Joshua Gillard

All Publications

• Antiviral responses induced by Tdap-IPV vaccination are associated with persistent humoral immunity to Bordetella pertussis. Nature communications Gillard, J., Suffiotti, M., Brazda, P., Venkatasubramanian, P. B., Versteegen, P., de Jonge, M. I., Kelly, D., Bibi, S., Pinto, M. V., Simonetti, E., Babiceanu, M., Kettring, A., Teodosio, C., de Groot, R., Berbers, G., Stunnenberg, H. G., Schanen, B., Fenwick, C., Huynen, M. A., Diavatopoulos, D. A. 2024; 15 (1): 2133

  Abstract

  Many countries continue to experience pertussis epidemics despite widespread vaccination. Waning protection after booster vaccination has highlighted the need for a better understanding of the immunological factors that promote durable protection. Here we apply systems vaccinology to investigate antibody responses in adolescents in the Netherlands (N = 14; NL) and the United Kingdom (N = 12; UK) receiving a tetanus-diphtheria-acellular pertussis-inactivated poliovirus (Tdap-IPV) vaccine. We report that early antiviral and interferon gene expression signatures in blood correlate to persistence of pertussis-specific antibody responses. Single-cell analyses of the innate response identified monocytes and myeloid dendritic cells (MoDC) as principal responders that upregulate antiviral gene expression and type-I interferon cytokine production. With public data, we show that Tdap vaccination stimulates significantly lower antiviral/type-I interferon responses than Tdap-IPV, suggesting that IPV may promote antiviral gene expression. Subsequent in vitro stimulation experiments demonstrate TLR-dependent, IPV-specific activation of the pro-inflammatory p38 MAP kinase pathway in MoDCs. Together, our data provide insights into the molecular host response to pertussis booster vaccination and demonstrate that IPV enhances innate immune activity associated with persistent, pertussis-specific antibody responses.

  View details for DOI 10.1038/s41467-024-46560-w

  View details for PubMedID 38459022

  View details for PubMedCentralID 7349943

• Discovery of sparse, reliable omic biomarkers with Stabl. Nature biotechnology Hédou, J., Marić, I., Bellan, G., Einhaus, J., Gaudillière, D. K., Ladant, F. X., Verdonk, F., Stelzer, I. A., Feyaerts, D., Tsai, A. S., Ganio, E. A., Sabayev, M., Gillard, J., Amar, J., Cambriel, A., Oskotsky, T. T., Roldan, A., Golob, J. L., Sirota, M., Bonham, T. A., Sato, M., Diop, M., Durand, X., Angst, M. S., Stevenson, D. K., Aghaeepour, N., Montanari, A., Gaudillière, B. 2024

  Abstract

  Adoption of high-content omic technologies in clinical studies, coupled with computational methods, has yielded an abundance of candidate biomarkers. However, translating such findings into bona fide clinical biomarkers remains challenging. To facilitate this process, we introduce Stabl, a general machine learning method that identifies a sparse, reliable set of biomarkers by integrating noise injection and a data-driven signal-to-noise threshold into multivariable predictive modeling. Evaluation of Stabl on synthetic datasets and five independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used sparsity-promoting regularization methods while maintaining predictive performance; it distills datasets containing 1,400-35,000 features down to 4-34 candidate biomarkers. Stabl extends to multi-omic integration tasks, enabling biological interpretation of complex predictive models, as it hones in on a shortlist of proteomic, metabolomic and cytometric events predicting labor onset, microbial biomarkers of pre-term birth and a pre-operative immune signature of post-surgical infections. Stabl is available at https://github.com/gregbellan/Stabl .

  View details for DOI 10.1038/s41587-023-02033-x

  View details for PubMedID 38168992

  View details for PubMedCentralID 7003173

• Longitudinal clinical phenotyping of post COVID condition in Mexican adults recovering from severe COVID-19: a prospective cohort study. Frontiers in medicine Núñez, I., Gillard, J., Fragoso-Saavedra, S., Feyaerts, D., Islas-Weinstein, L., Gallegos-Guzmán, A. A., Valente-García, U., Meyerowitz, J., Kelly, J. D., Chen, H., Ganio, E., Benkendorff, A., Flores-Gouyonnet, J., Dammann-Beltrán, P., Heredia-González, J. F., Rangel-Gutiérrez, G. A., Blish, C. A., Nadeau, K. C., Nolan, G., Crispín, J. C., McIlwain, D. R., Gaudillière, B., Valdés-Ferrer, S. I. 2023; 10: 1236702

