Nature Communications

Binding antibody levels against SARS-CoV-2 have shown to be correlates of protection against infection with pre-Omicron lineages. This has been challenged by the emergence of immune-evasive variants, notably the Omicron sublineages, in an evolving immune landscape with high levels of cumulative incidence and vaccination coverage. This in turn limits the use of commercially available high-throughput methods to quantify binding antibodies as a tool to monitor protection at the population-level. In...

The dynamics of innate and adaptive immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to SARS-CoV-2 infection in infants and young children in the first weeks and months of life by analyzing blood samples collected before, during, and after infection with Omicron and Non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, were stably maintained for >300 days. Antigen-specific memo...

Real-world data suggest that SARS-CoV-2 mRNA vaccines, administered within 100 days of immune checkpoint inhibitor (ICI) treatment ("peri-ICI vaccination"), may improve ICI effectiveness, potentially through synergistic immune priming. Although peri-ICI vaccination was associated with longer survival when we applied a previous framework to our independent dataset, additional patterns emerged. Peri-ICI vaccination benefit diminished after 2021, a pattern confirmed in re-analysis of a published co...

BackgroundNon-small cell lung cancer (NSCLC) frequently co-occurs with chronic inflammatory conditions such as COPD, RA, IPF, psoriasis, and Dermatomyositis. While epidemiological links are established, the genetic basis of this co-occurrence in specific cell types remains poorly resolved. MethodsWe applied a signal-driven colocalization approach to NSCLC GWAS index variants (p < 1 x 10-6), integrating single-cell eQTL (sc-eQTL) data across cell types within {+/-}100 kb windows to identify stab...

The orphan gene of SARS-CoV-2, ORF10, is the least studied gene in the virus responsible for the COVID-19 pandemic. Recent experimentation indicated ORF10 expression moderates innate immunity in vitro. However, whether ORF10 affects COVID-19 in humans remained unknown. We determine that the ORF10 sequence is identical to the Wuhan-Hu-1 ancestral haplotype in 95% of genomes across five variants of concern (VOC). Four ORF10 variants are associated with less virulent clinical outcomes in the human ...

Lung neuroendocrine tumours (NETs, also known as carcinoids) are rapidly rising in incidence worldwide but have unknown aetiology and limited therapeutic options beyond surgery. We conducted multi-omic analyses on over 300 lung NETs including whole-genome sequencing (WGS), transcriptome profiling, methylation arrays, spatial RNA sequencing, and spatial proteomics. The integration of multi-omic data provides definitive proof of the existence of four strikingly different molecular groups that vary...

The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the cellular disease dynamics remains limited. In our unique COVID-19 human challenge study we used single cell genomics of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in 16 seronegative individuals challenged with preAlpha-SARS-CoV-2. Our analyses revealed rapid changes in cell type proportions and dozens of highly dynamic cellular response states in epithelia...

SARS-CoV-2 breakthrough infection of vaccinated individuals is increasingly common with the circulation of highly immune evasive and transmissible Omicron variants. Here, we report the dynamics and durability of recalled spike-specific humoral immunity following BA.1 or BA.2 breakthrough infection, with longitudinal sampling up to 8 months post-infection. Both BA.1 and BA.2 infection robustly boosted neutralisation activity against the infecting strain while expanding breadth against other Omicr...

Measles resurgence in high-income countries that previously achieved elimination reveals a critical surveillance failure: current systems rely on county-level aggregates that obscure fine-scale clustering where outbreaks originate. We assembled the nationwide multiscale vaccination database spanning 45 US states (2013-2025), encompassing over 50,000 schools, 13,000 districts, and 3,000 counties. We developed a gravity-based transmission framework and demonstrate that school-level effective repro...

BackgroundThe worldwide pandemic caused by SARS-CoV-2 has claimed millions of lives and has had a profound effect on global life. Understanding the pathogenicity of the virus and the bodys response to infection is crucial in improving patient management, prognosis, and therapeutic strategies. To address this, we performed functional transcriptomic profiling to better understand the generic and specific effects of SARS-CoV-2 infection. MethodsWhole blood RNA sequencing was used to profile a well...

