Background Aging increases disease susceptibility and reduces vaccine responsiveness, highlighting the need to better understand the aging immune system and its clinical associations. Studying the human immune system, however, remains challenging due to its complexity and significant inter-individual variability. Methods We conducted an immune profiling study of 550 elderly participants (>= 60 years) and 100 young controls (20-40 years) from the RESIST Senior Individuals (SI) cohort. Extensive demographic, clinical, and laboratory data were collected. Multi-color spectral fl ow cytometry and 48-plex plasma cytokine assays were used for deep immune phenotyping. Data were analyzed using unsupervised clustering and multi-dataset integration approaches. Findings We studied 97 innate and adaptive immune cell populations, revealing intricate age- and sex-related changes in the elderly immune system. Our large sample size allowed detection of even subtle changes in cytokines and immune cell clusters. Integrative analysis combining clinical, laboratory, and immunological data revealed systems-level aging signatures, including shifts in specific immune cell subpopulations and cytokine concentrations (e.g., HGF and CCL27). Additionally, we identified unique immune signatures associated with smoking, obesity, and diseases such as osteoporosis, heart failure, and gout. Interpretation This study provides one of the most comprehensive immune profiles of elderly individuals, uncovering high-resolution immune changes associated with aging. Our fi ndings highlight clinically relevant immune signatures that enhance our understanding of aging-related diseases and could guide future research into new treatments, offering translational insights into human health and aging. Funding Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy-EXC 2155-project number 390874280. Copyright (c) 2025 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).

BACKGROUND:Eczema herpeticum (EH) is a potentially life-threatening disseminated skin infection caused by herpes simplex virus (HSV) in a subset of patients with atopic dermatitis (AD). The occurrence of EH in a subset of patients with AD and its frequent recurrence imply the importance of genetic factors in its pathogenesis. OBJECTIVE:We sought to identify novel genetic risk factors for EH and to study their impact on HSV-1 infection. METHODS:Using whole-exome sequencing we identified a heterozygous single nucleotide polymorphism (SNP) in the COL23A1 gene (encoding collagen type XXIII alpha 1 chain or COL23A1) that was associated with EH and validated it by PCR in a larger cohort. We studied the effect of upregulated COL23A1 expression on HSV-1 infection in primary keratinocytes and HaCaT cells and performed bulk RNA sequencing to address the underlying mechanism. RESULTS:Primary keratinocytes derived from patients with EH carrying this heterozygous SNP rs2973744 had elevated COL23A1 mRNA and protein levels as well as an increased susceptibility to HSV-1. Increasing the COL23A1 levels experimentally enhanced HSV-1 infection in human keratinocytes. COL23A1 overexpression elevated syndecan-1 and nectin-1 levels on the cell surface, which are HSV-1 attachment and entry factors, respectively, and downregulated genes involved in antiviral responses, such as IL1R1, IL32, TLR4, IRF1, S100A9, C3, and CFH. CONCLUSIONS:The SNP rs2973744 enhances COL23A1 expression in keratinocytes derived from patients with AD and a history of EH. Upregulation of COL23A1 promotes HSV-1 infection presumably by upregulating the HSV-1 attachment and entry factors syndecan-1 and nectin-1 on the cell surface and attenuating antiviral responses of keratinocytes.

The emergence of pandemic coronaviruses remains a global health concern, highlighting the need for broadly neutralizing antibodies (bnAbs) that can target multiple sarbecoviruses. In this study, we isolated and characterized a novel antibody, pT1679, that demonstrates exceptional neutralization breadth. The antibody prevented infection with SARS-CoV-2 variants of concern, such as Omicron BA.1, and effectively neutralized pseudotyped viruses displaying S proteins from many SARS-CoV-2 variants and various bat and pangolin sarbecoviruses, including both SARS-CoV-like and SARS-CoV-2-like viruses. In addition, pT1679 reduced the viral load in the lung of infected Syrian hamsters and prevented the severe lung pathology typical for SARS-CoV-2 infections. The cryo-electron microscopy structure of pT1679 in complex with SARS-CoV-2 S revealed that the antibody employs a YYDRxxG motif to recognize a highly conserved epitope on the RBD. Through detailed structural analysis, mutagenesis studies, and binding assays, we identified RBD residue 384 as a critical determinant of antibody recognition. Structure-function analyses of several related bnAbs, such as COVA1-16, allowed for the classification of YYDRxxG antibodies into two distinct groups that differ in neutralization breadth. Our findings provide crucial insights into the molecular basis of broad Sarbecovirus neutralization and offer strategic guidance for selecting therapeutic antibodies in preparation for future Sarbecovirus outbreaks.IMPORTANCEThe threat of emerging coronaviruses demands therapeutic strategies capable of targeting both current and future circulating viruses. We report the discovery and characterization of pT1679, a broadly neutralizing antibody that demonstrates cross-reactivity against diverse sarbecoviruses, including SARS-CoV, SARS-CoV-2 variants, and related viruses from bats and pangolins. pT1679 targets a highly conserved epitope via a YYDRxxG motif in the paratope, with RBD residue 384 serving as a critical determinant of recognition. Our analysis allows for a classification of YYDRxxG antibodies, providing a framework for predicting antibody effectiveness against emerging sarbecoviruses.

