Engineering Papers⌕ Search

SEARCH · Engineering Papers

Results for “Efficacy”

Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 235 records · Page 13
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Enhancing risk and crisis communication with computational methods: A systematic literature review

Abstract Recent developments in risk and crisis communication (RCC) research combine social science theory and data science tools to construct effective risk messages efficiently. However, current systematic literature reviews (SLRs) on RCC primarily focus on computationally assessing message efficacy as opposed to message efficiency. We conduct an SLR to highlight any current computational methods that improve message construction efficacy and efficiency. We found that most RCC research focuses on using theoretical frameworks and computational methods to analyze or classify message elements that improve efficacy. For improving message efficiency, computational and manual methods are only used in message classification. Specifying the computational methods used in message construction is sparse. We recommend that future RCC research apply computational methods toward improving efficacy and efficiency in message construction. By improving message construction efficacy and efficiency, RCC messaging would quickly warn and better inform affected communities impacted by current hazards. Such messaging has the potential to save as many lives as possible.

Mathematical Methods In Social Sciences↗
DOE OSTI2021

Predicted success of prophylactic antiviral therapy to block or delay SARS-CoV-2 infection depends on the drug's mechanism of action

Repurposed drugs that are safe and immediately available constitute a first line of defense against new viral infections. Despite limited antiviral activity against SARS-CoV-2, several drugs are being tested as medication or as prophylaxis to prevent infection. Using a stochastic model of early phase infection, we evaluate the success of prophylactic treatment with different drug types to prevent viral infection. We find that there exists a critical efficacy that a treatment must reach in order to block viral establishment. Treatment by a combination of drugs reduces the critical efficacy, most effectively by the combination of a drug blocking viral entry into cells and a drug increasing viral clearance. Below the critical efficacy, the risk of infection can nonetheless be reduced. Drugs blocking viral entry into cells or enhancing viral clearance reduce the risk of infection more than drugs that reduce viral production in infected cells. The larger the initial inoculum of infectious virus, the less likely is prevention of an infection. In our model, we find that as long as the viral inoculum is smaller than 10 infectious virus particles, viral infection can be prevented almost certainly with drugs of 90% efficacy (or more). Even when a viral infection cannot be prevented, antivirals delay the time to detectable viral loads. The largest delay of viral infection is achieved by drugs reducing viral production in infected cells. A delay of virus infection flattens the within-host viral dynamic curve, possibly reducing transmission and symptom severity. Thus, antiviral prophylaxis, even with reduced efficacy, could be efficiently used to prevent or alleviate infection in people at high risk.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Partitioning of Seven Different Classes of Antibiotics into LPS Monolayers Supports Three Different Permeation Mechanisms through the Outer Bacterial Membrane

The outer membrane (OM) of Gram-negative (G-) bacteria presents a barrier for x classes of antibacterial agents. Lipopolysaccharide (LPS), present in the outer leaflet of the OM, is stabilized by divalent cations and is considered to be the major impediment for antibacterial agent permeation. However, the actual affinities of major antibiotic classes toward LPS have not yet been determined. In the present work, we use Langmuir monolayers formed from E. coli Re and Rd types of LPS to record pressure-area isotherms in the presence of antimicrobial agents. Our observations suggest three general types of interactions. Firstly, some antimicrobials demonstrated no measurable interactions with LPS. This lack of interaction in the case of cefsulodin, a third-generation cephalosporin antibiotic, correlates with its low efficacy against G- bacteria. Ampicillin and ciprofloxacin also show no interactions with LPS, but in contrast to cefsulodin, both exhibit good efficacy against G- bacteria, indicating permeation through common porins. Secondly, we observe substantial intercalation of the more hydrophobic antibiotics novobiocin, rifampicin, azithromycin, and telithromycin into relaxed LPS monolayers. These largely re-partition back to the subphase with monolayer compression. We find that the hydrophobic area, charge, and dipole all show correlations with both the mole fraction of antibiotic retained in the monolayer at the monolayer-bilayer equivalence pressure and the efficacies of these antibiotics against G- bacteria. Thirdly, amine-rich gentamicin and the cationic antimicrobial peptides polymyxin B and colistin show no hydrophobic insertion but are instead strongly driven into the polar LPS layer by electrostatic interactions in a pressure-independent manner. Their intercalation stably increases the area per molecule (by up to 20%), which indicates massive formation of defects in the LPS layer. These defects support a self-promoted permeation mechanism of these antibiotics through the OM, which explains the high efficacy and specificity of these antimicrobials against G- bacteria.

