Center for Human Immunology

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CAMBRIDGE, Mass.--(BUSINESS WIRE)--Moderna Therapeutics, a clinical stage biotechnology company that is pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients, today announced new data demonstrating that its Zika mRNA vaccine prevented Zika virus transmission from pregnant mice to their fetuses. The findings, which were published today in Cell, also demonstrated that Moderna’s Zika mRNA vaccine protected the placenta and fetus from Zika virus-induced injury. In the study, Moderna’s Zika mRNA vaccine was evaluated in addition to a live-attenuated vaccine candidate developed by the University of Texas Medical Branch (UTMB). The research was conducted by scientists from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and Washington University School of Medicine and UTMB. Children born to mothers infected with Zika can develop microcephaly, a severe disease characterized by abnormally small heads and severe neurologic disabilities. Zika infection is also strongly associated with Guillain-Barré Syndrome (GBS), an autoimmune disease that attacks the peripheral nervous system, leading to rapidly progressive and potentially life-threatening muscle weakness. GBS can lead to death caused by respiratory arrest if a patient is not ventilated. There are no treatment options or approved vaccines for the Zika virus or congenital Zika syndrome. This is the first study to establish vaccine protection from the Zika virus during pregnancy. “We’re highly encouraged by these preclinical findings demonstrating the ability of our mRNA vaccine to provide robust prevention of maternal transmission of Zika and protection against congenital defects,” said Giuseppe Ciaramella, Ph.D., Chief Scientific Officer of Moderna’s infectious disease-focused venture, Valera, and an author on the paper. “The threat to pregnant women and women who may be planning on getting pregnant remains a serious concern in certain regions of the U.S. and abroad. We look forward to further study of our Zika mRNA vaccine to prevent Zika infections, with the ultimate goal of improving outcomes for mothers, their children, and families in the U.S. and globally.” The study was designed to evaluate protection of fetuses during pregnancy in mice. Researchers gave a cohort of non-pregnant female mice (n=20) a 10 µg intramuscular (IM) injection of the Zika mRNA vaccine followed by a boost at 28 days. An additional cohort of non-pregnant mice (n=20) received placebo injections at the same time points. At day 49, the mice that received the mRNA vaccine produced high levels of neutralizing antibodies against Zika virus in their blood compared to placebo. Both cohorts were then mated and infected with the Zika virus. After seven days, most fetuses in the vaccinated mice showed no evidence of having Zika virus transmitted to them from their pregnant mothers compared to placebo. In addition, vaccinated mice had significantly lower levels of Zika virus RNA in maternal, placental and fetal tissues compared to placebo-injected mice, resulting in protection against damage to the placenta and fetus. Specifically, The researchers repeated the experiment in order to determine the effects on fetal viability at birth, again comparing maternal mice who were vaccinated with Moderna’s mRNA vaccine (n=14) and maternal mice who received placebo (n=14). None of the mice in the placebo group delivered pups at term due to extensive placental injury and fetal demise. In contrast, 100% of the fetuses from mice who received Moderna’s mRNA vaccine were born without signs of damage, and the heads of newborn pups of mothers in this treatment group showed no measurable levels of viral RNA. “These are very promising findings and, as the first study to demonstrate protection from Zika in the pregnancy setting, are an important development in our efforts to combat Zika virus,” said Michael Diamond, M.D., Ph.D., Professor, Departments of Medicine, Molecular Microbiology, Pathology & Immunology, and Associate Director, Center for Human Immunology and Immunotherapy Program at Washington University School of Medicine, and a lead author on the Cell paper. “This type of collaboration, fusing the expertise of academia, government and industry, will be critical in order to speed advancement of novel vaccines like the mRNA vaccine and live-attenuated vaccine involved in this study.” Moderna’s Zika mRNA vaccine, mRNA-1325, is currently in Phase 1/2 clinical study in healthy volunteers. The company’s pipeline includes seven additional mRNA prophylactic vaccines, all of which address infectious diseases for which there currently are no approved vaccines. In February 2017, a paper published in Cell demonstrated that Moderna’s mRNA vaccine protected mice against Zika. In April 2017, Moderna published human data for its mRNA vaccine technology in Molecular Therapy, which showed that its first prophylactic vaccine candidate, mRNA-1440 -- an mRNA prophylactic vaccine against avian H10N8 influenza – induced high levels of immunogenicity and was safe and well tolerated. Messenger RNA (mRNA) plays a fundamental role in human biology, directing protein production in cells. When used as a drug, mRNA can direct cells to produce therapeutic proteins (mRNA therapeutics) to fight disease or antigenic proteins (mRNA vaccines) to prevent disease. Moderna’s Zika mRNA vaccine encodes for viral antigenic proteins (Zika virus prM and E) associated with the Zika virus. The mRNA directs cells to produce and express the proteins on the cell surface, much like a native infections would do, but without the ability to cause disease. This is because no other viral proteins are present to enable the production of an infectious Zika virus. As a result, the immune system recognizes the antigenic proteins as foreign to the body and produces antibodies that have the potential to neutralize the Zika virus, and prevent infections in the event the vaccinated person is exposed to the actual virus in the future. In 2016, Moderna received a funding award of up to $125 million from the Biomedical Advanced Research and Development Authority (BARDA), a division of the Office of the Assistant Secretary for Preparedness and Response (ASPR) within the U.S. Department of Health and Human Services (HHS), to accelerate development of its Zika mRNA vaccine. Moderna’s preclinical work for mRNA-1325 was funded through a grant from the Defense Advanced Research Projects Agency (DARPA). Moderna is a clinical stage pioneer of messenger RNA (mRNA) therapeutics and vaccines, an entirely new drug technology that directs the body’s cells to produce intracellular or secreted proteins. With its breakthrough platform, Moderna is developing a new class of mRNA medicines for a wide range of diseases and conditions, in many cases by addressing currently undruggable targets. Moderna is developing its innovative mRNA medicines for infectious diseases, cancer (immuno-oncology), rare diseases, cardiovascular disease and pulmonary disease, through proprietary development and collaborations with strategic partners. Headquartered in Cambridge, Mass., privately held Moderna currently has strategic agreements with AstraZeneca, Merck, Alexion Pharmaceuticals and Vertex Pharmaceuticals, as well as the Defense Advanced Research Projects Agency (DARPA), an agency of the U.S. Department of Defense; the Biomedical Advanced Research and Development Authority (BARDA), a division of the Office of the Assistant Secretary for Preparedness and Response (ASPR) within the U.S. Department of Health and Human Services (HHS); and the Bill & Melinda Gates Foundation. To learn more, visit www.modernatx.com.


