Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
102
result(s) for
"Broderick, Kate"
Sort by:
Something borrowed
Rachel is a generous and loyal pal to her engaged best friend Darcy. But after celebrating her 30th birthday, perpetual good girl Rachel unexpectedly ends up in the arms of Dex, the guy she's had a crush on since law school, and who happens to be Darcy's fiancé. In the frantic weeks leading up to Darcy's wedding, Rachel finds herself caught between her longtime friendship with Darcy and the prospect of losing the love of her life.
DVD
Intradermal SynCon® Ebola GP DNA Vaccine Is Temperature Stable and Safely Demonstrates Cellular and Humoral Immunogenicity Advantages in Healthy Volunteers
Nonlive vaccine approaches that are simple to deliver and stable at room temperature or 2-8°C could be advantageous in controlling future Ebola virus (EBOV) outbreaks. Using an immunopotent DNA vaccine that generates protection from lethal EBOV challenge in small animals and nonhuman primates, we performed a clinical study to evaluate both intramuscular (IM) and novel intradermal (ID) DNA delivery.
Two DNA vaccine candidates (INO-4201 and INO-4202) targeting the EBOV glycoprotein (GP) were evaluated for safety, tolerability, and immunogenicity in a phase 1 clinical trial. The candidates were evaluated alone, together, or in combination with plasmid-encoded human cytokine interleukin-12 followed by in vivo electroporation using either the CELLECTRA® IM or ID delivery devices.
The safety profile of all 5 regimens was shown to be benign, with the ID route being better tolerated. Antibodies to EBOV GP were generated by all 5 regimens with the fastest and steepest rise observed in the ID group. Cellular immune responses were generated with every regimen.
ID delivery of INO-4201 was well tolerated and resulted in 100% seroreactivity after 2 doses and elicited interferon-γ T-cell responses in over 70% of subjects, providing a new approach for EBOV prevention in diverse populations. Clinical Trials Registration. NCT02464670.
Journal Article
Immunotherapy with DNA vaccine and live attenuated rubella/SIV gag vectors plus early ART can prevent SIVmac251 viral rebound in acutely infected rhesus macaques
Anti-retroviral therapy (ART) has been highly successful in controlling HIV replication, reducing viral burden, and preventing both progression to AIDS and viral transmission. Yet, ART alone cannot cure the infection. Even after years of successful therapy, ART withdrawal leads inevitably to viral rebound within a few weeks or months. Our hypothesis: effective therapy must control both the replicating virus pool and the reactivatable latent viral reservoir. To do this, we have combined ART and immunotherapy to attack both viral pools simultaneously. The vaccine regimen consisted of DNA vaccine expressing SIV Gag, followed by a boost with live attenuated rubella/gag vectors. The vectors grow well in rhesus macaques, and they are potent immunogens when used in a prime and boost strategy. We infected rhesus macaques by high dose mucosal challenge with virulent SIVmac251 and waited three days to allow viral dissemination and establishment of a reactivatable viral reservoir before starting ART. While on ART, the control group received control DNA and empty rubella vaccine, while the immunotherapy group received DNA/gag prime, followed by boosts with rubella vectors expressing SIV gag over 27 weeks. Both groups had a vaccine \"take\" to rubella, and the vaccine group developed antibodies and T cells specific for Gag. Five weeks after the last immunization, we stopped ART and monitored virus rebound. All four control animals eventually had a viral rebound, and two were euthanized for AIDS. One control macaque did not rebound until 2 years after ART release. In contrast, there was only one viral rebound in the vaccine group. Three out of four vaccinees had no viral rebound, even after CD8 depletion, and they remain in drug-free viral remission more than 2.5 years later. The strategy of early ART combined with immunotherapy can produce a sustained SIV remission in macaques and may be relevant for immunotherapy of HIV in humans.
Journal Article
An engineered bispecific DNA-encoded IgG antibody protects against Pseudomonas aeruginosa in a pneumonia challenge model
The impact of broad-spectrum antibiotics on antimicrobial resistance and disruption of the beneficial microbiome compels the urgent investigation of bacteria-specific approaches such as antibody-based strategies. Among these, DNA-delivered monoclonal antibodies (DMAbs), produced by muscle cells in vivo, potentially allow the prevention or treatment of bacterial infections circumventing some of the hurdles of protein IgG delivery. Here, we optimize DNA-delivered monoclonal antibodies consisting of two potent human IgG clones, including a non-natural bispecific IgG1 candidate, targeting
Pseudomonas aeruginosa
. The DNA-delivered monoclonal antibodies exhibit indistinguishable potency compared to bioprocessed IgG and protect against lethal pneumonia in mice. The DNA-delivered monoclonal antibodies decrease bacterial colonization of organs and exhibit enhanced adjunctive activity in combination with antibiotics. These studies support DNA-delivered monoclonal antibodies delivery as a potential strategy to augment the host immune response to prevent serious bacterial infections, and represent a significant advancement toward broader practical delivery of monoclonal antibody immunotherapeutics for additional infectious pathogens.
