Stanford Pathology Research Centers
U19 Center: A vaccine design to induce protective B and T cell immunity against hepatitis C Virus (U19P)
PI: Steven Foung, MD
The CDC estimates that 3 million people are living with hepatitis C virus (HCV) infection in the United States and there is an annual infection rate of 34,000 new infections. A contributing factor is the consequence of an opioid epidemic that shows no signs of slowing down and is unfortunately associated with increased injection drug use as a major mode to consume illicit opioids. HCV is transmitted by mainly contaminated blood. Data from some states in areas struggling with this problem showed an astonishing 364% increase in infection amongst young adults. The U19 Program is to develop an HCV vaccine to prevent disease progression after virus exposure in a vaccinated individual. The projects focus on the development of a vaccine that will elicit broadly protective antibodies and cellular responses that are long-lasting.
Stanford Impact of Genomic Variation on Function Center (SIGVFC)
PI: Ansuman Satpathy, MD, PhD
A comprehensive map of gene expression and gene regulation in human cells is critical to understand how genetic variation impacts human health and disease. Since gene regulation can be exquisitely cell type-, tissue-, and disease-specific, a comprehensive catalog of these elements has been limited by the lack of scalable single-cell methods that can be applied to diverse human tissues. The mission of the Stanford Impact of Genomic Variation on Function Center is to create a high-quality, open-access, and single cell-resolution reference map of human gene expression and regulation in immune cells during human development, across organ systems in healthy adults, and in patient tissues from diverse immune-related diseases.
The Stanford Impact of Genomic Variation on Function Center is part of a consortium: Impact-of-Genomic-Variation-on-Function-Consortium
Stanford U54: Mechanisms and Duration of Immunity to SARS-CoV-2
Serological Sciences Center of Excellence (SUSS-COE)
PI: Scott Boyd, MD, PhD
We propose the Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence (SUSS-COE) as a member of the SeroNet consortium gathered to address the urgent need for better understanding of human immune responses to the SARS-CoV-2 coronavirus pandemic that has engulfed the U.S. and the world. We will emphasize deep mechanistic analysis of the adaptive immune responses of COVID-19 patients, spanning serological, B cell and T cell responses; analysis of immune responses in the blood as well as mucosal tissue sites; comparing immune responses induced by infection to those induced by candidate vaccines; and paying particular attention to the understanding the clinical needs and immune responses of underserved, underrepresented and at-risk patient populations. Within these parameters, we will attempt to determine the factors that result in effective and durable immunity to SARS-CoV-2 infection and provide useful knowledge and tools for physicians and patients.
The Stanford U54 SARS-CoV-2 Serological Sciences Center of Excellence is part of a consortium. For more information about SeroNet (SUSS-COE) please go to: Stanford SeroNet Center for Excellence. National Cancer Institute (NCI) description: Serological Sciences Centers of Excellence
Stanford Mendelian Genomics Research Center (U01 HG011762-01)
PI: Stephen Montgomery, MD, PhD
Rapid advances in genomics have ushered in new opportunities for Mendelian disease discovery and diagnosis. In the last decade, exome and genome sequencing have moved from the research domain to clinical practice. These approaches have identified new disease genes and causative variants for ~30% of individuals suffering from a rare genetic disease. We believe that the systematic application of promising new genomics assays coupled with innovative computational approaches will foster discovery benefitting the 70% of symptomatic individuals without a genetic diagnosis. To this end we are applying long-read whole genome sequencing, RNA-sequencing, epigenomics assays, metabolomics and targeted in vitro and in vivo assays to evaluate a cohort of undiagnosed individuals suspected to have a Mendelian disorder. Our approach is augmented through the development and application of computational strategies enabling improved gene and phenotype matching, integrative multi-omics analysis, and variant interpretation. This work is expected to establish a new frontier in Mendelian disease discovery.
The Stanford Mendelian Genomics Research Center (MRGC) team has developed key prior expertise and leadership in the use of diverse state-of-the-art experimental and computational methods for the diagnosis and discovery of Mendelian disorders. We hypothesize that the next phase of Mendelian genomics research will be defined by assessing and deploying the most effective ‘omics’ strategies. We have proposed that ongoing and iterative integration of functional genomics data into the translational genomics toolkit will significantly increase discovery of new gene and variant disease associations beyond the capabilities of DNA-sequencing assays alone. Work at our site will potentiate the broad impact of the MGRC sites across the country by providing a platform for functional genomics research, validation and diagnosis in Mendelian disease.
