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At least 271 records · Page 15
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Designed, highly expressing, thermostable dengue virus 2 envelope protein dimers elicit quaternary epitope antibodies

Dengue virus (DENV) is a worldwide health burden, and a safe vaccine is needed. Neutralizing antibodies bind to quaternary epitopes on DENV envelope (E) protein homodimers. However, recombinantly expressed soluble E proteins are monomers under vaccination conditions and do not present these quaternary epitopes, partly explaining their limited success as vaccine antigens. Using molecular modeling, we found DENV2 E protein mutations that induce dimerization at low concentrations (<100 pM) and enhance production yield by more than 50-fold. Cross-dimer epitope antibodies bind to the stabilized dimers, and a crystal structure resembles the wild-type (WT) E protein bound to a dimer epitope antibody. Mice immunized with the stabilized dimers developed antibodies that bind to E dimers and not monomers and elicited higher levels of DENV2-neutralizing antibodies compared to mice immunized with WT E antigen. Our findings demonstrate the feasibility of using structure-based design to produce subunit vaccines for dengue and other flaviviruses.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Enhancing the solubility of SARS-CoV-2 inhibitors to increase future prospects for clinical development

SARS-CoV-2 poses an ongoing threat to human health as variants continue to emerge. Several effective vaccines are available, but a diminishing number of Americans receive the updated vaccines (only 22% received the 2023 update). Public hesitancy towards vaccines and common occurrence of “breakthrough” infections (i.e., infections of vaccinated individuals) highlight the need for alternative methods to reduce viral transmission. SARS-CoV-2 enters cells by fusing its envelope with the target cell membrane in a process mediated by the viral spike protein, S. The S protein operates via a Class I fusion mechanism in which fusion between the viral envelope and host cell membrane is mediated by structural rearrangements of the S trimer. We previously reported lipopeptides derived from the C-terminal heptad repeat (HRC) domain of SARS-CoV-2 S that potently inhibit fusion by SARS-CoV-2, both in vitro and in vivo. These lipopeptides bear an attached cholesterol unit to anchor them in the membrane. Here, to improve prospects for experimental development and future clinical utility, we employed structure-guided design to incorporate charged residues at specific sites in the peptide to enhance aqueous solubility. This effort resulted in two new, potent lipopeptide inhibitors.

36 MATERIALS SCIENCE↗
DOE OSTI2022

Comprehensive compartmental model and calibration algorithm for the study of clinical implications of the population-level spread of COVID-19: a study protocol

The complex dynamics of the coronavirus disease 2019 (COVID-19) pandemic has made obtaining reliable long-term forecasts of the disease progression difficult. Simple mechanistic models with deterministic parameters are useful for short-term predictions but have ultimately been unsuccessful in extrapolating the trajectory of the pandemic because of unmodelled dynamics and the unrealistic level of certainty that is assumed in the predictions. We propose a 22-compartment epidemiological model that includes compartments not previously considered concurrently, to account for the effects of vaccination, asymptomatic individuals, inadequate access to hospital care, post-acute COVID-19 and recovery with long-term health complications. Additionally, new connections between compartments introduce new dynamics to the system and provide a framework to study the sensitivity of model outputs to several concurrent effects, including temporary immunity, vaccination rate and vaccine effectiveness. Subject to data availability for a given region, we discuss a means by which population demographics (age, comorbidity, socioeconomic status, sex and geographical location) and clinically relevant information (different variants, different vaccines) can be incorporated within the 22-compartment framework. Considering a probabilistic interpretation of the parameters allows the model's predictions to reflect the current state of uncertainty about the model parameters and model states. We propose the use of a sparse Bayesian learning algorithm for parameter calibration and model selection. This methodology considers a combination of prescribed parameter prior distributions for parameters that are known to be essential to the modelled dynamics and automatic relevance determination priors for parameters whose relevance is questionable. This is useful as it helps prevent overfitting the available epidemiological data when calibrating the parameters of the proposed model. Population-level administrative health data will serve as partial observations of the model states.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Trivalent mosaic or consensus HIV immunogens prime humoral and broader cellular immune responses in adults

