OBJECTIVE: The "Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)" disease has caused a worldwide challenging and threatening pandemic (COVID-19), with huge health and economic losses. The US Food and Drug Administration, (FDA) has granted emergency use authorization for treatment with the Pfizer/BioNTech and Moderna COVID-19 vaccines. Many people have a history of a significant allergic reaction to a specific food, medicine, or vaccine; hence, people all over the world have great concerns about these two authorized vaccines. This article compares the pharmacology, indications, contraindications, and adverse effects of the Pfizer/BioNTech and Moderna vaccines. MATERIALS AND METHODS: The required documents and information were collected from the relevant databases, including Web of Science (Clarivate Analytics), PubMed, EMBASE, World Health Organization (WHO), Food and Drug Authorities (FDA) USA, Local Ministries, Health Institutes, and Google Scholar. The key terms used were: Coronavirus, SARS-COV-2, COVID-19 pandemic, vaccines, Pfizer/BioNTech vaccine, Moderna vaccine, pharmacology, benefits, allergic responses, indications, contraindications, and adverse effects. The descriptive information was recorded, and we eventually included 12 documents including research articles, clinical trials, and websites to record the required information. RESULTS: Based on the currently available literature, both vaccines are beneficial to provide immunity against SARS-CoV-2 infection. Pfizer/BioNTech Vaccine has been recommended to people 16 years of age and older, with a dose of 30 μg (0.3 m) at a cost of $19.50. It provides immunogenicity for at least 119 days after the first vaccination and is 95% effective in preventing the SARS-COV-2 infection. However, Moderna Vaccine has been recommended to people 18 years of age and older, with a dose of 50 μg (0.5 mL) at a cost of $32-37. It provides immunogenicity for at least 119 days after the first vaccination and is 94.5% effective in preventing the SARS-CoV-2 infection. However, some associated allergic symptoms have been reported for both vaccines. The COVID-19 vaccines can cause mild adverse effects after the first or second doses, including pain, redness or swelling at the site of vaccine shot, fever, fatigue, headache, muscle pain, nausea, vomiting, itching, chills, and joint pain, and can also rarely cause anaphylactic shock. The occurrence of adverse effects is reported to be lower in the Pfizer/BioNTech vaccine compared to the Moderna vaccine; however, the Moderna vaccine compared to the Pfizer vaccine is easier to transport and store because it is less temperature sensitive. CONCLUSIONS: The FDA has granted emergency use authorization for the Pfizer/BioNTech and Moderna COVID-19 vaccines. These vaccines can protect recipients from a SARS-CoV- 2 infection by formation of antibodies and provide immunity against a SARS-CoV-2 infection. Both vaccines can cause various adverse effects, but these reactions are reported to be less frequent in the Pfizer/BioNTech vaccine compared to the Moderna COVID-19 vaccine; however, the Moderna vaccine compared to the Pfizer vaccine is easier to transport and store because it is less temperature sensitive.
Predicting the efficacy and toxicity of mRNA vaccines remains challenging. We describe an in vitro human model that replicates immune responses to lipid nanoparticle (LNP)-based mRNA vaccines upon intramuscular injection. Vaccines are administered to human skeletal myoblasts and antigen-presenting cells (APCs). Non-amplifying mRNA (NAM) vaccines directly induce antigen expression in APCs, whereas self-amplifying mRNA (SAM) vaccines require muscle cell-APC contact. The transfer of APCs and soluble factors to a microfluidic human lymphoid follicle chip (LF Chip), to mimic lymphatic drainage, induces LF expansion, de novo immunoglobulin G (IgG) production against a naive antigen, and cytokine release, with responses varying by LNP type. Similar vaccination of LF chips with Moderna vaccine against SARS-CoV-2 spike recall antigen generates neutralizing antibodies and induces somatic hypermutation (SHM). These studies offer an all-human alternative for evaluating vaccine-induced immunity, limiting the need for non-human primates and accelerating vaccine development.
