SARS-CoV-2 rapid antigen test sensitivity and viral load in newly symptomatic hospital employees in Berlin, Germany, December, 2020 to February, 2022: an observational study.

BACKGROUND: Evolving SARS-CoV-2 variants and changing levels of pre-existing immunity require re-evaluation of antigen-detecting rapid diagnostic test (Ag-RDT) performance. We investigated possible associations between Ag-RDT sensitivity and various potential influencing factors, such as immunisation status and viral variant, in symptomatic hospital employees. METHODS: In this observational study, RT-PCR, Ag-RDT, and symptom-specific data were collected at three SARS-CoV-2 test centres for employees of the Charité-Universitätsmedizin Berlin hospital (Berlin, Germany). Employees reporting SARS-CoV-2-like symptoms, those at an increased risk of infection (eg, due to contact with an infected person), those testing positive in a previous self-administered Ag-RDT, or those seeking release-testing to return to work at least 7 days after a positive RT-PCR test were eligible for combined testing by RT-PCR and Ag-RDT. Only data from individuals with an ongoing SARS-CoV-2 infection as assessed by RT-PCR were used for further analysis. Bayesian regression analyses were done to evaluate possible differences in viral load and Ag-RDT sensitivity according to viral variant and immunisation status (previous vaccination or recovery from infection), using data from first RT-PCR positive samples in an infection. A comprehensive logistic regression analysis was used to investigate potential concomitant associations between Ag-RDT sensitivity and level of pre-existing immunity, time post symptom onset, viral load, gender, age, and Ag-RDT device. Ag-RDT performance was also compared between supernatants from cell cultures infected with the omicron variant of concern (VOC) or the wild-type strain (pre-VOC). FINDINGS: Between Nov 30, 2020 and Feb 11, 2022, a total of 14 773 samples from 7675 employees were tested for SARS-CoV-2 by both RT-PCR and Ag-RDT. We found a negative association between immunisation status and Ag-RDT sensitivity in symptomatic employees, with an observed sensitivity of 82% (94% highest posterior density interval [HPDI] 78-86) in immunologically naive participants compared with 73% (68-78) in multiply immunised individuals (ie, those with at least two vaccinations or recoveries from infection) and median log10 viral loads of 7·02 (IQR 5·83-8·07) and 8·08 (6·80-8·89), respectively. The dominant viral variant changed several times during the study period, from the pre-VOC period (sensitivity 80% [94% HPDI 75-85] in symptomatic participants) through the alpha variant (82% [70-94]), delta variant (75% [69-82]), and omicron variant (72% [65-79]) waves, concomitantly with a steep increase in vaccination coverage in our dataset. In a comparison of Ag-RDT performance on cell culture supernatants, we found no difference between the wild-type and omicron viral variants. INTERPRETATION: On the basis of our findings and data from other studies, we hypothesise that the observed reduction in clinical Ag-RDT sensitivity, despite higher SARS-CoV-2 RNA loads, is due to shorter incubation times later in our study period resulting from increased population immunity or changes in immune response dynamics caused by later SARS-CoV-2 VOCs. FUNDING: Berlin University Alliance, German Ministry of Education and Research, the EU (Projects EU4Health and ReCoVer), and the Berlin Institute of Health.

Humoral immune escape by current SARS-CoV-2 variants BA.2.86 and JN.1, December 2023.

Variant BA.2.86 and its descendant, JN.1, of SARS-CoV-2 are rising in incidence across Europe and globally. We isolated recent JN.1, BA.2.86, EG.5, XBB.1.5 and earlier variants. We tested live virus neutralisation of sera taken in September 2023 from vaccinated and exposed healthy persons (n = 39). We found clear neutralisation escape against recent variants but no specific pronounced escape for BA.2.86 or JN.1. Neutralisation escape corresponds to recent variant predominance but may not be causative of the recent upsurge in JN.1 incidence.

A Rare Case of Diffuse Alveolar Hemorrhage Caused by Fentanyl Inhalation.

Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening pulmonary disorder characterized by blood accumulation in alveolar spaces, often associated with autoimmune diseases and infections. Drug-induced causes of DAH, including inhalation of substances like fentanyl, are emerging concerns. A 40-year-old male with bipolar disorder and polysubstance abuse presented with altered mental status and hemoptysis after inhaling an unknown substance. Physical examination revealed respiratory distress, pinpoint pupils, and severe hypoxemia. Naloxone administration improved his condition. The workup showed negative infection markers, positive fentanyl-specific urine test, and diffuse bilateral opacities on imaging. Bronchoalveolar lavage confirmed DAH with >20% hemosiderin-laden macrophages. Steroid treatment resulted in marked improvement. Drug-induced DAH, such as fentanyl inhalation, should be considered in patients with altered mental status and pulmonary symptoms following substance use. Comprehensive evaluation and targeted treatment are crucial for optimal outcomes.

Divergent Genotype of Hepatitis A Virus in Alpacas, Bolivia, 2019.

Hepatitis A virus (HAV) is a common human pathogen found exclusively in primates. In a molecular and serologic study of 64 alpacas in Bolivia, we detected RNA of distinct HAV in ≈9% of animals and HAV antibodies in ≈64%. Complete-genome analysis suggests a long association of HAV with alpacas.

A Rare Case of Valproic Acid Toxicity Requiring Hemodialysis.

Valproic acid poisoning can have mild to fatal consequences depending on its body concentration. There are rare case reports and barely any known controlled studies on the use of hemodialysis as a last treatment resort. We report a rare valproic acid poisoning case at One Brooklyn Health/Interfaith campus, New York City, warranting intubation and hemodialysis. The patient is a 47-year-old male with a past medical history of seizure disorder, polysubstance use disorder, schizophrenia, and gastroesophageal reflux disease (GERD) who was brought to the medical emergency department (ED) for intentional valproic acid overdose with 60 tablets of his prescribed home Depakote DR 500 mg (~30 g). The patient's other outpatient medications included valproic acid, trazodone, acetaminophen, famotidine, fluoxetine, folic acid, hydrocortisone-aloe, multivitamin, nicotine polacrilex, and thiamine. The patient's initial blood tests showed high valproic acid, ammonia, ethanol, and lactate. About six hours after ED admission, the patient became somnolent, desaturated to 74% on a non-rebreather oxygen mask, warranting intubation and hemodialysis after noticing persistently high serum concentrations of valproic acid. The relatively low molecular weight (144 Daltons) and low volume of distribution of valproic acid suggest a potential benefit from hemodialysis, especially at a serum concentration of >850 mg/L or in the event of a shock. In this patient, mentation and stability status were improved after hemodialysis. Hemodialysis appears to be the last treatment resort for severe valproic acid poisoning.

The concepts of muscle activity generation driven by upper limb kinematics.

BACKGROUND: The underlying motivation of this work is to demonstrate that artificial muscle activity of known and unknown motion can be generated based on motion parameters, such as angular position, acceleration, and velocity of each joint (or the end-effector instead), which are similarly represented in our brains. This model is motivated by the known motion planning process in the central nervous system. That process incorporates the current body state from sensory systems and previous experiences, which might be represented as pre-learned inverse dynamics that generate associated muscle activity. METHODS: We develop a novel approach utilizing recurrent neural networks that are able to predict muscle activity of the upper limbs associated with complex 3D human arm motions. Therefore, motion parameters such as joint angle, velocity, acceleration, hand position, and orientation, serve as input for the models. In addition, these models are trained on multiple subjects (n=5 including , 3 male in the age of 26±2 years) and thus can generalize across individuals. In particular, we distinguish between a general model that has been trained on several subjects, a subject-specific model, and a specific fine-tuned model using a transfer learning approach to adapt the model to a new subject. Estimators such as mean square error MSE, correlation coefficient r, and coefficient of determination R2 are used to evaluate the goodness of fit. We additionally assess performance by developing a new score called the zero-line score. The present approach was compared with multiple other architectures. RESULTS: The presented approach predicts the muscle activity for previously through different subjects with remarkable high precision and generalizing nicely for new motions that have not been trained before. In an exhausting comparison, our recurrent network outperformed all other architectures. In addition, the high inter-subject variation of the recorded muscle activity was successfully handled using a transfer learning approach, resulting in a good fit for the muscle activity for a new subject. CONCLUSIONS: The ability of this approach to efficiently predict muscle activity contributes to the fundamental understanding of motion control. Furthermore, this approach has great potential for use in rehabilitation contexts, both as a therapeutic approach and as an assistive device. The predicted muscle activity can be utilized to guide functional electrical stimulation, allowing specific muscles to be targeted and potentially improving overall rehabilitation outcomes.

