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Immunoprophylaxis and Therapy Commons

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Cd4 T Cell Help Prevents Cd8 T Cell Exhaustion And Promotes Control Of Mycobacterium Tuberculosis Infection [Preprint], Yu-Jung Lu, Palmira Barreira-Silva, Shayla Boyce, Jennifer Powers, Kelly Cavallo, Samuel M. Behar 2021 University of Massachusetts Medical School

Cd4 T Cell Help Prevents Cd8 T Cell Exhaustion And Promotes Control Of Mycobacterium Tuberculosis Infection [Preprint], Yu-Jung Lu, Palmira Barreira-Silva, Shayla Boyce, Jennifer Powers, Kelly Cavallo, Samuel M. Behar

University of Massachusetts Medical School Faculty Publications

CD4 T cells are essential for immunity to tuberculosis because they produce cytokines including interferon-γ. Whether CD4 T cells act as “helper” cells to promote optimal CD8 T cell responses during Mycobacterium tuberculosis is unknown. Using two independent models, we show that CD4 T cell help enhances CD8 effector functions and prevents CD8 T cell exhaustion. We demonstrate synergy between CD4 and CD8 T cells in promoting the survival of infected mice. Purified helped, but not helpless, CD8 T cells efficiently restrict intracellular bacterial growth in vitro. Thus, CD4 T cell help plays an essential role in generating protective CD8 ...


Vaccines, Troy Moon 2021 Vanderbilt University

Vaccines, Troy Moon

PEER Liberia Project

This is a lecture in the PEER Liberia Infectious Disease Lecture Series. This presentation provides an overview of: prevention and control of vaccine preventable diseases; global impact of vaccines - successes and challenges; and vaccine fundamentals - basic immunology, introduction to vaccinology.


A Novel Dna And Protein Combination Covid-19 Vaccine Formulation Provides Full Protection Against Sars-Cov-2 In Rhesus Macaques, Yuzhong Li, Guangnan Hu, Shixia Wang, Qihan Li, Shan Lu, Wei Cun 2021 Peking Union Medical College

A Novel Dna And Protein Combination Covid-19 Vaccine Formulation Provides Full Protection Against Sars-Cov-2 In Rhesus Macaques, Yuzhong Li, Guangnan Hu, Shixia Wang, Qihan Li, Shan Lu, Wei Cun

COVID-19 Publications by UMMS Authors

The current study aims to develop a safe and highly immunogenic COVID-19 vaccine. The novel combination of a DNA vaccine encoding the full-length Spike (S) protein of SARS-CoV-2 and a recombinant S1 protein vaccine induced high level neutralizing antibody and T cell immune responses in both small and large animal models. More significantly, the co-delivery of DNA and protein components at the same time elicited full protection against intratracheal challenge of SARS-CoV-2 viruses in immunized rhesus macaques. As both DNA and protein vaccines have been proven safe in previous human studies, and DNA vaccines are capable of eliciting germinal center ...


Identification Of A Neutralizing Epitope Within Minor Repeat Region Of Plasmodium Falciparum Cs Protein, J. Mauricio Calvo-Calle, Robert Mitchell, Rita Altszuler, Caroline Othoro, Elizabeth Nardin 2021 University of Massachusetts Medical School

Identification Of A Neutralizing Epitope Within Minor Repeat Region Of Plasmodium Falciparum Cs Protein, J. Mauricio Calvo-Calle, Robert Mitchell, Rita Altszuler, Caroline Othoro, Elizabeth Nardin

Open Access Publications by UMMS Authors

Malaria remains a major cause of morbidity and mortality worldwide with 219 million infections and 435,000 deaths predominantly in Africa. The infective Plasmodium sporozoite is the target of a potent humoral immune response that can protect murine, simian and human hosts against challenge by malaria-infected mosquitoes. Early murine studies demonstrated that sporozoites or subunit vaccines based on the sporozoite major surface antigen, the circumsporozoite (CS) protein, elicit antibodies that primarily target the central repeat region of the CS protein. In the current murine studies, using monoclonal antibodies and polyclonal sera obtained following immunization with P. falciparum sporozoites or synthetic ...


The Intellectual Property Of Covid-19, Ana Santos Rutschman 2021 Saint Louis University School of Law

The Intellectual Property Of Covid-19, Ana Santos Rutschman

All Faculty Scholarship

The response to COVID-19 is indissolubly tied to intellectual property. In an increasingly globalized world in which infectious disease pathogens travel faster and wider than before, the development of vaccines, treatments and other forms of medical technology has become an integral part of public health preparedness and response frameworks. The development of these technologies, and to a certain extent the allocation and distribution of resulting outputs, is informed by intellectual property regimes. These regimes influence the commitment of R&D resources, shape scientific collaborations and, in some cases, may condition the widespread availability of emerging technologies. As seen throughout this ...