Visit the main site at NIH (National Human Genome Research Institute) for more information: The GREGoR Consortium, genomcs research to elucidate the genetics of rare diseases
eDyNAmiC (extrachromosomal DNA in Cancer)
Cancer Grand Challenges
PI: Paul Mischel, MD
Tackling the extrachromosomal (ecDNA) Cancer Grand Challenge has the potential to transform the care of up-to a third of all cancer patients. ecDNA doesn’t play by the normal “rules” of chromosomal inheritance, enabling tumors to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible. ecDNA hides in plain sight, enabling tumors to be relentless beasts that are especially treatment resistant, adaptive, and aggressive resulting in patients with shorter survivals. Currently, cancer patients do not have a way of knowing whether their tumors have ecDNA, nor are there effective therapies including drugs, radiation, and surgery to address it. A new paradigm to find ecDNA cancer and effectively treat it is needed.
To meet this Grand Challenge, the eDyNAmiC programme brings forward the most comprehensive strategic approach ever to understand ecDNA and create plans, tools, and capabilities to find it in patients, disarm it, and treat it with uniquely designed therapies. eDyNAmiC’s seven Work Packages (WPs) will advance toward their goals in parallel but also as one team synergising in real time.
ecDNA is a different adversary than oncology has faced before. To be able to find it and attack it, we must first understand it. Two of the seven WPs are designed to do just that: WP1 learns how ecDNA forms and functions and WP2 identifies how the structure of ecDNA changes cancer-causing genes to become even more aggressive and resistant to treatment. WP3 and WP4 focus on the theme of finding ecDNA diagnostically through blood analysis, finding what gave rise to it in the first place, and finding vulnerabilities to target with therapies. WP5 and WP6 take on perhaps the toughest challenge—to figure out why ecDNA cancers are so resistant to treatment, adaptive to treatment, and why these tumors are less responsive than most to immuno-therapy. These two WPs will tell us a lot about whether we can take on ecDNA cancer with today’s arsenal of treatments. Finally, WP7 delivers hope by focusing on the development of new, novel classes of medicines designed to transform and cure these cancers. To make this WP realistic yet visionary, we will use advanced medicinal chemistry that is capable of building new molecules and adapting existing drugs to face the ecDNA challenge.
The combined scientific and patient advocacy team bring a uniquely integrated and complementary set of motivations, talents, and resources to this programme. We have the right group for this endeavor because of the leadership of the scientists who made the paradigm shifting discoveries of ecDNA driving cancer growth in the last decade. We are a team of committed people spanning essential disciplines for all WPs, who also add diversity of scientific perspective and offer proven track records of accomplishment and expertise essential for taking on this unprecedented challenge in cancer. Uniting researchers, patients, and patient advocates is a fierce commitment to patients, their families, and the personal experience with cancer in our own lives.
Sponsors: NCI & Cancer Research UK
Center website: Cancer Grand Challenges
NIH U19 Center: Systems Biological Assessment of
Innate and Adaptive Immunity to Vaccination
NIH HIPC (Human Immune Profiling Consortium)
PI: Bali Pulendran, PhD
Despite the enormous public health impact of vaccines, there is a paucity of understanding of the molecular mechanisms by which effective vaccines stimulate protective immune responses. Recent advances in the application of systems biology to vaccinology have revealed the molecular mechanisms and correlates underlying protective immunity induced by vaccination.
The Stanford HIPC center will use a systems biological approach to address two fundamental questions in vaccinology: (i) What are the mechanisms by which novel COVID-19 vaccines stimulate immune responses? (ii) What is the impact of the microbiome on immunity to vaccination?
