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September 2012 - September 2014
Publications
Publications (89)
Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis b...
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 provide...
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...
To date, our understanding of how HIV infection impacts vaccine-induced cellular immunity is limited. Here, we investigate inflammation, immune activation and antigen-specific T cell responses in HIV-uninfected and antiretroviral-treated HIV-infected people. Our findings highlight lower recall responses of antigen-specific CD4 T cells that correlat...
Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge. In this study, we performed unsupervised subtyping of...
mRNA vaccines have demonstrated efficacy during the COVID-19 pandemic and are now being investigated for multiple diseases. However, concerns linger about the durability of immune responses, and the high incidence of breakthrough infections among vaccinated individuals highlights the need for improved mRNA vaccines. In this study, we investigated t...
Systems vaccinology studies have been used to build computational models that predict individual vaccine responses and identify the factors contributing to differences in outcome. Comparing such models is challenging due to variability in study designs. To address this, we established a community resource to compare models predicting B. pertussis b...
Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigate the ef...
Viral vectors are being used for the treatment of cancer. Yet, their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple...
BACKGROUND
Patients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coord...
The V1-deleted DNA/ALVAC/gp120 anti-HIV vaccine significantly decreased the risk of SIV and SHIV acquisition in macaques. CD14+ monocytes and the Antibody-dependent cellular cytotoxicity to V2 (V2-ADCC) were correlated with reduced risk, indicating the central role of innate response in mounting an effective response. We hypothesized that in-depth...
mRNA vaccines have demonstrated efficacy against COVID-19. However, concerns regarding waning immunity and breakthrough infections have motivated the development of next-generation vaccines with enhanced efficacy. In this study, we investigated the impact of 4-1BB costimulation on immune responses elicited by mRNA vaccines in mice. We first vaccina...
The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and...
Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multid...
Viral vectors are being used for the treatment of cancer. Yet their efficacy varies among tumors and their use poses challenges in immunosuppressed patients, underscoring the need for alternatives. We report striking antitumoral effects by a nonlytic viral vector based on attenuated lymphocytic choriomeningitis virus (r3LCMV). We show in multiple t...
Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study,...
Schistosomiasis is a disease caused by parasitic flatworms of the Schistosoma spp., and is increasingly recognized to alter the immune system, and the potential to respond to vaccines. The impact of endemic infections on protective immunity is critical to inform vaccination strategies globally. We assessed the influence of Schistosoma mansoni worm...
The glycosylation of IgG plays a critical role during human SARS-CoV-2, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during acute viral infection in humans. In vitro evidence suggests that the glycosylation of IgM inhibits T cell proliferation and alters complement activatio...
The IMPACC cohort, composed of >1,000 hospitalized COVID-19 participants, contains five illness trajectory groups (TGs) during acute infection (first 28 days), ranging from milder (TG1-3) to more severe disease course (TG4) and death (TG5). Here, we report deep immunophenotyping, profiling of >15,000 longitudinal blood and nasal samples from 540 pa...
Unlabelled:
The impact of endemic infections on protective immunity is critical to inform vaccination strategies. In this study, we assessed the influence of Schistosoma mansoni infection on host responses in a Ugandan fishing cohort given a Hepatitis B (HepB) vaccine. Concentrations of schistosome-specific circulating anodic antigen (CAA) pre-vac...
The development of an effective vaccine to protect against HIV acquisition will be greatly bolstered by in-depth understanding of the innate and adaptive responses to vaccination. We report here that the efficacy of DNA/ALVAC/gp120/alum vaccines, based on V2-specific antibodies mediating apoptosis of infected cells (V2-ADCC), is complemented by eff...
Systems vaccinology has defined molecular signatures and mechanisms of immunity to vaccination. However, comparative analysis of immunity to different vaccines is lacking. We integrated transcriptional data of over 3,000 samples, from 820 adults across 28 studies of 13 vaccines and analyzed vaccination-induced signatures of antibody responses. Most...
Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern ‘omic profiling techniques and computational modeling to promote rapid and...
Several studies have shown that the pre-vaccination immune state is associated with the antibody response to vaccination. However, the generalizability and mechanisms that underlie this association remain poorly defined. Here, we sought to identify a common pre-vaccination signature and mechanisms that could predict the immune response across 13 di...
