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At least 397 records · Page 22

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DOE OSTI2020

HIV-1 GP140 immunogens comprising modified NHR1 regions that stabilize pre-fusion conformations

The present invention provides HIV-1 vaccine immunogens. Some of the immunogens contain a soluble gp140-derived protein that harbors a modified N-terminus of the HR1 region in gp41. Some of the immunogens contain an HIV-1 Env-derived trimer protein that is presented on a nanoparticle platform. The invention also provides methods of using the HIV-1 vaccine immunogens for eliciting an immune response or treating HIV infections.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Nucleic acids encoding HIV-1 GP140 immunogens comprising modified NHR1 regions that stabilize pre-fusion conformations

Kong, Leopold↗

DOE OSTI2023

HIV-1 GP140 immunogens comprising modified NHR1 regions that stabilize pre-fusion envelope conformations

Kong, Leopold↗

DOE OSTI2023

A new class of antibodies that overcomes a steric barrier to cross-group neutralization of influenza viruses

Antibody titers that inhibit the influenza virus hemagglutinin (HA) from engaging its receptor are the accepted correlate of protection from infection. Many potent antibodies with broad, intra-subtype specificity bind HA at the receptor binding site (RBS). One barrier to broad H1-H3 cross-subtype neutralization is an insertion (133a) between positions 133 and 134 on the rim of the H1 HA RBS. We describe here a class of antibodies that overcomes this barrier. These genetically unrestricted antibodies are abundant in the human B cell memory compartment. Analysis of the affinities of selected members of this class for historical H1 and H3 isolates suggest that they were elicited by H3 exposure and broadened or diverted by later exposure(s) to H1 HA. RBS mutations in egg-adapted vaccine strains cause the new H1 specificity of these antibodies to depend on the egg adaptation. The results suggest that suitable immunogens might elicit 133a-independent, H1-H3 cross neutralization by RBS-directed antibodies.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Raccoon densities across four land cover types in the southeastern United States

Raccoons (Procyon lotor) are the primary reservoir for rabies virus in eastern North America. Management of rabies in raccoons is achieved primarily with the use of oral rabies vaccination (ORV) and effective ORV bait densities are determined in part by the densities of raccoons. Decisions regarding ORV bait densities, however, are limited by an incomplete understanding of raccoon densities across the spectrum of landscapes they occupy. We carried out a mark-recapture study of raccoons on the Savannah River Site in South Carolina, USA, from 2017–2019, to develop sex- and landscape-specific raccoon density estimates across 4 rural land cover types in the southeastern United States: bottomland hardwood, riparian forest, isolated wetland, and upland pine (Pinus spp.). We captured 404 unique raccoons 773 times over the 3-year trapping period. Estimated densities were 5.44 ± 0.37 (SE) animals/km 2 in bottomland hardwood forest, 2.62 ± 0.32 animals/km 2 in riparian forest, 2.19 ± 0.29 animals/km 2 in isolated wetlands, and 2.14 ± 0.23 animals/km 2 in upland pine. Densities were significantly higher in bottomland hardwood than all other land cover types, whereas densities among the remaining cover types were similar. These patterns are likely the result of landscape fragmentation and configuration, with riparian forests typically embedded in a matrix of less suitable cover types, leading to low densities despite presumably high resource availability. There were higher densities of males than females in every cover type except upland pine, where the sex ratio was balanced. Densities on our site were low compared to other rural areas, which likely results from the lack of human influence in terms of agriculture or development. The financial cost of baiting for ORV distribution may be reduced by considering the comparatively low densities of raccoons in these rural landscapes in the southeastern United States.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

Evaluating size exclusion chromatography for nucleic acid removal in Klebsiella pneumoniae cell surface polysaccharide purification

Cell surface-associated polysaccharides in Klebsiella are major virulence determinants and crucial targets for developing vaccines. Traditionally, the purification of these cell surface polysaccharides from Klebsiella pneumoniae involves a multi-step process comprising phenol extraction, nuclease digestion, ultracentrifugation, and repeated ethanol extractions. In this study, we evaluated size exclusion chromatography for effectively eliminating nucleic acid contamination while purifying high molecular weight cell surface-associated polysaccharides. Post-initial extraction, the nucleic acid content remains significantly elevated, and kinetic analysis reveals that DNase I and RNase A digestion is neither economically viable nor effective for removing these contaminants. Employing an appropriate size exclusion resin removes over 99 % of nucleic acid contamination, as confirmed by nucleic acid content analysis and agarose gel electrophoresis. Purity and structural analysis using 1H 1D-NMR and 2D-NMR demonstrate that the cell surface-associated polysaccharide purified with this study is highly homogeneous and identified as antigenic O-polysaccharide. This approach streamlines the purification process by removing the need for nuclease digestion and additional ethanol precipitation steps.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Delineating the mechanism of anti-Lassa virus GPC-A neutralizing antibodies