HCMV is associated with severe disease in immunocompromised patients and is a cause of congenital disease. Already more than 30 years ago, IE1 was described to bind to mitotic chromosomes, however the implications of this finding have yet to be determined. HCMV can infect a wide range of cell types and was also detected in different tumours; however, the majority of molecular studies relating to this virus are performed in fibroblasts or monocytic cells. We examined the localization of HCMV IE1 across multiple cell types, including tumour cell lines, to better understand how the protein behaves in these cellular contexts. IE1 is one of the first HCMV genes expressed after lytic infection of the cell and it was observed to distribute evenly over the chromosomes in so-called 'chromosome painting' pattern. In leukemia and glioblastoma cells we detected a novel mitotic localization pattern of IE1 - in chromosome-associated spots (CAS), in addition to 'painting the chromosomes', as reported before. We demonstrate that the IE1 core domain mediates CAS localization and that the distribution pattern of IE1 on mitotic chromosomes is influenced by both the cell type being infected and the level of IE1 expression. The novel CAS localization of IE1 suggests a new, possibly cell-type specific function of this protein, distinct from its role in transcriptional regulation. ### Competing Interest Statement The authors have declared no competing interest. National Science Centre, https://ror.org/03ha2q922, 2017/26/E/NZ6/01124 to MWG

Volume 87, no. 23, p. 12721–12736, 2013, https://doi.org/10.1128/jvi.01942-13. Several accidental mistakes occurred when Fig. 2A, 2B, 3A, 3B, 6C, and 8B of this article were put together for publication or during final production. The figure panels should appear as shown in this correction. In Fig. 2A, the Western blot at the bottom of the panel, labeled "BRD2-GFP Input," was incorrect and has been replaced with the correct blot, which shows that equal amounts of proteins were used for this immunoprecipitation experiment. In Fig. 2B, a control Western blot image was replaced with the correct image, which shows that equal amounts of proteins were used for this immunoprecipitation experiment. In Fig. 3A, lanes had been accidentally mislabeled, and the wrong Western blot showing the input controls had been inserted. In Fig. 3B, the wrong image was used for the second and fourth Western blots. Figure 6C was a duplicate of Fig. 6B, an error introduced during production. In Fig. 8B, second image from the top, the wrong control Western blot had been shown; the correct Western blot shows that the input controls for this experiment were comparable. This correction does not affect the results drawn from these experiments. The authors apologize for these multiple mistakes, which occurred unintentionally.

