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HIPC Centers
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Pickering H, Schaenman J, Phan HV, Maguire C, Tsitsiklis A, Rouphael N, Higuita NIA, Atkinson MA, Brakenridge S, Fung M, Messer W, Salehi-Rad R, Altman MC, Becker PM, Bosinger SE, Eckalbar W, Hoch A, Doni Jayavelu N, Kim-Schulze S, Jenkins M, Kleinstein SH, Krammer F, Maecker HT, Ozonoff A, ...
Nature communications
2025-01-10
PMID: 39794319
Adult
Aged
Antibodies, Viral
Chemokines
COVID-19
Female
Gene Expression Profiling
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Host Microbial Interactions
Humans
Immunity, Innate
Male
Middle Aged
Organ Transplantation
Prospective Studies
SARS-CoV-2
Transplant Recipients
Yale University
Abstract:
Coronavirus disease 2019 (COVID-19) poses significant risks for solid organ transplant recipients, who have atypical but poorly characterized immune responses to infection. We aim to understand the host immunologic and microbial features of COVID-19 in transplant recipients by leveraging a prospective multicenter cohort of 86 transplant recipients age- and sex-matched with 172 non-transplant controls. We find that transplant recipients have higher nasal SARS-CoV-2 viral abundance and impaired viral clearance, and lower anti-spike IgG levels. In addition, transplant recipients exhibit decreased plasmablasts and transitional B cells, and increased senescent T cells. Blood and nasal transcriptional profiling demonstrate unexpected upregulation of innate immune signaling pathways and increased levels of several proinflammatory serum chemokines. Severe disease in transplant recipients, however, is characterized by a less robust induction of pro-inflammatory genes and chemokines. Together, our study reveals distinct immune features and altered viral dynamics in solid organ transplant recipients.
da Silva Antunes R, Fajardo-Rosas V, Yu ED, Gálvez RI, Abawi A, Alexandar Escarrega E, Martínez-Pérez A, Johansson E, Goodwin B, Frazier A, Dan JM, Crotty S, Seumois G, Weiskopf D, Vijayanand P, Sette A
bioRxiv : the preprint server for biology
2025-01-09
PMID: 39829792
HIPC 2 (2015)
HIPC 3 (2022)
La Jolla Institute for Immunology
Abstract:
The long-term effects of repeated COVID-19 vaccinations on adaptive immunity remain incompletely understood. Here, we conducted a comprehensive three-year longitudinal study examining T cell and antibody responses in 78 vaccinated individuals without reported symptomatic infections. We observed distinct dynamics in Spike-specific humoral and cellular immune responses across multiple vaccine doses. While antibody titers incrementally increased and stabilized with each booster, T cell responses rapidly plateaued, maintaining remarkable stability across CD4+ and CD8+ subsets. Notably, approximately 30% of participants showed CD4+ T cell reactivity to non-Spike antigens, consistent with asymptomatic infections. Single-cell RNA sequencing revealed a diverse landscape of Spike-specific T cell phenotypes, with no evidence of increased exhaustion or significant functional impairment. However, qualitative changes were observed in individuals with evidence of asymptomatic infection, exhibiting unique immunological characteristics, including increased frequencies of Th17-like CD4+ T cells and GZMKhi/IFNR CD8+ T cell subsets. Remarkably, repeated vaccinations in this group were associated with a progressive increase in regulatory T cells, potentially indicating a balanced immune response that may mitigate immunopathology. By regularly stimulating T cell memory, boosters contribute to a stable and enhanced immune response, which may provide better protection against symptomatic infections.