lateral pressure↗
DOE OSTI2023

A Medium-/Low-Voltage Joint State Estimator Through Linear Uncertainty Propagation

Traditionally, distribution system state estimations (DSSE) are challenged by the lack of measurements at both primary and secondary sides of the system. The widely available cable television (CATV) voltage sensors installed in low-voltage (LV) networks bring opportunities to achieve higher quality DSSE covering a broader area of the distribution network. This study proposes a medium-/low-voltage (MV/LV) joint distribution system state estimation approach using the untapped CATV measurements. It aims at addressing the need for system situational awareness at the grid edge while improving the estimation accuracy at both the primary and secondary sides compared to its disjointed counterpart. Linearized measurement functions and boundary condition uncertainty propagation rules are derived to ensure the computational efficiency and accuracy of the joint state estimator. Numerical experiments are conducted on an IEEE test feeder to demonstrate the efficacy of the proposed method and the value of CATV measurements.

joint state estimation↗
DOE OSTI2023

Optimizing invader suppression to restore native species: Leveraging species traits to overcome collateral damage

Strategies to control ongoing biological invasions are often developed by modelling the invasive species' population and aiming to reduce its abundance. However, if the ultimate objective is to protect and restore native species, focussing solely on the invader may not be optimal because it does not account for (i) species interactions that can cause the invader's impacts to depend nonlinearly on its abundance, (ii) collateral damages to native species incurred due to nonspecific removal methods or (iii) native-invader trait differences. Here, to identify an invader suppression strategy that maximizes average native population size, we applied optimal control theory to a two-species model of a native species threatened by an invasive competitor. We examined trade-offs between iterative physical removals that selectively target invaders and intensifiable chemical control that is nonselective but has higher efficacy. We found that while iterative removals were capable of supporting large native populations when applied continuously, cost could be prohibitively high. In contrast, when favourable native-invader trait differences enabled native species to re-establish more quickly than invaders, intensifiable methods could achieve substantial restoration benefits at lower cost by focussing removal effort into periodic, high-efficacy events. In a metapopulation, removals that rotated among spatial patches were optimal when the native species had higher dispersal, whereas synchronous removals were preferred when native recovery was initiated locally and the invader could disperse. For a case study in Hawaiian streams, we compared how effective two alternative methods of removing invasive live-bearing fishes (poeciliids) might be at restoring the endemic freshwater goby Sicyopterus stimpsoni. We found that rotenone (a piscicidal chemical) offered superior benefits when the control budget was small and efficacy was high, but that electrofishing (use of electricity to manually collect target fish) was better with larger budgets and in many lower-efficacy scenarios. Synthesis and applications. Our findings demonstrate that, by accounting for species interactions and collateral damage, invasive species control strategies can be optimized in light of species traits. Choices about the timing, locations and types of removal events present opportunities to increase the efficiency with which invasive species suppression benefits native species.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

CpG ODN D35 improves the response to abbreviated low-dose pentavalent antimonial treatment in non-human primate model of cutaneous leishmaniasis

Cutaneous leishmaniasis (CL) affects the lives of 0.7–1 million people every year causing lesions that take months to heal. These lesions can result in disfiguring scars with psychological, social and economic consequences. Antimonials are the first line of therapy for CL, however the treatment is lengthy and linked to significant toxicities; further, its efficacy is variable and resistant parasites are emerging. Shorter or lower dose antimonial treatment regimens, which would decrease the risk of adverse events and improve patient compliance, have shown reduced efficacy and further increase the risk emergence of antimonial-resistant strains. The progression of lesions in CL is partly determined by the immune response it elicits, and previous studies showed that administration of immunomodulatory type D CpG ODNs, magnifies the immune response to Leishmania and reduces lesion severity in nonhuman primates (NHP) challenged with Leishmania major or Leishmania amazonensis. Here we explored whether the addition of a single dose of immunomodulating CpG ODN D35 augments the efficacy of a short-course, low-dose pentavalent antimonial treatment regimen. Results show that macaques treated with D35 plus 5mg/kg sodium stibogluconate (SbV ) for 10 days had smaller lesions and reduced time to re-epithelization after infection with Leishmania major. No toxicities were evident during the studies, even at doses of D35 10 times higher than those used in treatment. Critically, pentavalent antimonial treatment did not modify the ability of D35 to induce type I IFNs. The findings support the efficacy of D35 as adjuvant therapy for shorter, low dose pentavalent antimonial treatment.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Nanobody screening and machine learning guided identification of cross-variant anti-SARS-CoV-2 neutralizing heavy-chain only antibodies