DNA-delivered monoclonal antibodies (DMAbs) can be produced by muscle cells in vivo, potentially allowing prevention or treatment of infectious diseases. Here, the authors show that two DMAbs targeting
Pseudomonas aeruginosa
proteins confer protection against lethal pneumonia in mice.
Journal Article
Protection against dengue disease by synthetic nucleic acid antibody prophylaxis/immunotherapy
Dengue virus (DENV) is the most important mosquito-borne viral infection in humans. In recent years, the number of cases and outbreaks has dramatically increased worldwide. While vaccines are being developed, none are currently available that provide balanced protection against all DENV serotypes. Advances in human antibody isolation have uncovered DENV neutralizing antibodies (nAbs) that are capable of preventing infection from multiple serotypes. Yet delivering monoclonal antibodies using conventional methods is impractical due to high costs. Engineering novel methods of delivering monoclonal antibodies could tip the scale in the fight against DENV. Here we demonstrate that simple intramuscular delivery by electroporation of synthetic DNA plasmids engineered to express modified human nAbs against multiple DENV serotypes confers protection against DENV disease and prevents antibody-dependent enhancement (ADE) of disease in mice. This synthetic nucleic acid antibody prophylaxis/immunotherapy approach may have important applications in the fight against infectious disease.
Journal Article
Altered Response Hierarchy and Increased T-Cell Breadth upon HIV-1 Conserved Element DNA Vaccination in Macaques
HIV sequence diversity and potential decoy epitopes are hurdles in the development of an effective AIDS vaccine. A DNA vaccine candidate comprising of highly conserved p24(gag) elements (CE) induced robust immunity in all 10 vaccinated macaques, whereas full-length gag DNA vaccination elicited responses to these conserved elements in only 5 of 11 animals, targeting fewer CE per animal. Importantly, boosting CE-primed macaques with DNA expressing full-length p55(gag) increased both magnitude of CE responses and breadth of Gag immunity, demonstrating alteration of the hierarchy of epitope recognition in the presence of pre-existing CE-specific responses. Inclusion of a conserved element immunogen provides a novel and effective strategy to broaden responses against highly diverse pathogens by avoiding decoy epitopes, while focusing responses to critical viral elements for which few escape pathways exist.
Journal Article
Safety, tolerability, and immunogenicity of INO-4500, a synthetic DNA-based vaccine against Lassa virus, in a phase 1b clinical trial in healthy Ghanaian adults
Lassa fever (LF) is an acute viral hemorrhagic illness endemic to West Africa, with no licensed vaccines or targeted treatments available, highlighting a critical gap in global health preparedness. T cell-mediated immunity plays a central role in viral control and survival. Synthetic DNA vaccines offer a promising strategy to induce both humoral and cellular immunity against LF.
A Phase 1b, randomized, double-blind, placebo-controlled trial was conducted to assess the safety, tolerability, and immunogenicity of INO-4500, a DNA vaccine encoding the Lassa virus (Josiah strain) glycoprotein precursor (GPC). A total of 220 healthy adults were randomized to receive either 1 mg or 2 mg of INO-4500 (intervention), or placebo, administered intradermally (ID) followed by electroporation (EP) at Day 0 and Week 4. Safety was evaluated through Week 48. Primary immunogenicity endpoints included humoral and cellular immune responses at multiple timepoints post-vaccination.
INO-4500 was well tolerated, with no Grade 3 or higher treatment-emergent adverse events (TEAEs) deemed to be related to the intervention; 88.6% of all TEAEs were Grade 1. No cases of attributable hearing loss were reported. INO-4500 groups demonstrated statistically significant increases in Lassa virus GPC-specific binding antibodies at Weeks 6 and 12 compared to placebo, with the 2 mg group eliciting the strongest responses. T cell responses remained elevated above baseline through Week 48 in both INO-4500 groups, indicating durable cellular immunity.
DNA vaccine INO-4500 was well tolerated and elicited durable humoral and cellular immune responses in healthy adults. These findings support further clinical development of INO-4500 as a potential preventive vaccine to reduce LF-associated morbidity and mortality in endemic regions.
https://clinicaltrials.gov, identifier NCT04093076.