Castiello L.,U.S. National Institutes of Health | Sabatino M.,U.S. National Institutes of Health | Zhao Y.,U.S. National Cancer Institute | Tumaini B.,U.S. National Institutes of Health | And 7 more authors.
Molecular Therapy | Year: 2013

Cell-based immunotherapies are among the most promising approaches for developing effective and targeted immune response. However, their clinical usefulness and the evaluation of their efficacy rely heavily on complex quality control assessment. Therefore, rapid systematic methods are urgently needed for the in-depth characterization of relevant factors affecting newly developed cell product consistency and the identification of reliable markers for quality control. Using dendritic cells (DCs) as a model, we present a strategy to comprehensively characterize manufactured cellular products in order to define factors affecting their variability, quality and function. After generating clinical grade human monocyte-derived mature DCs (mDCs), we tested by gene expression profiling the degrees of product consistency related to the manufacturing process and variability due to intra-and interdonor factors, and how each factor affects single gene variation. Then, by calculating for each gene an index of variation we selected candidate markers for identity testing, and defined a set of genes that may be useful comparability and potency markers. Subsequently, we confirmed the observed gene index of variation in a larger clinical data set. In conclusion, using high-throughput technology we developed a method for the characterization of cellular therapies and the discovery of novel candidate quality assurance markers. © The American Society of Gene &Cell Therapy.