Mosaic and consensus HIV-1 immunogens provide two distinct approaches to elicit greater breadth of coverage against globally circulating HIV-1 and have shown improved immunologic breadth in nonhuman primate models. This double-blind randomized trial enrolled 105 healthy HIV-uninfected adults who received 3 doses of either a trivalent global mosaic, a group M consensus (CON-S), or a natural clade B (Nat-B) gp160 env DNA vaccine followed by 2 doses of a heterologous modified vaccinia Ankara–vectored HIV-1 vaccine or placebo. We performed prespecified blinded immunogenicity analyses at day 70 and day 238 after the first immunization. T cell responses to vaccine antigens and 5 heterologous Env variants were fully mapped. Env-specific CD4 + T cell responses were induced in 71% of the mosaic vaccine recipients versus 48% of the CON-S recipients and 48% of the natural Env recipients. The mean number of T cell epitopes recognized was 2.5 (95% CI, 1.2–4.2) for mosaic recipients, 1.6 (95% CI, 0.82–2.6) for CON-S recipients, and 1.1 (95% CI, 0.62–1.71) for Nat-B recipients. Mean breadth was significantly greater in the mosaic group than in the Nat-B group using overall (P = 0.014), prime-matched (P = 0.002), heterologous (P = 0.046), and boost-matched (P = 0.009) measures. Overall T cell breadth was largely due to Env-specific CD4 + T cell responses. Priming with a mosaic antigen significantly increased the number of epitopes recognized by Env-specific T cells and enabled more, albeit still limited, cross-recognition of heterologous variants. Mosaic and consensus immunogens are promising approaches to address global diversity of HIV-1.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

A single, improbable B cell receptor mutation confers potent neutralization against cytomegalovirus

Cytomegalovirus (CMV) is a leading cause of infant hearing loss and neurodevelopmental delay, but there are no clinically licensed vaccines to prevent infection, in part due to challenges eliciting neutralizing antibodies. One of the most well-studied targets for CMV vaccines is the viral fusogen glycoprotein B (gB), which is required for viral entry into host cells. Within gB, antigenic domain 2 site 1 (AD-2S1) is a target of potently neutralizing antibodies, but gB-based candidate vaccines have yet to elicit robust responses against this region. We mapped the genealogy of B cells encoding potently neutralizing anti-gB AD-2S1 antibodies from their inferred unmutated common ancestor (UCA) and characterized the binding and function of early lineage ancestors. Surprisingly, we found that a single amino acid heavy chain mutation A33N, which was an improbable mutation rarely generated by somatic hypermutation machinery, conferred broad CMV neutralization to the non-neutralizing UCA antibody. Structural studies revealed that this mutation mediated key contacts with the gB AD-2S1 epitope. Collectively, these results provide insight into potently neutralizing gB-directed antibody evolution in a single donor and lay a foundation for using this B cell-lineage directed approach for the design of next-generation CMV vaccines.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Assessment of a reconfiguration of the InterSpread Plus US national FMD model as a potential tool to analyze a foot-and-mouth disease outbreak on a single large cattle feedlot in the United States

An incursion of foot-and-mouth disease (FMD) into the United States remains a concern of high importance and would have devastating socioeconomic impacts to the livestock and associated industries. This highly transmissible and infectious disease poses continual risk for introduction into the United States (US), due to the legal and illegal global movement of people, animals, and animal products. While stamping out has been shown to effectively control FMD, depopulation of large cattle feedlots (>50,000 head) presents a number of challenges for responders due to the resources required to depopulate and dispose of large numbers of animals in a timely and effective manner. However, evaluating alternative strategies for FMD control on large feedlots requires a detailed within-farm modeling approach, which can account for the unique structure of these operations. To address this, we developed a single feedlot, within-farm spread model using a novel configuration within the InterSpread Plus (ISP) framework. As proof of concept we designed six scenarios: (i) depopulation - the complete depopulation of the feedlot, (ii) burn-through – a managed “burn-through” where the virus is allowed to spread through the feedlot and only movement restriction and biosecurity are implemented, (iii) firebreak-NV – targeted depopulation of infected pens and adjacent pens without vaccination; (iv) firebreak - targeted depopulation of infected pens and adjacent pens with vaccination of remaining pens; (v) harvest-NV - selective harvest of pens where a 100% movement restriction is applied for 28-30 days, then pens are set for selection to be sent to slaughter, while allowing a controlled “burn-through” without vaccination; and (vi) harvest - selective harvest of pens with vaccination. Overall, the burn-through scenario (ii) had the shortest epidemic duration (31d (30, 33)) median (25th, 75th percentiles), while the firebreak scenario (iv) had the longest (47d (38,55)). Additionally, we found that scenarios implementing depopulation delayed the peak day of infection and reduced the total number of pens infected compared to non-depopulation scenarios.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Complementary antibody lineages achieve neutralization breadth in an HIV-1 infected elite neutralizer

