Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Sarah J. Schlesinger is active.

Publication


Featured researches published by Sarah J. Schlesinger.


Journal of Experimental Medicine | 2003

DC-SIGN (CD209) Mediates Dengue Virus Infection of Human Dendritic Cells

Boonrat Tassaneetrithep; Timothy Burgess; Angela Granelli-Piperno; Christine Trumpfheller; Jennifer S. Finke; Wellington Sun; Michael A. Eller; Kovit Pattanapanyasat; Suttipant Sarasombath; Deborah L. Birx; Ralph M. Steinman; Sarah J. Schlesinger; Mary Marovich

Dengue virus is a single-stranded, enveloped RNA virus that productively infects human dendritic cells (DCs) primarily at the immature stage of their differentiation. We now find that all four serotypes of dengue use DC-SIGN (CD209), a C-type lectin, to infect dendritic cells. THP-1 cells become susceptible to dengue infection after transfection of DC-specific ICAM-3 grabbing nonintegrin (DC-SIGN), or its homologue L-SIGN, whereas the infection of dendritic cells is blocked by anti–DC-SIGN antibodies and not by antibodies to other molecules on these cells. Viruses produced by dendritic cells are infectious for DC-SIGN– and L-SIGN–bearing THP-1 cells and other permissive cell lines. Therefore, DC-SIGN may be considered as a new target for designing therapies that block dengue infection.


Proceedings of the National Academy of Sciences of the United States of America | 2008

The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine

Christine Trumpfheller; Marina Caskey; Godwin Nchinda; Maria Paula Longhi; Olga Mizenina; Yaoxing Huang; Sarah J. Schlesinger; Marco Colonna; Ralph M. Steinman

CD4+ Th1 type immunity is implicated in resistance to global infectious diseases. To improve the efficacy of T cell immunity induced by human immunodeficiency virus (HIV) vaccines, we are developing a protein-based approach that directly harnesses the function of dendritic cells (DCs) in intact lymphoid tissues. Vaccine proteins are selectively delivered to DCs by antibodies to DEC-205/CD205, a receptor for antigen presentation. We find that polyriboinosinic:polyribocytidylic acid (poly IC) independently serves as an adjuvant to allow a DC-targeted protein to induce protective CD4+ T cell responses at a mucosal surface, the airway. After two doses of DEC-targeted, HIV gag p24 along with poly IC, responder CD4+ T cells have qualitative features that have been correlated with protective function. The T cells simultaneously make IFN-γ, tumor necrosis factor (TNF)-α, and IL-2, and in high amounts for prolonged periods. The T cells also proliferate and continue to secrete IFN-γ in response to HIV gag p24. The adjuvant role of poly IC requires Toll-like receptor (TLR) 3 and melanoma differentiation-associated gene-5 (MDA5) receptors, but its analog poly IC12U requires only TLR3. We suggest that poly IC be tested as an adjuvant with DC-targeted vaccines to induce numerous multifunctional CD4+ Th1 cells with proliferative capacity.


Journal of Experimental Medicine | 2006

Intensified and protective CD4+ T cell immunity in mice with anti-dendritic cell HIV gag fusion antibody vaccine.

Christine Trumpfheller; Jennifer S. Finke; Carolina B. López; Thomas M. Moran; Bruno Moltedo; Helena Soares; Yaoxing Huang; Sarah J. Schlesinger; Chae Gyu Park; Michel C. Nussenzweig; Angela Granelli-Piperno; Ralph M. Steinman

Current human immunodeficiency virus (HIV) vaccine approaches emphasize prime boost strategies comprising multiple doses of DNA vaccine and recombinant viral vectors. We are developing a protein-based approach that directly harnesses principles for generating T cell immunity. Vaccine is delivered to maturing dendritic cells in lymphoid tissue by engineering protein antigen into an antibody to DEC-205, a receptor for antigen presentation. Here we characterize the CD4+ T cell immune response to HIV gag and compare efficacy with other vaccine strategies in a single dose. DEC-205–targeted HIV gag p24 or p41 induces stronger CD4+ T cell immunity relative to high doses of gag protein, HIV gag plasmid DNA, or recombinant adenovirus-gag. High frequencies of interferon (IFN)-γ– and interleukin 2–producing CD4+ T cells are elicited, including double cytokine-producing cells. In addition, the response is broad because the primed mice respond to an array of peptides in different major histocompatibility complex haplotypes. Long-lived T cell memory is observed. After subcutaneous vaccination, CD4+ and IFN-γ–dependent protection develops to a challenge with recombinant vaccinia-gag virus at a mucosal surface, the airway. We suggest that a DEC-targeted vaccine, in part because of an unusually strong and protective CD4+ T cell response, will improve vaccine efficacy as a stand-alone approach or with other modalities.