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to persist, demonstrating the risks posed by emerging infectious diseases to national security, public health, and the economy. Development of new vaccines and antibodies for emerging viral threats requires substantial resources and time, and traditional development platforms for vaccines and antibodies are often too slow to combat continuously evolving immunological escape variants, reducing their efficacy over time. Previously, we designed a next-generation synthetic humanized nanobody (Nb) phage display library and demonstrated that this library could be used to rapidly identify highly specific and potent neutralizing heavy chain-only antibodies (HCAbs) with prophylactic and therapeutic efficacy in vivo against the original SARS-CoV-2. In this study, we used a combination of high throughput screening and machine learning (ML) models to identify HCAbs with potent efficacy against SARS-CoV-2 viral variants of interest (VOIs) and concern (VOCs). To start, we screened our highly diverse Nb phage display library against several pre-Omicron VOI and VOC receptor binding domains (RBDs) to identify panels of cross-reactive HCAbs. Using HCAb affinity for SARS-CoV-2 VOI and VOCs (pre-Omicron variants) and model features from other published data, we were able to develop a ML model that successfully identified HCAbs with efficacy against Omicron variants, independent of our experimental biopanning workflow. This biopanning informed ML approach reduced the experimental screening burden by 78% to 90% for the Omicron BA.5 and Omicron BA.1 variants, respectively. The combined approach can be applied to other emerging viruses with pandemic potential to rapidly identify effective therapeutic antibodies against emerging variants.

Antibodies↗
DOE OSTI2021

Codelivery of Paclitaxel and Parthenolide in Discoidal Bicelles for a Synergistic Anticancer Effect: Structure Matters

Nanotechnology has long been used to improve the tumor targeting of chemotherapeutics. The structure of these nanocarriers greatly affects their efficacy and toxicity. Herein, structurally stable nanodiscoidal phospholipid bicelles, which are capable of encapsulating anticancer drugs, paclitaxel (PTX) and parthenolide (PTL), are designed. This nanodiscoidal bicelle structure is shown previously to exhibit longer blood circulation, deeper tumor penetration, and increased tumor cell uptake compared with spherical particles of similar compositions. Structural characterization and loading capacity of the PTX‐ and PTL‐ loaded nanodiscs are conducted along with an investigation into the cytotoxicity of the bicelles based on the drug‐to‐lipid ratios of both drugs loaded separately and in combination. A significant synergistic effect between both loaded drugs is also observed in A549 lung cancer and drug‐resistant MDA‐MB‐231 cell lines. An in vivo study using mice bearing subcutaneous A549 tumors shows a long circulation time of the intravenously injected DiR‐loaded bicelles and significant antitumor efficacy of the PTX‐ and PTL‐loaded bicelles. This efficacious self‐assembled nanoparticle system displays great potential as a nanoplatform to codeliver multiple therapeutics or diagnostics for improving cancer therapy.

Rad, Armin Tahmasbi↗
DOE OSTI2023

Next-generation poly-L-histidine formulations for miRNA mimic delivery

Many diseases, especially cancer, are caused by the abnormal expression of non-coding microRNAs (miRNAs), which regulate gene expression, leading to the development of miRNA-based therapeutics. Synthetic miRNA inhibitors have shown promising efficacy in blocking the activity of aberrant miRNAs that are upregulated in disease-specific pathologies. On the other hand, miRNAs that aid in preventing certain diseases and are reduced in expression in the disease state need different strategies. To tackle this, miRNA mimics, which mimic the activity of endogenous miRNAs, can be delivered for those miRNAs downregulated in different disease states. However, the delivery of miRNA mimics remains a challenge. Here, we report a cationic polylactic-co-glycolic acid (PLGA)-poly-L-histidine delivery system to deliver miRNA mimics. We chose miR-34a mimics as a proof of concept for miRNA delivery. miR-34a-loaded PLGA-poly-L-histidine nanoparticles (NPs) were formulated and biophysically characterized to analyze the structural properties of miRNA mimic-loaded NPs. In vitro efficacy was determined by investigating miR-34a and downstream target levels and performing cell viability and apoptosis assays. We confirmed in vivo efficacy through prolonged survival of miR-34a NP-treated A549-derived xenograft mice treated intratumorally. The results of these studies establish PLGA-poly-L-histidine NPs as an effective delivery system for miRNA mimics for treating diseases characterized by downregulated miRNAs.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Computationally restoring the potency of a clinical antibody against Omicron