Background
Better understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management.
Methods
Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1164 patients from 20 hospitals ac...
Systems biology approaches have been used to define molecular signatures and mechanisms of immunity to vaccination. However, most such studies have been done with single vaccines, and comparative analysis of the response to different vaccines is lacking. We integrated temporal transcriptional data of over 3,000 samples, obtained from 820 healthy ad...
Ly6Chi inflammatory monocytes show high IFN responses, and contribute to both protective and pathogenic functions following influenza virus infection. In order to understand the significance of IFN responses in this subset, we examined monocytes during infection with a lethal H5N1 virus that induces high levels of IFN and a low-pathogenicity H1N1 v...
Vaccines are among the most cost-effective public health interventions for preventing infection-induced morbidity and mortality, yet much remains to be learned regarding the mechanisms by which vaccines protect. Systems immunology combines traditional immunology with modern 'omic profiling techniques and computational modeling to promote rapid and...
The prognosis of most patients with AML is poor due to frequent disease relapse. The cause of relapse is thought to be from the persistence of leukemia initiating cells (LIC’s) following treatment. Here we assessed RNA based changes in LICs from matched patient diagnosis and relapse samples using single-cell RNA sequencing. Previous studies on AML...
Many factors determine whether an individual responding to vaccination will generate an immune response that can lead to protection. Several studies have shown that the pre-vaccination immune state associate with the antibody response to vaccines. However, the generalizability and mechanisms that underlie this association remain poorly defined. Her...
Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquis...
Current therapeutic interventions to eradicate latent HIV (“reservoir”) and restore immune function in ART-treated HIV infection have yet to show efficacy. To explore mechanisms of HIV persistence, we apply an integrated systems biology approach and identify a distinct group of individuals with poor CD4 T-cell reconstitution (Immunologic non-respon...
A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of thi...
Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with strain 68–1 Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although pre...
The impact of the microbiome on HIV disease is widely acknowledged although the mechanisms downstream of fluctuations in microbial composition remain speculative. We detected rapid, dynamic changes in translocated microbial constituents during two years after cART initiation. An unbiased systems biology approach revealed two distinct pathways drive...
A gene signature previously correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus (SIV) and SHIV challenge models in non-human primates (NHP). In this report we investigated presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanism for protection. The absence of thi...
Antiretroviral therapy (ART) fails to fully restore immune function and is not curative. A single infusion of CCR5 gene-edited autologous CD4 ⁺ T cells (SB-728-T) led to sustained increases in CD4 ⁺ T cell counts, improved T cell homeostasis, and reduced the estimated size of the HIV reservoir. These outcomes were associated with the expansion and...
Simian immunodeficiency virus (SIV) challenge of rhesus macaques (RMs) vaccinated with Rhesus Cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV) results in a binary outcome: stringent control and subsequent clearance of highly pathogenic SIV in ~55% of vaccinated RMs with no protection in the remaining 45%. Although previous work s...
Current therapeutic interventions to eradicate latent HIV ("reservoir") and restore immune function in ART-treated HIV infection have yet to show efficacy. To explore mechanisms of HIV persistence, we apply an integrated systems biology approach and identify a distinct group of individuals with poor CD4 T-cell reconstitution (Immunologic non-respon...
Significance
Neutralizing antibodies (NAbs) against HIV-1 are under clinical development. Despite demonstrated antiviral activity when used as treatment in HIV-infected people, the mechanism of action of NAbs remains controversial. Quantification of the relative contribution of Fab-mediated (neutralization of free virus) and Fc-mediated functions s...
The recombinant Canarypox ALVAC-HIV/gp120/alum vaccine regimen was the first to significantly decrease the risk of HIV acquisition in humans, with equal effectiveness in both males and females. Similarly, an equivalent SIV-based ALVAC vaccine regimen decreased the risk of virus acquisition in Indian rhesus macaques of both sexes following intrarect...
Vaccination with DNA-SIV + ALVAC-SIV + gp120 alum results in inflammasome activation, high levels of IL-1β production, emergency myelopoiesis, and the egress of CXCR4⁺ CD14⁺ pre-monocytes from bone marrow. Previously we have shown that this vaccine-induced innate monocyte memory is associated with decreased risk of SIVmac251 acquisition. Because IL...
