Selected Grantee Publications
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- 197 results found
- COVID-19/Coronavirus
- HIV/AIDS
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 Large Repertoire of B Cell Lineages Targeting One Cluster of Epitopes in a Vaccinated Rhesus Macaque
Li et al., Vaccine. 2021.
https://www.sciencedirect.com/science/article/pii/S0264410X21010355?via%3Dihub=
A rhesus macaque that was serially immunized six times with the 8-mer epitope for human monoclonal antibody (mAb) 447-52D—specific to the V3 region of gp120 HIV-1—provided a rare opportunity to study the repertoire of antibodies produced upon vaccination against a particular antigenic site. From a blood sample taken 3 weeks after the last immunization, researchers produced 41 V3-specific recombinant mAbs by single B cell isolation and cloning. Sequence analysis revealed 21 B cell lineages (single and clonally related). The broad repertoire of Abs directed to a small antigenic site shows the targeting potency of a vaccine-elicited immune response in rhesus macaques. Supported by ORIP (P51OD011092, U42OD010246) and NIAID.
IL-21 Enhances Influenza Vaccine Responses in Aged Macaques with Suppressed SIV Infection
Kvistad et al., JCI Insight. 2021.
https://doi.org/10.1172/jci.insight.150888
Aging with HIV is associated with low-grade systemic inflammation, immune senescence, and impaired antibody (Ab) responses to such vaccines as influenza (flu). Researchers investigated the role of interleukin (IL)-21, a CD4 T follicular helper cell regulator, on flu vaccine Ab response in rhesus macaques in the context of age and controlled simian immunodeficiency virus (SIV) mac239 infection. They found that IL-21 enhanced flu vaccine-induced Ab responses in SIV+ (anti-retroviral therapy-suppressed) aged rhesus macaques, adjuvanting the flu vaccine by modulating lymph node germinal center activity. Thus, strategies to supplement IL-21 in aging might improve vaccine responses in people aging with HIV. Supported by ORIP (R24OD010947) and NIAID.
Circulating Integrin α4β7+ CD4 T Cells Are Enriched for Proliferative Transcriptional Programs in HIV Infection
Lakshmanappa et al., Federation of European Biochemical Societies Letters. 2021.
https://doi.org/10.1002/1873-3468.14163
HIV preferentially infects α4β7+ CD4 T cells, forming latent reservoirs that contribute to HIV persistence, yet the properties of α4β7+ CD4 T cells are poorly understood. Investigating HIV-infected humans and SHIV-infected rhesus macaques, investigators demonstrated that α4β7+ CD4 T cells in blood are enriched for genes regulating cell cycle progression and cellular metabolism. In contrast, rectal α4β7+ CD4 T cells exhibited a core tissue-residency gene expression program. These features were conserved across primate species, suggesting that the tissue environment influences memory T-cell transcriptional networks. These findings provide an important foundation for understanding the role of α4β7 in HIV infection. Supported by ORIP (K01OD023034, R24OD010976) and NIAID.
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.
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.
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.