Selected Grantee Publications
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- Infectious Diseases
- Vaccines/Therapeutics
- Microscopy
A Single-Dose Intranasal Live-Attenuated Codon Deoptimized Vaccine Provides Broad Protection Against SARS-CoV-2 and Its Variants
Liu et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39187479
Researchers developed an intranasal, single-dose, live-attenuated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) vaccine (CDO-7N-1) using codon deoptimization. This vaccine demonstrates broad protection against SARS-CoV-2 variants, with highly attenuated replication and minimal lung pathology across multiple in vivo passages. The vaccine induced robust mucosal and systemic neutralizing antibodies, as well as T-cell responses, in male and female hamsters, female K18-hACE2 mice, and male HFH4-hACE2 mice. In male and female cynomolgus macaques, CDO-7N-1 effectively prevented infection, reduced severe disease, and limited transmission of SARS-CoV-2 variants. This innovative approach offers potential advantages over traditional spike-protein vaccines by providing durable protection and targeting emerging variants to curb virus transmission. Supported by ORIP (K01OD026529).
Placental Gene Therapy in Nonhuman Primates: A Pilot Study of Maternal, Placental, and Fetal Response to Non-Viral, Polymeric Nanoparticle Delivery of IGF1
Wilson et al., Molecular Human Reproduction. 2024.
https://academic.oup.com/molehr/article/30/11/gaae038/7876288#493719584
This study investigates a novel nanoparticle-mediated gene therapy approach for addressing fetal growth restriction (FGR) in pregnant female nonhuman primates. Using polymer-based nanoparticles delivering a human insulin-like growth factor 1 (IGF1) transgene, the therapy targets the placenta via ultrasound-guided injections. Researchers evaluated maternal, placental, and fetal responses by analyzing tissues, immunomodulatory proteins, and hormones (progesterone and estradiol). Findings highlight the potential of IGF1 nanoparticles to correct placental insufficiency by enhancing fetal growth, providing a groundbreaking advancement for in utero treatments. This research supports further exploration of nonviral gene therapies for improving pregnancy outcomes and combating FGR-related complications. Supported by ORIP (P51OD011106) and NICHD.
Gene Editing of Pigs to Control Influenza A Virus Infections
Kwon et al., Emerging Microbes & Infections. 2024.
https://pubmed.ncbi.nlm.nih.gov/39083026/
A reduction in the efficacy of vaccines and antiviral drugs for combating infectious diseases in agricultural animals has been observed. Generating genetically modified livestock species to minimize susceptibility to infectious diseases is of interest as an alternative approach. The researchers developed a homozygous transmembrane serine protease 2 (TMPRSS2) knockout (KO) porcine model to investigate resistance to two influenza A virus (IAV) subtypes, H1N1 and H3N2. TMPRSS2 KO pigs demonstrated diminished nasal cavity viral shedding, lower viral burden, and reduced microscopic lung pathology compared with wild-type (WT) pigs. In vitro culturing of primary bronchial epithelial cells (PBECs) demonstrated delayed viral replication in TMPRSS2 KO pigs compared with WT pigs. This study demonstrates the potential use of genetically modified pigs to mitigate IAV infections in pigs and limit transmission to humans. Supported by ORIP (U42OD011140), NHLBI, NIAID, and NIGMS.
Enterohemorrhagic Escherichia coli (EHEC) Disrupts Intestinal Barrier Integrity in Translational Canine Stem Cell-Derived Monolayers
Nagao et al., Microbiology Spectrum. 2024.
https://pubmed.ncbi.nlm.nih.gov/39162490/
EHEC produces Shiga toxin, which causes acute colitis with symptoms such as hemolytic uremic syndrome and bloody diarrhea. The researchers developed a colonoid-derived monolayer model to understand EHEC’s impact on canine gut health. Colonoid-derived monolayers co-cultured with EHEC demonstrated key differences compared with the control and nonpathogenic E. coli co-cultures. Scanning electron microscopy displayed EHEC aggregated and attached to the microvilli. EHEC-infected monolayers demonstrated significantly weakened membrane integrity and increased inflammatory cytokine production, specifically TNFα. The researchers developed a novel in vitro model that offers an additional platform for understanding the mechanisms of EHEC pathogenicity, developing therapeutics for EHEC, and studying additional enteric pathogens. Supported by ORIP (K01OD030515, R21OD031903).
Administration of Anti-HIV-1 Broadly Neutralizing Monoclonal Antibodies With Increased Affinity to Fcγ Receptors During Acute SHIV AD8-EO Infection
Dias et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-51848-y
Anti-HIV broadly neutralizing antibodies (bNAbs) mediate virus neutralization and antiviral effector functions through Fab and Fc domains, respectively. This study investigated the efficacy of wild-type (WT) bNAbs and modified bNAbs with enhanced affinity for Fcγ receptors (S239D/I332E/A330L [DEL]) after acute simian-HIVAD8-EO (SHIVAD8-EO) infection in male and female rhesus macaques. The emergence of the virus in the plasma and lymph nodes occurred earlier in macaques given DEL bNAbs than in those given WT bNAbs. Overall, the administration of DEL bNAbs revealed higher levels of immune responses. The results suggest that bNAbs with an enhanced Fcγ receptor affinity offer a potential therapeutic strategy by targeting HIV more effectively during early infection stages. Supported by ORIP (P40OD028116), NCI, and NIAID.