Iga As A Potential Candidate For Enteric Monoclonal Antibody Therapeutics With Improved Gastrointestinal Stability, Aaron L. Wallace, Matthew I. Schneider, Jacqueline R. Toomey, Ryan M. Schneider, Mark S. Klempner, Yang Wang, Lisa A. Cavacini 2020 University of Massachusetts Medical School

Iga As A Potential Candidate For Enteric Monoclonal Antibody Therapeutics With Improved Gastrointestinal Stability, Aaron L. Wallace, Matthew I. Schneider, Jacqueline R. Toomey, Ryan M. Schneider, Mark S. Klempner, Yang Wang, Lisa A. Cavacini

Open Access Publications by UMMS Authors

Mucosal surfaces of the gastrointestinal tract play an important role in immune homeostasis and defense and may be compromised by enteric disorders or infection. Therapeutic intervention using monoclonal antibody (mAb) offers the potential for treatment with minimal off-target effects as well as the possibility of limited systemic exposure when administered orally. Critically, to achieve efficacy at luminal surfaces, mAb must remain stable and functionally active in the gastrointestinal environment. To better understand the impact of isotype, class, and molecular structure on the intestinal stability of recombinant antibodies, we used an in vitro simulated intestinal fluid (SIF) assay to evaluate a ...


Is Smaller Better? Vaccine Targeting Recombinant Receptor-Binding Domain Might Hold The Key For Mass Production Of Effective Prophylactics To Fight The Covid-19 Pandemic, Manish Muhuri, Guangping Gao 2020 University of Massachusetts Medical School

Is Smaller Better? Vaccine Targeting Recombinant Receptor-Binding Domain Might Hold The Key For Mass Production Of Effective Prophylactics To Fight The Covid-19 Pandemic, Manish Muhuri, Guangping Gao

COVID-19 Publications by UMMS Authors

A recent report by Yang et al. published in Nature reported a recombinant vaccine utilizing recombinant receptor-binding domain (RBD) of SARS-CoV-2 Spike Protein.This vaccine candidate successfully induced potent functional antibody responses in the immunized mice, rabbits, and non-human primates. The study highlights the critical role of the immunogenicity of the RBD domain upon SARS-CoV-2 infection and the alternate vaccine designs that could serve as effective prophylactics against the pandemic.


An In-Depth Investigation Of The Safety And Immunogenicity Of An Inactivated Sars-Cov-2 Vaccine [Preprint], Jing Pu, Shan Lu, Qihan Li 2020 Peking Union Medical College

An In-Depth Investigation Of The Safety And Immunogenicity Of An Inactivated Sars-Cov-2 Vaccine [Preprint], Jing Pu, Shan Lu, Qihan Li

University of Massachusetts Medical School Faculty Publications

BACKGROUND: 50 In-depth investigations of the safety and immunogenicity of inactivated SARS-CoV-2 vaccines 51 are needed. 52

METHOD: 53 In a phase I randomized, double-blinded, and placebo-controlled trial involving 192 healthy 54 adults 18-59 years of age, two injections of three different doses (50 EU, 100 EU and 150 EU) 55 of an inactivated SARS-CoV-2 vaccine or the placebo were administered intramuscularly with 56 a 2- or 4-week interval between the injections. The safety and immunogenicity of the vaccine 57 were evaluated within 28 days. 58

FINDING: 59 In this study, 191 subjects assigned to three doses groups or the ...


Non-Neutralizing Antibody Responses Following A(H1n1)Pdm09 Influenza Vaccination With Or Without As03 Adjuvant System, Damien Friel, Mary Dawn T. Co, Thierry Ollinger, Bruno Salaun, Anne Schuind, Ping Li, Karl Walravens, Francis A. Ennis, David W. Vaughn 2020 GlaxoSmithKline, Belgium

Non-Neutralizing Antibody Responses Following A(H1n1)Pdm09 Influenza Vaccination With Or Without As03 Adjuvant System, Damien Friel, Mary Dawn T. Co, Thierry Ollinger, Bruno Salaun, Anne Schuind, Ping Li, Karl Walravens, Francis A. Ennis, David W. Vaughn

Open Access Publications by UMMS Authors

BACKGROUND: Non-neutralizing antibodies inducing complement-dependent lysis (CDL) and antibody-dependent cell-mediated cytotoxicity (ADCC) activity may contribute to protection against influenza infection. We investigated CDL and ADCC responses in healthy adults randomized to receive either non-adjuvanted or AS03-adjuvanted monovalent A(H1N1)pdm09 vaccine (containing 15 microg/3.75 mug of hemagglutinin, respectively) on a 2-dose schedule 21 days apart.