  Abstract

  Few studies have evaluated the presence of Post COVID-19 conditions (PCC) in people from Latin America, a region that has been heavily afflicted by the COVID-19 pandemic. In this study, we describe the frequency, co-occurrence, predictors, and duration of 23 symptoms in a cohort of Mexican patients with PCC.We prospectively enrolled and followed adult patients hospitalized for severe COVID-19 at a tertiary care centre in Mexico City. The incidence of PCC symptoms was determined using questionnaires. Unsupervised clustering of PCC symptom co-occurrence and Kaplan-Meier analyses of symptom persistence were performed. The effect of baseline clinical characteristics was evaluated using Cox regression models and reported with hazard ratios (HR).We found that amongst 192 patients with PCC, respiratory problems were the most prevalent and commonly co-occurred with functional activity impairment. 56% had ≥5 persistent symptoms. Symptom persistence probability at 360 days 0.78. Prior SARS-CoV-2 vaccination and infection during the Delta variant wave were associated with a shorter duration of PCC. Male sex was associated with a shorter duration of functional activity impairment and respiratory symptoms. Hypertension and diabetes were associated with a longer duration of functional impairment. Previous vaccination accelerated PCC recovery.In our cohort, PCC symptoms were frequent (particularly respiratory and neurocognitive ones) and persistent. Importantly, prior SARS-CoV-2 vaccination resulted in a shorter duration of PCC.

  View details for DOI 10.3389/fmed.2023.1236702

  View details for PubMedID 37727759

  View details for PubMedCentralID PMC10505811

• Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19. Cell reports. Medicine Feyaerts, D., Hédou, J., Gillard, J., Chen, H., Tsai, E. S., Peterson, L. S., Ando, K., Manohar, M., Do, E., Dhondalay, G. K., Fitzpatrick, J., Artandi, M., Chang, I., Snow, T. T., Chinthrajah, R. S., Warren, C. M., Wittman, R., Meyerowitz, J. G., Ganio, E. A., Stelzer, I. A., Han, X., Verdonk, F., Gaudillière, D. K., Mukherjee, N., Tsai, A. S., Rumer, K. K., Jacobsen, D. R., Bjornson-Hooper, Z. B., Jiang, S., Saavedra, S. F., Valdés Ferrer, S. I., Kelly, J. D., Furman, D., Aghaeepour, N., Angst, M. S., Boyd, S. D., Pinsky, B. A., Nolan, G. P., Nadeau, K. C., Gaudillière, B., McIlwain, D. R. 2022: 100680

  Abstract

  The biological determinants underlying the range of coronavirus 2019 (COVID-19) clinical manifestations are not fully understood. Here, over 1,400 plasma proteins and 2,600 single-cell immune features comprising cell phenotype, endogenous signaling activity, and signaling responses to inflammatory ligands are cross-sectionally assessed in peripheral blood from 97 patients with mild, moderate, and severe COVID-19 and 40 uninfected patients. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identify and independently validate a multi-variate model classifying COVID-19 severity (multi-class area under the curve [AUC]training = 0.799, p = 4.2e-6; multi-class AUCvalidation = 0.773, p = 7.7e-6). Examination of informative model features reveals biological signatures of COVID-19 severity, including the dysregulation of JAK/STAT, MAPK/mTOR, and nuclear factor κB (NF-κB) immune signaling networks in addition to recapitulating known hallmarks of COVID-19. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for prevention and/or treatment of COVID-19 progression.

