cells as well as binding and neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show evidence of virologic, immunologic, histopathologic, or clinical enhancement of disease compared with sham controls. These data demonstrate that a single immunization with a relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques. Moreover, our findings show that a higher vaccine dose may be required for protection in the upper respiratory tract compared with the lower respiratory tract.