METHODS: We conducted an exploratory analysis of a subset of 106 subjects having no prior history of A(H1N1)pdm09 infection or seasonal influenza vaccination enrolled in a previously reported study (NCT00985673). Antibody responses against the homologous A/California/7/2009 (H1N1) vaccine ...


Cd4 Effectors Need To Recognize Antigen Locally To Become Cytotoxic Cd4 And Follicular Helper T Cells [Preprint], Priyadharshini Devarajan, Allen M. Vong, Catherine H. Castonguay, Bianca L. Bautista, Michael C. Jones, Olivia Kugler-Umana, Karen A. Kelly, Susan L. Swain 2020 University of Massachusetts Medical School

Cd4 Effectors Need To Recognize Antigen Locally To Become Cytotoxic Cd4 And Follicular Helper T Cells [Preprint], Priyadharshini Devarajan, Allen M. Vong, Catherine H. Castonguay, Bianca L. Bautista, Michael C. Jones, Olivia Kugler-Umana, Karen A. Kelly, Susan L. Swain

University of Massachusetts Medical School Faculty Publications

T follicular helper (TFH) and Cytotoxic CD4 (ThCTL) are tissue-restricted CD4 effector subsets, functionally specialized to mediate optimal Ab production and cytotoxicity of infected cells. Influenza infection generates robust CD4 responses, including lung ThCTL and SLO TFH, that protect against reinfection by variant strains. Antigen (Ag) presentation after infection, lasts through the effector phase of the response. Here, we show that this effector phase Ag presentation, well after priming, is required to drive CD4 effectors to ThCTL and TFH. Using in vivo influenza models, we varied Ag presentation to effectors acutely, just at the effector phase. Ag ...


A Cross-Reactive Human Iga Monoclonal Antibody Blocks Sars-Cov-2 Spike-Ace2 Interaction, Ejemel Monir, Qi Li, Shurong Hou, Zachary Schiller, Aaron Wallace, Alla Amcheslavsky, Nese Kurt Yilmaz, Jacqueline R. Toomey, Ryan Schneider, Anudeep S. Ramchetty, Chandrashekar Ganesa, Lisa Cavacini, Mark S. Klempner, Celia A. Schiffer, Yan Wang 2020 University of Massachusetts Medical School

A Cross-Reactive Human Iga Monoclonal Antibody Blocks Sars-Cov-2 Spike-Ace2 Interaction, Ejemel Monir, Qi Li, Shurong Hou, Zachary Schiller, Aaron Wallace, Alla Amcheslavsky, Nese Kurt Yilmaz, Jacqueline R. Toomey, Ryan Schneider, Anudeep S. Ramchetty, Chandrashekar Ganesa, Lisa Cavacini, Mark S. Klempner, Celia A. Schiffer, Yan Wang

COVID-19 Publications by UMMS Authors

COVID-19 caused by SARS-CoV-2 has become a global pandemic requiring the development of interventions for the prevention or treatment to curtail mortality and morbidity. No vaccine to boost mucosal immunity, or as a therapeutic, has yet been developed to SARS-CoV-2. In this study, we discover and characterize a cross-reactive human IgA monoclonal antibody, MAb362. MAb362 binds to both SARS-CoV and SARS-CoV-2 spike proteins and competitively blocks ACE2 receptor binding, by overlapping the ACE2 structural binding epitope. Furthermore, MAb362 IgA neutralizes both pseudotyped SARS-CoV and SARS-CoV-2 in 293 cells expressing ACE2. When converted to secretory IgA, MAb326 also neutralizes authentic SARS-CoV-2 ...


The Dhodh Inhibitor Ptc299 Arrests Sars-Cov-2 Replication And Suppresses Induction Of Inflammatory Cytokines [Preprint], Jeremy Luban, Caterina Strambio De Castilla, Yetao Wang, Allan Jacobson, Stuart Peltz 2020 University of Massachusetts Medical School

The Dhodh Inhibitor Ptc299 Arrests Sars-Cov-2 Replication And Suppresses Induction Of Inflammatory Cytokines [Preprint], Jeremy Luban, Caterina Strambio De Castilla, Yetao Wang, Allan Jacobson, Stuart Peltz

University of Massachusetts Medical School Faculty Publications

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC50 range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known ...