Lassa virus (LASV) is the etiologic agent of Lassa Fever, a hemorrhagic disease that is endemic to West Africa. During LASV infection, LASV glycoprotein (GP) engages with multiple host receptors for cell entry. Neutralizing antibodies against GP are rare and principally target quaternary epitopes displayed only on the metastable, pre-fusion conformation of GP. Currently, the structural features of the neutralizing GPC-A antibody competition group are understudied. Structures of two GPC-A antibodies presented here demonstrate that they bind the side of the pre-fusion GP trimer, bridging the GP1 and GP2 subunits. Complementary biochemical analyses indicate that antibody 25.10C, which is broadly specific, neutralizes by inhibiting binding of the endosomal receptor LAMP1 and also by blocking membrane fusion. The other GPC-A antibody, 36.1F, which is lineage-specific, prevents LAMP1 association only. These data illuminate a site of vulnerability on LASV GP and will guide efforts to elicit broadly reactive therapeutics and vaccines.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Convergent Evolution in Breadth of Two V H 6-1-Encoded Influenza Antibody Clonotypes from a Single Donor

Understanding how broadly neutralizing antibodies (bnAbs) to influenza hemagglutinin (HA) naturally develop in humans is critical to the design of universal influenza vaccines. Several classes of bnAbs directed to the conserved HA stem were found in multiple individuals, including one encoded by heavy-chain variable domain V H 6-1. We describe two genetically similar V H 6-1 bnAb clonotypes from the same individual that exhibit different developmental paths toward broad neutralization activity. One clonotype evolved from a germline precursor recognizing influenza group 1 subtypes to gain breadth to group 2 subtypes. The other clonotype recognized group 2 subtypes and developed binding to group 1 subtypes through somatic hypermutation. Crystal structures reveal that the specificity differences are primarily mediated by complementarity-determining region H3 (CDR H3). Thus, while V H 6-1 provides a framework for development of HA stem-directed bnAbs, sequence differences in CDR H3 junctional regions during VDJ recombination can alter reactivity and evolutionary pathways toward increased breadth.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Epstein-Barr virus gH/gL has multiple sites of vulnerability for virus neutralization and fusion inhibition

Epstein-Barr virus (EBV) is nearly ubiquitous in adults. EBV causes infectious mononucleosis and is associated with B cell lymphomas, epithelial cell malignancies, and multiple sclerosis. The EBV gH/gL glycoprotein complex facilitates fusion of virus membrane with host cells and is a target of neutralizing antibodies. Here, in this study, we examined the sites of vulnerability for virus neutralization and fusion inhibition within EBV gH/gL. We developed a panel of human monoclonal antibodies (mAbs) that targeted five distinct antigenic sites on EBV gH/gL and prevented infection of epithelial and B cells. Structural analyses using X-ray crystallography and electron microscopy revealed multiple sites of vulnerability and defined the antigenic landscape of EBV gH/gL. One mAb provided near-complete protection against viremia and lymphoma in a humanized mouse EBV challenge model. Our findings provide structural and antigenic knowledge of the viral fusion machinery, yield a potential therapeutic antibody to prevent EBV disease, and emphasize gH/gL as a target for herpesvirus vaccines and therapeutics.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes

Increased immune evasion by SARS-CoV-2 variants of concern highlights the need for new therapeutic neutralizing antibodies. Immunization with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicits cross-reactive polyclonal antibodies against conserved sarbecovirus RBD epitopes. Here, we identified monoclonal antibodies (mAbs) capable of cross-reactive binding and neutralization of animal sarbecoviruses and SARS-CoV-2 variants by screening single mouse B cells secreting IgGs that bind two or more sarbecovirus RBDs. Single-particle cryo-EM structures of antibody-spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes. Structural analyses revealed neutralization mechanisms, potentials for intra-spike trimer cross-linking by IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb-resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticle vaccination to generate and identify therapeutic pan-sarbecovirus and pan-variant mAbs.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Succinate based polymers drive immunometabolism in dendritic cells to generate cancer immunotherapy

Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of succinate metabolite to phagocytic immune cells activates them and modulates their metabolism in the presence of metabolic inhibitors. In young immunocompetent mice, polymeric microparticles, with succinate incorporated in the backbone, induced strong pro-inflammatory anti-melanoma responses. Administration of poly(ethylene succinate) (PES MP)-based vaccines and glutaminase inhibitor to young immunocompetent mice with aggressive and large, established B16F10 melanoma tumors increased their survival three-fold, a result of increased cytotoxic T cells expressing RORγT (Tc17). Mechanistically, PES MPs directly modulate glutamine and glutamate metabolism, upregulate succinate receptor SUCNR1, activate antigen presenting cells through and HIF-1alpha, TNFa and TSLP-signaling pathways, and are dependent on alpha-ketoglutarate dehydrogenase for their activity, which demonstrates correlation of succinate delivery and these pathways. Altogether, our findings suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Affinity-matured homotypic interactions induce spectrum of PfCSP structures that influence protection from malaria infection

The generation of high-quality antibody responses to Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP), the primary surface antigen of Pf sporozoites, is paramount to the development of an effective malaria vaccine. Here we present an in-depth structural and functional analysis of a panel of potent antibodies encoded by the immunoglobulin heavy chain variable (IGHV) gene IGHV3-33, which is among the most prevalent and potent antibody families induced in the anti-PfCSP immune response and targets the Asn-Ala-Asn-Pro (NANP) repeat region. Cryo-electron microscopy (cryo-EM) reveals a remarkable spectrum of helical antibody-PfCSP structures stabilized by homotypic interactions between tightly packed fragments antigen binding (Fabs), many of which correlate with somatic hypermutation. We demonstrate a key role of these mutated homotypic contacts for high avidity binding to PfCSP and in protection from Pf malaria infection. Together, these data emphasize the importance of anti-homotypic affinity maturation in the frequent selection of IGHV3–33 antibodies and highlight key features underlying the potent protection of this antibody family.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

Visualization of the HIV-1 Env glycan shield across scales

The dense array of N-linked glycans on the HIV-1 envelope glycoprotein (Env), known as the “glycan shield,” is a key determinant of immunogenicity, yet intrinsic heterogeneity confounds typical structure–function analysis. Here, we present an integrated approach of single-particle electron cryomicroscopy (cryo-EM), computational modeling, and site-specific mass spectrometry (MS) to probe glycan shield structure and behavior at multiple levels. We found that dynamics lead to an extensive network of interglycan interactions that drive the formation of higher-order structure within the glycan shield. This structure defines diffuse boundaries between buried and exposed protein surface and creates a mapping of potentially immunogenic sites on Env. Analysis of Env expressed in different cell lines revealed how cryo-EM can detect subtle changes in glycan occupancy, composition, and dynamics that impact glycan shield structure and epitope accessibility. Importantly, this identified unforeseen changes in the glycan shield of Env obtained from expression in the same cell line used for vaccine production. Finally, by capturing the enzymatic deglycosylation of Env in a time-resolved manner, we found that highly connected glycan clusters are resistant to digestion and help stabilize the prefusion trimer, suggesting the glycan shield may function beyond immune evasion.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Spatial and temporal coevolution of N2 neuraminidase and H1 and H3 hemagglutinin genes of influenza A virus in US swine

Abstract The neuraminidase (NA) and hemagglutinin (HA) are essential surface glycoproteins of influenza A virus (IAV). In this study, the evolution of subtype N2 NA paired with H1 and H3 subtype HA in swine was evaluated to understand if the genetic diversity of HA and NA were linked. Using time-scaled Bayesian phylodynamic analyses, the relationships of paired swine N2 with H1 or H3 from 2009 to 2018 were evaluated. These data demonstrated increased relative genetic diversity within the major N2 clades circulating in swine in the USA (N2.1998 between 2014 and 2017 and N2.2002 between 2010 and 2016). Preferential pairing was observed among specific NA and HA genetic clades. Gene reassortment between cocirculating influenza A strains resulted in novel pairings that persisted. The changes in genetic diversity in the NA gene were quantified using Bayesian phylodynamic analyses, and increases in diversity were observed subsequent to novel NA–HA reassortment events. The rate of evolution among NA–N2 clades and HA–H1 and HA–H3 clades were similar. Bayesian phylodynamic analyses demonstrated strong spatial patterns in N2 genetic diversity, but frequent interstate movement of rare N2 clades provided opportunity for reassortment and emergence of new N2–HA pairings. The frequent regional movement of pigs and their influenza viruses is an explanation for the documented patterns of reassortment and subsequent changes in gene diversity. The reassortment and evolution of NA and linked HA evolution may result in antigenic drift of both major surface glycoproteins, reducing vaccine efficacy, with subsequent impact on animal health.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

A Prevalent Focused Human Antibody Response to the Influenza Virus Hemagglutinin Head Interface