Three respiratory syncytial virus (RSV) vaccines are marketed in the U.S. for use in adults aged ≥18 years: Arexvy® (GSK), Abrysvo® (Pfizer), and mRESVIA® (Moderna), with only Abrysvo® approved for use during pregnancy. This study describes post-marketing adverse event (AE) reports after RSV vaccination and detected reporting risk signals of administration-related errors using the U.S. Vaccine Adverse Event Reporting System (VAERS). We searched the VAERS database for reports of AE following RSV vaccination during January 1, 2023 - December 31, 2025. We assessed the characteristics of these reports and described the most commonly reported AEs by RSV vaccine brand. The top 15 most frequently reported AEs and top 10 most frequently reported vaccine administration errors were examined for Arexvy® and Abrysvo®. Disproportionality analyses (reporting odds ratio) were conducted to detect disproportionate reporting risk signals of vaccine administration errors (SAS version 9.4). During the study period, VAERS received 8365 AE reports following RSV vaccination; most were after Arexvy® (68.2%) and Abrysvo® (29.9%). The 5 most frequently reported AEs for Arexvy® were extra dose administered (15.0%), injection site pain (12.8%), injection site erythema (11.3%), injection site swelling (9.0%), and pain (9.0%); while for Abrysvo®, they included exposure during pregnancy (10.6%), extra dose administered (9.9%), headache (7.7%), fatigue (7.7%) and injection site pain (7.3%). Although not recommended for use during the study period, 4.2% (n = 244) of reports after Arexvy® vaccination were from individuals <50 years old; 6.6% (n = 375) were exposure during pregnancy. Both Arexvy® and Abrysvo® exhibited significant signals for vaccine administration errors such as extra dose administered and product administered to patient of inappropriate age. Most AE reports following RSV vaccination were non-serious. The potential misuse of Arexvy® during pregnancy and excess dose for both Arexvy® and Abrysvo® highlight potential gaps in healthcare provider education and vaccine record retrieval.
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Mavacamten, a cardiac myosin inhibitor, has been shown to improve symptoms and reduce left ventricular outflow tract gradients in obstructive hypertrophic cardiomyopathy (oHCM). However, real-world data regarding longer-term clinical outcomes, safety, and impact on septal reduction therapy (SRT) eligibility are limited. The objective of the study was to evaluate the real-world effectiveness and safety of mavacamten in patients with oHCM who met guideline-based criteria for SRT. We retrospectively reviewed patients with oHCM treated with mavacamten at our institution between April 2022 and December 2025 who met guideline-based SRT eligibility criteria. Clinical and echocardiographic outcomes were assessed at baseline and follow-up. Institutional SRT volumes before and after mavacamten approval were compared. Of the 84 patients treated with mavacamten, 53 met SRT eligibility criteria. The mean age was 67 ± 13 years, and 72% were females. Over a median follow-up of 82 weeks, resting left ventricular outflow tract gradients decreased from 51 ± 39 mm Hg to 4 ± 7 mm Hg and gradients with Valsalva from 79 ± 35 mm Hg to 9 ± 15 mm Hg (both P < 0.001). Overall, 49 patients (92%) improved by ≥1 NYHA functional class and no patients remained guideline-eligible for SRT or elected to undergo SRT at the time of most recent follow-up. Transient left ventricular ejection fraction reduction to <50% occurred in 6 patients (11%), and 7 (13%) developed new or recurrent atrial fibrillation. Institutional SRT volume declined significantly after mavacamten approval. In SRT-eligible oHCM, mavacamten use was associated with sustained hemodynamic and symptomatic improvement and was generally well tolerated in this real-world cohort. Institutional SRT volumes also declined during the post-mavacamten era.