The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs and revealed how quickly viral escape can curtail effective options. When the SARS-CoV-2 Omicron variant emerged in 2021, many antibody drug products lost potency, including Evusheld and its constituent, cilgavimab. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign and renew the efficacy of COV2-2130 against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and subsequent variants of concern, and provides protection in vivo against the strains tested: WA1/2020, BA.1.1 and BA.5. Deep mutational scanning of tens of thousands of pseudovirus variants reveals that 2130-1-0114-112 improves broad potency without increasing escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Our computational approach does not require experimental iterations or pre-existing binding data, thus enabling rapid response strategies to address escape variants or lessen escape vulnerabilities.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Paclitaxel loading in cationic liposome vectors is enhanced by replacement of oleoyl with linoleoyl tails with distinct lipid shapes

Abstract Lipid carriers of hydrophobic paclitaxel (PTX) are used in clinical trials for cancer chemotherapy. Improving their loading capacity requires enhanced PTX solubilization. We compared the time-dependence of PTX membrane solubility as a function of PTX content in cationic liposomes (CLs) with lipid tails containing one (oleoyl; DOPC/DOTAP) or two (linoleoyl; DLinPC/newly synthesized DLinTAP) cis double bonds by using microscopy to generate kinetic phase diagrams. The DLin lipids displayed significantly increased PTX membrane solubility over DO lipids. Remarkably, 8 mol% PTX in DLinTAP/DLinPC CLs remained soluble for approximately as long as 3 mol% PTX (the solubility limit, which has been the focus of most previous studies and clinical trials) in DOTAP/DOPC CLs. The increase in solubility is likely caused by enhanced molecular affinity between lipid tails and PTX, rather than by the transition in membrane structure from bilayers to inverse cylindrical micelles observed with small-angle X-ray scattering. Importantly, the efficacy of PTX-loaded CLs against prostate cancer cells (their IC50 of PTX cytotoxicity) was unaffected by changing the lipid tails, and toxicity of the CL carrier was negligible. Moreover, efficacy was approximately doubled against melanoma cells for PTX-loaded DLinTAP/DLinPC over DOTAP/DOPC CLs. Our findings demonstrate the potential of chemical modifications of the lipid tails to increase the PTX membrane loading while maintaining (and in some cases even increasing) the efficacy of CLs. The increased PTX solubility will aid the development of liposomal PTX carriers that require significantly less lipid to deliver a given amount of PTX, reducing side effects and costs.

36 MATERIALS SCIENCE↗
DOE OSTI2025

Artemether-Lumefantrine Treatment Selects Plasmodium falciparum Multidrug Resistance 1 ( pfmdr1 ) Increased Copy Number Among African Malaria Infections

Abstract Background Decreased efficacy of artemether-lumefantrine, the globally most used antimalarial, has recently emerged in Africa. Methods An efficacy trial was carried out based on directly observed artemether-lumefantrine therapy at Bengo, Northern Angola. One-hundred Plasmodium falciparum uncomplicated malaria patients (2–10 years old) were enrolled, hospitalized for the treatment period, and followed up for 42 days. Polymerase chain reaction (PCR) correction was performed with pfmsp1/2 plus glurp, with analysis considering 2 or 3 coincident markers. Infections were tested by quantitative PCR (qPCR) for pfmdr1 copy number (pfmdr1×N), a potential P. falciparum marker of lumefantrine resistance previously identified in the region. In vitro clone mixtures were built and used to determine the relation between qPCR copy number scores and actual intrainfection quantitative fractions of pfmdr1×N. Results We observed a significant posttreatment selection of gene amplification, suggesting a role in the parasite in vivo response to this drug. pfmdr1×2 qPCR scores of 1.3, 1.4, and 1.5 were determined to correspond to 15%, 25%, and 35% intrainfection rates. Patients carrying infections with a score ≥1.4 at baseline were linked to decreased artemether-lumefantrine day 42 efficacy (79% vs 97% single-copy pfmdr1). All infections were pfmdr1 N86 carriers and no pfk13 mutations were found. Conclusions Our study suggests pfmdr1×N as a marker of P. falciparum in vivo response to lumefantrine in Africa, while indicating patients carrying infections with a pretreatment pfmdr1×N score ≥1.4 before treatment are a group experiencing decreased artemether-lumefantrine performance.