Carrillo FAB, Ojeda S, Sanchez N, Plazaola M, Collado D, Miranda T, Saborio S, Mercado BL, Monterrey JC, Arguello S, Campredon L, Chu Z, Carlson CJ, Gordon A, Balmaseda A, Kuan G, Harris E
medRxiv : the preprint server for health sciences
2025-01-07
PMID: 39830280
HIPC 2 (2015)
Abstract:
[{'@Label': 'BACKGROUND', '@NlmCategory': 'UNASSIGNED', '#text': 'Dengue, chikungunya, and Zika are mosquito-borne diseases of major human concern. Differential diagnosis is complicated in children and adolescents by their overlapping clinical features (signs, symptoms, and complete blood count results). Few studies have directly compared the three diseases. We assessed clinical features of cases aged 2-17 years experiencing these diseases.'}, {'@Label': 'METHODS', '@NlmCategory': 'UNASSIGNED', '#text': 'We characterized 1,405 dengue, 517 chikungunya, and 522 Zika pediatric cases occurring from January 2006 through December 2023 in a Nicaraguan cohort study. Clinical records and laboratory results across the first 10 days of illness were examined from a primary care health center. All cases were laboratory-confirmed. Data were analyzed with generalized additive models, generalized mixed models, and machine learning models.'}, {'@Label': 'FINDINGS', '@NlmCategory': 'UNASSIGNED', '#text': 'The prevalence of many clinical features exhibited by dengue, chikungunya, and Zika cases differed substantially overall, by age, and by day of illness. Dengue cases were differentiated most by abdominal pain, leukopenia, nausea/vomiting, and basophilia; chikungunya cases were differentiated most by arthralgia and the absence of leukopenia and papular rash; and Zika cases were differentiated most by rash and lack of fever and lymphocytopenia. Dengue and chikungunya cases exhibited similar temperature dynamics during acute illness, and their temperatures were higher than Zika cases. Sixty-two laboratory-confirmed afebrile dengue cases, which would not be captured by any widely used international case definition, presented very similarly to afebrile Zika cases, though some exhibited warning signs of disease severity. The presence of arthralgia, the presence of basophilia, and the absence of fever were the most important model-based predictors of chikungunya, dengue, and Zika, respectively.'}, {'@Label': 'INTERPRETATIONS', '@NlmCategory': 'UNASSIGNED', '#text': 'These findings substantially update our understanding of dengue, chikungunya, and Zika in children while identifying various clinical features that could improve differential diagnoses. The occurrence of afebrile dengue warrants reconsideration of current case definitions.'}, {'@Label': 'FUNDING', '@NlmCategory': 'UNASSIGNED', '#text': 'US National Institutes of Health R01AI099631, P01AI106695, U01AI153416, U19AI118610.'}]
Cortese M, Hagan T, Rouphael N, Wu SY, Xie X, Kazmin D, Wimmers F, Gupta S, van der Most R, Coccia M, Aranuchalam PS, Nakaya HI, Wang Y, Coyle E, Horiuchi S, Wu H, Bower M, Mehta A, Gunthel C, Bosinger SE, Kotliarov Y, Cheung F, Schwartzberg PL, Germain RN, Tsang J, ...
Nature immunology
2025-01-01
PMID: 39747435
Adjuvants, Immunologic
Adult
Antibodies, Viral
Antibody Formation
Blood Platelets
Female
HIPC 3 (2022)
Humans
Influenza, Human
Influenza Vaccines
Male
Megakaryocytes
Plasma Cells
Stanford
Vaccinology
Abstract:
We performed a systems vaccinology analysis to investigate immune responses in humans to an H5N1 influenza vaccine, with and without the AS03 adjuvant, to identify factors influencing antibody response magnitude and durability. Our findings revealed a platelet and adhesion-related blood transcriptional signature on day 7 that predicted the longevity of the antibody response, suggesting a potential role for platelets in modulating antibody response durability. As platelets originate from megakaryocytes, we explored the effect of thrombopoietin (TPO)-mediated megakaryocyte activation on antibody response longevity. We found that TPO administration enhanced the durability of vaccine-induced antibody responses. TPO-activated megakaryocytes also promoted survival of human bone-marrow plasma cells through integrin β1/β2-mediated cell-cell interactions, along with survival factors APRIL and the MIF-CD74 axis. Using machine learning, we developed a classifier based on this platelet-associated signature, which predicted antibody response longevity across six vaccines from seven independent trials, highlighting a conserved mechanism for vaccine durability.
