Selected Grantee Publications
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- 119 results found
- Vaccines/Therapeutics
- P51
PD-1 Blockade and Vaccination Provide Therapeutic Benefit Against SIV by Inducing Broad and Functional CD8+ T Cells in Lymphoid Tissue
Rahman et al., Science Immunology. 2021.
https://doi.org/10.1126/sciimmunol.abh3034
Effective HIV therapies must induce functional CD8+ T cells and clear latent viral reservoirs during antiretroviral therapy (ART). Using a rhesus macaque model, researchers showed that therapeutic vaccination under ART using a CD40L plus TLR7 agonist-adjuvanted DNA/modified vaccinia Ankara vaccine regimen induced robust SIV-specific CD4+ and CD8+ T cell responses. Addition of an anti-PD-1 antibody to the SIV vaccine increased cytotoxic CD8+ T cells in lymph nodes after ART interruption, correlating to the control of virus and prolonged survival compared with the vaccine alone. Thus, combining immune checkpoint blockade with vaccination may be a promising avenue toward an HIV cure. Supported by ORIP (P51OD011132) and NIAID.
Neuropeptide S Receptor 1 is a Nonhormonal Treatment Target in Endometriosis
Tapmeier et al., Science Translational Medicine. 2021.
https://pubmed.ncbi.nlm.nih.gov/34433639
Investigators analyzed genetic sequences of humans (n=32 families) and pedigree rhesus macaques (n=849) with spontaneous endometriosis to uncover potential targets for treatment. Target associations indicated a common insertion/deletion variant in NPSR1, the gene encoding neuropeptide S receptor 1. Immunocytochemistry, RT-PCR, and flow cytometry experiments indicated NPSR1 was expressed in the glandular epithelium of eutopic and ectopic endometrium. In a mouse model for endometriosis, an inhibitor of NPSR1-mediated signaling blocked proinflammatory TNFα release, monocyte chemotaxis, and inflammatory cell infiltrate. Further studies in nonhuman primates are needed; however, these results provide support for a nonhormonal treatment of endometriosis. Supported by ORIP (R24OD011173, P51OD011106).
Blocking α4β7 Integrin Delays Viral Rebound in SHIVSF162P3-Infected Macaques Treated with Anti-HIV Broadly Neutralizing Antibodies
Frank et al., Science Translational Medicine. 2021.
https://doi.org/10.1126/scitranslmed.abf7201
To explore therapeutic potentials of combining anti-HIV broadly neutralizing antibodies (bNAbs) with α4β7 integrin blockade using the monoclonal antibody Rh-α4β7, investigators treated SHIVSF162P3-infected, viremic macaques with bNAbs only or bNAbs and Rh-α4β7. Treatment with bNAbs alone decreased viremia below 200 copies/ml in eight out of eight macaques, but seven of the monkeys rebounded within 3 weeks. In contrast, three of six macaques treated with both Rh-α4β7 and bNAbs maintained viremia below 200 copies/ml for 21 weeks, whereas three of those monkeys rebounded after 6 weeks. These findings suggest that α4β7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques. Supported by ORIP (P51OD011104, U42OD010568, U42OD024282, P40OD028116), NIAID, and NCI.
Cytomegalovirus Mediates Expansion of IL-15-Responsive Innate-Memory Cells with SIV Killing Function
Méndez-Lagares et al., Journal of Clinical Investigation. 2021.
https://doi.org/10.1172/JCI148542
Researchers investigated the effects of rhesus cytomegalovirus (RhCMV) on the immune system in young rhesus macaques to determine if it could modulate the protection mediated by RhCMV-vectored vaccines. RhCMV was associated with dramatic changes in antigen presenting cells, T cells, and NK cells and marked expansion of innate-memory CD8+ T cells via host interleukin-15 (IL-15) production. The researchers also investigated immune changes following administration of RhCMV 68-1–vectored SIV vaccines, which led to expansion of CD8+ T cells with capacity to inhibit SIV replication ex vivo. These results suggest that innate-memory expansion could be achieved by other vaccine platforms expressing IL-15. Supported by ORIP (P51OD011107) and NIAID.
Previous Exposure to Dengue Virus Is Associated with Increased Zika Virus Burden at the Maternal-Fetal Interface in Rhesus Macaques
Crooks et al., PLOS Neglected Tropical Diseases. 2021.
https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0009641
Pre-existing immunity to dengue virus (DENV) results in antibody-dependent enhancement (ADE) among DENV serotypes; Zika virus (ZIKV) has homology with DENV suggesting pre-existing DENV immunity may have an impact on ZIKV pathogenesis during pregnancy. In a rhesus macaque model, prior DENV-2 exposure resulted in a higher burden of ZIKV viral RNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma; all pregnancies progressed to term without adverse outcomes at delivery. Investigating potential ADE in pregnant women is important as vaccines against DENV and ZIKV are developed. Supported by ORIP (P51OD011106) and NIAID.
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.
Interleukin-15 Response Signature Predicts RhCMV/SIV Vaccine Efficacy
Barrenäs et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009278
Standard immunogenicity measures do not predict efficacy of a vaccine based on strain 68-1 rhesus cytomegalovirus (RhCMV) vectors expressing SIV proteins (RhCMV/SIV). This vaccine robustly protects just over half of immunized monkeys. Using functional genomics, researchers found that RhCMV/SIV efficacy is correlated with a vaccine-induced response to interleukin-15 (IL-15) that includes modulation of immune cell, inflammation, toll-like receptor signaling, and cell death programming pathways. RhCMV/SIV imparts a coordinated and persistent induction of innate and adaptive immune pathways featuring IL-15, a known regulator of CD8+ T cell function, that support the ability of vaccine-elicited CD8+ T cells to mediate protection against SIV. Supported by ORIP (P51OD010425, P51OD011092), NIAID, and NCI.
Recrudescence of Natural Coccidioidomycosis During Combination Antiretroviral Therapy in a Pigtail Macaque Experimentally Infected with Simian Immunodeficiency Virus
Guerriero et al., AIDS Research and Human Retroviruses. 2021.
https://doi.org/10.1089/AID.2020.0228
Coccidioidomycosis is a common fungal infection in people living with HIV, particularly in regions where Coccidioides is endemic, such as the U.S. Southwest. Researchers diagnosed a recrudescent case of previously treated, naturally occurring coccidioidomycosis in a pigtail macaque experimentally infected with simian immunodeficiency virus (SIV) and virally suppressed on combination antiretroviral therapy (cART). Coccidioides IgG antibody titer became detectable before discontinuation of cART, but symptomatic coccidioidomycosis developed after cART withdrawal. This animal was screened and treated in accordance with the guidelines for coccidioidomycosis prevention and treatment. The researchers conclude that macaques with coccidioidomycosis history should be excluded from HIV studies. Supported by ORIP (P51OD010425), NIAID, and NIMH.