90K/LGALS3BP expression is upregulated in COVID-19 but may not restrict SARS-CoV-2 infection.

Glycoprotein 90K, encoded by the interferon-stimulated gene LGALS3BP, displays broad antiviral activity. It reduces HIV-1 infectivity by interfering with Env maturation and virion incorporation, and increases survival of Influenza A virus-infected mice via antiviral innate immune signaling. Its antiviral potential in SARS-CoV-2 infection remains largely unknown. Here, we analyzed the expression of 90K/LGALS3BP in 44 hospitalized COVID-19 patients at multiple levels. We quantified 90K protein concentrations in serum and PBMCs as well as LGALS3BP mRNA levels. Complementary, we analyzed two single cell RNA-sequencing datasets for expression of LGALS3BP in respiratory specimens and PBMCs from COVID-19 patients. Finally, we analyzed the potential of 90K to interfere with SARS-CoV-2 infection of HEK293T/ACE2, Calu-3 and Caco-2 cells using authentic virus. 90K protein serum concentrations were significantly elevated in COVID-19 patients compared to uninfected sex- and age-matched controls. Furthermore, PBMC-associated concentrations of 90K protein were overall reduced by SARS-CoV-2 infection in vivo, suggesting enhanced secretion into the extracellular space. Mining of published PBMC scRNA-seq datasets uncovered monocyte-specific induction of LGALS3BP mRNA expression in COVID-19 patients. In functional assays, neither 90K overexpression in susceptible cell lines nor exogenous addition of purified 90K consistently inhibited SARS-CoV-2 infection. Our data suggests that 90K/LGALS3BP contributes to the global type I IFN response during SARS-CoV-2 infection in vivo without displaying detectable antiviral properties in vitro.

Humoral immune responses remain quantitatively impaired but improve qualitatively in anti-CD20-treated patients with multiple sclerosis after three or four COVID-19 vaccinations.

OBJECTIVE: To analyze anti-SARS-CoV-2-S1-IgG levels, avidity, Omicron BA.2 variant neutralizing capacity, and SARS-CoV-2-specific T cells in anti-CD20-treated patients with multiple sclerosis (aCD20pwMS) after two, three, or four COVID-19 vaccinations. RESULTS: Frequencies of aCD20pwMS with detectable SARS-CoV-2-S1-IgG increased moderately between two (31/61 (51%)), three (31/57 (54%)), and four (17/26 (65%)) vaccinations. However, among patients with detectable SARS-CoV-2-S1-IgG, frequencies of high avidity (6/31 (19%) vs 11/17 (65%)) and Omicron neutralizing antibodies (0/10 (0%) vs 6/10 (60%)) increased strongly between two and four vaccinations. SARS-CoV-2-specific T cells were detectable in >92% after two or more vaccinations. CONCLUSION: Additional vaccinations qualitatively improve SARS-CoV-2 antibody responses.

Preclinical safety and efficacy of a therapeutic antibody that targets SARS-CoV-2 at the sotrovimab face but is escaped by Omicron.

The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2.

SARS-CoV-2 variant Alpha has a spike-dependent replication advantage over the ancestral B.1 strain in human cells with low ACE2 expression.