Transgenic Goats Producing An Improved Version Of Cetuximab In Milk [Preprint], Götz Laible, Sally Cole, Brigid Brophy, Paul Maclean, Li How Chen, Dan P. Pollock, Lisa A. Cavacini, Nathalie Fournier, Christophe De Romeuf, Nicholas C. Masiello, William G. Gavin, David N. Wells, Harry M. Meade 2020 University of Auckland

Transgenic Goats Producing An Improved Version Of Cetuximab In Milk [Preprint], Götz Laible, Sally Cole, Brigid Brophy, Paul Maclean, Li How Chen, Dan P. Pollock, Lisa A. Cavacini, Nathalie Fournier, Christophe De Romeuf, Nicholas C. Masiello, William G. Gavin, David N. Wells, Harry M. Meade

University of Massachusetts Medical School Faculty Publications

Therapeutic monoclonal antibodies (mAbs) represent one of the most important classes of pharmaceutical proteins to treat human diseases. Most are produced in cultured mammalian cells which is expensive, limiting their availability. Goats, striking a good balance between a relatively short generation time and copious milk yield, present an alternative platform for the cost-effective, flexible, large-scale production of therapeutic mAbs. Here, we focused on cetuximab, a mAb against epidermal growth factor receptor, that is commercially produced under the brand name Erbitux and approved for anti-cancer treatments. We generated several transgenic goat lines that produce cetuximab in their milk. Two lines were ...


Histidine-Triad Hydrolases Provide Resistance To Peptide-Nucleotide Antibiotics., Eldar Yagmurov, Darya Tsibulskaya, Alexey Livenskyi, Marina Serebryakova, Yury I Wolf, Sergei Borukhov, Konstantin Severinov, Svetlana Dubiley 2020 Skolkovo Institute of Science and Technology

Histidine-Triad Hydrolases Provide Resistance To Peptide-Nucleotide Antibiotics., Eldar Yagmurov, Darya Tsibulskaya, Alexey Livenskyi, Marina Serebryakova, Yury I Wolf, Sergei Borukhov, Konstantin Severinov, Svetlana Dubiley

School of Osteopathic Medicine Faculty Scholarship

The Escherichia coli microcin C (McC) and related compounds are potent Trojan horse peptide-nucleotide antibiotics. The peptide part facilitates transport into sensitive cells. Inside the cell, the peptide part is degraded by nonspecific peptidases releasing an aspartamide-adenylate containing a phosphoramide bond. This nonhydrolyzable compound inhibits aspartyl-tRNA synthetase. In addition to the efficient export of McC outside the producing cells, special mechanisms have evolved to avoid self-toxicity caused by the degradation of the peptide part inside the producers. Here, we report that histidine-triad (HIT) hydrolases encoded in biosynthetic clusters of some McC homologs or by standalone genes confer resistance to McC-like ...


Comparisons Of Antibody Populations In Different Pre-Fusion F Vlp-Immunized Cotton Rat Dams And Their Offspring, Lori McGinnes Cullen, Marina S. Boukhvalova, Jorge C. G. Blanco, Trudy G. Morrison 2020 University of Massachusetts Medical School

Comparisons Of Antibody Populations In Different Pre-Fusion F Vlp-Immunized Cotton Rat Dams And Their Offspring, Lori Mcginnes Cullen, Marina S. Boukhvalova, Jorge C. G. Blanco, Trudy G. Morrison

Open Access Publications by UMMS Authors

Respiratory syncytial virus (RSV) infection poses a significant risk for infants. Since the direct vaccination of infants is problematic, maternal vaccination may provide a safer, more effective approach to their protection. In the cotton rat (CR) model, we have compared the immunization of pregnant CR dams with virus-like particles assembled with the prototype mutation stabilized pre-fusion F protein, DS-Cav1, as well two alternative mutation stabilized pre-fusion proteins (UC-2 F, UC-3 F) and showed that the alternative pre-fusion F VLPs protected the offspring of immunized dams significantly better than DS-Cav1 F VLPs (Blanco, et al. J. Virol. 93: e00914). Here, we ...


Timely Development Of Vaccines Against Sars-Cov-2, Shan Lu 2020 University of Massachusetts Medical School

Timely Development Of Vaccines Against Sars-Cov-2, Shan Lu

COVID-19 Publications by UMMS Authors

The rapidly emerging SARS-2-CoV (SARS-2) has been spreading through China and entering many parts of the world with easy human-to-human transmission and thousands of deaths. Development of a vaccine, and a vaccine which can be quickly deployed on a global scale, is no longer merely a discussion or part of a debate whether such a vaccine is ultimately needed.