Abstract Background: A subgroup of atopic dermatitis (AD) patients is prone to develop severe, disseminated cutaneous infection with herpes simplex virus (HSV), known as eczema herpeticum (EH). The occurrence of EH in a subset of AD patients and its frequent recurrence implies the importance of genetic factors in its pathogenesis. Objective: We aimed to identify novel genetic risk factors for EH and study their impact on HSV-1 infection. Methods: We performed whole exome sequencing on nine AD patients with (ADEH+) and without (ADEH-) a history of EH in comparison to healthy controls. We validated the finding of a variant of COL23A1 gene (encoding Collagen type XXIII alpha 1 chain) in ADEH in a larger cohort of 117 ADEH+, 117 ADEH- patients and 118 healthy controls by PCR. We studied the expression of COL23A1 in keratinocytes from ADEH+ and ADEH- patients, and the upregulated COL23A1 expression in primary keratinocytes and in the cell line HaCaT to study its role in HSV-1 infection. Results: We identified a single nucleotide polymorphism (SNP), rs2973744 in COL23A1, as a risk factor for EH observed in 5% of ADEH+ patients, 1.6% of healthy donors and 0% of ADEH- patients. Primary human keratinocytes from an ADEH+ patient with SNP rs2973744 expressed higher COL23A1 levels and were more susceptible to HSV-1 than keratinocytes from ADEH- patients. In functional assays we showed that HSV-1 gene expression and cell-to-cell spread was more efficient in keratinocytes with increased expression of COL23A1. Moreover, COL23A1 overexpression in HaCaT cells resulted in transcriptional downregulation of several genes that are involved in an effective immune response (IL1R1, IL32, TLR4, CFH, C3, S100A9, IRF1, and ADAM23) and a notable upregulation of TNC and SPINK5 that are associated with AD. Conclusion: Upregulation of COL23A1 promotes HSV-1 infection presumably by attenuating antiviral responses of keratinocytes. Among other markers, the COL23A1 SNP rs2973744 could be included in the screening of AD patients to identify patients at risk of EH, thus allowing early initiation of therapy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanys Excellence Strategy-EXC 2155 RESIST- project number 390874280. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The ethics committee of Hannover Medical School (No. 8733\_BO\_S_2019) approved this study and all study participants provided written informed consent. DNA samples from AD patients with and without a history of EH were derived from the GENEVA cohort, Biobank of the University Hospital Schleswig-Holstein (UKSH), Kiel, Germany. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

RNA segments. In addition to viral genome expression, overexpression of NSP2 and NSP5 has been used to increase the rescue efficiency of recombinant RVs. Here, we showed that the overexpression of nucleotide sequence-modified NSP2 and NSP5 enabled the rapid and efficient production of recombinant RVs. Using improved reverse genetics, we established a reverse genetics system for human and bovine RV clinical isolates, as well as laboratory strains of bovine RV (NCDV and UK) and porcine RV (Gottfried). In addition, we rescued low-replicating recombinant RVs carrying a mutant NSP4 lacking the double-layered particle-binding domain, which was deficient in the efficient production of mature virions. These advancements in reverse genetics enabled the generation of molecular clones of RV clinical isolates and recombinant RVs harboring critical amino acid mutations, offering a versatile platform for investigating RV biology and pathogenesis. IMPORTANCE Recombinant rotavirus (RV) synthesis via reverse genetics relies on both the viral propagation capacity and the efficiency of the experimental system. Since the establishment of our reverse genetics system, several enhancements have been implemented to augment the rescue efficiency. Nevertheless, challenges persist in

Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs' host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha- and a Betacoronavirus. This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses.

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC 50 : 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection causes neurological disease in some patients suggesting that infection can affect both the peripheral and central nervous system (PNS and CNS, respectively). It is not clear whether the outcome of SARS-CoV-2 infection of PNS and CNS neurons is similar, and which are the key factors that cause neurological disease: SARS-CoV-2 infection or the subsequent immune response. Here, we addressed these questions by infecting human induced-pluripotent stem cell-derived CNS and PNS neurons with the β strain of SARS-CoV-2. Our results show that SARS-CoV-2 infects PNS neurons more efficiently than CNS neurons, despite lower expression levels of angiotensin converting enzyme 2. Infected PNS neurons produced interferon λ1, several interferon stimulated genes and proinflammatory cytokines. They also displayed neurodegenerative-like alterations, as indicated by increased levels of sterile alpha and Toll/interleukin receptor motif-containing protein 1, amyloid precursor protein and α-synuclein and lower levels of nicotinamide mononucleotide adenylyltransferase 2 and β-III-tubulin. Interestingly, blockade of the Janus kinase and signal transducer and activator of transcription pathway by Ruxolitinib did not increase SARS-CoV-2 infection, but reduced neurodegeneration, suggesting that an exacerbated neuronal innate immune response contributes to pathogenesis in the PNS.