Fançony, Claudia (ORCID:0000000344211769)↗
DOE OSTI2025

Identifying a next-generation antimalarial trioxolane in a landscape of artemisinin partial resistance

For over two decades, artemisinin-based combination therapy (ACT) has been the standard of care for the treatment of uncomplicated falciparum malaria. However, artemisinin partial resistance (ART-R) is now prevalent in Southeast Asia and has emerged in eastern Africa, threatening ACT efficacy. Artefenomel, a synthetic 1,2,4-trioxolane, exhibits an extended pharmacokinetic exposure profile that predicts for efficacy against ART-R parasites. Unfortunately, the development of artefenomel was halted recently after almost a decade in the clinic. Here, we describe studies of an artefenomel-adjacent chemotype that combines potent in vitro activity against clinical ART-R parasites, an extended pharmacokinetic profile with single-exposure efficacy in a murine malaria model, and enhanced stability in human microsomes and hepatocytes. Overall, our studies reveal a heretofore underexplored trioxolane chemotype with the potential to address ART-R in a next-generation trioxolane development candidate.

Science & Technology - Other Topics↗
DOE OSTI2022

Defective Interfering Viral Particle Treatment Reduces Clinical Signs and Protects Hamsters from Lethal Nipah Virus Disease

Defective interfering particles (DIs) contain a considerably smaller genome than the parental virus but retain replication competency. As DIs can directly or indirectly alter propagation kinetics of the parental virus, they offer a novel approach to antiviral therapy, capitalizing on knowledge from natural infection. However, efforts to translate in vitro inhibition to in vivo screening models remain limited. We investigated the efficacy of virus-like particles containing DI genomes (therapeutic infectious particles [TIPs]) in the Syrian hamster model of lethal Nipah virus (NiV) disease. We found that coadministering a high dose of TIPs intraperitoneally with virus challenge improved clinical course and reduced lethality. To mimic natural exposure, we also evaluated lower-dose TIP delivery and virus challenge intranasally, finding equally efficacious reduction in disease severity and overall lethality. Eliminating TIP replicative capacity decreased efficacy, suggesting protection via direct inhibition. These data provide evidence that TIP-mediated treatment can confer protection against disease and lethal outcome in a robust animal NiV model, supporting further development of TIP treatment for NiV and other high-consequence pathogens.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Novel Anti-LY6G6D/CD3 T-Cell–Dependent Bispecific Antibody for the Treatment of Colorectal Cancer

Abstract New therapeutics and combination regimens have led to marked clinical improvements for the treatment of a subset of colorectal cancer. Immune checkpoint inhibitors have shown clinical efficacy in patients with mismatch-repair–deficient or microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC). However, patients with microsatellite-stable (MSS) or low levels of microsatellite instable (MSI-L) colorectal cancer have not benefited from these immune modulators, and the survival outcome remains poor for the majority of patients diagnosed with mCRC. In this article, we describe the discovery of a novel T-cell–dependent bispecific antibody (TDB) targeting tumor-associated antigen LY6G6D, LY6G6D-TDB, for the treatment of colorectal cancer. RNAseq analysis showed that LY6G6D was differentially expressed in colorectal cancer with high prevalence in MSS and MSI-L subsets, whereas LY6G6D expression in normal tissues was limited. IHC confirmed the elevated expression of LY6G6D in primary and metastatic colorectal tumors, whereas minimal or no expression was observed in most normal tissue samples. The optimized LY6G6D-TDB, which targets a membrane-proximal epitope of LY6G6D and binds to CD3 with high affinity, exhibits potent antitumor activity both in vitro and in vivo. In vitro functional assays show that LY6G6D-TDB–mediated T-cell activation and cytotoxicity are conditional and target dependent. In mouse xenograft tumor models, LY6G6D-TDB demonstrates antitumor efficacy as a single agent against established colorectal tumors, and enhanced efficacy can be achieved when LY6G6D-TDB is combined with PD-1 blockade. Our studies provide evidence for the therapeutic potential of LY6G6D-TDB as an effective treatment option for patients with colorectal cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Improved Radiative Recombination in AlInGaP LEDs