Understanding pathogen transmission is key to effective infection prevention. From February to December 2021, we implemented genomics-enhanced contact tracing for SARS-CoV-2 in Dusseldorf, Germany, integrating data on 32,380 cases, 49,906 contact tracing records, 162 outbreaks, and 8,028 viral genomes (sequencing coverage 24.5%). Combining epidemiological and genetic data, we found a putative infection source for 19% of sequenced and 44% of all cases. Household-associated transmission accounted ...

Colorectal adenocarcinoma is caused in part by widespread epigenetic deregulation, yet the analysis of genome-wide DNA methylation of colorectal adenocarcinoma is complicated due to spatial correlation among CpG, multiscale patterns of differential methylation, and confounding cellular heterogeneity in bulk tissue. This study develops a simple yet effective framework that combines rigorous statistical modelling with modern machine learning-based prediction, on the Illumina 450K data from The Can...

Most causal variants for complex diseases are expected to affect gene regulation in a cell- and context-specific manner. Hence, identification of such dynamically functioning variants requires functional readouts in disease-relevant tissues and context. In this study, we prioritized causal variants for psoriasis by enhancing functional annotations from disease-relevant cells. We demonstrate that disease-relevant immune cells, unlike most body tissues, possess functional annotations matching cand...

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association ...

BackgroundGenome-wide association studies (GWAS) have identified many loci linked to lung cancer, but connecting these loci to causal genes and relevant cell types remains difficult. Traditional Mendelian randomization (MR) using bulk tissue eQTLs averages signals across diverse cells, masking cell-specific effects. Here, we apply single-cell eQTL based MR to infer causal relationships at immune-cell resolution, revealing mechanisms not detectable in bulk analyses. MethodsWe conducted single-ce...

Understanding genetic variation underlying differences in plasma protein levels can elucidate human disease mechanisms, but prior evidence was almost entirely derived from white Europeans using protein-preselected affinity reagents. Here, we integrate exome sequencing and common non-coding variation with untargeted nanoparticle enriched mass spectrometry (MS)-based plasma proteomics (Seer Proteograph XT: n=8067 protein groups) in >1,400 British-Bangladeshi and British-Pakistani individuals. We g...

Genome-wide association studies (GWAS) have been instrumental in uncovering the genetic basis of complex traits. When integrated with expression quantitative trait loci (eQTL) mapping, they can elucidate how risk loci influence traits through gene regulatory mechanisms. Recent single-cell eQTL (sc-eQTL) studies suggest that genetic effects on gene expression are often cell type- and subtype-specific, but such datasets have so far been underpowered for causal inference. Here, we leverage results ...

Current predictive biomarkers generally leverage technologies such as immunohis-tochemistry or genetic analysis, which may require specialized equipment, be time-intensive to deploy, or incur human error. In this paper, we present an alternative approach for the development and deployment of a class of predictive biomarkers, leveraging deep learning on digital images of hematoxylin and eosin (H&E)-stained biopsy samples to simultaneously predict a range of molecular factors that are relevant to ...

Transcription factors play key roles in cellular biology. Their genomic binding events are enriched at disease- and trait-associated genetic risk loci in particular cellular contexts. To examine this phenomenon in depth, we constructed a PU.1 (SPI1) binding atlas by uniformly processing 260 PU.1 ChIP-seq datasets spanning many immune cell types. Comparison of ChIP-seq peaks across eight major immune cell types identifies shared and cell type-specific PU.1 binding events. DNA sequence analyses re...

Expansion of the SARS-CoV-2 BA.4 and BA.5 Omicron subvariants in populations with prevalent immunity from prior infection and vaccination, and associated burden of severe COVID-19, has raised concerns about epidemiologic characteristics of these lineages including their association with immune escape or severe clinical outcomes. Here we show that BA.4/BA.5 cases had 15% (95% confidence interval: 9-21%) and 38% (27-49%) higher adjusted odds of having received 3 and [&ge;]4 COVID-19 vaccine doses,...