Epidemiological data demonstrate that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) Alpha and Delta are more transmissible, infectious, and pathogenic than previous variants. Phenotypic properties of VOC remain understudied. Here, we provide an extensive functional study of VOC Alpha replication and cell entry phenotypes assisted by reverse genetics, mutational mapping of spike in lentiviral pseudotypes, viral and cellular gene expression studies, and infectivity stability assays in an enhanced range of cell and epithelial culture models. In almost all models, VOC Alpha spread less or equally efficiently as ancestral (B.1) SARS-CoV-2. B.1. and VOC Alpha shared similar susceptibility to serum neutralization. Despite increased relative abundance of specific sgRNAs in the context of VOC Alpha infection, immune gene expression in infected cells did not differ between VOC Alpha and B.1. However, inferior spreading and entry efficiencies of VOC Alpha corresponded to lower abundance of proteolytically cleaved spike products presumably linked to the T716I mutation. In addition, we identified a bronchial cell line, NCI-H1299, which supported 24-fold increased growth of VOC Alpha and is to our knowledge the only cell line to recapitulate the fitness advantage of VOC Alpha compared to B.1. Interestingly, also VOC Delta showed a strong (595-fold) fitness advantage over B.1 in these cells. Comparative analysis of chimeric viruses expressing VOC Alpha spike in the backbone of B.1, and vice versa, showed that the specific replication phenotype of VOC Alpha in NCI-H1299 cells is largely determined by its spike protein. Despite undetectable ACE2 protein expression in NCI-H1299 cells, CRISPR/Cas9 knock-out and antibody-mediated blocking experiments revealed that multicycle spread of B.1 and VOC Alpha required ACE2 expression. Interestingly, entry of VOC Alpha, as opposed to B.1 virions, was largely unaffected by treatment with exogenous trypsin or saliva prior to infection, suggesting enhanced resistance of VOC Alpha spike to premature proteolytic cleavage in the extracellular environment of the human respiratory tract. This property may result in delayed degradation of VOC Alpha particle infectivity in conditions typical of mucosal fluids of the upper respiratory tract that may be recapitulated in NCI-H1299 cells closer than in highly ACE2-expressing cell lines and models. Our study highlights the importance of cell model evaluation and comparison for in-depth characterization of virus variant-specific phenotypes and uncovers a fine-tuned interrelationship between VOC Alpha- and host cell-specific determinants that may underlie the increased and prolonged virus shedding detected in patients infected with VOC Alpha.

A Rare but Life-Threatening Case of Fournier's Gangrene Caused by Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitor, Empagliflozin.

Fournier's gangrene (FG) is a rare but severe infection in the soft tissue, leading to necrosis in the perineum, perianal and genitourinary area. This infection can spread rapidly in the body and lead to multi-organ failure, septic shock, and death. This life-threatening infection is usually caused by polymicrobial agents like Group A - Beta Hemolytic Streptococcus- Streptococcus pyogenes, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Proteus, and anaerobes like Bacteroides and Clostridium perfringes. Risk factors related to the development of FG are obesity, uncontrolled diabetes, lack of education, poor personal hygiene, especially in the genital region, history of fungal infection, recurrent urinary tract infection, smoking, immunosuppression, and medication. In 2018, a safety warning was issued by The U.S. Food and Drug Administration (FDA) on sodium-glucose cotransporter-2 (SGLT2) inhibitors, causing a rare but serious adverse outcome of FG in patients with type 2 diabetes mellitus. It is established that the increased urinary glucose concentration caused by SGLT-2 inhibitors creates a suitable environment for the growth of the infection in the urinary and genital area, leading to the development of FG. Here we present a case of life-threatening FG in an obese female with a past medical history of type 2 diabetes mellitus with recurrent history of genital yeast infection four months after starting an SGLT2 inhibitor, empagliflozin. This study aims to understand the relationship between the FG and SGLT-2 inhibitor, overall the benefits of SGLT2 inhibitors outweighs the risk manyfold, therefore, raising awareness among clinician to be vigilant, keep a high index of suspicion and focus on the safe use of SGLT2 inhibitors, especially before and after prescribing SGLT-2 inhibitor with a close follow-up to prevent its serious and life-threatening emergency like Fournier's gangrene and necrotizing fasciitis.

Endobronchial Foreign Bodies Presenting as Intermittent Chest Pain and Productive Cough.