Mechanistic heterogeneity is a major obstacle to the development of effective treatment for Sjögren's disease, and there is a pressing need to stratify Sjögren's disease according to precision medicine principles. Aberrant activation of the type 1 interferon (IFN) pathway represents a leading candidate pathway, but a causal role of elevated IFNα in driving Sjögren's disease has yet to be established. We aimed to examine the role of IFNα in driving a Sjögren's disease endotype and relevance to precision medicine principles. We used data from the UK Primary Sjögren's Syndrome Registry (UKPSSR), a multicentre observational cohort of participants with Sjögren's disease, and UK Biobank, a large population-based cohort which includes people with and without Sjögren's disease, to study the role of IFNα in Sjögren's disease. Ultrasensitive single molecule ELISA and an oligoprotein IFN signature score derived from broad capture proteomics were used to analyse samples from UKPSSR and data from the UK Biobank Pharma Proteomics Project (a subset of individuals from UK Biobank) to establish the timecourse and immune endotype associated with elevated IFNα. To address causality, we created a new transgenic mouse model of IFNα overexpression to establish whether chronically elevated IFNα drives this immune endotype. People with lived experience of Sjögren's disease were involved in the design of the UKPSSR and shaping of research questions. Between Aug 1, 2009, and March 31, 2012, we identified 177 people with Sjögren's disease in UKPSSR (mean age 57·5 years [IQR 46·0-65·0], 163 [92%] women, 14 [8%] men, and 162 [92%] White ethnicity). In addition, between March 13, 2006, to Oct 1, 2010, we identified 47 606 people without Sjögren's disease and 257 people with Sjögren's disease in the UK Biobank Pharma Proteomics Project, including 137 individuals sampled before diagnosis. IFNα concentrations were elevated in 108 (61%) of 177 people with Sjögren's disease in the UKPSSR. Oligoprotein IFN signatures were detected up to 14 years before diagnosis of Sjögren's disease in the UK Biobank Pharma Proteomics Project. Individuals in UKPSSR with elevated IFNα had a distinct immunological endotype characterised by cytopenia, hypergammaglobulinaemia, multiple autoantibodies, and autoimmunity against the Sjögren autoantigen TRIM21/Ro52. In a mouse model of systemic chronic IFNα elevation, in which IFNα4 was overexpressed by conventional dendritic cells, the key features of the endotype were recapitulated and could be partly reversed by type 1 interferon receptor (IFNAR1) blockade. We found that the elevation of IFNα drives an immune endotype of Sjögren's disease, and elevated IFNα can be detected over a decade before diagnosis. People with Sjögren's disease with elevated IFNα concentrations were broadly clinically similar to those with normal IFNα concentrations, yet were immunologically distinct. This highlights the mechanistic heterogeneity of Sjögren's disease and the need for immunological stratification along precision medicine principles, using high resolution biomarkers. In addition to demonstrating causal direction, biological modelling in a mouse model showed that chronic IFNα elevation over the lifecourse had the potential to establish persistent immune dysregulation, which responded only partly to IFNAR1 blockade. These findings provide insights into Sjögren's disease and other interferonopathic rheumatological disorders. Precision Medicine Alliance Scotland (Chief Scientist Office, Scottish Government), Wellcome Trust, Medical Research Council UKRI, Deutsche Forschungsgemeinschaft.
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We studied current vaccination policies for health-care personnel (HCP) in 34 European countries. All (34) countries have vaccination policies for hepatitis B, 33 countries for influenza, and 22 countries for COVID-19. Vaccination policies for measles, mumps, rubella, and varicella exist in 28, 23, 24, and 26 countries, respectively, and for tetanus, diphtheria, pertussis, and poliomyelitis in 21, 23, 23, and 15 countries, respectively. Vaccination policies for hepatitis A exist in 20 countries, and for tuberculosis (BCG vaccine), pneumococcus, herpes zoster, and human papillomavirus in 6, 6, 2, and 1 country, respectively. Lastly, 16 countries have vaccination policies for meningococcus B, 4 for meningococcus C, and 19 for meningococci ACWY (quadrivalent vaccine). Sixteen countries mandate particular vaccinations for HCP (mainly against hepatitis B and measles), including nine as a prerequisite for employment. Comparing the current vaccination policies with those we reported in 2018, we found that on several occasions vaccination programs improved and include an average of four more vaccinations. However, in several countries there are gaps in vaccination policies, particularly against measles, mumps, rubella, varicella, and pertussis. Currently, most countries have vaccination recommendations for healthcare students before entering healthcare facilities. In conclusion, European countries have more comprehensive vaccination policies for HCP compared with 2018, however there are still significant differences between countries, in terms of the number of vaccinations, target personnel, and implementation frame (recommended or mandatory vaccinations). Given the resurgence of multiple vaccine-preventable diseases in recent years, evidence-based and harmonized vaccination policies for HCP in Europe are needed to protect HCP and patients and to enhance safety in healthcare facilities.