The highly collaborative projects and cores of the Stanford-HIPC will address these issues leading to new and potentially actionable insight about human immunity to vaccines. The Human Immunology Project Consortium (HIPC) Center at Stanford is part of the NIH HIPC focused on systems biological analysis of human immunity to vaccination and infection: https://immunespace.org/hipc-centers/
NIH Center for Adjuvant Comparison and Characterization:
A Molecular Atlas for Benchmarking Adjuvants
(funding: NIH contract)
PI: Bali Pulendran, PhD
The goal of the research described in this proposal is to use a systems biological approach to profile the innate and adaptive immune responses induced by adjuvanted subunit vaccines in mice, nonhuman primates (NHPs) and human organoid cultures, with a view to: (i) establishing comparative “immune fingerprints” of different adjuvants, (ii) defining early molecular signatures that correlate with and predict the durability of the immune response, (iii) establishing a correlation of multi-omic immune profiles with disease outcome in an NHP challenge study, and (iv) generating a Molecular Atlas of Adjuvants which can be used to benchmark novel adjuvant candidates. Such an atlas will also serve as a guidepost for hypothesis driven research on the mechanism of action of adjuvants. These objectives will be accomplished in a highly collaborative and integrated program involving the analysis of innate and adaptive immune responses in NHPs (Focus 1), mice (Focus 2) and human tonsil organoids (Focus 3), supported by a strong Data Management & Analysis platform.
The ACC research program at Stanford is part of the Vaccine Adjuvant Compendium (VAC) at the NIH:
DARPA Center grant: Systems Biological Assessment of
the Durability of Vaccine Responses
(funding: Defense Advanced Research Projects Agency – DARPA)
PI: Bali Pulendran, PhD
Many vaccines — including those for flu, COVID and other diseases — may lose their effectiveness faster than official immunization recommendations suggest. DARPA has selected teams of researchers to support the Assessing Immune Memory (AIM) program, which seeks to develop a research and evaluation tool that can predict early on whether a given vaccine candidate will provide long-lasting immune protection.
Warfighters must deploy to regions of the world that present immunological challenges due to endemic diseases not previously encountered, or where there are pathogens or biothreats for which there are no vaccine options. The ability to rapidly select a future vaccine candidate that offers the longest duration of immune protection among all the potential options would greatly enhance operational readiness. By leveraging host-immune mechanisms in response to vaccination, AIM intends to provide the Department of Defense with the capability to predict effective vaccine duration of response prior to engaging in years-long clinical studies.
AIM will take a systems-level view of the response to vaccination and explore the mechanisms that lead to long-lasting protection. The plan is that this will then be implemented as a tool to predict vaccine duration of protection without waiting years for clinical trial results.”
AIM is a five-year program that is divided into two sequential phases. The goal of Phase 1, “Immune Memory Road Map,” is to identify cell and signaling contributors to generate a “road map” of immune memory. Phase 2, “Road Map Generalizability and Tool Validation,” will focus on assembling and validating an accurate assessment tool. The varied approaches will utilize measurements from preclinical animal models and advanced computational techniques with a goal to establish a way to predict how long a vaccine may protect a person, without needing to wait years for clinical trials.
NIH U01 Center grant: Systems Biological Assessment of
Vaccination-induced Protective Immunity in African Children (U01)
PI: Bali Pulendran, PhD
Utilization of multi-omics to define baseline and vaccine-induced signatures that predict RTS,S vaccine immunogenicity and protection from Malaria in young children in Malawi.
Plasmodium falciparum (Pf) malaria remains a major global health problem with more than 400,000 deaths annually, mainly in young African children. The most advanced malaria vaccine candidate, RTS,S, provides only partial efficacy against clinical malaria episodes when given to young children. However, efficacy wanes within 12-18 months post vaccination, with lack of durability of antibody responses, and post-booster antibody responses are lower than following primary vaccination.
We will leverage an extraordinary opportunity to comprehensively study baseline and vaccine-induced immune responses to the RTS,S Malaria vaccine in young children through a collaboration with the Malawi International Centers of Excellence in Malaria Research (ICEMR). The World Health Organization (WHO), in partnership with the Malawian government has been administering the RTS,S vaccine in Malawi as part of a large implementation study. The Malawi ICEMR is studying the effectiveness of RTS,S to prevent malaria infection and transmission in a longitudinal cohort of children.
We will collect systems level data using cutting edge tools, including cytometry by time of flight with epigenetic profiling (EpiTOF), plasma metabolomics, single-cell RNA-sequencing, and single-cell ATAC-seq. Vaccine immunogenicity will be assessed by measuring both the magnitude and quality of the RTS,S-specific humoral and cellular immune response. State-of-the-art computational pipelines will be applied to define molecular signatures that predict vaccine immunogenicity and protection.