A 51-year-old male presented with intermittent chest pain for one month and productive cough with yellow sputum for seven days. He had a history of chronic kidney disease stage G3, depression, and polysubstance abuse. His chest X-ray revealed mild hazy opacity in the right lower lobe, followed by a chest computed tomography without contrast that indicated multiple nodular opacities in the left mainstem bronchus with clear lungs. The patient underwent flexible bronchoscopy where the left mainstem bronchus was found to be completely occluded by three clear plastic bags, about 1 x 0.5 cm in size containing whitish content consistent with the appearance of crack cocaine. A high index of suspicion is crucial in patients with suspected foreign body aspiration as prompt extraction of foreign bodies may prevent complications.

A Rare Case of Empyema Complicated With Bronchopleural Fistula Secondary to Mucormycosis in a Young Immunocompromised Diabetic Patient With COVID-19.

Mucormycosis is an opportunistic fungal infection caused by the zygomycetes Mucor and Rhizopus. Most documented conditions and risk factors that predispose to mucormycosis are uncontrolled diabetes mellitus (DM), with or without ketoacidosis, hematological malignancies (HM), transplantation, immunosuppression, and chronic sinusitis. Pulmonary empyema secondary to Mucor in coronavirus disease 2019 (COVID-19)-infected patients is rarely documented. Here we present an extremely rare case of pulmonary empyema secondary to Mucor infection complicated by bronchocutaneous fistula in a human immunodeficiency virus (HIV)-infected patient in the setting of acute COVID-19 infection.

Hypocalcemia Induced Bronchospasm.

Bronchospasm is acute narrowing of the airways of lungs, which gives rise to wheezing and shortness of breath. Commonly seen in obstructive lung disease, but a rare finding in patients with hypocalcemia. This is a case that outlines a rare presentation of hypocalcemia induced bronchospasm in a patient with no known history of asthma or chronic obstructive pulmonary disease (COPD). In this report, we present a case of a 57 years old male with no history of asthma or COPD who presented with intractable bronchospasm. Initial work-up for common entities was negative. Patient was found to be profoundly hypocalcemic and treatment provided resolution of symptoms. Early recognition of hypocalcemia induced bronchospasm is important in clinical practice to optimize management and provide improvement in symptoms.

A Case of Bilateral Hemorrhagic Pleural Effusion Due to Dual Antiplatelet Therapy in a Dialysis Patient.

Etiologies of hemorrhagic pleural effusions (hemithoraces) are multifactorial. They can be traumatic, non-traumatic, or idiopathic in nature. In this report, we present a rare case of a 64-year-old male with end-stage renal disease (ESRD) on chronic hemodialysis and dual antiplatelet therapy (DAPT), due to a recent history of coronary arterial stent placement, who presented with progressive shortness of breath for one month. The CT of the chest revealed bilateral large pleural effusions (left > right) with a complete collapse of the left lung and partial collapse of the right lung. Ultrasound-guided left-sided thoracentesis revealed hemorrhagic pleural effusions. After the discontinuation of DAPT, drainage from the right-sided pleural effusion via a pigtail catheter showed continued drainage of pleural fluid without hemorrhage. The effusion on the left side was also noted to have resolved on the repeat chest X-ray. Prompt recognition of this rare cause of any hemorrhagic pleural effusion is essential for patients on dialysis to avoid complications. This report focuses on the possible etiology and potential complications of a hemorrhagic pleural effusion, followed by a brief discussion on the rare but significant association involving the incidence of a hemorrhagic pleural effusion in a dialysis patient receiving DAPT.

SARS-CoV-2 Beta variant infection elicits potent lineage-specific and cross-reactive antibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant of concern (VOC) resists neutralization by major classes of antibodies from COVID-19 patients and vaccinated individuals. In this study, serum of Beta-infected patients revealed reduced cross-neutralization of wild-type virus. From these patients, we isolated Beta-specific and cross-reactive receptor-binding domain (RBD) antibodies. The Beta-specificity results from recruitment of VOC-specific clonotypes and accommodation of mutations present in Beta and Omicron into a major antibody class that is normally sensitive to these mutations. The Beta-elicited cross-reactive antibodies share genetic and structural features with wild type-elicited antibodies, including a public VH1-58 clonotype that targets the RBD ridge. These findings advance our understanding of the antibody response to SARS-CoV-2 shaped by antigenic drift, with implications for design of next-generation vaccines and therapeutics.