mRNA vaccines represent a transformative advance in vaccinology, combining rapid development timelines, scalable manufacturing, and strong immunogenicity with a favourable safety profile. Global deployment of mRNA vaccines during the COVID-19 pandemic provided an unprecedented real-world evaluation of this platform, with billions of doses administered across diverse populations. In this Review, we critically examine the safety and efficacy of mRNA vaccines from mechanistic, preclinical, clinical, and public health perspectives. We outline the biological basis of mRNA vaccines, including their transient cytoplasmic expression, lack of genomic integration, and rapid clearance, distinguishing them clearly from other gene therapies. We synthesise evidence on vaccine components, manufacturing quality controls, and regulatory standards that underpin safety, alongside data from randomised trials, post-authorisation surveillance, and active pharmacovigilance systems. We also review real-world effectiveness across age groups, pregnancy, and populations that are immunocompromised, along with the effects on transmission. Last, we address public perception and vaccine confidence, and discuss implications for next-generation mRNA vaccines, including strategies to reduce reactogenicity, improve breadth and durability of immunity, enhance global access, and support sustainable public trust. Together, the accumulated evidence affirms mRNA vaccines as a safe, effective, and adaptable platform with enduring relevance for future infectious disease prevention and public health preparedness, and for the treatment of cancer and autoimmunity.
TOPAZ-1 (NCT03875235) demonstrated improved overall survival (OS) with durvalumab plus gemcitabine and cisplatin vs. placebo plus gemcitabine and cisplatin with manageable safety in advanced biliary tract cancer (aBTC). The phase IIIb TOURMALINE study (NCT05771480) is evaluating the safety and efficacy of first-line durvalumab plus seven gemcitabine-based chemotherapy regimens in a close-to-real-world aBTC population, including participants with poor prognosis. Participants received 1500 mg IV durvalumab (first infusion: 60 minutes; subsequent infusions: 30 minutes) plus investigator's choice of one of seven gemcitabine-based chemotherapy regimens. The primary endpoint was incidence of Grade 3/4 adverse events (AEs) possibly related to treatment (PRAEs) within 6 months of first durvalumab dose. Secondary endpoints included progression-free survival (PFS), OS, objective response rate (ORR), and safety. As of 17 September 2025, 142 participants (median age 68.0 years) had follow-up ≥6 months and received ≥1 treatment dose; most had metastatic disease (72.5%). Participants received a median of 9 cycles of durvalumab; median (IQR) follow-up was 11.63 (6.87-17.25) months. Overall, 50.7% (95% confidence interval [CI] 42.19-59.19) of participants experienced Grade 3/4 PRAEs within 6 months of durvalumab initiation, with no serious AEs of special interest with an outcome of death. Median PFS was 7.39 months (95% CI 6.74-9.07); median OS was 13.50 months (95% CI 11.24-20.53); ORR was 33.1% (95% CI 25.44-41.48). Safety profiles of durvalumab plus seven gemcitabine-based chemotherapy regimens were manageable, and shorter durvalumab infusion duration (30 minutes vs. 60 minutes) did not increase infusion-related reactions. Efficacy data are indicative of potential clinical activity across treatment arms. These findings demonstrate the feasibility of combining durvalumab with alternative gemcitabine-based regimens in a broad aBTC population. The choice of gemcitabine-based chemotherapy backbones for the treatment of advanced biliary tract cancer (aBTC) varies globally and their use in conjunction with immunotherapy has not been fully investigated. The TOURMALINE phase IIIb study demonstrated manageable safety and efficacy data showed potential clinical activity in a close-to-real-world population of participants with aBTC receiving durvalumab plus one of seven gemcitabine-based chemotherapy regimens. These findings point towards the feasibility of combining durvalumab with different gemcitabine-based chemotherapy regimens, even in participants with less favourable disease characteristics. NCT05771480 TRIAL REGISTRATION: ClinicalTrials.gov: NCT05771480; https://clinicaltrials.gov/study/NCT05771480.