News Article | November 7, 2016
Site: www.eurekalert.org

Researchers at Vanderbilt University Medical Center and Washington University School of Medicine in St. Louis, Missouri, have isolated a human monoclonal antibody that in a mouse model "markedly reduced" infection by the Zika virus. The antibody, called ZIKV-117, also protected the fetus in pregnant mice infected with the virus, the researchers reported today in the journal Nature. Zika is believed to cause microcephaly, unusually small heads, and other congenital malformations in children born to infected women. Similar protection studies in primates are warranted, and if the findings hold up, ZIKV-177 could be developed as a protective antibody treatment for pregnant women at risk of Zika infection, the researchers concluded. The findings may also aid efforts to develop an effective anti-Zika vaccine, said James Crowe Jr., M.D., director of the Vanderbilt Vaccine Center and co-corresponding author of the paper with Michael S. Diamond, M.D., Ph.D., at Washington University. "These naturally occurring human antibodies isolated from humans represent the first medical intervention that prevents Zika infection and damage to fetuses," said Crowe, who also is Ann Scott Carell Professor in the Departments of Pediatrics and Pathology, Microbiology & Immunology in the Vanderbilt University School of Medicine. "We're excited because the data suggests we may have antibody treatments in hand that could be developed for use in pregnant women," he said. "The remarkable potency and breadth of inhibition by ZIKV-117 has great promise," Diamond said, "as it was able to inhibit infection by strains from both Africa and America in cell culture and in animals, including during pregnancy." Diamond is associate director of The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs at Washington University. Zika is a mosquito-borne virus that has emerged as a global public health threat. In addition to its association with congenital birth defects, Zika has been linked to Guillain-Barre syndrome, a neurological disorder that can lead to paralysis and death. Since a major outbreak was reported in Brazil last year, Zika infections transmitted by mosquitoes have been reported throughout Africa, Asia, the Pacific, and the Americas, including Miami-Dade County, Florida. During the past 15 years, Crowe and his colleagues have developed a high-efficiency method for isolating human monoclonal antibodies that has enabled to them identify neutralizing antibodies against a wide range of viral infections, from Ebola to HIV. The Crowe and Diamond laboratories have collaborated recently on several projects including the generation of protective human monoclonal antibodies against Dengue, West Nile, Chikungunya and now Zika viruses. Monoclonal antibodies are made from a single clone of B cells, a type of white blood cell, that have been fused to myeloma (cancer) cells to form fast-growing "hybridomas." This allows researchers to quickly generate large quantities of antibodies against specific viral targets. In the current study, the researchers isolated antibodies from the blood of people who'd been previously infected with the Zika virus in different parts of the world. The antibodies reacted to the envelope or "E" protein on the surface of the virus. The researchers then generated a variety of monoclonal antibodies. In cell culture studies, they identified one, ZIKV-117, which broadly neutralized several different strains of the virus. In mice infected by the Zika virus, injection of the antibody markedly reduced disease and mortality, and reduced transmission from mother to fetus. The paper's first authors were Gopal Sapparapu, Ph.D., research assistant professor of Pediatrics in the Crowe lab, and by Estefania Fernandez, a graduate student in Diamond's lab. Nurgun Kose, senior research specialist in Crowe's lab, made the antibodies. The research was supported in part by National Institutes of Health grants AI073755 and AI104972.


