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Bos S, Zambrana JV, Duarte E, Graber AL, Huffaker J, Montenegro C, Premkumar L, Gordon A, Kuan G, Balmaseda A, Harris E
The Lancet. Infectious diseases
2025-03-01
PMID: 39489898
Adolescent
Child
Child, Preschool
Cohort Studies
Dengue
Dengue Virus
Enzyme-Linked Immunosorbent Assay
Female
HIPC 2 (2015)
Humans
Male
Nicaragua
Prospective Studies
Serogroup
Serotyping
Abstract:
[{'@Label': 'BACKGROUND', '@NlmCategory': 'BACKGROUND', '#text': 'Dengue is the most prevalent mosquito-borne viral disease and a major public health problem worldwide. Most primary infections with the four dengue virus serotypes (DENV1-4) are inapparent; nonetheless, whether the distribution of symptomatic versus inapparent infections by serotype varies remains unknown. Here, we present (1) the evaluation of a DENV1-4 envelope domain III multiplex microsphere-based assay (EDIII-MMBA) to serotype inapparent primary infections and (2) its application leveraging 17 years of prospective sample collection from the Nicaraguan Pediatric Dengue Cohort Study (PDCS).'}, {'@Label': 'METHODS', '@NlmCategory': 'METHODS', '#text': 'We analysed primary DENV infections in the PDCS from 2004 to 2022 detected by inhibition ELISA (iELISA) or RT-PCR. First, we evaluated the performance of the EDIII-MMBA for serotyping with samples characterised by RT-PCR or focus reduction neutralisation test. Next, we analysed a subset of inapparent primary DENV infections in the PDCS with the EDIII-MMBA to evaluate the epidemiology of inapparent infections. Remaining infections were inferred using stochastic imputation, taking year and neighbourhood into account. Infection incidence and percentage of inapparent, symptomatic, and severe infections were analysed by serotype.'}, {'@Label': 'FINDINGS', '@NlmCategory': 'RESULTS', '#text': 'Between Aug 30, 2004, and March 10, 2022, a total of 5931 DENV-naive participants were followed in the PDCS. There were 1626 primary infections (382 symptomatic, 1244 inapparent) detected by iELISA or RT-PCR over the study period. The EDIII-MMBA demonstrated excellent overall accuracy (100%, 95% CI 95·8-100) for serotyping inapparent primary DENV infections when evaluated against gold-standard serotyping methods. Of the 1244 inapparent infections, we analysed 574 (46%) using the EDIII-MMBA. We found that the majority of primary infections were inapparent, with DENV3 exhibiting the highest likelihood of symptomatic (pooled odds ratio compared with DENV1: 2·13, 95% CI 1·28-3·56) and severe (6·75, 2·01-22·62) primary infections, whereas DENV2 was similar to DENV1 in both analyses. Considerable within-year and between-year variation in serotype distribution between symptomatic and inapparent infections and circulation of serotypes undetected in symptomatic cases were observed in multiple years.'}, {'@Label': 'INTERPRETATION', '@NlmCategory': 'CONCLUSIONS', '#text': 'Our study indicates that case surveillance skews the perceived epidemiological footprint of DENV. We reveal a more complex and intricate pattern of serotype distribution in inapparent infections. The substantial differences in infection outcomes by serotype emphasises the need for vaccines with balanced immunogenicity and efficacy across serotypes.'}, {'@Label': 'FUNDING', '@NlmCategory': 'BACKGROUND', '#text': 'National Institute of Allergy and Infectious Diseases (National Institutes of Health) and Bill & Melinda Gates Foundation.'}, {'@Label': 'TRANSLATION', '@NlmCategory': 'UNASSIGNED', '#text': 'For the Spanish translation of the abstract see Supplementary Materials section.'}]
Gabernet G, Maciuch J, Gygi JP, Moore JF, Hoch A, Syphurs C, Chu T, Jayavelu ND, Corry DB, Kheradmand F, Baden LR, Sekaly RP, McComsey GA, Haddad EK, Cairns CB, Rouphael N, Fernandez-Sesma A, Simon V, Metcalf JP, Agudelo Higuita NI, Hough CL, Messer WB, Davis MM, Nadeau KC, Pulendran B, ...
bioRxiv : the preprint server for biology
2025-02-14
PMID: 39990442
HIPC 1 (2010)
HIPC 2 (2015)
HIPC 3 (2022)
Yale University
Abstract:
Following SARS-CoV-2 infection, ~10-35% of COVID-19 patients experience long COVID (LC), in which often debilitating symptoms persist for at least three months. Elucidating the biologic underpinnings of LC could identify therapeutic opportunities. We utilized machine learning methods on biologic analytes and patient reported outcome surveys provided over 12 months after hospital discharge from >500 hospitalized COVID-19 patients in the IMPACC cohort to identify a multi-omics "recovery factor". IMPACC participants who experienced LC had lower recovery factor scores compared to participants without LC. Biologic characterization revealed increased levels of plasma proteins associated with inflammation, elevated transcriptional signatures of heme metabolism, and decreased androgenic steroids in LC patients. The recovery factor was also associated with altered circulating immune cell frequencies. Notably, recovery factor scores were predictive of LC occurrence in patients as early as hospital admission, irrespective of acute disease severity. Thus, the recovery factor identifies patients at risk of LC early after SARS-CoV-2 infection and reveals LC biomarkers and potential treatment targets.