Broadly neutralizing antibodies (bNAbs) have remarkable breadth and potency against most HIV-1 subtypes and are able to prevent HIV-1 infection in animal models. However, bNAbs are extremely difficult to induce by vaccination. Defining the developmental pathways towards neutralization breadth can assist in the design of strategies to elicit protective bNAb responses by vaccination. Here, HIV-1 envelope glycoproteins (Env)-specific IgG + B cells were isolated at various time points post infection from an HIV-1 infected elite neutralizer to obtain monoclonal antibodies (mAbs). Multiple antibody lineages were isolated targeting distinct epitopes on Env, including the gp120-gp41 interface, CD4-binding site, silent face and V3 region. The mAbs each neutralized a diverse set of HIV-1 strains from different clades indicating that the patient’s remarkable serum breadth and potency might have been the result of a polyclonal mixture rather than a single bNAb lineage. High-resolution cryo-electron microscopy structures of the neutralizing mAbs (NAbs) in complex with an Env trimer generated from the same individual revealed that the NAbs used multiple strategies to neutralize the virus; blocking the receptor binding site, binding to HIV-1 Env N-linked glycans, and disassembly of the trimer. These results show that diverse NAbs can complement each other to achieve a broad and potent neutralizing serum response in HIV-1 infected individuals. Hence, the induction of combinations of moderately broad NAbs might be a viable vaccine strategy to protect against a wide range of circulating HIV-1 viruses.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Longitudinal SARS-CoV-2 seroprevalence in Portugal and antibody maintenance 12 months after infection

During the COVID-19 pandemic, Portugal has experienced three distinct SARS-CoV-2 infection waves. We previously documented the prevalence of SARS-CoV-2 immunity, measured by specific antibodies, in September 2020, 6 months after the initial moderate wave. Here, we show the seroprevalence changes 6 months later, up to the second week of March 2021, shortly following the third wave, which was one of the most severe in the world, and 2 months following the start of the vaccination campaign. A longitudinal epidemiological study was conducted, with a stratified quota sample of the Portuguese population. Serological testing was performed, including ELISA determination of antibody class and titers. The proportion of seropositives, which was 2.2% in September 2020, rose sharply to 17.3% (95% CI: 15.8–18.8%) in March 2021. Importantly, circulating IgG and IgA antibody levels were very stable 6 months after the initial determination and up to a year after initial infection, indicating long-lasting infection immunity against SARS-CoV-2. Moreover, vaccinated people had higher IgG levels from 3 weeks post-vaccination when compared with previously infected people at the same time post-infection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Neutralization escape by SARS-CoV-2 Omicron subvariant BA.2.86

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variant BA.2.86 has over 30 mutations in spike compared with BA.2 and XBB.1.5, which raised the possibility that BA.2.86 might evade neutralizing antibodies (NAbs) induced by vaccination or infection. In this study, we show that NAb titers are substantially lower to BA.2.86 compared with BA.2 but are similar or slightly higher than to other current circulating variants, including XBB.1.5, EG.5.1, and FL.1.5.1. Moreover, NAb titers against all these variants were higher in vaccinated individuals with a history of XBB.1.5 infection compared with vaccinated individuals with no history of XBB.1.5 infection, suggesting the potential utility of the monovalent XBB.1.5 mRNA boosters.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Structure-based design of prefusion-stabilized human metapneumovirus fusion proteins

The human metapneumovirus (hMPV) fusion (F) protein is essential for viral entry and is a key target of neutralizing antibodies and vaccine development. The prefusion conformation is thought to be the optimal vaccine antigen, but previously described prefusion F proteins expressed poorly and were not well stabilized. Here, we use structures of hMPV F to guide the design of 42 variants containing stabilizing substitutions. Through combinatorial addition of disulfide bonds, cavity-filling substitutions, and improved electrostatic interactions, we describe a prefusion-stabilized F protein (DS-CavEs2) that expresses at 15mg/L and has a melting temperature of 71.9°C. Crystal structures of two prefusion-stabilized hMPV F variants reveal that antigenic surfaces are largely unperturbed. Importantly, immunization of mice with DS-CavEs2 elicits significantly higher neutralizing antibody titers against hMPV A1 and B1 viruses than postfusion F. The improved properties of DS-CavEs2 will advance the development of hMPV vaccines and the isolation of therapeutic antibodies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Priming antibody responses to the fusion peptide in rhesus macaques

