Selected Grantee Publications
- Clear All
- 137 results found
- Nonhuman Primate Models
- Vaccines/Therapeutics
Neutralizing Antibody Vaccine for Pandemic and Pre-Emergent Coronaviruses
Saunders et al., Nature. 2021.
https://doi.org/10.1038/s41586-021-03594-0
SARS-CoV-2 is a new member of the betacoronavirus (beta-CoV) genus, which also includes two common mild beta-CoVs and the life-threatening SARS-CoV-1 and MERS-CoV. Vaccines that elicit protective immunity against SARS-CoV-2 and beta-CoVs that circulate in animals could prevent future pandemics. Researchers designed a novel 24-mer SARS-CoV-2 receptor binding domain-sortase A conjugated nanoparticle vaccine (RBD-scNP). Investigators demonstrated that the immunization of macaques with RBD-scNP, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV, and multiple SARS-CoV-2 variants of concern. This pioneering approach serves as a multimeric protein platform for the further development of generalized anti-beta-CoV vaccines. Supported by ORIP (U42OD021458), NIAID, and NCI.
Modulation of MHC-E Transport by Viral Decoy Ligands Is Required for RhCMV/SIV Vaccine Efficacy
Verweij et al., Science. 2021.
https://doi.org/10.1126/science.abe9233
Rhesus cytomegalovirus (RhCMV) strain 68-1-vectored simian immunodeficiency virus (SIV) vaccines elicit strong CD8+ T cell responses that can clear SIV infections. Peptides targeted by these T cells are presented on major histocompatibility complex (MHC) II and MHC-E rather than MHC-Ia. Researchers showed that VL9 drives intracellular transport of MHC-E and recognition of RhCMV-infected targets by MHC-E-restricted CD8+ T cells. Specific-pathogen-free (SPF) rhesus macaques vaccinated with a mutant 68-1 RhCMV lacking VL9 showed no priming of MHC-E-restricted CD8+ T cells and no protection against SIV, suggesting that future effective CMV-based HIV vaccines will require MHC-E-restricted CD8+ T cell priming. Supported by ORIP (U42OD023038, P51OD011092), NIAID, and NCI.
Evidence in Primates Supporting the Use of Chemogenetics for the Treatment of Human Refractory Neuropsychiatric Disorders
Roseboom et al., Molecular Therapy. 2021.
https://doi.org/10.1016/j.ymthe.2021.04.021
A rhesus macaque model for pathological anxiety was used to investigate the feasibility of decreasing anxiety using chemogenetics, known as DREADDs (designer receptors exclusively activated by designer drugs), to reduce amygdala neuronal activity. A low-dose clozapine administration strategy was developed to induce DREADD-mediated amygdala inhibition. Compared to controls, clozapine selectively decreased anxiety-related freezing behavior in the human intruder paradigm in the chemogentic monkeys, while coo vocalizations and locomotion were unaffected. These results are an important step in establishing chemogenetic strategies for patients with refractory neuropsychiatric disorders in which amygdala alterations are central to disease pathophysiology. Supported by ORIP (P51OD011106), NIMH, and NICHD.
Functional Convergence of a Germline-Encoded Neutralizing Antibody Response in Rhesus Macaques Immunized with HCV Envelope Glycoproteins
Chen et al., Immunity. 2021.
https://doi.org/10.1016/j.immuni.2021.02.013
Immunoglobulin heavy chain variable gene IGHV1-69-encoded broadly neutralizing antibodies (bnAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein (Env) E2 are important for protection against HCV infection in humans. An IGHV1-69 ortholog, VH1.36, is preferentially used for bnAbs isolated from rhesus macaques immunized against HCV Env. Researchers investigated the genetic, structural, and functional properties of VH1.36-encoded bnAbs generated by HCV Env vaccination of macaques and compared their findings to IGHV1-69-encoded bnAbs from HCV patients. The investigators found that macaque VH1.36- and human IGHV1-69-encoded bnAbs share many common features, which provides an excellent framework for rational HCV vaccine design and testing. Supported by ORIP (P51OD011133, U42OD010442), NIAID, NCI, and NIGMS.
Cytomegaloviral Determinants of CD8+ T Cell Programming and RhCMV/SIV Vaccine Efficacy
Malouli et al., Science Immunology. 2021.
https://www.science.org/doi/10.1126/sciimmunol.abg5413
Cytomegalovirus (CMV)-based vaccine vectors were developed to leverage the ability of CMVs to elicit sustained CD4+ and CD8+ T cell responses with broad tissue distribution. The 68-1 rhesus cytomegalovirus (RhCMV) vectors that express simian immunodeficiency virus (SIV) inserts induce major histocompatibility complex E (MHC-E)- and MHC-II-restricted, SIV-specific CD8+T cell responses. The contribution of this unconventional MHC restriction to RhCMV/SIV vaccine efficacy are poorly understood. Researchers demonstrated that these responses result from genetic rearrangements in 68-1 RhCMV that disrupt the function of eight immunomodulatory proteins encoded by the virus. Repair of each of these genes with either RhCMV or human CMV counterparts shifted responses to MHC-Ia-restricted, or MHC-Ia- and MHC-II-restricted, CD8 T cell responses, but repairing the RhCMV genes did not protect against SIV. These findings suggest that MHC-E-restricted CD8+ T cell responses may be critical to protection against SIV. Supported by ORIP (U42OD023038, P51OD011092).