Comparison of the Immunogenicity of mRNA-Encoded and Protein HIV-1 Env-ferritin Nanoparticle Designs
Mu et al., Journal of Virology. 2024.
https://journals.asm.org/doi/10.1128/jvi.00137-24
Inducing broadly neutralizing antibodies (bNAbs) against HIV-1 remains a challenge because of immune system limitations. This study compared the immunogenicity of mRNA-encoded membrane-bound envelope (Env) gp160 to HIV-1 Env-ferritin nanoparticle (NP) technology in inducing anti-HIV-1 bNAbs. Membrane-bound mRNA encoding gp160 was more immunogenic than the Env-ferritin NP design in DH270 UCA KI mice, but at lower doses. These results suggest further analysis of mRNA design expression and low-dose immunogenicity studies are necessary for anti-HIV-1 bNAbs. Supported by ORIP (P40OD012217, U42OD021458) and NIAID.
Anti–PD-1 Chimeric Antigen Receptor T Cells Efficiently Target SIV-Infected CD4+ T Cells in Germinal Centers
Eichholtz et al., The Journal of Clinical Investigation. 2024.
https://pubmed.ncbi.nlm.nih.gov/38557496/
Researchers conducted adoptive transfer of anti–programmed cell death protein 1 (PD-1) chimeric antigen receptor (CAR) T cells in simian immunodeficiency virus (SIV)–infected rhesus macaques of both sexes on antiretroviral therapy (ART). In some macaques, anti–PD-1 CAR T cells expanded and persisted concomitant with the depletion of PD-1+ memory T cells—including lymph node CD4+ follicular helper T cells—associated with depletion of SIV RNA from the germinal center. Following CAR T infusion and ART interruption, SIV replication increased in extrafollicular portions of lymph nodes, plasma viremia was higher, and disease progression accelerated, indicating that anti–PD-1 CAR T cells depleted PD-1+ T cells and eradicated SIV from this immunological sanctuary. Supported by ORIP (U42OD011123, U42OD010426, P51OD010425, P51OD011092), NCI, NIAID, and NIDDK.
Disruption of Myelin Structure and Oligodendrocyte Maturation in a Macaque Model of Congenital Zika Infection
Tisoncik-Go et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49524-2
Maternal infection during pregnancy can have severe consequences on fetal development and survival. Using a pigtail macaque model for Zika virus infection, researchers show that in utero exposure of a fetus to Zika virus due to maternal infection results in significantly decreased myelin formation around neurons. Myelin is a protective sheath that forms around neurons and is required for brain processing speed. This study suggests that reduced myelin resulting from Zika infection in utero is likely a contributing factor to severe deficits in brain development and microcephaly. Supported by ORIP (P51OD010425), NEI, and NIAID.
Loss of Lymphatic IKKα Disrupts Lung Immune Homeostasis, Drives BALT Formation, and Protects Against Influenza
Cully et al., Immunohorizons. 2024.
https://pubmed.ncbi.nlm.nih.gov/39007717/
Tertiary lymphoid structures (TLS) have context-specific roles, and more work is needed to understand how they function in separate diseases to drive or reduce pathology. Researchers showed previously that lymph node formation is ablated in mice constitutively lacking IκB kinase alpha (IKKα) in lymphatic endothelial cells (LECs). In this study, they demonstrated that loss of IKKα in lymphatic endothelial cells leads to the formation of bronchus-associated lymphoid tissue in the lung. Additionally, they showed that male and female mice challenged with influenza A virus (IAV) exhibited markedly improved survival rates and reduced weight loss, compared with littermate controls. They concluded that ablating IKKα in this tissue reduces the susceptibility of the mice to IAV infection through a decrease in proinflammatory stimuli. This work provides a new model to explore the mechanisms of TLS formation and the immunoregulatory function of lung lymphatics. Supported by ORIP (T35OD010919), NHLBI, NIAID, and NIAMS.
Vaccination Induces Broadly Neutralizing Antibody Precursors to HIV gp41
Schiffner et al., Nature Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38816615
Primary immunogens that induce rare broadly neutralizing antibody (bnAb) precursor B cells are needed to develop vaccines against viruses of high antigenic diversity. 10E8-class bnAbs must possess a long, heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. Researchers developed germline-targeting epitope scaffolds with an affinity for 10E8-class precursors that exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens. Protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. This study showed that germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features. Supported by ORIP (P51OD011132, U42OD011023), NIAID, and NIGMS.