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AO_SCPLOWBSTRACTC_SCPLOWVaccination elicits a complex combination of immune responses. Immune memory formation is observed not only in the antibody responses of B-cells, but also in the T-cell response. Moreover, some live attenuated vaccines such as measles-containing vaccines can induces heterologous protection, likely through induction of memory characteristics in the innate immune response. Little is known about the immunological interaction that may occur when different vaccines are administered soon after one another, especially in relation to the novel COVID-19 vaccines. The aim of this study was to compare the innate and adaptive immune responses between persons randomized to receive either a MMR or a placebo (0.9% NaCl) injection prior to their SARS-CoV-2 mRNA vaccination. We compared: i) the cytokine and chemokine production (tumor necrosis factor [TNF]-, interleukin [IL]-1{beta}, IL-6, IL-10, IL-17, IL-22, interferon [IFN]- and IFN-{gamma}) after in-vitro stimulation of peripheral blood mononuclear cells (PBMCs) with heterologous stimuli (severe acute respiratory syndrome coronavirus [SARS-CoV]-2, measles mumps and rubella [MMR] vaccine, Toll-like receptor [TLR]-3 ligand, TLR-7/8 ligand, or TLR-4 ligand), and ii) the SARS-CoV-2 neutralizing antibody responses. Ninety-five participants in the CROWN CORONATION trial (NCT04333732; a randomized control trial comparing MMR to placebo for prevention of COVID-19) agreed to an additional single blood sample collection for this immunological study. Samples were collected around 196 (SD 22) days after administration of MMR or placebo, and around 105 (SD 27) days after their second SARS-CoV-2 mRNA vaccine injection. Twenty-four percent of participants were older than fifty and sixty-seven percent were female. The median TNF- response to stimulation with MMR was 8315.3 pg/mL in the MMR group and 4340.5 pg/mL in the placebo group; adjusted median difference (95% CI) 3012.5 (-4734.1; -323.5); p=0.017. No other significant differences were noted in the cytokine and chemokine responses between treatment groups. The SARS-CoV-2 neutralization assay geometric mean (SD) IC50 in the MMR group was 507.6 (2.6) and in the placebo group was 515.7 (2.2); ratio of geometric means (95% CI) 1.0 (0.7; 1.5). Pre-exposure to MMR vaccine was generally not associated with changes in cytokine and chemokine responses of stimulated PBMCs at 105 (27) days after SARS-CoV-2 mRNA vaccination. MMR vaccination led only to an increase of TNF- production in response to an additional ex-vivo stimulation with the MMR vaccine. The SARS-CoV-2 neutralization IC50 values did not differ between MMR and placebo groups. Further studies using a repeated measures design would be better suited to explore or rule-out any short-lived vaccine response and vaccine-vaccine immunological interaction.
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IntroductionLong COVID (LC), the persistent symptoms [≥]12 weeks following acute COVID-19, presents major threats to individual and public health across countries, affecting over 1.5 million people in the UK alone. Evidence-based interventions are urgently required and an integrated care pathway (ICP) approach in pragmatic trials, which include investigations, treatments and rehabilitation for LC, could provide scalable and generalisable solutions at pace. Methods and analysisThis is a pragmatic, multi-centre, cluster-randomised clinical trial of two components of an ICP (Coverscan, a multi-organ MRI, and Living with COVID Recovery, a digitally enabled rehabilitation platform) with a nested, Phase III, open label, platform randomised drug trial in individuals with LC. Cluster randomisation is at level of primary care networks so that ICP interventions are delivered as "standard of care" in that area. The drug trial randomisation is at individual level and initial arms are rivaroxaban, colchicine, famotidine/loratadine, compared with no drugs, with potential to add in further drug arms. The trial is being carried out in 6-10 NHS LC clinics in the UK and is evaluating the effectiveness of a pathway of care for adults with LC in reducing fatigue and other physical, psychological and functional outcomes (e.g. EQ-5D-5L, GAD-7, PHQ-9, WSAS, PDQ-5, CFQ, SF-12, MRC Dyspnoea score) at 3 months. The trial also includes an economic evaluation which will be described separately. Ethics and disseminationThe protocol was reviewed by South Central - Berkshire Research Ethics Committee (reference: 21/SC/0416). All participating sites obtained local approvals prior to recruitment. Coverscan has UKCA certification (752965). The first participant was recruited in July 2022 and interim/final results will be disseminated in 2023, in a plan co-developed with public and patient representatives. The results will be presented at national and international conferences, published in peer reviewed medical journals, and shared via media (mainstream and social) and patient support organisations. Trial registration numberISRCTN10665760
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BackgroundEarly antiviral treatment is effective for COVID-19 but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on SARS-CoV-2 viral load trajectory when administered early. MethodsWe conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2x2 factorial, double-blind trial of outpatients with early COVID-19 (within 7 days of symptom onset) at two sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1800mg twice daily on Day 1 followed by 400mg four times daily on Days 2-7) plus lopinavir-ritonavir (400mg/100mg twice daily on Day 1, followed by 200mg/50mg four times daily on Days 2-7); favipiravir plus lopinavir-ritonavir placebo; lopinavir-ritonavir plus favipiravir placebo; or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. ClinicalTrials{middle dot}gov: NCT04499677. FindingsBetween 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo and placebo-only arms, we recruited 61, 59, 60 and 60 participants and analysed 55, 56, 55 and 58 participants respectively who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had decreased by 0.57 log10 (95% CI -1.21 to 0.07, p=0.08) and in the lopinavir-ritonavir+placebo arm by 0.18 log10 (95% CI -0.82 to 0.46, p=0.58) more than in the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log10, 95% CI -0.32 to 1.50, p=0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% vs 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p=0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm. InterpretationAt the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations. FundingLifeArc, UK.