News Article | November 7, 2016
Site: www.sciencedaily.com

Researchers at Vanderbilt University Medical Center and Washington University School of Medicine in St. Louis, Missouri, have isolated a human monoclonal antibody that in a mouse model "markedly reduced" infection by the Zika virus. The antibody, called ZIKV-117, also protected the fetus in pregnant mice infected with the virus, the researchers reported in the journal Nature. Zika is believed to cause microcephaly, unusually small heads, and other congenital malformations in children born to infected women. Similar protection studies in primates are warranted, and if the findings hold up, ZIKV-177 could be developed as a protective antibody treatment for pregnant women at risk of Zika infection, the researchers concluded. The findings may also aid efforts to develop an effective anti-Zika vaccine, said James Crowe Jr., M.D., director of the Vanderbilt Vaccine Center and co-corresponding author of the paper with Michael S. Diamond, M.D., Ph.D., at Washington University. "These naturally occurring human antibodies isolated from humans represent the first medical intervention that prevents Zika infection and damage to fetuses," said Crowe, who also is Ann Scott Carell Professor in the Departments of Pediatrics and Pathology, Microbiology & Immunology in the Vanderbilt University School of Medicine. "We're excited because the data suggests we may have antibody treatments in hand that could be developed for use in pregnant women," he said. "The remarkable potency and breadth of inhibition by ZIKV-117 has great promise," Diamond said, "as it was able to inhibit infection by strains from both Africa and America in cell culture and in animals, including during pregnancy." Diamond is associate director of The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs at Washington University. Zika is a mosquito-borne virus that has emerged as a global public health threat. In addition to its association with congenital birth defects, Zika has been linked to Guillain-Barre syndrome, a neurological disorder that can lead to paralysis and death. Since a major outbreak was reported in Brazil last year, Zika infections transmitted by mosquitoes have been reported throughout Africa, Asia, the Pacific, and the Americas, including Miami-Dade County, Florida. During the past 15 years, Crowe and his colleagues have developed a high-efficiency method for isolating human monoclonal antibodies that has enabled to them identify neutralizing antibodies against a wide range of viral infections, from Ebola to HIV. The Crowe and Diamond laboratories have collaborated recently on several projects including the generation of protective human monoclonal antibodies against Dengue, West Nile, Chikungunya and now Zika viruses. Monoclonal antibodies are made from a single clone of B cells, a type of white blood cell, that have been fused to myeloma (cancer) cells to form fast-growing "hybridomas." This allows researchers to quickly generate large quantities of antibodies against specific viral targets. In the current study, the researchers isolated antibodies from the blood of people who'd been previously infected with the Zika virus in different parts of the world. The antibodies reacted to the envelope or "E" protein on the surface of the virus. The researchers then generated a variety of monoclonal antibodies. In cell culture studies, they identified one, ZIKV-117, which broadly neutralized several different strains of the virus. In mice infected by the Zika virus, injection of the antibody markedly reduced disease and mortality, and reduced transmission from mother to fetus. The paper's first authors were Gopal Sapparapu, Ph.D., research assistant professor of Pediatrics in the Crowe lab, and by Estefania Fernandez, a graduate student in Diamond's lab. Nurgun Kose, senior research specialist in Crowe's lab, made the antibodies.