A false-negative diagnosis of cancer can lead to a delay in effective treatment and a poorer prognosis. Here, we use the example of cutaneous melanoma to examine how many years of life are lost after a false-negative diagnosis compared to a primarily correct diagnosis. From 1996 to 2015, 9,063 patients are prospectively registered in the German Central Malignant Melanoma Registry and followed up until December 2023. A false-negative diagnosis is found in 206 (2.3%) patients. The median time to correct diagnosis is 24.0 months. The 10-year recurrence-free survival probabilities are 32.9% for false-negative diagnoses and 76.2% for correct diagnoses (p < 0.001). The 10-year melanoma-specific survival probabilities are 62.1% versus 85.0% (p < 0.001). On average, each person with an initial false-negative diagnosis loses 8.2 years of life compared to people with a correct diagnosis. This high number of years of life lost raises the question of whether similar results also apply to other types of cancer.
Recent innovations in vaccine design have reignited optimism about the feasibility of developing a safe and effective HIV vaccine. For instance, germline-targeting (GT) immunogens have been designed to selectively expand naïve B cell precursors with broadly neutraliing antibodies (bnAbs)-associated germline-encoded features, thereby priming them for structure-guided maturation. The frequencies and affinities of these precursors in the populations targeted for vaccination are critical to the success of GT vaccine strategies, but limited information is currently available across different geographies and demographics. We set up a study to characterise CD4 binding site-targeting VRC01-class bnAb precursor frequencies in 60 healthy Kenyan adults with varied levels of prior exposure to malaria. Naïve VRC01-class bnAb precursors were detected using the germline-targeting eOD-GT8 immunogen. The overall frequency of these precursors was similar to that reported in North American populations, with IGHV1-2 allelic composition rather than prior long-term exposure to malaria impacting the precursor frequency estimates. Our findings also revealed four new allelic variants of the IGHV1-2 gene that are not currently included in the immunogenetic reference database. Notably, a novel IGHV1-2 allele (IGHV1-2*06_S5416) demonstrated the ability to engage eOD-GT8, unlike the reference *06 allele. Overall, our results support the development of GT vaccines to induce VRC01-class bnAbs in this population and reiterate the need for participant genotyping in GT vaccine trials, particularly in African populations where genetic diversity is high yet understudied.
The global COVID-19 vaccine rollout faces challenges from persistent hesitancy, especially in rural and underserved regions. Alaska's unique geographic, cultural, and infrastructural challenges create complex dynamics for vaccine uptake. This study uses machine learning on survey data to identify key sociodemographic and attitudinal predictors of hesitancy, informing targeted public health strategies. This study surveyed 720 Alaska adults, selected via targeted sampling to capture diverse COVID-19 vaccine attitudes across demographics and regions. A structured questionnaire assessed hesitancy through 17 indicators. We applied extreme gradient boosting, random forest, and K-nearest neighbors models for both regression and classification, and interpreted classification results via Shapley Additive Explanations values. Analysis of 720 respondents showed that in Alaska, 1.8% (13/720) of surveyed individuals completed the full primary vaccination series (doses 1-3) and received all 3 booster doses. A vaccination rate of 63.47% (at least 1 dose), with Pfizer preferred over Moderna. A total of 34% (238/720) of participants reported receiving the first dose of the COVID-19 vaccine, 43% (310/720) received the second dose, 18% (130/720) received a third dose, 22% (158/720) received the first booster, 13% (94/720) received the second booster, and only 4% (29/720) received a third booster. Geographic data revealed higher uptake in urban centers and variability in rural areas. Young adult males exhibited the highest hesitancy, while lesbian, gay, bisexual, and transgender individuals showed the lowest. Trust in the health care system was the strongest predictor, confirmed by machine learning analyses. Focusing on a geographically and demographically distinct US population, this study advances the scientific understanding of vaccine hesitancy while informing context-sensitive public health strategies. The findings offer actionable evidence to guide targeted communication, equitable outreach, and data-driven policy in Alaska and similarly underserved regions across the United States, underscoring the importance of culturally tailored, trust-centered interventions to promote vaccine uptake and health equity.