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BackgroundComplications following SARS-CoV-2 infection require simultaneous characterisation and management to plan policy and health system responses. We describe the 12-month experience of the first UK dedicated Post-COVID clinical service to include both hospitalised and non-hospitalised patients. MethodsIn a single-centre, observational analysis, we report outcomes for 1325 individuals assessed in the University College London Hospitals NHS Foundation Trust Post-COVID service between April 2020 and April 2021. Demography, symptoms, comorbidities, investigations, treatments, functional recovery, specialist referral and rehabilitation were compared by referral route ("post hospitalisation", PH; "non-hospitalised", NH; and "post emergency department", PED). Symptoms associated with poor recovery or inability to return to work full-time were assessed using multivariable logistic regression. Findings1325 individuals were assessed (PH 547 [41.3%], PED 212 [16%], NH 566 [42.7%]. Compared with PH and PED groups, NH were younger (median 44.6 [35.6-52.8] vs 58.3 [47.0-67.7] and 48.5 [39.4-55.7] years), more likely to be female (68.2%, 43.0% and 59.9%), less likely to be from an ethnic minority (30.9%, 52.7% and 41.0%) and seen later after symptom onset (median [IQR]:194 [118-298], 69 [51-111] and 76 [55-128] days) (all p<0.0001). NH patients had similar rates of onward specialist referral as PH and PED groups (18.7%, 16.1% and 18.9%, p=0.452), and were more likely to require support for breathlessness (23.7%, 5.5% and 15.1%, p<0.001) and fatigue (17.8%, 4.8%, 8.0%, p<0.001). Hospitalised patients had higher rates of pulmonary emboli, persistent lung interstitial abnormalities, and other organ impairment. 716 (54.0%) individuals reported <75% of optimal health (median [IQR] 70% [55%-85%]). Overall, less than half of employed individuals felt able to return to work full-time at first assessment. InterpretationSymptoms following SARS-CoV-2 infection were significant in both post- and non-hospitalised patients, with significant ongoing healthcare needs and utilisation. Trials of interventions and patient-centred pathways for diagnostic and treatment approaches are urgently required. FundingUCLH/UCL BRC Research in contextO_ST_ABSPrevious evidenceC_ST_ABSLong COVID and post-COVID syndrome were first identified in April 2020. We searched PubMed and medrxiv for articles published up to April 30th, 2021, using the keywords "long COVID", "post-COVID syndrome", "persistent symptoms", "hospitalised", "community" and "non-hospitalised". We identified 17 articles and 7 systematic reviews. Fifteen studies have considered symptoms, multi-organ or functional impairment but only one study to-date has considered all these variables in non-hospitalised COVID patients. No studies have compared symptom burden and management between non-hospitalised and hospitalised individuals as systematically assessed and managed in a dedicated post-COVID service. Added value of this studyFor the first time, we report the baseline characteristics, investigation and outcomes of initial assessment of all eligible patients in a dedicated multi-professional post-COVID service, including 547 post-hospitalisation, 566 non-hospitalised and 212 patients discharged from emergency department. Despite relatively low comorbidity and risk factor burden in non-hospitalised patients, we show that both non-hospitalised and hospitalised patients presenting with persistent symptoms after SARS-CoV2 infection have high rates of functional impairment, specialist referral and rehabilitation, even 6-12 months after the acute infection. These real-world data will inform models of care during and beyond the pandemic. Implications of all the available evidenceThe significant, long-lasting health and social consequences of SARS-CoV-2 infection are not confined to those who required hospitalisation. As with other long-term conditions, care of patients experiencing Long COVID or specific end-organ effects require consistent, integrated, patient-centred approaches to investigation and management. At public health and policy level, burden of post-COVID morbidity demands renewed focus on effective infection suppression for all age groups.