Szabo PA, Levitin HM, Connors TJ, Chen D, Jin J, Thapa P, Guyer R, Caron DP, Gray JI, Matsumoto R, Kubota M, Brusko M, Brusko TM, Farber DL, Sims PA
bioRxiv : the preprint server for biology
2025-02-06
PMID: 39974963
Columbia University
HIPC 2 (2015)
HIPC 3 (2022)
Abstract:
The first years of life are essential for the development of memory T cells, which rapidly populate the body's diverse tissue sites during infancy. However, the degree to which tissue memory T cell responses in early life reflect those during adulthood is unclear. Here, we use single cell RNA-sequencing of resting and ex vivo activated T cells from lymphoid and mucosal tissues of infant (aged 2-9 months) and adult (aged 40-65 years) human organ donors to dissect the transcriptional programming of memory T cells over age. Infant memory T cells demonstrate a unique stem-like transcriptional profile and tissue adaptation program, yet exhibit reduced activation capacity and effector function relative to adults. Using CRISPR-Cas9 knockdown, we define Helios (IKZF2) as a critical transcriptional regulator of the infant-specific tissue adaptation program and restricted effector state. Our findings reveal key transcriptional mechanisms that control tissue T cell fate and function in early life.
Bramon Mora B, Lindsay H, Thiébaut A, Stuart KD, Gottardo R
Bioinformatics (Oxford, England)
2025-02-04
PMID: 39798134
Cluster Analysis
Computational Biology
HIPC 2 (2015)
HIPC 3 (2022)
Molecular Sequence Annotation
Seattle Children's Research Institute
Single-Cell Analysis
Software
Abstract:
[{'@Label': 'SUMMARY', '#text': 'In this article, we present tagtango, an innovative R package and web application designed for robust and intuitive comparison of single-cell clusters and annotations. It offers an interactive platform that simplifies the exploration of differences and similarities among different clustering and annotation methods. Leveraging single-cell data analysis and different visualizations, it allows researchers to dissect the underlying biological differences across groups. tagtango is a user-friendly application that is portable and works seamlessly across multiple operating systems.'}, {'@Label': 'AVAILABILITY AND IMPLEMENTATION', '#text': 'tagtango is freely available at https://github.com/bernibra/tagtango as an R package as well as an online web service at https://tagtango.unil.ch.'}]
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.
Sun Y, Sen S, Parmar R, Arakawa-Hoyt J, Cappelletti M, Rossetti M, Gjertson DW, Sigdel TK, Sarwal MM, Schaenman JM, Bunnapradist S, Lanier LL, Pickering H, Reed EF
Frontiers in immunology
2025-01-01
PMID: 40028342
Adult
Aged
CD8-Positive T-Lymphocytes
Cytomegalovirus
Cytomegalovirus Infections
Female
HIPC 2 (2015)
Humans
Interleukin-7 Receptor alpha Subunit
Kidney Transplantation
Lectins, C-Type
Male
Middle Aged
Receptors, Immunologic
Transplant Recipients
Virus Activation
Abstract:
[{'@Label': 'INTRODUCTION', '@NlmCategory': 'UNASSIGNED', '#text': 'Cytomegalovirus (CMV) viremia remains a major contributor to clinical complications in solid organ transplant (SOT) patients, including organ injury, morbidity and mortality. Given their critical role in antiviral defense, CD8+ T cells are essential for protective immunity against CMV.'}, {'@Label': 'METHODS', '@NlmCategory': 'UNASSIGNED', '#text': 'Using single-cell RNA sequencing, we investigated the transcriptional signatures and developmental lineages of CD8+ T cells in eight immunosuppressed kidney transplant recipients (KTRs) who received organs from CMV-seropositive donors. Results were validated in a cohort of 62 KTRs using immunophenotyping.'}, {'@Label': 'RESULTS', '@NlmCategory': 'UNASSIGNED', '#text': 'Our data revealed a significant influence of CMV serostatus on transcriptional variance of CD8+ memory T cells, associating with the first principal component from a global analysis of CD8+ T cells (p =0.0406), forming a continuum with five principal differentiation trajectories driven by CMV primary infection or reactivation. Following CMV primary infection, CD8+ T cells were hallmarked by restrained effector-memory differentiation. CD8+ T cells during CMV reactivation diverged non-linearly into senescent-like cells with signatures of arrested cell cycle, diminished translational activity and downregulated ZNF683 and longitudinally expanding effector cells with robust cytotoxic potential and upregulated ZNF683, acting as a reservoir for long-lived effector cells supporting long-term protection. Notably, CD28lo KLRG1hi IL-7R (CD127)lo HLA-DRhi CD8+ T cells present prior to the detection of viremia in CMV-seropositive patients emerged as a key feature distinguishing patients who did or did not undergo CMV reactivation after prophylaxis discontinuation (p =0.0163). Frequencies of these cells were also positively correlated with CMV-stimulated secretion of IFN-γ (p =0.0494), TNF-α (p =0.0358), MIP-1α (p =0.0262), MIP-1β (p =0.0043).'}, {'@Label': 'DISCUSSION', '@NlmCategory': 'UNASSIGNED', '#text': 'These results provide insights into the transcriptional regulation that influences the generation of CD8+ T cell immunity to CMV and may inform strategics for monitoring host immune response to CMV to better identify and introduce therapeutic intervention to patients at risk of developing clinically significant CMV viremia.'}]
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.'}]
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