A Novel Tau-Based Rhesus Monkey Model of Alzheimer’s Pathogenesis
Beckman et al., Alzheimer’s & Dementia. 2021.
https://pubmed.ncbi.nlm.nih.gov/33734581/
Alzheimer’s disease (AD) is becoming more prevalent as the population ages, but there are no effective treatments for this devastating condition. Researchers developed a rhesus monkey model of AD by targeting the entorhinal cortex with an adeno-associated virus expressing mutant tau protein. Within 3 months they observed evidence of misfolded tau propagation, similar to what is hypothesized for AD patients. Treated monkeys developed robust alterations in AD core biomarkers in cerebrospinal fluid and blood. These results highlight the initial stages of tau seeding and propagation in rhesus macaques, a potentially powerful translational model with which to test new AD therapies. Supported by ORIP (P51OD011107) and NIA.
Virus Control in Vaccinated Rhesus Macaques Is Associated with Neutralizing and Capturing Antibodies Against the SHIV Challenge Virus but Not with V1V2 Vaccine–Induced Anti-V2 Antibodies Alone
Hessell et al., Journal of Immunology. 2021.
https://doi.org/10.4049/jimmunol.2001010
In the RV144 human immunodeficiency virus (HIV) vaccine trial, the only immune response associated with reduced infection was a high level of antibodies (Abs) targeting the second variable (V2) loop of the HIV envelope protein (Env). The mechanism underlying this suggested contribution of V2 Abs to protection remains unknown. Researchers tested the role of vaccine-induced anti-V2 Abs in rhesus macaques. Three vaccines strategies were designed to induce only V1V2 Abs before simian-human immunodeficiency virus (SHIV) challenge. Vaccine-induced V2 Abs did not independently control SHIV infection. However, neutralizing and virus capture anti-Env Abs were found to correlate with SHIV control. Supported by ORIP (P51OD011092) and NIAID.
Polyfunctional Tier 2–Neutralizing Antibodies Cloned Following HIV-1 Env Macaque Immunization Mirror Native Antibodies in a Human Donor
Spencer et al., Journal of Immunology. 2021.
https://doi.org/10.4049/jimmunol.2001082
HIV vaccine efforts are limited by viral strain diversity and the shielding of neutralization epitopes on the viral envelope, yet isolation of broadly neutralizing antibodies from infected individuals suggests the potential for eliciting protective antibodies through vaccination. Researchers cloned 58 monoclonal antibodies (mAbs) from a rhesus monkey immunized with envelope glycoprotein immunogens from an HIV-1 clade C–infected volunteer. Twenty mAbs exhibited some neutralizing activity. Cloned mAbs targeting the V3 region and CD4 binding site were capable of tier 2 (i.e., moderate) neutralization. This study demonstrates partial recapitulation of the human donor’s humoral immune response through nonhuman primate vaccination. Supported by ORIP (P51OD011092) and NIAID.
Modified Adenovirus Prime–Protein Boost Clade C HIV Vaccine Strategy Results in Reduced Viral DNA in Blood and Tissues Following Tier 2 SHIV Challenge
Malherbe et al., Frontiers in Immunology. 2021.
https://doi.org/10.3389/fimmu.2020.626464
Researchers conducted a comparative vaccine challenge study in rhesus macaques. One group of monkeys was vaccinated using co-immunization with DNA Gag and Env expression plasmids and trimeric Env gp140 glycoprotein. The other group was primed with two replicating simian adenovirus-vectored vaccines expressing Gag and boosted with trimeric Env gp140. Both strategies elicited antigen-specific humoral and cellular immune responses, but neither approach provided significant protection from viral acquisition upon repeated mucosal challenges with a heterologous Tier 2 SHIV. Nevertheless, both regimens significantly lowered cell-associated viral DNA in multiple tissues, thus potentially dampening the infection and providing clues for further vaccine development. Supported by ORIP (U42OD023038, P51OD011092) and NIAID.
Evaluating a New Class of AKT/mTOR Activators for HIV Latency-Reversing Activity Ex Vivo and In Vivo
Gramatica et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.02393-20
Activation of latent HIV-1 expression could benefit many HIV cure strategies. Researchers evaluated two AKT/mTOR activators, SB-216763 and tideglusib, as a potential new class of LRAs. The drugs reactivated latent HIV-1 present in blood samples from aviremic individuals on antiretroviral therapy without causing T cell activation or impaired effector function of cytotoxic T lymphocytes or NK cells. When tested in vivo in monkeys, tideglusib showed unfavorable pharmacodynamic properties and did not reverse SIV latency. The discordance between the ex vivo and in vivo results underscores the importance of developing novel LRAs that allow systemic drug delivery to relevant anatomical compartments. Supported by ORIP (P51OD011092), NIAID, NIGMS, NIMH, and NCI.