News Article | November 7, 2016
Site: www.chromatographytechniques.com

Researchers at Vanderbilt University Medical Center and Washington University School of Medicine in St. Louis, Missouri, have isolated a human monoclonal antibody that in a mouse model "markedly reduced" infection by the Zika virus. The antibody, called ZIKV-117, also protected the fetus in pregnant mice infected with the virus, the researchers reported today in the journal Nature. Zika is believed to cause microcephaly, unusually small heads, and other congenital malformations in children born to infected women. Similar protection studies in primates are warranted, and if the findings hold up, ZIKV-177 could be developed as a protective antibody treatment for pregnant women at risk of Zika infection, the researchers concluded. The findings may also aid efforts to develop an effective anti-Zika vaccine, said James Crowe Jr., M.D., director of the Vanderbilt Vaccine Center and co-corresponding author of the paper with Michael S. Diamond, M.D., Ph.D., at Washington University. "These naturally occurring human antibodies isolated from humans represent the first medical intervention that prevents Zika infection and damage to fetuses," said Crowe, who also is Ann Scott Carell Professor in the Departments of Pediatrics and Pathology, Microbiology & Immunology in the Vanderbilt University School of Medicine. "We're excited because the data suggests we may have antibody treatments in hand that could be developed for use in pregnant women," he said. "The remarkable potency and breadth of inhibition by ZIKV-117 has great promise," Diamond said, "as it was able to inhibit infection by strains from both Africa and America in cell culture and in animals, including during pregnancy." Diamond is associate director of The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs at Washington University. Zika is a mosquito-borne virus that has emerged as a global public health threat. In addition to its association with congenital birth defects, Zika has been linked to Guillain-Barre syndrome, a neurological disorder that can lead to paralysis and death. Since a major outbreak was reported in Brazil last year, Zika infections transmitted by mosquitoes have been reported throughout Africa, Asia, the Pacific, and the Americas, including Miami-Dade County, Florida. During the past 15 years, Crowe and his colleagues have developed a high-efficiency method for isolating human monoclonal antibodies that has enabled to them identify neutralizing antibodies against a wide range of viral infections, from Ebola to HIV. The Crowe and Diamond laboratories have collaborated recently on several projects including the generation of protective human monoclonal antibodies against Dengue, West Nile, Chikungunya and now Zika viruses. Monoclonal antibodies are made from a single clone of B cells, a type of white blood cell, that have been fused to myeloma (cancer) cells to form fast-growing "hybridomas." This allows researchers to quickly generate large quantities of antibodies against specific viral targets. In the current study, the researchers isolated antibodies from the blood of people who'd been previously infected with the Zika virus in different parts of the world. The antibodies reacted to the envelope or "E" protein on the surface of the virus. The researchers then generated a variety of monoclonal antibodies. In cell culture studies, they identified one, ZIKV-117, which broadly neutralized several different strains of the virus. In mice infected by the Zika virus, injection of the antibody markedly reduced disease and mortality, and reduced transmission from mother to fetus.


Ruan X.,Center for Human Immunology | Loyola D.E.,University of Santiago de Chile | Marolda C.L.,Center for Human Immunology | Perez-Donoso J.M.,University of Santiago de Chile | And 2 more authors.
Glycobiology | Year: 2012

WaaL is a membrane enzyme that catalyzes a key step in lipopolysaccharide (LPS) synthesis: the glycosidic bonding of a sugar at the proximal end of the undecaprenyl-diphosphate (Und-PP) O-antigen with a terminal sugar of the lipid A-core oligosaccharide (OS). Utilizing an in vitro assay, we demonstrate here that ligation with purified Escherichia coli WaaL occurs without adenosine-5′-triphosphate (ATP) and magnesium ions. Furthermore, E. coli and Pseudomonas aeruginosa WaaL proteins cannot catalyze ATP hydrolysis in vitro. We also show that a lysine substitution of the arginine (Arg)-215 residue renders an active protein, whereas WaaL mutants with alanine replacements in the periplasmic-exposed residues Arg-215, Arg-288 and histidine (His)-338 and also the membrane-embedded aspartic acid-389 are nonfunctional. An in silico approach, combining predicted topological information with the analysis of sequence conservation, confirms the importance of a positive charge at the small periplasmic loop of WaaL, since an Arg corresponding to Arg-215 was found at a similar position in all the WaaL homologs. Also, a universally conserved H[NSQ]X 9GXX[GTY] motif spanning the C-terminal end of the predicted large periplasmic loop and the membrane boundary of the transmembrane helix was identified. The His residue in this motif corresponds to His-338. A survey of LPS structures in which the linkage between O-antigen and lipid A-core OS was elucidated reveals that it is always in the β-configuration, whereas the sugars bound to Und-PP are in the-configuration. Together, our biochemical and in silico data argue that WaaL proteins use a common reaction mechanism and share features of metal ion-independent inverting glycosyltransferases. © 2011 The Author.