Immunodominance of antibodies targeting non-neutralizing epitopes and the high level of somatic hypermutation within germinal centers (GCs) required for most HIV broadly neutralizing antibodies (bnAbs) are major impediments to the development of an effective HIV vaccine. Rational protein vaccine design and non-conventional immunization strategies are potential avenues to overcome these hurdles. Here, we report using implantable osmotic pumps to continuously deliver a series of epitope-targeted immunogens to rhesus macaques over the course of six months to prime and elicit antibody responses against the conserved fusion peptide (FP). GC responses and antibody specificities were tracked longitudinally using lymph node fine-needle aspirates and electron microscopy polyclonal epitope mapping (EMPEM), respectively, to show antibody responses to the FP/N611 glycan hole region were primed, although exhibited limited neutralization breadth. Application of cryoEMPEM delineated key residues for on-target and off-target responses that can drive the next round of structure-based vaccine design.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

A New Pneumococcal Capsule Type, 10D, is the 100th Serotype and Has a Large cps Fragment from an Oral Streptococcus

Streptococcus pneumoniae (pneumococcus) is a major human pathogen producing structurally diverse capsular polysaccharides. Widespread use of highly successful pneumococcal conjugate vaccines (PCVs) targeting pneumococcal capsules has greatly reduced infections by the vaccine types but increased infections by nonvaccine serotypes. Herein, we report a new and the 100th capsule type, named serotype 10D, by determining its unique chemical structure and biosynthetic roles of all capsule synthesis locus (cps) genes. The name 10D reflects its serologic cross-reaction with serotype 10A and appearance of cross-opsonic antibodies in response to immunization with 10A polysaccharide in a 23-valent pneumococcal vaccine. Genetic analysis showed that 10D cps has three large regions syntenic to and highly homologous with cps loci from serotype 6C, serotype 39, and an oral streptococcus strain (S. mitis SK145). The 10D cps region syntenic to SK145 is about 6 kb and has a short gene fragment of wciNα at the 5' end. The presence of this nonfunctional wciNα fragment provides compelling evidence for a recent interspecies genetic transfer from oral streptococcus to pneumococcus. Since oral streptococci have a large repertoire of cps loci, widespread PCV usage could facilitate the appearance of novel serotypes through interspecies recombination.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates

The induction of broad and potent immunity by vaccines is the key focus of research efforts aimed at protecting against HIV-1 infection. Soluble native-like HIV-1 envelope glycoproteins have shown promise as vaccine candidates as they can induce potent autologous neutralizing responses in rabbits and non-human primates. In this study, monoclonal antibodies were isolated and characterized from rhesus macaques immunized with the BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies reveal a diverse landscape of antibodies recognizing immunodominant strain-specific epitopes and non-neutralizing neo-epitopes. Additionally, we isolated a subset of mAbs against an epitope cluster at the gp120-gp41 interface that recognize the highly conserved fusion peptide and the glycan at position 88 and have characteristics akin to several human-derived broadly neutralizing antibodies.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Endemic Seroprevalence and Farmer Control Measures of Anthrax Among Ruminate Animals in Pakistan

Anthrax, caused by Bacillus anthracis (B. anthracis), is an important zoonotic disease of livestock that poses a threat to public safety. The present study aimed to determine the seroprevalence of Bacillus anthracis in sheep and cattle in endemic areas (Punjab and Balochistan provinces) of Pakistan by enzyme-linked immunosorbent assay (ELISA). Crosssectional survey was also done to assess the control measures of the farmers. Out of 401 serum samples from sheep and cattle, a total of 68 (16.9%) samples were seropositive for anti-PA antibodies; seroprevalence of B. anthracis in sheep and cattle was 22.11% (48/217) and 10.86% (20/184), respectively. Seroprevalence was significantly higher (p<0.05) in Baluchistan province (33.3%, 44/132) compared to Punjab province (8.92%, 24/269). Most farmers (65.90%, 29/44) were not disposing carcasses as recommended. Around 77.28%, 17/22 of the veterinary officials reported the nonavailability of vaccine against anthrax and 63.63% (14/22) stated the lack of cold chain for the vaccine storage and transportation. We concluded that seroprevalence of B. anthracis in unvaccinated sheep and cattle is evidence that the pathogen is circulating in Baluchistan and Punjab provinces. So must applied an active surveillance and, strengthened veterinary practices vaccination programs to control anthrax outbreaks in endemic areas.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Impact of changes in protective behaviors and out-of-household activities by age on COVID-19 transmission and hospitalization in Chicago, Illinois