Journal of Experimental Medicine | 2011

Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans

Marina Caskey; François Lefebvre; Abdelali Filali-Mouhim; Mark J. Cameron; Jean-Philippe Goulet; Elias K. Haddad; Gaëlle Breton; Christine Trumpfheller; Sarah Pollak; Irina Shimeliovich; Angela Duque-Alarcon; Li Pan; Annette Nelkenbaum; Andres M. Salazar; Sarah J. Schlesinger; Ralph M. Steinman; Rafick Pierre Sekaly

As shown by transcriptional analysis of blood samples from human volunteers, injection with synthetic dsRNA (an agonist of the TLR3 and MDA5 pattern recognition receptors) triggered up-regulation of genes involved in innate immune pathways, similar to those induced by vaccination with the efficacious yellow fever vaccine.


Journal of Clinical Investigation | 2008

The efficacy of DNA vaccination is enhanced in mice by targeting the encoded protein to dendritic cells

Godwin Nchinda; Janelle My Kuroiwa; Margarita Oks; Christine Trumpfheller; Chae Gyu Park; Yaoxing Huang; Drew Hannaman; Sarah J. Schlesinger; Olga Mizenina; Michel C. Nussenzweig; Klaus Überla; Ralph M. Steinman

DNA vaccines promote an immune response by providing antigen-encoding DNA to the recipient, but the efficacy of such vaccines needs improving. Many approaches have considerable potential but currently induce relatively weak immune responses despite multiple high doses of DNA vaccine. Here, we asked whether targeting vaccine antigens to DCs would increase the immunity and protection that result from DNA vaccines. To determine this, we generated a DNA vaccine encoding a fusion protein comprised of the vaccine antigen and a single-chain Fv antibody (scFv) specific for the DC-restricted antigen-uptake receptor DEC205. Following vaccination of mice, the vaccine antigen was expressed selectively by DCs, which were required for the increased efficacy of MHC class I and MHC class II antigen presentation relative to a control scFv DNA vaccine. In addition, a DNA vaccine encoding an HIV gag p41-scFv DEC205 fusion protein induced 10-fold higher antibody levels and increased numbers of IFN-gamma-producing CD4+ and CD8+ T cells. After a single i.m. injection of the DNA vaccine encoding an HIV gag p41-scFv DEC205 fusion protein, mice were protected from an airway challenge with a recombinant vaccinia virus expressing the HIV gag p41, even with 1% of the dose of nontargeted DNA vaccine. The efficacy of DNA vaccines therefore may be enhanced by inclusion of sequences such as single-chain antibodies to target the antigen to DCs.


PLOS ONE | 2011

In Vivo Electroporation Enhances the Immunogenicity of an HIV-1 DNA Vaccine Candidate in Healthy Volunteers

Sandhya Vasan; Arlene Hurley; Sarah J. Schlesinger; Drew Hannaman; David F. Gardiner; Daniel Dugin; Mar Boente-Carrera; Roselle Vittorino; Marina Caskey; Johanne Andersen; Yaoxing Huang; Josephine H. Cox; Tony Tarragona-Fiol; Dilbinder K. Gill; Hannah Cheeseman; Lorna Clark; Len Dally; Carol Smith; Claudia Schmidt; Harriet Park; Jakub Kopycinski; Jill Gilmour; Patricia Fast; Robert M. Bernard; David D. Ho

Background DNA-based vaccines have been safe but weakly immunogenic in humans to date. Methods and Findings We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines. Conclusions This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate. Trial Registration ClinicalTrials.gov NCT00545987