The incidence of Lyme borreliosis has risen, accompanied by persistent symptoms. The innate immune system and related cytokines are crucial in the host response and symptom development. We characterized cytokine production capacity before and after antibiotic treatment in 1,060 Lyme borreliosis patients. We observed a negative correlation between antibody production and IL-10 responses, as well as increased IL-1Ra responses in patients with disseminated disease. Genome-wide mapping the cytokine production allowed us to identify 34 cytokine quantitative trait loci (cQTLs), with 31 novel ones. We pinpointed the causal variant at the TLR1-6-10 locus and validated the regulation of IL-1Ra responses at transcritpome level using an independent cohort. We found that cQTLs contribute to Lyme borreliosis susceptibility and are relevant to other immune-mediated diseases. Our findings improve the understanding of cytokine responses in Lyme borreliosis and provide a genetic map of immune function as an expanded resource. Common genetic variants can affect an individual's immune response to pathogens. Here, the authors uncover and characterize variants regulating cytokine responses in Lyme Borreliosis in 1,060 patients.

ABSTRACT Background Epstein-Barr virus-associated Infectious Mononucleosis (EBV-IM) is a common disease following primary EBV infection in children and adolescents. While EBV-IM is mostly self-limiting, symptoms like fatigue may persist over several months or even result in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This large clinical observational study aimed at identifying risk factors for protracted courses of EBV-IM in young people. Methods A cohort of N=200 children, adolescents, and young adults with acute primary EBV infection was recruited from hospitals and private practices. Data on the patients’ medical history as well as clinical and laboratory parameters were collected at a baseline visit (V1) within four weeks after symptom onset (T onset ) and at two follow-up visits (V2 and V3) one and six months after T onset . Risk factors for protracted symptoms at V3 were modeled using multivariable logistic regressions. Results Protracted symptoms were observed in 55/183 (30.1%) and protracted fatigue in 34/181 (18.8%) patients at V3. A medical history indicating an increased susceptibility to infectious diseases as well as distinct severe IM symptoms, e.g. severe gastrointestinal symptoms, were significantly associated with protracted disease [OR: 2.31; P=0.011 and OR: 3.42; P=0.027] and with chronic fatigue [OR: 2.98; P=0.006 and OR: 3.54; P=0.034], respectively. Occurrence of twelve or more clinical and laboratory parameters until and including V1 discriminated between fatigue and no fatigue at V3 [OR 2.43, P=0.033]. Conclusion A clinical history of immune dysregulation as well as distinct severe IM symptoms might predict protracted post-viral disease and thus help in the identification of young patients at risk. Highlights Severe gastrointestinal symptoms are associated with protracted course of Epstein-Barr virus-associated Infectious Mononucleosis (EBV-IM). Signs of immune dysregulation prior to EBV-IM can indicate an increased risk of protracted symptoms. Greater number of initial symptoms helps to identify patients developing postviral fatigue.

Kaposi's sarcoma-associatedherpesvirus (KSHV) can establishlatent lifelong infections in infected individuals. During viral latency,the latency-associated nuclear antigen (LANA) mediates the replicationof the latent viral genome in dividing cells and tethers them to mitoticchromosomes, thus ensuring their partitioning into daughter cellsduring mitosis. This study aims to inhibit Kaposi's sarcoma-associatedherpesvirus (KSHV) latent replication by targeting the LANA-DNAinteraction using small molecular entities. Drawing from first-generationinhibitors and using growth vectors identified through STD-NMR, weexpanded these compounds using Suzuki-Miyaura cross-coupling.This led to a deeper understanding of SAR achieved by microscale thermophoresis(MST) measurements and cell-free tests via electrophoretic mobilityshift assays (EMSA). Our most potent compounds successfully inhibitLANA-mediated replication in cell-based assays and demonstrate favorable in vitro ADMET-profiles, including suitable metabolic stability,Caco-2 permeability, and cytotoxicity. These compounds could serveas qualified leads for the future refinement of small molecule inhibitorsof KSHV latent replication.

