Selected Grantee Publications
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- 56 results found
- Alzheimer's Disease
- COVID-19/Coronavirus
CAR/CXCR5–T Cell Immunotherapy Is Safe and Potentially Efficacious in Promoting Sustained Remission of SIV Infection
Pampusch et al., PLOS Pathogens. 2022.
https://www.doi.org/10.1371/journal.ppat.1009831
HIV and simian immunodeficiency virus (SIV) replication are concentrated within the B cell follicles of secondary lymphoid tissues. In this study, the researchers developed immunotherapeutic chimeric antigen receptor (CAR) T cells that home to follicles and clear SIV-infected cells in a rhesus macaque model. The CAR T cells localized to the follicle, replicated, and interacted directly with infected cells. Most of the treated animals maintained lower viral loads in the blood and follicles, compared to control animals. These findings demonstrate the safety and potential efficacy of this immunotherapy approach for long-term remission of HIV without requiring the lifelong use of antiretroviral therapy. Supported by ORIP (P51OD011106), NIAID, and NHLBI.
Simian Immunodeficiency Virus Infection Mediated Changes in Jejunum and Peripheral SARS-CoV-2 Receptor ACE2 and Associated Proteins or Genes in Rhesus Macaques
Boby et al., Frontiers in Immunology. 2022.
https://www.doi.org/10.3389/fimmu.2022.835686
Recent studies suggest that people with HIV—particularly those not receiving antiretroviral therapy or those with low CD4 cell counts—are at increased risk of severe illness from SARS‑CoV-2 coinfection. Angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, is likely to play an important role in modulating physiological and pathological events during HIV infection. In this study, the researchers used a rhesus macaque model to characterize the expression profiles of ACE2, other renin-angiotensin system (RAS)–associated genes (AGTR1/2, ADAM17, and TMPRSS2), and inflammatory cytokines (IL-1β, IL-6, and TNF‑α) in the jejunum and lung during simian immunodeficiency virus (SIV) infection. SIV infection was associated with multiple changes in gene expression, including downregulation of ACE2, which could lead to loss of gut homeostasis. Further studies could provide insight on the role of RAS-associated proteins during HIV and SARS-CoV-2 co-infection. Supported by ORIP (P51OD011104) and NIDDK.
Protection from SARS-CoV-2 Delta One Year After mRNA-1273 Vaccination in Rhesus Macaques Coincides with Anamnestic Antibody Response in the Lung
Gagne et al., Cell. 2022.
https://www.sciencedirect.com/science/article/pii/S0092867421014057?via%3Dihub=
Efficacy of the vaccine mRNA-1273 against SARS-CoV-2 Delta decreases with time, yet there are limited data on how durability of immune responses affects protection. Researchers immunized male rhesus macaques with mRNA-1273 and challenged them with Delta one year later. Serum neutralizing antibody responses to Delta and protection in upper airway were low one year after mRNA-1273 vaccination. However, mRNA-1273 provided durable protection against Delta in the lower airway and against severe lung disease one year after vaccination, likely through anamnestic induction of antibody responses in the lung. These findings highlight the importance of booster shots for sustained upper and lower airway protection. Supported by ORIP (P51OD011132) and NIAID.
Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial
Gilbert et al., Science. 2022.
https://pubmed.ncbi.nlm.nih.gov/34812653/
Investigators determined that antibodies are the correlate of protection in vaccinated individuals enrolled in the Moderna coronavirus efficacy phase 3 clinical trial. Vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines. Supported by ORIP (S10OD028685).
The Pigtail Macaque (Macaca nemestrina) Model of COVID-19 Reproduces Diverse Clinical Outcomes and Reveals New and Complex Signatures of Disease
Melton et al., PLOS Pathogens. 2021.
https://pubmed.ncbi.nlm.nih.gov/34929014/
Animal models that recapitulate human COVID-19 disease are critical for understanding SARS-CoV-2 viral and immune dynamics, mechanisms of disease, and testing of vaccines and therapeutics. A group of male pigtail macaques (PTMs) were euthanized either 6- or 21-days after SARS-CoV-2 viral challenge and demonstrated mild-to-moderate COVID-19 disease. Pulmonary infiltrates were dominated by T cells, virus-targeting T cells were predominantly CD4+, increases in circulating inflammatory and coagulation markers, pulmonary pathologic lesions, and the development of neutralizing antibodies were observed. Collectively, the data suggests PTMs are a valuable model to study COVID-19 pathogenesis and may be useful for testing vaccines and therapeutics. Supported by ORIP (P51OD011104) and NIAID.