Long Non-Coding Rna Lincrna-Eps Inhibits Host Defense Against Listeria Monocytogenes Infection, Federica Agliano, Katherine A. Fitzgerald, Anthony T. Vella, Vijay A. Rathinam, Andrei E. Medvedev 2020 University of Connecticut

Long Non-Coding Rna Lincrna-Eps Inhibits Host Defense Against Listeria Monocytogenes Infection, Federica Agliano, Katherine A. Fitzgerald, Anthony T. Vella, Vijay A. Rathinam, Andrei E. Medvedev

Open Access Publications by UMMS Authors

Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression in several biological systems. The long intergenic RNA-erythroid pro-survival (lincRNA-EPS) has been shown to play a critical role in restraining inflammatory gene expression. However, the function of lincRNA-EPS during bacterial infections remains unknown. Here, we demonstrate that following infection with the intracellular bacterium Listeria monocytogenes, both mouse macrophages and dendritic cells lacking lincRNA-EPS exhibit an enhanced expression of proinflammatory cytokine genes, as well as an increased expression of the inducible nitric oxide synthase (iNos) and nitric oxide (NO) production. Importantly, we found that lincRNA-EPS(-/-) mice intraperitoneally infected with ...


Co-Administration Of Injected And Oral Vaccine Candidates Elicits Improved Immune Responses Over Either Route Alone, Celine A. Hayden, Danilo Landrock, Chiung Yu Hung, Gary R. Ostroff, Gina M. Fake, John H. Walker, Ann Kier, John A. Howard 2020 Applied Biotechnology Institute

Co-Administration Of Injected And Oral Vaccine Candidates Elicits Improved Immune Responses Over Either Route Alone, Celine A. Hayden, Danilo Landrock, Chiung Yu Hung, Gary R. Ostroff, Gina M. Fake, John H. Walker, Ann Kier, John A. Howard

Open Access Publications by UMMS Authors

Infectious diseases continue to be a significant cause of morbidity and mortality, and although efficacious vaccines are available for many diseases, some parenteral vaccines elicit little or no mucosal antibodies which can be a significant problem since mucosal tissue is the point of entry for 90% of pathogens. In order to provide protection for both serum and mucosal areas, we have tested a combinatorial approach of both parenteral and oral administration of antigens for diseases caused by a viral pathogen, Hepatitis B, and a fungal pathogen, Coccidioides. We demonstrate that co-administration by the parenteral and oral routes is a useful ...


Glycan Profiles Of Gp120 Protein Vaccines From Four Major Hiv-1 Subtypes Produced From Different Host Cell Lines Under Non-Gmp Or Gmp Conditions, Shixia Wang, Yegor Voronin, Peng Zhao, Mayumi Ishihara, Nickita Mehta, Mindy Porterfield, Yuxin Chen, Christopher Bartley, Guangnan Hu, Dong Han, Lance Wells, Michael Tiemeyer, Shan Lu 2020 University of Massachusetts Medical School

Glycan Profiles Of Gp120 Protein Vaccines From Four Major Hiv-1 Subtypes Produced From Different Host Cell Lines Under Non-Gmp Or Gmp Conditions, Shixia Wang, Yegor Voronin, Peng Zhao, Mayumi Ishihara, Nickita Mehta, Mindy Porterfield, Yuxin Chen, Christopher Bartley, Guangnan Hu, Dong Han, Lance Wells, Michael Tiemeyer, Shan Lu

Open Access Publications by UMMS Authors

Envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) is an important target for the development of an HIV vaccine. Extensive glycosylation of Env is an important feature that both protects the virus from antibody responses and serves as a target for some highly potent broadly neutralizing antibodies. Therefore, analysis of glycans on recombinant Env proteins is highly significant. Here we present glycosylation profiles of recombinant gp120 proteins from four major clades of HIV-1 (A, B, C, and AE) produced either as research-grade material in 293 and CHO cells or as two independent lots of clinical material under GMP ...


Generating Broadly Protective Immune Responses To Viral Influenza, Evan Engelhardt 2020 Iowa State University

Generating Broadly Protective Immune Responses To Viral Influenza, Evan Engelhardt

Creative Components

Modern influenza vaccines are very effective against the strains they are composed of. However, variations between flu strains easily bypasses the induced immunity, rendering the vaccine outdated by the time the next flu season comes around. Current research into a “universal” influenza vaccine that can elicit a broadly protective response from the immune system has made great progress. Most methods are designed to induce broadly neutralizing antibodies to conserved sequences within surface glycoproteins. These methods can be adapted to induce broad cellular immunity as well. Memory to conserved sequences grants the immune system protection against divergent strains of influenza that ...


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