Novel animal influenza viruses emerge, initiate pandemics, and become endemic seasonal variants that have evolved to escape from prevalent herd immunity. These processes often outpace vaccine-elicited protection. Focusing immune responses on conserved epitopes may impart durable immunity. We describe a focused, protective antibody response, abundant in memory and serum repertoires, to a conserved region at the influenza virus hemagglutinin (HA) head interface. Structures of 11 examples, 8 reported here, from seven human donors demonstrate the convergence of responses on a single epitope. The 11 are genetically diverse, with one class having a common, IGκV1-39, light chain. All of the antibodies bind HAs from multiple serotypes. The lack of apparent genetic restriction and potential for elicitation by more than one serotype may explain their abundance. We define the head interface as a major target of broadly protective antibodies with the potential to influence the outcomes of influenza virus infection.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Genetic and Antigenic Characterization of an Expanding H3 Influenza A Virus Clade in U.S. Swine Visualized by Nextstrain

Defining factors that influence spatial and temporal patterns of influenza A virus (IAV) is essential to inform vaccine strain selection and strategies to reduce the spread of potentially zoonotic swine-origin IAV. The relative frequency of detection of the H3 phylogenetic clade 1990.4.a (colloquially known as C-IVA) in U.S. swine declined to 7% in 2017 but increased to 32% in 2019. We conducted phylogenetic and phenotypic analyses to determine putative mechanisms associated with increased detection. We created an implementation of Nextstrain to visualize the emergence, spatial spread, and genetic evolution of H3 IAV in swine, identifying two C-IVA clades that emerged in 2017 and cocirculated in multiple U.S. states. Phylodynamic analysis of the hemagglutinin (HA) gene documented low relative genetic diversity from 2017 to 2019, suggesting clonal expansion. The major H3 C-IVA clade contained an N156H amino acid substitution, but hemagglutination inhibition (HI) assays demonstrated no significant antigenic drift. The minor HA clade was paired with the neuraminidase (NA) clade N2-2002B prior to 2016 but acquired and maintained an N2-2002A in 2016, resulting in a loss of antigenic cross-reactivity between N2-2002B- and -2002A-containing H3N2 strains. The major C-IVA clade viruses acquired a nucleoprotein (NP) of the H1N1pdm09 lineage through reassortment in the replacement of the North American swine-lineage NP. Instead of genetic or antigenic diversity within the C-IVA HA, our data suggest that population immunity to H3 2010.1 along with the antigenic diversity of the NA and the acquisition of the H1N1pdm09 NP gene likely explain the reemergence and transmission of C-IVA H3N2 in swine.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Higher education responses to COVID-19 in the United States: Evidence for the impacts of university policy

With a dataset of testing and case counts from over 1,400 institutions of higher education (IHEs) in the United States, we analyze the number of infections and deaths from SARS-CoV-2 in the counties surrounding these IHEs during the Fall 2020 semester (August to December, 2020). We find that counties with IHEs that remained primarily online experienced fewer cases and deaths during the Fall 2020 semester; whereas before and after the semester, these two groups had almost identical COVID-19 incidence. Additionally, we see fewer cases and deaths in counties with IHEs that reported conducting any on-campus testing compared to those that reported none. To perform these two comparisons, we used a matching procedure designed to create well-balanced groups of counties that are aligned as much as possible along age, race, income, population, and urban/rural categories—demographic variables that have been shown to be correlated with COVID-19 outcomes. We conclude with a case study of IHEs in Massachusetts—a state with especially high detail in our dataset—which further highlights the importance of IHE-affiliated testing for the broader community. The results in this work suggest that campus testing can itself be thought of as a mitigation policy and that allocating additional resources to IHEs to support efforts to regularly test students and staff would be beneficial to mitigating the spread of COVID-19 in a pre-vaccine environment.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Non-Thermal Plasma as a Novel Strategy for Treating or Preventing Viral Infection and Associated Disease

Pathogenic viruses cause many human, animal, and plant diseases that are associated with substantial morbidity, mortality and socio-economic impact. Although effective strategies for combatting virus transmission and associated disease are available, global outbreaks of viral pathogens such as the virus responsible for the COVID-19 pandemic demonstrate that there is still a critical need for new approaches that can be used to interrupt the chain of viral infection and mitigate virus-associated pathogenesis. Recent studies point to non-thermal plasma (NTP), a partly ionized gas comprised of a complex mixture of reactive oxygen and nitrogen species along with physical effectors, as the potential foundation for new antiviral approaches. A more thorough understanding of the antiviral properties and safety of NTP has stimulated explorations of NTP as the basis for treatments of viral diseases. The recently described immunomodulatory properties of NTP are also being evaluated for potential use in immunotherapies of viral diseases as well as in antiviral vaccination strategies. In this review, we present the current state-of-the-art in addition to compelling arguments that NTP merits further exploration for use in the prevention and management of viral infections and associated diseases.

60 APPLIED LIFE SCIENCES↗