Patel K.B.,Center for Human Immunology | Ciepichal E.,Polish Academy of Sciences | Swiezewska E.,Polish Academy of Sciences | Valvano M.A.,Center for Human Immunology | Valvano M.A.,University of Western Ontario
Glycobiology | Year: 2012

Two families of membrane enzymes catalyze the initiation of the synthesis of O-antigen lipopolysaccharide. The Salmonella enterica Typhimurium WbaP is a prototypic member of one of these families. We report here the purification and biochemical characterization of the WbaP C-terminal (WbaPCT) domain harboring one putative transmembrane helix and a large cytoplasmic tail. An N-terminal thioredoxin fusion greatly improved solubility and stability of WbaPCT allowing us to obtain highly purified protein. We demonstrate that WbaPCT is sufficient to catalyze the in vitro transfer of galactose (Gal)-1-phosphate from uridine monophosphate (UDP)-Gal to the lipid carrier undecaprenyl monophosphate (Und-P). We optimized the in vitro assay to determine steady-state kinetic parameters with the substrates UDP-Gal and Und-P. Using various purified polyisoprenyl phosphates of increasing length and variable saturation of the isoprene units, we also demonstrate that the purified enzyme functions highly efficiently with Und-P, suggesting that the WbaPCT domain contains all the essential motifs to catalyze the synthesis of the Und-P-P-Gal molecule that primes the biosynthesis of bacterial surface glycans. © 2011 The Author.


PubMed | University of Western Ontario and Center for Human Immunology
Type: Journal Article | Journal: Journal of leukocyte biology | Year: 2014

The G-CSF is best known for its activity in the generation and activation of neutrophils. In addition, studies on G-CSF(-/-) or G-CSFR(-/-) mice and BMC cultures suggested a role of G-CSF in macrophage generation. However, our understanding on the role of G-CSF in macrophage development is limited. Here, using in vitro BMC models, we demonstrated that G-CSF promoted the generation of Gr-1(high)/F4/80(+) macrophage-like cells in M-BMCs, likely through suppressing cell death and enhancing generation of Gr-1(high)/F4/80(+) macrophage-like cells. These Gr-1(high) macrophage-like cells produced M2-like cytokines and surface markers in response to LPS and IL-4/IL-13, respectively. Adoptive transfer of EGFP-expressing (EGFP(+)) M-BMCs showed a dominant, gut-homing phenotype. The small intestinal lamina propria of G-CSFR(-/-) mice also harbored significantly reduced numbers of Gr-1(high)/F4/80(+) macrophages compared with those of WT mice, but levels of Gr-1(+)/F4/80(-) neutrophil-like cells were similar between these mice. Collectively, these results suggest a novel function of G-CSF in the generation of gut-homing, M2-like macrophages.


PubMed | Copenhagen University, NCI Inc, National Human Genome Research Institute, Center for Human Immunology and 3 more.
Type: Clinical Trial, Phase II | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B-cell receptor (BCR) signaling. Ibrutinib, a Bruton tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of tumor cells from the microenvironment. Although the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment.Patients received single-agent ibrutinib on an investigator-initiated phase II trial. Serial blood and tissue samples were collected pretreatment and during treatment. Changes in cytokine levels, cellular subsets, and microenvironmental interactions were assessed.Serum levels of key chemokines and inflammatory cytokines decreased significantly in patients on ibrutinib. Furthermore, ibrutinib treatment decreased circulating tumor cells and overall T-cell numbers. Most notably, a reduced frequency of the Th17 subset of CD4(+)T cells was observed concurrent with reduced expression of activation markers and PD-1 on T cells. Consistent with direct inhibition of T cells, ibrutinib inhibited Th17 differentiation of murine CD4(+)T cells in vitro Finally, in the bone marrow microenvironment, we found that ibrutinib disaggregated the interactions of macrophages and CLL cells, inhibited secretion of CXCL13, and decreased the chemoattraction of CLL cells.In conjunction with inhibition of BCR signaling, these changes in the tumor microenvironment likely contribute to the antitumor activity of ibrutinib and may impact the efficacy of immunotherapeutic strategies in patients with CLL. See related commentary by Bachireddy and Wu, p. 1547.

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