  View details for DOI 10.1016/j.xcrm.2022.100680

  View details for PubMedID 35839768

• BCG-induced trained immunity enhances acellular pertussis vaccination responses in an explorative randomized clinical trial. NPJ vaccines Gillard, J., Blok, B. A., Garza, D. R., Venkatasubramanian, P. B., Simonetti, E., Eleveld, M. J., Berbers, G. A., van Gageldonk, P. G., Joosten, I., de Groot, R., de Bree, L. C., van Crevel, R., de Jonge, M. I., Huynen, M. A., Netea, M. G., Diavatopoulos, D. A. 2022; 7 (1): 21

  Abstract

  Acellular pertussis (aP) booster vaccines are central to pertussis immunization programs, although their effectiveness varies. The Bacille Calmette-Guérin (BCG) vaccine is a prototype inducer of trained immunity, which enhances immune responses to subsequent infections or vaccinations. While previous clinical studies have demonstrated that trained immunity can protect against heterologous infections, its effect on aP vaccines in humans is unknown. We conducted a clinical study in order to determine the immunological effects of trained immunity on pertussis vaccination. Healthy female volunteers were randomly assigned to either receive BCG followed by a booster dose of tetanus-diphteria-pertussis inactivated polio vaccine (Tdap-IPV) 3 months later (BCG-trained), BCG + Tdap-IPV concurrently, or Tdap-IPV followed by BCG 3 months later. Primary outcomes were pertussis-specific humoral, T- and B-cell responses and were quantified at baseline of Tdap-IPV vaccination and 2 weeks thereafter. As a secondary outcome in the BCG-trained cohort, ex vivo leukocyte responses were measured in response to unrelated stimuli before and after BCG vaccination. BCG vaccination 3 months prior to, but not concurrent with, Tdap-IPV improves pertussis-specific Th1-cell and humoral responses, and also increases total memory B cell responses. These responses were correlated with enhanced IL-6 and IL-1β production at the baseline of Tdap-IPV vaccination in the BCG-trained cohort. Our study demonstrates that prior BCG vaccination potentiates immune responses to pertussis vaccines and that biomarkers of trained immunity are the most reliable correlates of those responses.

  View details for DOI 10.1038/s41541-022-00438-4

  View details for PubMedID 35177621

  View details for PubMedCentralID PMC8854388

• SARS-CoV-2 mucosal antibody development and persistence and their relation to viral load and COVID-19 symptoms. Nature communications Fröberg, J., Gillard, J., Philipsen, R., Lanke, K., Rust, J., van Tuijl, D., Teelen, K., Bousema, T., Simonetti, E., van der Gaast-de Jongh, C. E., Bos, M., van Kuppeveld, F. J., Bosch, B. J., Nabuurs-Franssen, M., van der Geest-Blankert, N., van Daal, C., Huynen, M. A., de Jonge, M. I., Diavatopoulos, D. A. 2021; 12 (1): 5621

  Abstract

  Although serological studies have shown that antibodies against SARS-CoV-2 play an important role in protection against (re)infection, the dynamics of mucosal antibodies during primary infection and their potential impact on viral load and the resolution of disease symptoms remain unclear. During the first pandemic wave, we assessed the longitudinal nasal antibody response in index cases with mild COVID-19 and their household contacts. Nasal and serum antibody responses were analysed for up to nine months. Higher nasal receptor binding domain and spike protein-specific antibody levels at study inclusion were associated with lower viral load. Older age was correlated with more frequent COVID-19 related symptoms. Receptor binding domain and spike protein-specific mucosal antibodies were associated with the resolution of systemic, but not respiratory symptoms. Finally, receptor binding domain and spike protein-specific mucosal antibodies remained elevated up to nine months after symptom onset.

  View details for DOI 10.1038/s41467-021-25949-x

  View details for PubMedID 34556667

  View details for PubMedCentralID PMC8460778

• Functional Programming of Innate Immune Cells in Response to Bordetella pertussis Infection and Vaccination. Advances in experimental medicine and biology Gillard, J., van Schuppen, E., Diavatopoulos, D. A. 2019; 1183: 53-80

  Abstract

  Despite widespread vaccination, B. pertussis remains one of the least controlled vaccine-preventable diseases. Although it is well known that acellular and whole cell pertussis vaccines induce distinct immune functionalities in memory cells, much less is known about the role of innate immunity in this process. In this review, we provide an overview of the known differences and similarities in innate receptors, innate immune cells and inflammatory signalling pathways induced by the pertussis vaccines either licensed or in development and compare this to primary infection with B. pertussis. Despite the crucial role of innate immunity in driving memory responses to B. pertussis, it is clear that a significant knowledge gap remains in our understanding of the early innate immune response to vaccination and infection. Such knowledge is essential to develop the next generation of pertussis vaccines with improved host defense against B. pertussis.

  View details for DOI 10.1007/5584_2019_404

  View details for PubMedID 31432398