The RV144 vaccine trial showed reduced risk of HIV-1 acquisition by 31.2%, although mechanisms that led to protection remain poorly understood. Here we identify transcriptional correlates for reduced HIV-1 acquisition after vaccination. We assess the transcriptomic profile of blood collected from 223 participants and 40 placebo recipients. Pathway-...
The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral...
The response to respiratory viruses varies substantially between individuals, and there are
currently no known molecular predictors from the early stages of infection. Here we conduct a
community-based analysis to determine whether pre- or early post-exposure molecular factors
could predict physiologic responses to viral exposure. Using peripheral...
The response to respiratory viruses varies substantially between individuals, and there are
currently no known molecular predictors from the early stages of infection. Here we conduct a
community-based analysis to determine whether pre- or early post-exposure molecular factors
could predict physiologic responses to viral exposure. Using peripheral...
Qualitative differences in the innate and adaptive responses elicited by different HIV vaccine candidates have not been thoroughly investigated. We tested the ability of the Aventis Pasteur live recombinant canarypox vector (ALVAC)-SIV, DNA-SIV and Ad26-SIV vaccine prime modalities together with two ALVAC-SIV + gp120 protein boosts to reduce the ri...
Respiratory viruses are highly infectious; however, the variation of individuals' physiologic responses to viral exposure is poorly understood. Most studies examining molecular predictors of response focus on late stage predictors, typically near the time of peak symptoms. To determine whether pre- or early post-exposure factors could predict respo...
Vaccination with recombinant ALVAC + gp120 alum boosts has decreased the risk of acquisition of HIV/SIV in humans and in macaques. We tested whether the substitution of the first ALVAC-SIV immunization with either a DNA- or an Ad26-based SIV vaccine would affect vaccine efficacy. We found that the DNA prime was associated with 52% vaccine efficacy...
A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) an...
Over the last three decades, a myriad of data has been generated regarding HIV/SIV evolution, immune evasion, immune response, and pathogenesis. Much of this data can be integrated and potentially used to generate a successful vaccine. Although individual approaches have begun to shed light on mechanisms involved in vaccine-conferred protection fro...
A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) an...
Aging is associated with hyporesponse to vaccination, whose mechanisms remain unclear. In this study hepatitis B virus (HBV)-naive older adults received three vaccines, including one against HBV. Here we show, using transcriptional and cytometric profiling of whole blood collected before vaccination, that heightened expression of genes that augment...
Supplementary Figures 1-7 and Supplementary Tables 1-5
Pearson correlation coefficients of pre-processed microarray probe expression values between the three primary vaginal cell cultures.DOI:
http://dx.doi.org/10.7554/eLife.04525.010
CONSORT checklist.
DOI:
http://dx.doi.org/10.7554/eLife.04525.020
Lists of genes significantly up- or down-regulated by tenofovir 1% or nonoxynol-9 2% gels in 9 cm rectal biopsies over 7 days of treatment.
DOI:
http://dx.doi.org/10.7554/eLife.04525.017
CONSORT flow chart.
DOI:
http://dx.doi.org/10.7554/eLife.04525.021
Summary of effect sizes and statistical significance testing.
DOI:
http://dx.doi.org/10.7554/eLife.04525.016
Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV transmission. Because this is a new prevention strategy, we broadly assessed its effects on the mucosa. In MTN-007, a phase-1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% g...
We perform whole transcriptome analysis of distinct CD8+ T-cell memory populations arising endogenously following immunization with clinical and pre-clinical vaccines regimens.•We find that transcriptional proximity relationships between endogenous TN, TCM, TEM and TEFF place memory cells at an intermediate state of differentiation between TN and T...
OA25.01
Background: The RV144 HIV vaccine trial resulted in limited, but significant protection, from HIV acquisition. Serum antibodies directed to the Env variable regions 1 and 2 (V1/V2) inversely correlated with the risk of HIV-1 infection and sieve analysis demonstrated immunologic pressure on two regions of the V2. Prior macaque studies demon...
BACKGROUND Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against sexual HIV transmission. Because this is a new prevention strategy targeting large numbers of healthy people, we broadly assessed its effects on the mucosa. METHODS AND FINDINGS In MTN-007, a phase 1, randomized, double-blinded rectal microbicide tri...