Even with an efficacious vaccine, protective behaviors (social distancing, masking) are essential for preventing COVID-19 transmission and could become even more important if current or future variants evade immunity from vaccines or prior infection. Here we created an agent-based model representing the Chicago population and conducted experiments to determine the effects of varying adult out-of-household activities (OOHA), school reopening, and protective behaviors across age groups on COVID-19 transmission and hospitalizations. From September-November 2020, decreasing adult protective behaviors and increasing adult OOHA both substantially impacted COVID-19 outcomes; school reopening had relatively little impact when adult protective behaviors and OOHA were maintained. As of November 1, 2020, a 50% reduction in young adult (age 18-40) protective behaviors resulted in increased latent infection prevalence per 100,000 from 15.93 (IQR 6.18, 36.23) to 40.06 (IQR 14.65, 85.21)and 19.87 (IQR 6.83, 46.83) to 47.74 (IQR 18.89, 118.77) with 15% and 45% school reopening. Increasing adult (age ≥18) OOHA from 65% to 80% of pre-pandemic levels resulted in increased latent infection prevalence per 100,000 from 35.18 (IQR 13.59, 75.00) to 69.84 (IQR 33.27, 145.89) and 38.17 (IQR 15.84, 91.16) to 80.02 (IQR 30.91, 186.63) with 15% and 45% school reopening. Similar patterns were observed for hospitalizations. In areas without widespread vaccination coverage, interventions to maintain adherence to protective behaviors, particularly among younger adults and in out-of-household settings, remain a priority for preventing COVID-19 transmission.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Elimination of human rabies in Goa, India through an integrated One Health approach

Dog-mediated rabies kills tens of thousands of people each year in India, representing one third of the estimated global rabies burden. Whilst the World Health Organization (WHO), World Organization for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO) have set a target for global dog-mediated human rabies elimination by 2030, examples of large-scale dog vaccination programs demonstrating elimination remain limited in Africa and Asia. We describe the development of a data-driven rabies elimination program from 2013 to 2019 in Goa State, India, culminating in human rabies elimination and a 92% reduction in monthly canine rabies cases. Smartphone technology enabled systematic spatial direction of remote teams to vaccinate over 95,000 dogs at 70% vaccination coverage, and rabies education teams to reach 150,000 children annually. An estimated 2249 disability-adjusted life years (DALYs) were averted over the program period at 526 USD per DALY, making the intervention ‘very cost-effective’ by WHO definitions. This One Health program demonstrates that human rabies elimination is achievable at the state level in India.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Assembly of respiratory syncytial virus matrix protein lattice and its coordination with fusion glycoprotein trimers

Respiratory syncytial virus (RSV) is an enveloped, filamentous, negative-strand RNA virus that causes significant respiratory illness worldwide. RSV vaccines are available, however there is still significant need for research to support the development of vaccines and therapeutics against RSV and related Mononegavirales viruses. Individual virions vary in size, with an average diameter of ~130 nm and ranging from ~500 nm to over 10 µm in length. Though the general arrangement of structural proteins in virions is known, we use cryo-electron tomography and sub-tomogram averaging to determine the molecular organization of RSV structural proteins. We show that the peripheral membrane-associated RSV matrix (M) protein is arranged in a packed helical-like lattice of M-dimers. We report that RSV F glycoprotein is frequently observed as pairs of trimers oriented in an anti-parallel conformation to support potential interactions between trimers. Our sub-tomogram averages indicate the positioning of F-trimer pairs is correlated with the underlying M lattice. These results provide insight into RSV virion organization and may aid in the development of RSV vaccines and anti-viral targets.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Structural basis for Zika envelope domain III recognition by a germline version of a recurrent neutralizing antibody

Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. However, vaccine design is complicated by concern that elicited antibodies (Abs) may cross-react with other flaviviruses that share a similar envelope protein, such as dengue virus, West Nile virus, and yellow fever virus. This cross-reactivity may worsen symptoms of a subsequent infection through Ab-dependent enhancement. To better understand the neutralizing Ab response and risk of Ab-dependent enhancement, further information on germline Ab binding to ZIKV and the maturation process that gives rise to potently neutralizing Abs is needed. In this work, we use binding and structural studies to compare mature and inferred-germline Ab binding to envelope protein domain III of ZIKV and other flaviviruses. We show that affinity maturation of the light-chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing Abs to ZIKV envelope protein domain III, and identify interacting residues that contribute to weak, cross-reactive binding to West Nile virus. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing Abs, informing precautions for protein-based vaccines designed to elicit germline versions of neutralizing Abs.

59 BASIC BIOLOGICAL SCIENCES↗