Enhanced fitness of SARS-CoV-2 variant of concern Alpha but not Beta.

Emerging variants of concern (VOCs) are driving the COVID-19 pandemic1,2. Experimental assessments of replication and transmission of major VOCs and progenitors are needed to understand the mechanisms of replication and transmission of VOCs3. Here we show that the spike protein (S) from Alpha (also known as B.1.1.7) and Beta (B.1.351) VOCs had a greater affinity towards the human angiotensin-converting enzyme 2 (ACE2) receptor than that of the progenitor variant S(D614G) in vitro. Progenitor variant virus expressing S(D614G) (wt-S614G) and the Alpha variant showed similar replication kinetics in human nasal airway epithelial cultures, whereas the Beta variant was outcompeted by both. In vivo, competition experiments showed a clear fitness advantage of Alpha over wt-S614G in ferrets and two mouse models-the substitutions in S were major drivers of the fitness advantage. In hamsters, which support high viral replication levels, Alpha and wt-S614G showed similar fitness. By contrast, Beta was outcompeted by Alpha and wt-S614G in hamsters and in mice expressing human ACE2. Our study highlights the importance of using multiple models to characterize fitness of VOCs and demonstrates that Alpha is adapted for replication in the upper respiratory tract and shows enhanced transmission in vivo in restrictive models, whereas Beta does not overcome Alpha or wt-S614G in naive animals.

Autochthonous West Nile virus infection in Germany: Increasing numbers and a rare encephalitis case in a kidney transplant recipient.

West Nile Virus (WNV) infections are increasingly detected in birds and horses in central Europe, with the first mosquito-borne autochthonous human infection detected in Germany in 2019. Human infections are typically asymptomatic, with occasional severe neurological disease. Because of a low number of cases in central Europe, awareness regarding potential cases is low and WNV diagnostic testing is not routine. We tested cerebrospinal fluid (CSF) samples from unsolved encephalitis and meningitis cases from Berlin from 2019 to 2020, and describe a WNV-encephalitis case in a 33-year-old kidney transplant recipient. The infectious course was resolved by serology, RT-PCR and sequencing of stored samples. Phylogenetic sequence analysis revealed a close relationship of the patient's WNV strain to German sequences from 2019 and 2020. A lack of travel history and patient self-isolation during the SARS-CoV-2 pandemic suggest the infection was acquired in the patient's home or garden. Serological tests of four people sharing the living space were negative. Retrospective RT-PCR and WNV-IgM testing of 671 CSF samples from unsolved encephalitis and meningitis cases from Berlin detected no additional infections. The recent increase of WNV cases illustrates the importance of considering WNV in cases of meningoencephalitis, especially in immunocompromised patients, as described here. Proper education and communication and a revised diagnostic strategy will help to raise awareness and to detect future WNV infections.

Cocaine Hurts Your Kidneys Too: A Rare Case of Acute Interstitial Nephritis Caused by Cocaine Abuse.

Cocaine is a powerfully addictive recreational drug that is extracted from the leaves of the Erythroxylon coca plant native to Central and South America. It is a widely abused substance, despite being banned since the early 19th century due to fatalities. Cocaine may result in acute kidney injury (AKI) by different mechanisms, but acute interstitial nephritis (AIN) is scarcely recognized as the cause of acute kidney injury (AKI). Here, we present a case of AKI from both AIN and acute tubular necrosis (ATN) following cocaine insufflation. The purpose of this article is to review the rare but significant association of AIN associated with cocaine use. The nature of the treatment of cocaine-related kidney disease may differ from other causes of acute kidney insult. Prompt recognition of the underlying cause of renal dysfunction is vital for this group of patients to prevent the rapid deterioration of renal function.

Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study.

BACKGROUND: Heterologous vaccine regimens have been widely discussed as a way to mitigate intermittent supply shortages and to improve immunogenicity and safety of COVID-19 vaccines. We aimed to assess the reactogenicity and immunogenicity of heterologous immunisations with ChAdOx1 nCov-19 (AstraZeneca, Cambridge, UK) and BNT162b2 (Pfizer-BioNtech, Mainz, Germany) compared with homologous BNT162b2 and ChAdOx1 nCov-19 immunisation. METHODS: This is an interim analysis of a prospective observational cohort study enrolling health-care workers in Berlin (Germany) who received either homologous ChAdOx1 nCov-19 or heterologous ChAdOx1 nCov-19-BNT162b2 vaccination with a 10-12-week vaccine interval or homologous BNT162b2 vaccination with a 3-week vaccine interval. We assessed reactogenicity after the first and second vaccination by use of electronic questionnaires on days 1, 3, 5, and 7. Immunogenicity was measured by the presence of SARS-CoV-2-specific antibodies (full spike-IgG, S1-IgG, and RBD-IgG), by an RBD-ACE2 binding inhibition assay (surrogate SARS-CoV-2 virus neutralisation test), a pseudovirus neutralisation assay against two variants of concerns (alpha [B.1.1.7] and beta [B.1.351]), and anti-S1-IgG avidity. T-cell reactivity was measured by IFN-γ release assay. FINDINGS: Between Dec 27, 2020, and June 14, 2021, 380 participants were enrolled in the study, with 174 receiving homologous BNT162b2 vaccination, 38 receiving homologous ChAdOx1 nCov-19 vaccination, and 104 receiving ChAdOx1 nCov-19-BNT162b2 vaccination. Systemic symptoms were reported by 103 (65%, 95% CI 57·1-71·8) of 159 recipients of homologous BNT162b2, 14 (39%, 24·8-55·1) of 36 recipients of homologous ChAdOx1 nCov-19, and 51 (49%, 39·6-58·5) of 104 recipients of ChAdOx1 nCov-19-BNT162b2 after the booster immunisation. Median anti-RBD IgG levels 3 weeks after boost immunisation were 5·4 signal to cutoff ratio (S/co; IQR 4·8-5·9) in recipients of homologous BNT162b2, 4·9 S/co (4·3-5·6) in recipients of homologous ChAdOx1 nCov-19, and 5·6 S/co (5·1-6·1) in recipients of ChAdOx1 nCov-19- BNT162b2. Geometric mean of 50% inhibitory dose against alpha and beta variants were highest in recipients of ChAdOx1 nCov-19-BNT162b2 (956·6, 95% CI 835·6-1095, against alpha and 417·1, 349·3-498·2, against beta) compared with those in recipients of homologous ChAdOx1 nCov-19 (212·5, 131·2-344·4, against alpha and 48·5, 28·4-82·8, against beta; both p<0·0001) or homologous BNT162b2 (369·2, 310·7-438·6, against alpha and 72·4, 60·5-86·5, against beta; both p<0·0001). SARS-CoV-2 S1 T-cell reactivity 3 weeks after boost immunisation was highest in recipients of ChAdOx1 nCov-19-BNT162b2 (median IFN-γ concentration 4762 mIU/mL, IQR 2723-8403) compared with that in recipients of homologous ChAdOx1 nCov-19 (1061 mIU/mL, 599-2274, p<0·0001) and homologous BNT162b2 (2026 mIU/mL, 1459-4621, p=0·0008) vaccination. INTERPRETATION: The heterologous ChAdOx1 nCov-19-BNT162b2 immunisation with 10-12-week interval, recommended in Germany, is well tolerated and improves immunogenicity compared with homologous ChAdOx1 nCov-19 vaccination with 10-12-week interval and BNT162b2 vaccination with 3-week interval. Heterologous prime-boost immunisation strategies for COVID-19 might be generally applicable. FUNDING: Forschungsnetzwerk der Universitätsmedizin zu COVID-19, the German Ministry of Education and Research, Zalando SE.