Lower respiratory tract infections represent a major public health burden, but adult data on respiratory viruses except influenza and COVID-19 are limited. Most European surveillance systems report aggregate data lacking patient-level detail. We utilised the multicountry id.DRIVE surveillance study data to describe the epidemiology, clinical characteristics, and outcomes of adults hospitalised with pathogen-specific severe acute respiratory infections (SARI) during 2024-2025. Adults (≥ 18 years) hospitalised with SARI across 17 hospitals in Spain, Italy, and Germany between 1 September 2024 and 31 August 2025 were included. All participants were tested using reverse transcription polymerase chain reaction for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial virus (RSV), and influenza A/B (testing additional respiratory pathogens varied by hospital). Descriptive analyses were stratified by pathogen. Of 8730 included participants (median age, 77 years), 14.3% (n = 1249) tested positive for influenza A, 6.9% (n = 606) SARS-CoV-2, 6.4% (n = 554) RSV, and 0.8% (n = 74) for influenza B. Positivity peaked for influenza and RSV in December-January, and for SARS-CoV-2 in July. Comorbidity burden was substantial: 51.9% of all SARI participants had ≥ 3 chronic conditions, reaching 62.3% in those with RSV. RSV-positive SARI patients were older (median age, 80 years); oxygen therapy was required in 72.0%, non-invasive ventilation in 12.3%, and in-hospital mortality was 9.4%. Over 75.0% of SARI cases positive for a respiratory virus received antibiotics during hospitalisation. Viral pathogens remain a major cause of adult SARI hospitalisations in Europe. Our findings highlight the continued burden and seasonal diversity of viral respiratory pathogens, supporting the value of integrated, pathogen-specific SARI surveillance guiding prevention strategies.
Metastasis remains the leading cause of cancer-related mortality and is driven by pronounced tumour cell plasticity1. Here we identify the transmembrane glycoprotein trophoblast cell-surface antigen 2 (TROP2) as a marker of poor-prognosis colorectal cancer (CRC) associated with WNTlow, fetal-like tumour cell states that are linked to metastasis and therapy resistance. Functional analyses demonstrate that TROP2+ cells exhibit context-dependent stem-like capacity and the ability to initiate metastatic outgrowth. Given that these detrimental tumour states converge on the cell-surface antigen TROP2, we explored therapeutic targeting of this cell population using clinically relevant TROP2-directed antibody-drug conjugates. Time-resolved analyses reveal therapy-associated dynamics in tumour cell state composition between WNThi LGR5+ states and WNTlowTROP2+ fetal-like states. Conventional chemotherapy promotes the induction of TROP2-expressing cells, whereas TROP2 antibody-drug conjugates selectively target these populations and remodel the tumour cell state landscape. Exploiting this plasticity, combined chemotherapy and TROP2 targeting enhances anti-tumour efficacy in patient-derived models. Together, our findings identify TROP2 as a therapeutic vulnerability of CRC and highlight the importance of targeting tumour cell states to improve therapeutic efficacy and overcome resistance in advanced disease.
Vaccination remains a cornerstone of public health, yet concerns regarding serious adverse events continue to contribute to vaccine hesitancy. While systemic and local vaccine reactions are well described, renal complications such as acute kidney injury (AKI) and immune-mediated glomerular disease are less well characterised. With widespread and sustained use of coronavirus disease 2019 (COVID-19) and influenza vaccines, a comprehensive synthesis of reported renal adverse outcomes is needed. To synthesise and critically evaluate the existing evidence on AKI and other renal manifestations reported following influenza and COVID-19 vaccination. Specifically, it aims to characterise the spectrum of reported renal presentations, summarise clinical features and timelines described in case reports and case series, and contextualise these findings using population-level observational and pharmacovigilance data to assess the overall renal safety profile of these vaccines. We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. PubMed and EMBASE were searched from inception to 6 December 2025 for studies reporting renal outcomes following COVID-19 or influenza vaccination. Eligible studies included observational studies, pharmacovigilance analyses, case reports, and case series. Data on incidence, clinical presentation, timing of onset, management, and outcomes were extracted and synthesised narratively due to heterogeneity. Risk of bias in observational studies was assessed using the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) tool. A total of 255 COVID-19 vaccine-related studies and 73 influenza vaccine-related studies met the inclusion criteria, supplemented by additional studies identified through reference screening. Population-level observational studies consistently demonstrated a low absolute risk of renal adverse outcomes following vaccination, with several studies reporting reduced AKI-related risk among vaccinated individuals. In contrast, pharmacovigilance analyses and case reports described serious instances of de novo or relapsing renal disease, including minimal change disease, immunoglobulin A nephropathy, membranous nephropathy, pauci-immune glomerulonephritis, and systemic inflammatory syndromes with secondary renal involvement. Symptom onset typically occurred within days to weeks of vaccination. Most cases responded favourably to supportive or disease-specific therapy, with recovery observed over weeks to months; irreversible renal outcomes were uncommon. Current evidence indicates that both COVID-19 and influenza vaccines are associated with a low population-level risk of adverse renal outcomes. Serious immune-mediated renal events have been reported in temporal association with vaccination, likely reflecting idiosyncratic immune responses or unmasking of pre-existing disease rather than a widespread nephrotoxic effect. The overall benefits of vaccination substantially outweigh potential renal risks. Ongoing surveillance and well-designed population-based studies remain essential to refine risk estimates and identify susceptible subgroups.