Human cytomegalovirus (HCMV, human herpesvirus 5) is an opportunistic pathogen responsible for serious disease in immunocompromised patients. Current antiviral therapies rely predominantly on drugs interfering with viral DNA replication and packaging. However, the serious side effects of existing drugs and the emergence of drug resistance indicate the need for new targets for anti-HCMV therapy. One such target is the viral alkaline nuclease (AN), an enzyme highly conserved among the Herpesviridae. In this study, we validated the HCMV AN, encoded by the viral UL98 open reading frame, as a drug target by demonstrating that a UL98-deficient HCMV mutant is severely attenuated and shows a reduced ability to spread in cell culture. We established a fluorescence-based enzyme assay suitable for high-throughput screening and used it on a small-molecule compound library. The most promising hit, a thioxothiazolo[3,4-a]quinazoline derivative, blocked AN activity in vitro and inhibited HCMV replication in plaque reduction (PRA) and fluorescence reduction assays (FRA). Several derivatives of the hit compound were tested, some of which had similar or better inhibitory activities. The most potent derivative of hit scaffold A, compound AD-51, inhibited HCMV replication with a 50% effective concentrations (EC50) of 0.9 μM in the FRA and 1.1 μM in the PRA. AD-51 was also active against ganciclovir, foscarnet, and letermovir-resistant HCMVs. Moreover, it inhibited herpes simplex virus, Kaposi's sarcoma-associated herpesvirus, and murine CMV, a mouse virus serving as a model for HCMV. These results suggest that thioxothiazolo[3,4-a]quinazoline derivatives are a new class of herpesvirus inhibitors targeting the viral AN.

AbstractDeriving active pharmaceutical agents from renewable resources is crucial to increasing the economic feasibility of modern biorefineries and promises to alleviate critical supply‐chain dependencies in pharma manufacturing. Our multidisciplinary approach combines research in lignin‐first biorefining, sustainable catalysis, and alternative solvents with bioactivity screening, an in vivo efficacy study, and a structural‐similarity search. The resulting sustainable path to novel anti‐infective, anti‐inflammatory, and anticancer molecules enabled the rapid identification of frontrunners for key therapeutic indications, including an anti‐infective against the priority pathogen Streptococcus pneumoniae with efficacy in vivo and promising plasma and metabolic stability. Our catalytic methods provided straightforward access, inspired by the innate structural features of lignin, to synthetically challenging biologically active molecules with the core structure of dopamine, namely, tetrahydroisoquinolines, quinazolinones, 3‐arylindoles and the natural product tetrahydropapaveroline. Our diverse array of atom‐economic transformations produces only harmless side products and uses benign reaction media, such as tunable deep eutectic solvents for modulating reactivity in challenging cyclization steps.

Kaposi sarcoma-associated herpesvirus (KSHV), or human herpesvirus-8, is an oncogenic herpesvirus. Its latency-associated nuclear antigen (LANA) is essential for the persistence of KSHV in latently infected cells. LANA mediates replication of the latent viral genome during the S phase of a dividing cell and partitions episomes to daughter cells by attaching them to mitotic chromosomes. It also mediates the establishment of latency in newly infected cells through epigenetic mechanisms and suppresses the activation of the productive replication cycle. Furthermore, LANA promotes the proliferation of infected cell by acting as a transcriptional regulator and by modulating the cellular proteome through the recruitment of several cellular ubiquitin ligases. Finally, LANA interferes with the innate and adaptive immune system to facilitate the immune escape of infected cells.

INTRODUCTION:The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted the health-care system both in Australia and internationally, and has rapidly transformed the delivery of health care in hospitals and the community. Implementation of social isolation and distancing measures to stop the spread of the disease and to reduce potential harm to patients has necessitated the use of alternate models of health-care delivery. Changes that would normally take months or years have occurred within days to weeks.METHODS:We conducted analysis of outpatient clinic data during the period of the pandemic and compared this to previous telehealth use. We also present the results of clinician and patient telehealth experience surveys.RESULTS:We describe a 2255% increase in the use of telehealth at a tertiary hospital within a period of six weeks, and a significant simultaneous reduction in the outpatient clinic failure-to-attend rate. The vast majority of patients and clinicians agreed that the standard of care provided by telehealth was the same as that provided by on-site appointments.DISCUSSION:Telehealth that previously had only limited utilisation has now become a main method for the delivery of outpatient care. Clinicians and patients agreed that consultations provided by telehealth were of the same standard as those provided on site. Health care in the post-pandemic period should embed the use of telehealth for outpatient care and consider the range of other clinical contexts where this can be utilised.

The emergence of several new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in recent months has raised concerns around the potential impact on ongoing vaccination programs. Data from clinical trials and real-world evidence suggest that current vaccines remain highly effective against the alpha variant (B.1.1.7), while some vaccines have reduced efficacy and effectiveness against symptomatic disease caused by the beta variant (B.1.351) and the delta variant (B.1.617.2); however, effectiveness against severe disease and hospitalization caused by delta remains high.