Journal Article
In vivo delivery of synthetic DNA–encoded antibodies induces broad HIV-1–neutralizing activity
Interventions to prevent HIV-1 infection and alternative tools in HIV cure therapy remain pressing goals. Recently, numerous broadly neutralizing HIV-1 monoclonal antibodies (bNAbs) have been developed that possess the characteristics necessary for potential prophylactic or therapeutic approaches. However, formulation complexities, especially for multiantibody deliveries, long infusion times, and production issues could limit the use of these bNAbs when deployed, globally affecting their potential application. Here, we describe an approach utilizing synthetic DNA-encoded monoclonal antibodies (dmAbs) for direct in vivo production of prespecified neutralizing activity. We designed 16 different bNAbs as dmAb cassettes and studied their activity in small and large animals. Sera from animals administered dmAbs neutralized multiple HIV-1 isolates with activity similar to that of their parental recombinant mAbs. Delivery of multiple dmAbs to a single animal led to increased neutralization breadth. Two dmAbs, PGDM1400 and PGT121, were advanced into nonhuman primates for study. High peak-circulating levels (between 6 and 34 μg/ml) of these dmAbs were measured, and the sera of all animals displayed broad neutralizing activity. The dmAb approach provides an important local delivery platform for the in vivo generation of HIV-1 bNAbs and for other infectious disease antibodies.
Journal Article
Safety, tolerability, and immunogenicity of a DNA-based vaccine (INO-4700) against Middle East respiratory syndrome coronavirus: phase 2a study in healthy volunteers
Middle East respiratory syndrome coronavirus (MERS-CoV) poses an ongoing public health risk with a 36% case-fatality rate and no licensed vaccines. This Phase 2a, randomized, blinded, placebo-controlled, multi-center trial (MERS-201; NCT04588428) evaluated the safety, tolerability, and immunogenicity of INO-4700, a DNA vaccine against the MERS-CoV spike glycoprotein, in healthy adult volunteers.
Participants received INO-4700 or placebo intradermally followed by electroporation upon enrollment into any one of five active treatment groups, resulting from three-dose levels (0.6 mg, 1 mg, and 2 mg total) during each of two dosing days or four placebo groups. Doses were administered as 1 or 2 concurrent injections to achieve the total dose level at Week 0 and at either Week 4 or 8. Safety endpoints included incidence of treatment-emergent adverse events (TEAEs), their toxicity grading scale, seriousness, and relationship to study treatment and AEs of special interest (AESI). Immunogenicity endpoints included evaluation of humoral and cellular immune responses, assessed pre-dose (Screening and/or Week 0) and at Weeks 6 and 10.
One hundred and ninety-two participants were randomized across the nine study groups and followed up between June 2021 and January 2023. Treatment with INO-4700 was well-tolerated and had a favorable safety profile with low incidence of TEAEs, which were overall similar between INO-4700 and placebo groups, with most of the TEAEs assessed as Grade 1 or Grade 2, non-serious, and unrelated to treatment. Group E, the highest INO-4700 dose tested (2 mg total), showed greater immune responses compared to other groups, with significantly elevated MERS-CoV receptor-binding domain (RBD) and spike-binding IgG levels, and seroreactivity at Week 10 peaking at 42% and 32%, respectively. Spike-specific T cell responses further contributed to INO-4700 immunogenicity, ranging from 29% in Group C to 50% in Group E.
DNA vaccine INO-4700 was well-tolerated in healthy adults across all groups after each dose was administered and elicited humoral and cellular immune responses. These results warrant further evaluation of INO-4700 as a candidate vaccine for MERS-CoV outbreak preparedness and prevention.
https://clinicaltrials.gov,
.
Journal Article
Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates
The enhanced transmissibility and immune evasion associated with emerging SARS-CoV-2 variants demands the development of next-generation vaccines capable of inducing superior protection amid a shifting pandemic landscape. Since a portion of the global population harbors some level of immunity from vaccines based on the original Wuhan-Hu-1 SARS-CoV-2 sequence or natural infection, an important question going forward is whether this immunity can be boosted by next-generation vaccines that target emerging variants while simultaneously maintaining long-term protection against existing strains. Here, we evaluated the immunogenicity of INO-4800, our synthetic DNA vaccine candidate for COVID-19 currently in clinical evaluation, and INO-4802, a next-generation DNA vaccine designed to broadly target emerging SARS-CoV-2 variants, as booster vaccines in nonhuman primates. Rhesus macaques primed over one year prior with the first-generation INO-4800 vaccine were boosted with either INO-4800 or INO-4802 in homologous or heterologous prime-boost regimens. Both boosting schedules led to an expansion of T cells and antibody responses which were characterized by improved neutralizing and ACE2 blocking activity across wild-type SARS-CoV-2 as well as multiple variants of concern. These data illustrate the durability of immunity following vaccination with INO-4800 and additionally support the use of either INO-4800 or INO-4802 in prime-boost regimens.
Journal Article