Licensure of influenza vaccines relies on serum hemagglutination inhibition (HAI) titers, a correlate of protection (CoP) that was developed more than 50 years ago and which is only poorly predictive of protection. This is especially true of immunity induced by intranasal live attenuated influenza vaccines (LAIVs). Unlike intramuscular inactivated influenza vaccines (IIVs), LAIV and natural infection selectively stimulate mucosal immunity. Developments in mucosal immunology now enable measurement of diverse aspects of mucosal immunity, including the frequencies and functions of nasal antibodies, T cells, and B cells. This review assesses the potential of new sampling and assay approaches that may overcome inconsistent findings from previous methodologies. Standardization of the collection and assessment of mucosal samples is essential in developing new CoPs for vaccine development and licensure of novel vaccines that induce nasal protection and are more effective in prevention of viral transmission.
Rheumatic heart disease is increasingly recognized as an immunologically active condition characterized by persistent low-grade inflammation contributing to atrial dysfunction. The authors aimed to evaluate whether colchicine reduces systemic inflammation and improves left atrial (LA) mechanical function in chronic rheumatic mitral valve disease. In this prospective, double-blind, randomized controlled trial, 90 patients with chronic moderate-to-severe rheumatic mitral valve disease were randomized (1:1) to colchicine (0.5 mg twice daily) or placebo for 6 months in addition to standard therapy. The primary outcome was change in interleukin (IL)-6 at 6 months. Secondary outcomes included changes in other inflammatory markers, LA strain parameters, NYHA functional class, and correlations between inflammatory markers and LA mechanics. Colchicine significantly reduced inflammatory markers (IL-6, high-sensitivity C-reactive protein, erythrocyte sedimentation rate; all P < 0.001). IL-6 decreased from 98.0 (86.9-112.1) to 11.2 (7.3-21.5) pg/mL in the colchicine group, while increasing in placebo (P < 0.001). LA reservoir strain improved significantly (23.6% ± 2.0% vs 16.5% ± 1.6%, P < 0.001). IL-6 showed strong inverse correlation with LA reservoir strain (r = -0.65, P < 0.001). Functional status improved, with 69.2% of NYHA functional class III patients improving to class II. Colchicine significantly attenuates systemic inflammation and improves LA mechanical function and functional status in chronic rheumatic mitral valve disease, supporting an inflammation-driven atrial myopathy phenotype.
With notification rates for Legionnaires' disease (LD) rising in Europe and the United States, accurate case detection becomes increasingly important for individual patient management and public health surveillance. A six-predictor score has been proposed to identify community-acquired pneumonia (CAP) patients at increased risk of LD. We externally validated and updated this score to improve its practical usability. We analysed data from 196 patients with LD across 20 Swiss hospitals and 196 matched Legionella test-negative CAP controls (August 2022-March 2024). We evaluated the availability of the six original score predictors (fever, no/dry cough, hyponatremia, elevated CRP, elevated LDH, low platelet count) in routine care and assessed the score's discriminative performance. The dataset was split into development and validation cohorts to assess if model simplicity and predictive performance could be improved. The original score yielded 91% sensitivity (95% CI: 86-96%) and 35% (95% CI: 28-42%) specificity at a cut-off ≥2. LDH was infrequently measured, and platelet count was a poor predictor. The simplified SwissLEGIO score (fever >38°C, sodium <133 mmol/L, CRP >180 mg/L, no/dry cough, prior β-lactam therapy) showed high sensitivity (88-92%) and improved specificity (46-58%) at a cut-off ≥2. The SwissLEGIO score is an easy-to-apply screening tool to rule out LD in hospitalised CAP patients. A scores <2 could reduce Legionella-specific testing by 36-52% (at a disease prevalence of 4%) while maintaining high sensitivity for case detection.