Nature | 2016

HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption

Johannes F. Scheid; Joshua A. Horwitz; Yotam Bar-On; Edward F. Kreider; Ching Lan Lu; Julio C. C. Lorenzi; Anna Feldmann; Malte Braunschweig; Lilian Nogueira; Thiago Y. Oliveira; Irina Shimeliovich; Roshni Patel; Leah A. Burke; Yehuda Z. Cohen; Sonya Hadrigan; Allison Settler; Maggi Witmer-Pack; Anthony P. West; Boris Juelg; Tibor Keler; Thomas Hawthorne; Barry Zingman; Roy M. Gulick; Nico Pfeifer; Gerald H. Learn; Michael S. Seaman; Pamela J. Bjorkman; Florian Klein; Sarah J. Schlesinger; Bruce D. Walker

Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=<1e-5). Rebound viruses arose predominantly from a single provirus. In most individuals, emerging viruses showed increased resistance indicating escape. However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg/ml, and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks. We conclude that administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during ATI in humans.


Journal of Internal Medicine | 2012

Dendritic cell-targeted protein vaccines: a novel approach to induce T-cell immunity

Christine Trumpfheller; Maria Paula Longhi; Marina Caskey; Juliana Idoyaga; Leonia Bozzacco; T. Keler; Sarah J. Schlesinger; Ralph M. Steinman

Abstract.  Trumpfheller C, Longhi MP, Caskey M, Idoyaga J, Bozzacco L, Keler T, Schlesinger SJ, Steinman RM (The Rockefeller University, New York, NY; and Celldex Therapeutics, Phillipsburg, NJ; USA). Dendritic cell‐targeted protein vaccines: a novel approach to induce T‐cell immunity (Review). J Intern Med 2012; 271: 183–192.


Journal of Experimental Medicine | 2015

Circulating precursors of human CD1c+ and CD141+ dendritic cells

Gaëlle Breton; Jaeyop Lee; Yu Jerry Zhou; Joseph J. Schreiber; Tibor Keler; Sarah Puhr; Niroshana Anandasabapathy; Sarah J. Schlesinger; Marina Caskey; Kang Liu; Michel C. Nussenzweig

The Liu and Nussenzweig groups identify the immediate precursor of CD1c+ and CD141+ dendritic cells in the circulation of healthy donors. These precursor cells (hpre-cDC) were detectable in cord blood, bone marrow, blood, and peripheral lymphoid organs.


Nature Medicine | 2017

Antibody 10-1074 suppresses viremia in HIV-1-infected individuals

Marina Caskey; Till Schoofs; Henning Gruell; Allison Settler; Theodora Karagounis; Edward F. Kreider; Ben Murrell; Nico Pfeifer; Lilian Nogueira; Thiago Y. Oliveira; Gerald H. Learn; Yehuda Z. Cohen; Clara Lehmann; Daniel Gillor; Irina Shimeliovich; Cecilia Unson-O'Brien; Daniela Weiland; Alexander Robles; Tim Kümmerle; Christoph Wyen; Rebeka Levin; Maggi Witmer-Pack; Kemal Eren; Caroline C. Ignacio; Szilard Kiss; Anthony P. West; Hugo Mouquet; Barry Zingman; Roy M. Gulick; Tibor Keler

Monoclonal antibody 10-1074 targets the V3 glycan supersite on the HIV-1 envelope (Env) protein. It is among the most potent anti-HIV-1 neutralizing antibodies isolated so far. Here we report on its safety and activity in 33 individuals who received a single intravenous infusion of the antibody. 10-1074 was well tolerated and had a half-life of 24.0 d in participants without HIV-1 infection and 12.8 d in individuals with HIV-1 infection. Thirteen individuals with viremia received the highest dose of 30 mg/kg 10-1074. Eleven of these participants were 10-1074-sensitive and showed a rapid decline in viremia by a mean of 1.52 log10 copies/ml. Virologic analysis revealed the emergence of multiple independent 10-1074-resistant viruses in the first weeks after infusion. Emerging escape variants were generally resistant to the related V3-specific antibody PGT121, but remained sensitive to antibodies targeting nonoverlapping epitopes, such as the anti-CD4-binding-site antibodies 3BNC117 and VRC01. The results demonstrate the safety and activity of 10-1074 in humans and support the idea that antibodies targeting the V3 glycan supersite might be useful for the treatment and prevention of HIV-1 infection.

Collaboration


Dive into the Sarah J. Schlesinger's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Yaoxing Huang

Aaron Diamond AIDS Research Center

View shared research outputs
Top Co-Authors

Avatar

Anthony P. West

California Institute of Technology

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge