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- Vaccines/Therapeutics
Functional and Structural Basis of Human Parainfluenza Virus Type 3 Neutralization With Human Monoclonal Antibodies
Suryadevara et al., Nature Microbiology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38858594
Human parainfluenza virus type 3 (hPIV3) can cause severe disease in older people and infants, and the haemagglutinin-neuraminidase (HN) and fusion (F) surface glycoproteins of hPIV3 are major antigenic determinants. Researchers isolated seven neutralizing HN-reactive antibodies and a pre-fusion conformation F-reactive antibody from human memory B cells. They also delineated the structural basis of neutralization for HN and F monoclonal antibodies (mAbs). Rats were protected against infection and disease in vivo by mAbs that neutralized hPIV3 in vitro. This work establishes correlates of protection for hPIV3 and highlights the potential clinical utility of mAbs. Supported by ORIP (K01OD036063), NIAID, and NIGMS.
Genetic Diversity of 1,845 Rhesus Macaques Improves Genetic Variation Interpretation and Identifies Disease Models
Wang et al., Nature Communications. 2024.
https://www.nature.com/articles/s41467-024-49922-6
Nonhuman primates are ideal models for certain human diseases, including retinal and neurodevelopmental disorders. Using a reverse genetics approach, researchers profiled the genetic diversity of rhesus macaque populations across eight primate research centers in the United States and uncovered rhesus macaques carrying naturally occurring pathogenic mutations. They identified more than 47,000 single-nucleotide variants in 374 genes that had been previously linked with retinal and neurodevelopmental disorders in humans. These newly identified variants can be used to study human disease pathology and to test novel treatments. Supported by ORIP (P51OD011107, P51OD011106, P40OD012217, S10OD032189), NEI, NIAID, and NIMH.
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.
Physiologically Based Pharmacokinetic Model Validated to Enable Predictions of Multiple Drugs in a Long-Acting Drug-Combination Nano-Particles (DcNP): Confirmation With 3 HIV Drugs, Lopinavir, Ritonavir, and Tenofovir in DcNP Products
Perazzolo et al., Journal of Pharmaceutical Sciences. 2024.
https://jpharmsci.org/article/S0022-3549(24)00060-1/fulltext
Drug-combination nanoparticles synchronize delivery of multiple drugs in a single, long-acting, targeted dose. Two distinct classes of long-acting injectable products are proposed based on pharmacokinetic mechanisms. Class I involves sustained release at the injection site, and Class II involves a drug-carrier complex composed of lopinavir, ritonavir, and tenofovir uptake and retention in the lymphatic system before systemic access. This review used data from three nonhuman primate studies, consisting of nine pharmacokinetic data sets, to support clinical development of Class II products. Eight of nine models passed validation, and the drug–drug interaction identified in the ninth model can be accounted for in the final model. Supported by ORIP (P51OD010425, U42OD011123), NIAID, and NHLBI.
CD8+ T Cell Targeting of Tumor Antigens Presented by HLA-E
Iyer, Science Advances. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11086602/
Researchers have hypothesized that human leukocyte antigen-E (HLA-E)–positive cancer cells could be targeted by HLA-E–restricted CD8+ T cells. In this study, the authors assessed whether major histocompatibility complex E (MHC-E) expression by cancer cells can be targeted for MHC-E–restricted T cell control. Using male rhesus macaques, they found that a cytomegalovirus can be used as a vector to generate specific immune cells that can target cancer cells. The authors conclude that targeting HLA-E with restricted, specific CD8+ T cells could offer a new approach for immunotherapy of prostate cancer. Overall, this study supports the concept of a cancer vaccine. Supported by ORIP (P51OD011092) and NIAID.
Neutralizing Antibody Response to SARS‐CoV‐2 Bivalent mRNA Vaccine in SIV‐Infected Rhesus Macaques: Enhanced Immunity to XBB Subvariants by Two‐Dose Vaccination
Faraone, Journal of Medical Virology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38528837/
Researchers have shown that mRNA vaccination is less effective for people with advanced or untreated HIV infection, but data on the efficacy of mRNA vaccination against SARS-CoV-2 in this population are limited. Using rhesus macaques (sex not specified) with simian immunodeficiency virus (SIV), investigators examined the neutralizing antibody (nAb) response to SARS-CoV-2 vaccination. They found that administration of the bivalent vaccine alone can generate robust nAb titers against Omicron subvariants. Additionally, dams that received antiretroviral therapy had lower nAb titers than untreated dams. Overall, these findings highlight the need for further investigations into the nAb response in people with HIV. Supported by ORIP (P51OD011104), NCI, NIAID, NICHD, and NIMH.
SIV Infection Is Associated With Transient Acute-Phase Steatosis in Hepatocytes In Vivo
Derby, Viruses. 2024.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10892327/
Metabolic dysfunction–associated fatty liver disease (MAFLD) in people with HIV has become an increasing concern, but little is known about liver-specific changes underlying HIV-related MAFLD. Using rhesus macaques (sex not specified), researchers examined the timing of pathogenic changes within the liver during simian immunodeficiency virus (SIV) infection. Their findings suggest differential pathologies associated with the acute and chronic phases of infection. This work highlights the early damage inflicted on the liver by SIV/HIV infection and indicates that damage to the hepatocytes plays a specific role. Overall, the authors conclude that therapeutic interventions targeting metabolic function may benefit liver health in people who have recently received an HIV diagnosis. Supported by ORIP (P51OD011107, P51OD011092) and NIAID.
Potent HPIV3-Neutralizing IGHV5-51 Antibodies Identified from Multiple Individuals Show L Chain and CDRH3 Promiscuity
Abu-Shmais et al., Journal of Immunology. 2024.
https://pubmed.ncbi.nlm.nih.gov/38488511/
Human parainfluenza virus 3 fusion glycoprotein (HPIV3 F), responsible for facilitating viral entry into host cells, is a major target of neutralizing antibodies that inhibit infection. More work is needed to understand these dynamics. Researchers characterized the genetic signatures, epitope specificity, neutralization potential, and publicness of HPIV3-specific antibodies identified across multiple individuals. From this work, they identified 12 potently neutralizing antibodies targeting three nonoverlapping epitopes on HPIV3 F. Six of the antibodies used immunoglobulin heavy variable gene, IGHV 5-51. These antibodies used different L chain variable genes (VL) and diverse H chain CDR 3 (CDRH3) sequences. These findings help elucidate the genetic and functional characteristics of HPIV3-neutralizing antibodies and indicate the existence of a reproducible H chain variable–dependent antibody response associated with VL and CDRH3 promiscuity. Supported by ORIP (K01OD036063), NCATS, NCI, NEI, NIAID, and NIDDK.
Proof-of-Concept Studies With a Computationally Designed Mpro Inhibitor as a Synergistic Combination Regimen Alternative to Paxlovid
Papini et al., PNAS. 2024.
As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection. Results indicate favorable pharmacological properties, efficacy, and drug synergy, as well as complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate. Supported by ORIP (R24OD026440, S10OD021527), NIAID, and NIGMS.
Potent Antibody-Dependent Cellular Cytotoxicity of a V2-Specific Antibody Is Not Sufficient for Protection of Macaques Against SIV Challenge
Grunst et al., PLOS Pathogens. 2024.
https://pubmed.ncbi.nlm.nih.gov/38252675/
Antibody-dependent cellular cytotoxicity (ADCC) has been correlated with decreased risk of HIV acquisition. Researchers tested the ability of PGT145, an antibody that neutralizes genetically diverse HIV-1 isolates, to protect rhesus macaques against simian immunodeficiency virus (SIV) via ADCC activity. They found that a single amino acid substitution in the V2 core epitope of the SIV envelope increases PGT145 binding and confers sensitivity to neutralization. Peak and chronic phase viral loads were lower, and time to peak viremia was delayed. They concluded that ADCC is insufficient for protection by this antibody, but increasing the affinity of antibody binding could confer partial protection. Supported by ORIP (P51OD011106), NIAID, and NCI.