Direct-emitting red and amber LEDs based on the AlInGaP material system offer a higher efficacy potential than phosphor-converted (pc) red and amber LEDs due to the absence of Stokes losses. Direct red LEDs (~610-620nm) are increasingly used in color-mixed and color-tunable illumination applications, where they have a significant advantage over pc-red LEDs, with high power conversion efficiency (PCE) and narrower emission enabling higher luminous efficacy of radiation (LER). Still, adoption is limited as the complexities associated with mixing different emitters offset the value of the efficacy gain. Adoption of direct amber LEDs (~580-595nm) in illumination applications is virtually non-existent due to their lower PCE and the availability of very efficient pc-amber emitters, which suffer less from Stokes loss and LER penalties associated with the broader bandwidth than pc-red. Further improvement in PCE of direct red and amber LEDs is needed to achieve wider adoption and ultimately enable more energy savings than possible with pc-LEDs. In this project, Lumileds has developed improved high-power amber and red LEDs incorporating tensile-strain barriers into the active region to improve carrier confinement and thereby increase external quantum efficiency (EQE). This approach is most beneficial for the short (amber) end of the AlInGaP wavelength range where carrier confinement is lowest. An EQE of 22% was achieved for amber LEDs, exceeding the project target of 20%

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗
DOE OSTI2025

Computationally Selected Multivalent HIV-1 Subtype C Vaccine Protects Against Heterologous SHIV Challenge

Background: The RV144 trial in Thailand is the only HIV-1 vaccine efficacy trial to date to demonstrate any efficacy. Genetic signatures suggested that antibodies targeting the variable loop 2 (V2) of the HIV-1 envelope played an important protective role. The ALVAC prime and protein boost follow-up trial in southern Africa (HVTN702) failed to show any efficacy. One hypothesis for this is the greater diversity of subtype C viruses in southern Africa relative to CRF01_AE in Thailand. Methods: Here, we determined whether an ALVAC prime with computationally selected gp120 boost immunogens maximizing coverage of diversity of subtype C viruses in the variable V1 and V2 regions (V1V2) improved the protection of non-human primates (NHPs) from a heterologous subtype C SHIV challenge compared to more traditional regimens. Results: An ALVAC prime with Trivalent subtype C gp120 boosts resulted in statistically significant protection from repeated intrarectal SHIV challenges compared to the control. Evaluation of the immunogenicity of each vaccine regimen at the time of challenge demonstrated that different gp120 combination boosts elicited similar high magnitudes of gp120 and breadth of V1V2-binding antibodies, as well as strong Fc-mediated immune responses. Low-to-no neutralization of the challenge virus was detected. A Cox proportional hazard analysis of five pre-selected immune parameters at the time of challenge identified ADCC against the challenge envelope as a correlate of protection. Systems serology analysis revealed that immune responses elicited by the different vaccine regimens were distinct and identified further correlates of resistance to infection. Conclusions: Computationally designed vaccines with maximized subtype C V1V2 coverage mediated protection of NHPs from a heterologous Tier-2 subtype C SHIV challenge.

Immunology↗
DOE OSTI2021

Protection against Different Genotypes of Newcastle Disease Viruses (NDV) Afforded by an Adenovirus-Vectored Fusion Protein and Live NDV Vaccines in Chickens

The efficacy of an adenovirus-vectored Newcastle disease virus (NDV) vaccine expressing the fusion (F) NDV protein (adeno-F) was evaluated against challenges with virulent heterologous and homologous NDV strains to the F protein. In a preliminary study, two different doses (low and high) of adeno-F were tested against a virulent NDV strain containing the homologous NDV F protein, CA02. In a second study, at three weeks post-vaccination, the efficacy of the high dose of adeno-F was compared to a live attenuated NDV vaccine strain (LaSota) against three antigenically distinct virulent NDV challenge strains, one homologous (CA02) and two heterologous (TZ12, EG14) to F in the vectored vaccine. In both experiments, clinical signs, mortality, virus shedding, and humoral response were evaluated. In the first experiment, the survival rates from birds vaccinated with adeno-F at a high and low dose were 100% and 25%, respectively. In the second experiment, birds vaccinated with the high dose of adeno-F had a survival rate of 80%, 75%, and 65% after challenge with the CA02, TZ12, and EG14 viruses, respectively. All of the LaSota-vaccinated birds survived post-challenge no matter the NDV challenge strain. High antibody titers were detected after vaccination with LaSota by HI and ELISA tests. The majority of adeno-F-vaccinated birds had detectable antibodies using the ELISA test, but not using the HI test, before the challenge. The data show that both the similarity of the F protein of the adeno-F vaccine to the challenge virus and the adeno-F vaccination dose affect the efficacy of an adenovirus-vectored NDV vaccine against a virulent NDV challenge.

Ferreira, Helena L. (ORCID:0000000232613712)↗