Post-acute sequelae of COVID-19 or post-COVID-19 condition (also known as long COVID) affects 1-5% of adults globally, most commonly with fatigue, and no evidence-based therapies are available. We aimed to evaluate the efficacy of repurposed medications in fatigue management in adults with long COVID. We did a phase 3, four-group, randomised, controlled, adaptive platform, open-label drug trial nested within a pragmatic, multicentre, cluster-randomised trial of an integrated care pathway (ICP) for long COVID across 12 UK National Health Service (NHS) specialist long COVID care clinics in the UK. Participants had to be adults (>18 years) with long COVID who had not been hospitalised with COVID-19. In addition to NHS specialist-led long COVID care (hereafter, usual care), participants in the ICP trial could receive multiorgan MRI and clinical decision support and/or app-based rehabilitation. Initially, participants in the ICP trial were invited to enrol in the drug trial, but slow recruitment to the drug trial led to establishment of additional drug-only trial sites. Participants enrolled at either ICP trial sites or drug-only trial sites were randomly assigned (1:1:1:1) to receive colchicine 500 μg twice daily, rivaroxaban 10 mg once daily, famotidine 40 mg with loratadine 10 mg once daily, or no drug for 12 weeks. All participants received usual care. Randomisation was done electronically in blocks (various block sizes) and stratified by site, birth sex, ICP trial group allocation, and being a new or previous patient of a drug-only site. The primary endpoint was 12-week fatigue, assessed with the Fatigue Assessment Scale (FAS; with scores ranging from 10 [no fatigue] to 50 [debilitating fatigue], and a >10% change considered clinically meaningful) among randomly assigned individuals who had available baseline and 12-week data, adjusting for baseline fatigue and clinically relevant covariates. Secondary endpoints included 24-week FAS. The nested drug trial is registered, ISRCTN10665760. The trial is complete. Of 6035 eligible participants, 778 (383 co-enrolled in the ICP trial and 395 directly enrolled in the drug trial) were randomly assigned between Aug 22, 2022, and Aug 7, 2024 to colchicine (n=192), famotidine-loratadine (n=193), rivaroxaban (n=197), or no drug (usual long COVID care only; n=196). The mean age of participants was 46 years (SD 12·4), 495 (64%) of 778 were female, and 91 (12%) were from a non-White ethnic group. Across all trial groups, there was severe baseline fatigue (mean FAS score 36·8 [SD 7·49]) and a clinically relevant mean FAS reduction of 4·3 points to 32·5 (SD 9·13) at 12 weeks. Adjusted analyses showed small, statistically significant FAS reductions in the colchicine (-1·49 points [95% CI -2·92 to -0·06], p=0·041) and famotidine-loratadine (-1·48 points [-2·88 to -0·08], p=0·038) groups, but not in the rivaroxaban group (-1·06 points [-2·47 to 0·35, p=0·139), compared with no study drug at 12 weeks. However, 24-week FAS scores, 12 weeks after drug cessation, were not significantly different between groups. Treatment was well tolerated, with ten serious adverse events (requiring hospitalisation but unrelated to trial drugs) reported in eight (1·0%) of the 778 participants, five of which were in three participants in the rivaroxaban group. In participants with long COVID, severe fatigue reduced in all study groups-including the no drug group-over 12 weeks, with small additional reductions in the colchicine and famotidine-loratadine groups compared with the no drug group. Modest effects on FAS were not sustained after drug withdrawal. Long-term long COVID symptom benefit is unlikely with these drugs alone. Future trials could investigate the use of these or other repurposed drugs in specific subgroups of patients with long COVID, combination therapies, and how care is delivered. UK National Institute for Health and Care Research.