Selected Grantee Publications
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.
Protection of Newborn Macaques by Plant-Derived HIV Broadly Neutralizing Antibodies: A Model for Passive Immunotherapy During Breastfeeding
Rosenberg et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.00268-21
Preventing vertical transmission of HIV to newborns is an unmet medical need in resource poor countries. Using a breastfeeding macaque model with multiple simian-human immunodeficiency virus challenge, researchers assessed the protective efficacy of two human broadly neutralizing antibodies (bnAbs) against HIV, PGT121 and VRC07-523, which are produced by a plant expression system. Despite the transient presence of plasma viral RNA, the bnAbs prevented productive infection in all newborns with no sustained plasma viremia, compared to viral loads ranging from 103 to 5x108 in four untreated controls. Thus, plant-expressed antibodies show promise as passive immunoprophylaxis in a breastfeeding model in newborns. Supported by ORIP (U42OD023038, P51OD011092) and NIAID.
Tissue-Specific Transcriptional Profiling of Plasmacytoid Dendritic Cells Reveals a Hyperactivated State in Chronic SIV Infection
Lee et al., PLOS Pathogens. 2021.
https://doi.org/10.1371/journal.ppat.1009674
Persistent immune activation is an obstacle to optimal health for people living with HIV. Using RNA sequencing, researchers investigated the immunostimulatory potential of plasmacytoid dendritic cells (pDCs) in chronic SIV infection in rhesus macaques. They observed that pDCs have highly activated profiles in these animals. In contrast, pDCs from SIV-infected sooty mangabeys (natural hosts for SIV) had expression profiles similar to uninfected animals. In chronically infected rhesus macaques, interferon alpha transcripts were readily detected in lymph node-homing pDCs, but not those from blood. Therefore, pDCs are a major producer of type-I interferon in chronic SIV infection and could be a useful immunotherapy target. Supported by ORIP (R24OD010445, P51OD011132, P51OD011092, S10OD026799) and NIAID.
Immune Inactivation of Anti-Simian Immunodeficiency Virus Chimeric Antigen Receptor T Cells in Rhesus Macaques
Haeseleer et al., Molecular Therapy–Methods & Clinical Development. 2021.
https://doi.org/10.1016/j.omtm.2021.06.008
Chimeric antigen receptor (CAR) T cell therapies are under development as potential HIV cures. Researchers found that CAR T cells expressing a single-chain variable fragment (scFv) that recognizes V1 or V3 of the SIV envelope eliminated SIV-infected T cells in vitro. However, in vivo infusion of these CAR T cells in rhesus macaques resulted in no detectable antiviral activity. Anti-SIV IgG antibodies in the SIV-infected animals were associated with inhibited CAR T cell effector functions. Thus, lack of in vivo efficacy of CAR T cells might be due to antibodies blocking the interaction between the CAR scFv and its epitope. Supported by ORIP (P51OD011092) and NIAID.
Gut Germinal Center Regeneration and Enhanced Antiviral Immunity by Mesenchymal Stem/Stromal Cells
Weber et al., JCI Insight. 2021.
https://doi.org/10.1172/jci.insight.149033
Researchers investigated the effects of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, antiviral immunity, and viral suppression in SIV-infected rhesus macaques. MSC treatment heightened virus-specific responses and reduced viral load. Clearance of SIV-positive cells from gut mucosal effector sites was correlated with regeneration of germinal centers, restoration of follicular B cells and T follicular helper cells, and enhanced antigen presentation by viral trapping within the follicular dendritic cell network. These changes were associated with enhanced gene expression for type I/II interferon signaling, B cell proliferation, and interleukin 7. MSC treatment also activated metabolic pathways associated with enhanced immunity and viral reduction. Supported by ORIP (P51OD011107) and NIAID.
Western-Style Diet Consumption Impairs Maternal Insulin Sensitivity and Glucose Metabolism During Pregnancy in a Japanese Macaque Model
Elsakr et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-92464-w
Using a Japanese macaque model, investigators assessed the metabolic effects of obesity and a calorically dense, Western-style diet (WSD; 36.3% fat), either alone or together, on maternal glucose tolerance and insulin levels in dams during pregnancy (n = 95 females followed over multiple pregnancies [n = 273]). With prolonged WSD feeding, multiple diet switches, and/or increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. The results suggest that prolonged or recurrent calorically dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. Supported by ORIP (P51OD011092), NIDDK and NIMH.
SARS-CoV-2 Vaccines Elicit Durable Immune Responses in Infant Rhesus Macaques
Garrido et al., Science Immunology. 2021.
https://immunology.sciencemag.org/content/6/60/eabj3684
The immunogenicity of two SARS-CoV-2 vaccines was evaluated in both sexes of infant rhesus macaques (n=8/group). Neither vaccine, stabilized prefusion SARS-CoV-2 S-2P spike (S) protein encoded by mRNA encapsulated in lipid nanoparticles or the purified S protein mixed with 3M-052, a synthetic TLR7/8 agonist in a squalene emulsion, induced adverse effects. Both elicited high magnitude neutralizing antibody titers peaking at week 6. S-specific T cell responses were dominated by IL-17, IFN-γ, or TNF-α. Antibody and cellular responses were stable through week 22. These data provide proof-of concept for a pediatric SARS-CoV-2 vaccine with the potential for durable immunity to decrease transmission of COVID-19. Supported by ORIP (P51OD011107), NIAID, and NCI.