Monoclonal Antibodies Protect Aged Rhesus Macaques From SARS-CoV-2-Induced Immune Activation and Neuroinflammation
Verma et al., Cell Reports. 2021.
https://www.sciencedirect.com/science/article/pii/S2211124721014157?via%3Dihub%C2%A0=
In aged diabetic female rhesus macaques, prophylactic administration of neutralizing monoclonal antibodies (mAbs) effectively limits SARS-CoV-2 replication in both the upper and lower respiratory tract, and decreases immune activation, including reducing interferon-induced chemokines and limiting effector CD4 T cell influx into the cerebrospinal fluid. These protective mechanisms took place in the areas of the body targeted by the virus and may prevent adverse inflammatory consequences of SARS-CoV-2 infection in high-risk populations. Supported by ORIP (P51OD011107), NIAID, and NIA.
Prior Infection With SARS-CoV-2 WA1/2020 Partially Protects Rhesus Macaques Against Re-Infection With B.1.1.7 and B.1.351 Variants
Chandrashekar et al., Science Translational Medicine. 2021.
https://doi.org/10.1126/scitranslmed.abj2641
Using the rhesus macaque model, researchers addressed whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against re-challenge with B.1.1.7 and B.1.351, known as the alpha and beta variants of concern, respectively. The investigators infected rhesus macaques with WA1/2020 and re-challenged them on day 35 with WA1/2020 or with the alpha or beta variants. Natural immunity to WA1/2020 led to robust protection against re-challenge with WA1/2020, partial protection against beta, and an intermediate degree of protection against alpha. These findings have important implications for vaccination and public health strategies in the context of emerging SARS-CoV-2 variants of concern. Supported by ORIP (P51OD011106) and NCI.
A Yeast Expressed RBD-Based SARS-CoV-2 Vaccine Formulated with 3M-052-alum Adjuvant Promotes Protective Efficacy in Non-Human Primates
Pino et al., Science Immunology. 2021.
https://immunology.sciencemag.org/content/6/61/eabh3634
Using a rhesus macaque model (n=5 males per group), investigators tested a receptor binding domain (RBD) recombinant protein formulation COVID-19 vaccine candidate combined with an aluminum-based formulation of 3M’s Toll-like receptor 7 and 8 agonist 3M-052 (3M-052/Alum) and found the RBD+3M-052/Alum formulation produced a superior overall immune response than RBD+alum alone as demonstrated by higher SARS-CoV-2 neutralizing antibodies, improved Th1 biased CD4+ T cell reactions, and increased CD8+ T cell responses. Collectively, these data suggest that the RBD+3M-052-alum formulation provides robust immune responses against SARS-CoV-2 and supports the development of this potential effective and easy to scale COVID-19 vaccine candidate. Supported by ORIP (P51OD011132) and NIAID.
Systems Vaccinology of the BNT162b2 mRNA Vaccine in Humans
Arunachalam et al., Nature . 2021.
https://doi.org/10.1038/s41586-021-03791-x
It was poorly understood how mRNA vaccines against SARS-CoV-2 stimulate protective immune responses. To address this, researchers comprehensively profiled innate and adaptive immune responses of healthy volunteers vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in robust production of neutralizing antibodies against wild-type SARS-CoV-2, to a lesser extent, the beta variant, as well as significant increases in antigen-specific polyfunctional CD4+ and CD8+ T cells after the second dose. Booster vaccination stimulated an enhanced innate immune response compared to primary vaccination, demonstrating the capacity of BNT162b2 to prime the innate immune system to mount a more potent response after booster immunization. Supported by ORIP (P51OD011132, S10OD026799) and NIAID.
Early Treatment With a Combination of Two Potent Neutralizing Antibodies Improves Clinical Outcomes and Reduces Virus Replication and Lung Inflammation in SARS CoV-2 Infected Macaques
Van Rompay et al., PLOS Pathogens. 2021.
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009688
The therapeutic efficacy of a combination of two SARS-CoV-2 monoclonal antibodies (mAbs), C135-LS and C144-LS, were investigated in young adult macaques (3 groups of 4 animals; equal sex distribution). Animals were treated intravenously with low or high doses of C135-LS and C144-LS mAbs or control mAb 24 hours post-infection with SARS-CoV-2. Compared to controls, animals treated with either dose of the anti-SARS-CoV-2 mAbs showed improved clinical scores, lower levels of virus replication in upper and lower respiratory tract, and reduced interstitial pneumonia, as measured by lung histology. The study provides proof-of-concept for development of these mAbs for treatment of COVID-19 during early infection. Supported by ORIP (P51OD011107) and NIAID.