Narvaez F, Montenegro C, Juarez JG, Zambrana JV, Gonzalez K, Videa E, Arguello S, Barrios F, Ojeda S, Plazaola M, Sanchez N, Camprubí-Ferrer D, Kuan G, Paz Bailey G, Harris E, Balmaseda A
PLoS neglected tropical diseases
2025-01-01
PMID: 39792951
Adolescent
Child
Child, Preschool
Cohort Studies
Dengue
Dengue Virus
Female
HIPC 2 (2015)
Humans
Infant
Male
Nicaragua
Serogroup
Severity of Illness Index
Abstract:
[{'@Label': 'BACKGROUND', '@NlmCategory': 'BACKGROUND', '#text': 'Dengue virus, a major global health threat, consists of four serotypes (DENV1-4) that cause a range of clinical manifestations from mild to severe and potentially fatal disease.'}, {'@Label': 'METHODS', '@NlmCategory': 'METHODS', '#text': 'This study, based on 19 years of data from the Pediatric Dengue Cohort Study and Pediatric Dengue Hospital-based Study in Managua, Nicaragua, investigates the relationship of serotype and immune status with dengue severity. Dengue cases were confirmed by molecular, serological, and/or virological methods, and study participants 6 months to 17 years old were followed during their hospital stay or as ambulatory patients.'}, {'@Label': 'RESULTS', '@NlmCategory': 'RESULTS', '#text': 'We enrolled a total of 15,833 participants, of whom 3,308 (21%) were positive for DENV infection. Of 2,644 cases with serotype result by RT-PCR, 559 corresponded to DENV1, 1,002 to DENV2, 760 to DENV3 and 323 to DENV4. Severe disease was more prevalent among secondary DENV2 and DENV4 cases, while similar disease severity was observed in both primary and secondary DENV1 and DENV3 cases. According to the 1997 World Health Organization (WHO) severity classification, both DENV2 and DENV3 caused a higher proportion of severe disease compared to other serotypes, whereas DENV3 caused the greatest percentage of severity according to the WHO-2009 classification. DENV2 was associated with increased odds of pleural effusion and low platelet count, while DENV3 was associated with both hypotensive and compensated shock.'}, {'@Label': 'CONCLUSIONS', '@NlmCategory': 'CONCLUSIONS', '#text': 'These findings demonstrate differences in dengue severity by serotype and immune status and emphasize the critical need for a dengue vaccine with balanced effectiveness against all four serotypes, particularly as existing vaccines show variable efficacy by serotype and serostatus.'}]
Mikelov A, Nefediev G, Tashkeev A, Rodriguez OL, Aguilar Ortmans D, Skatova V, Izraelson M, Davydov AN, Poslavsky S, Rahmouni S, Watson CT, Chudakov D, Boyd SD, Bolotin D
Genome research
2024-12-23
PMID: 39433438
Algorithms
Alleles
Genetic Variation
High-Throughput Nucleotide Sequencing
HIPC 3 (2022)
Humans
Receptors, Antigen, B-Cell
Receptors, Antigen, T-Cell
Sequence Analysis, DNA
Software
Stanford
Abstract:
Allelic variability in the adaptive immune receptor loci, which harbor the gene segments that encode B cell and T cell receptors (BCR/TCR), is of critical importance for immune responses to pathogens and vaccines. Adaptive immune receptor repertoire sequencing (AIRR-seq) has become widespread in immunology research making it the most readily available source of information about allelic diversity in immunoglobulin (IG) and T cell receptor (TR) loci. Here, we present a novel algorithm for extrasensitive and specific variable (V) and joining (J) gene allele inference, allowing the reconstruction of individual high-quality gene segment libraries. The approach can be applied for inferring allelic variants from peripheral blood lymphocyte BCR and TCR repertoire sequencing data, including hypermutated isotype-switched BCR sequences, thus allowing high-throughput novel allele discovery from a wide variety of existing data sets. The developed algorithm is a part of the MiXCR software. We demonstrate the accuracy of this approach using AIRR-seq paired with long-read genomic sequencing data, comparing it to a widely used algorithm, TIgGER. We applied the algorithm to a large set of IG heavy chain (IGH) AIRR-seq data from 450 donors of ancestrally diverse population groups, and to the largest reported full-length TCR alpha and beta chain (TRA and TRB) AIRR-seq data set, representing 134 individuals. This allowed us to assess the genetic diversity within the IGH, TRA, and TRB loci in different populations and to establish a database of alleles of V and J genes inferred from AIRR-seq data and their population frequencies with free public access through VDJ.online database.
Wang S, Myers AJ, Irvine EB, Wang C, Maiello P, Rodgers MA, Tomko J, Kracinovsky K, Borish HJ, Chao MC, Mugahid D, Darrah PA, Seder RA, Roederer M, Scanga CA, Lin PL, Alter G, Fortune SM, Flynn JL, Lauffenburger DA
Cell systems
2024-12-18
PMID: 39504969
Administration, Intravenous
Animals
BCG Vaccine
B-Lymphocytes
HIPC 3 (2022)
Immune System
Macaca
Macaca mulatta
Markov Chains
Massachusetts Institute of technology
Tuberculosis
Vaccination
Abstract:
Analysis of multi-modal datasets can identify multi-scale interactions underlying biological systems but can be beset by spurious connections due to indirect impacts propagating through an unmapped biological network. For example, studies in macaques have shown that Bacillus Calmette-Guerin (BCG) vaccination by an intravenous route protects against tuberculosis, correlating with changes across various immune data modes. To eliminate spurious correlations and identify critical immune interactions in a public multi-modal dataset (systems serology, cytokines, and cytometry) of vaccinated macaques, we applied Markov fields (MFs), a data-driven approach that explains vaccine efficacy and immune correlations via multivariate network paths, without requiring large numbers of samples (i.e., macaques) relative to multivariate features. We find that integrating multiple data modes with MFs helps remove spurious connections. Finally, we used the MF to predict outcomes of perturbations at various immune nodes, including an experimentally validated B cell depletion that induced network-wide shifts without reducing vaccine protection.
Dib SM, Wimalasena S, Graciaa DS, Rouphael N
The Journal of infectious diseases
2024-12-16
PMID: 39424292
HIPC 3 (2022)
Humans
Precision Medicine
Stanford
Systems Biology
Vaccination
Vaccines
Vaccine Development
Vaccinology
Abstract:
Systems vaccinology integrates a range of "omics" technologies to identify key immune signatures and enhance vaccine development. This approach aids in understanding variations in immune responses, driven by genetics, health status, and the microbiome. Consequently, systems vaccinology helps pave the way for personalized vaccination strategies, essential for addressing diverse populations.
Davis-Porada J, George AB, Lam N, Caron DP, Gray JI, Huang J, Hwu J, Wells SB, Matsumoto R, Kubota M, Lee Y, Morrison-Colvin R, Jensen IJ, Ural BB, Shaabani N, Weiskopf D, Grifoni A, Sette A, Szabo PA, Teijaro JR, Sims PA, Farber DL
Immunity
2024-12-10
PMID: 39510068
Adult
Aged
Aged, 80 and over
B-Lymphocytes
Columbia University
COVID-19
COVID-19 Vaccines
Female
HIPC 2 (2015)
HIPC 3 (2022)
Humans
Immunologic Memory
Lung
Lymphoid Tissue
Male
Memory T Cells
Middle Aged
SARS-CoV-2
Spike Glycoprotein, Coronavirus
Vaccination
Young Adult
Abstract:
Memory T and B cells in tissues are essential for protective immunity. Here, we performed a comprehensive analysis of the tissue distribution, phenotype, durability, and transcriptional profile of COVID-19 mRNA vaccine-induced immune memory across blood, lymphoid organs, and lungs obtained from 63 vaccinated organ donors aged 23-86, some of whom experienced SARS-CoV-2 infection. Spike (S)-reactive memory T cells were detected in lymphoid organs and lungs and variably expressed tissue-resident markers based on infection history, and S-reactive B cells comprised class-switched memory cells resident in lymphoid organs. Compared with blood, S-reactive tissue memory T cells persisted for longer times post-vaccination and were more prevalent with age. S-reactive T cells displayed site-specific subset compositions and functions: regulatory cell profiles were enriched in tissues, while effector and cytolytic profiles were more abundant in circulation. Our findings reveal functional compartmentalization of vaccine-induced T cell memory where surveilling effectors and in situ regulatory responses confer protection with minimal tissue damage.
Suryadevara V, Hudgins AD, Rajesh A, Pappalardo A, Karpova A, Dey AK, Hertzel A, Agudelo A, Rocha A, Soygur B, Schilling B, Carver CM, Aguayo-Mazzucato C, Baker DJ, Bernlohr DA, Jurk D, Mangarova DB, Quardokus EM, Enninga EAL, Schmidt EL, Chen F, Duncan FE, Cambuli F, Kaur G, Kuchel GA, ...
Nature reviews. Molecular cell biology
2024-12-01
PMID: 38831121
Animals
Biomarkers
Cellular Senescence
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Humans
Mice
Organ Specificity
Yale University
Abstract:
Once considered a tissue culture-specific phenomenon, cellular senescence has now been linked to various biological processes with both beneficial and detrimental roles in humans, rodents and other species. Much of our understanding of senescent cell biology still originates from tissue culture studies, where each cell in the culture is driven to an irreversible cell cycle arrest. By contrast, in tissues, these cells are relatively rare and difficult to characterize, and it is now established that fully differentiated, postmitotic cells can also acquire a senescence phenotype. The SenNet Biomarkers Working Group was formed to provide recommendations for the use of cellular senescence markers to identify and characterize senescent cells in tissues. Here, we provide recommendations for detecting senescent cells in different tissues based on a comprehensive analysis of existing literature reporting senescence markers in 14 tissues in mice and humans. We discuss some of the recent advances in detecting and characterizing cellular senescence, including molecular senescence signatures and morphological features, and the use of circulating markers. We aim for this work to be a valuable resource for both seasoned investigators in senescence-related studies and newcomers to the field.
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