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1.
Neuromodulation ; 25(5):S43-S44, 2022.
Article in English | EMBASE | ID: covidwho-1937039

ABSTRACT

Introduction: A novel spinal cord stimulation (SCS) system with a battery-free micro-implantable pulse generator (mIPG;Nalu Medical, Inc. CA, USA) is available for the treatment of intractable chronic pain. The system utilizes an external power source that bi-directionally communicates with the mIPG (∼1.5 cc volume). Methods: A prospective, multi-center clinical study was initiated to confirm the safety and performance of this novel system, in the treatment of trunk and limb intractable chronic pain. Specifically, subjects with leg(s) and/or back pain, meeting eligibility criteria were recruited and consented into the study. Subjects underwent a SCS trial utilizing a menu of therapy options, including tonic and the novel pulsed stimulation pattern (PSP) therapy. Eligible subjects received the permanent implant and were followed-up for up to 12-months from activation. Due to global COVID-19 restrictions, subjects were moved into a long-term follow-up (LTFU) phase, with study visits planned every 6-months, for an additional 2-years from their last visit. This reports on the long-term clinical and functional (depression, activities of daily living, overall change in quality of life) outcomes. The study was approved by an independent Ethics Committee and conducted in compliance with local regulations. Results: Twenty-five (25) intractable chronic back and/or leg pain subjects, using the PSP therapy, passed a screening and trial phase with ≥50% pain reduction in leg(s) and/or back and moved into the long-term implant phase of the study. Of these 25 subjects, 13 subjects have currently completed an average of 22-months follow-up;the average pain reduction was 73% (n=12) in the leg and 64% (n=11) in the back, from baseline to this time point. The responder rate (≥50% pain relief) was 92% in the leg (11/12) and 64% (7/11) in the back. In addition, all subjects wore the external power source via an adhesive clip and rated both its average comfort and ease of use as <1 on an 11-point scale (0=Very Comfortable, 10=Very Uncomfortable;0=Very Easy, 10=Very Difficult). The average percent improvement on the Beck’s Depression Inventory (BDI) was 40% (n=13) from screening to 22-months;the average improvement in Oswestry Disability Index (ODI) was 34% (n=13) at this time point. Sixty-nine percent (69%;9/13) of subjects indicated “very much improved” on the Patient Global Impression of Change. Conclusion: These results continue to demonstrate the favorable performance of this novel, battery-free, externally-powered micro-implantable SCS through 22-months post implantation. Further investigation is warranted to confirm these preliminary findings. Disclosure: Paul Verrills, FAFMM GDMM (Hons) MM (Pain Medicine) FIPP AMA: Abbott: Consulting Fee: Self, Abbott: Speakers Bureau: Self, Nalu: Ownership Interest - Future Stock Options: Self, Nalu: Contracted Research: Self, Nevro: Contracted Research: Self, Saluda: Contracted Research: Self, Nalu: Speakers Bureau: Self, Biotronik: Consulting Fee: Self, Presidio: Contracted Research: Self, John Salmon, MBBS: None, Dan Bates, MBBS: None, James Yu, MD: None, Bruce Mitchell, MD: None, Neels Du Toit, MBChB: None, Matthew Green, MD: None, Murray Taverner, MBBS: None, Vahid Mohabbati, MD: None, Peter Staats, MBA,MD: Saluda Medical: Consulting Fee: Self, Grunenthal: Royalty:, Medtronic: Fees for Non-CME/CE Services (e.g. advisor):, electroCore: Employee:, SPR therapeutics: Ownership Interest:, Nalu: Fees for Non-CME/CE Services (e.g. advisor):, Gary Heit, MD, PhD: Nalu Medical Inc: Consultant: Self, Robert Levy, MD, PhD: Nalu: Ownership Interest:, Saluda: Ownership Interest:, James Makous, PhD: Nalu Medical: Consulting Fee:, Nalu Medical: Ownership Interest:

2.
Chinese Journal of Microbiology and Immunology (China) ; 42(1):16-22, 2022.
Article in Chinese | EMBASE | ID: covidwho-1928714

ABSTRACT

Objective To detect the serum levels of SARS-CoV-2-specific IgM and IgG antibodies in patients infected with SARS-CoV-2 and recipients of inactivated vaccine in different periods for understanding their variation patterns in vivo. Methods Chemiluminescence immunoassay was used to detect the levels of SARS-CoV-2-specific IgM and IgG antibodies in 144 serum samples of 44 COVID-19 patients, 381 serum samples of 118 asymptomatic infected cases and 398 serum samples of 273 inactivated vaccine recipients collected at different periods. The results were statistically analyzed together with basic characteristics and vaccination status. Results The positive rates of IgM antibody in COVID-19 patients, asymptomatic infected cases and inactivated vaccine recipients were 52. 27% (23 / 44), 23. 73% (28 / 118) and 14. 29% (39 / 273). The positive rate of IgM antibody was higher in COVID-19 patients than in asymptomatic infected cases and vaccine recipients (χ2 = 12. 106, P = 0. 001;χ2 = 34. 755, P<0. 001). The positive rates of IgG antibody in the three populations were 100. 00% (44 / 44), 97. 46% (115 / 118) and 98. 81% (166 / 168), and the differences were not statistically significant (χ2 = 2. 944, P = 0. 229). In COVID-19 patients, the concentration of IgM antibody in <40 years old group was lower than that in ≥40 years old group (Waldχ2 = 6. 609, P = 0. 010), and the concentration of IgG antibody in patients with vaccination was higher than that in patients without vaccination (Waldχ2 = 12. 402,P<0. 001). In asymptomatic infected cases, the concentration of IgG antibody was higher in people with vaccination than in those without vaccination (Waldχ2 = 4. 530, P = 0. 033). In SARS-CoV-2 vaccine recipients, the concentration of IgG antibody in <40 years old group was higher than that in ≥40 years old group (Waldχ2 = 9. 565, P = 0. 002). Dynamic analysis of antibody levels showed that from week 1 to week 9, the concentrations of IgM and IgG antibodies in COVID-19 patients were higher than those in asymptomatic infected cases and vaccine recipients. Conclusions The concentrations of IgM and IgG antibodies in COVID-19 patients were higher than those in asymptomatic infected cases and inactivated vaccine recipients. COVID-19 patients aged ≥40 years had higher level of IgM antibody. COVID-19 patients and asymptomatic infected cases who had received vaccination had higher concentration of IgG antibody. Inactivated vaccine showed good immunogenicity after whole course of immunization, and the IgG antibody level in <40 years old group was higher.

3.
Zhonghua Gan Zang Bing Za Zhi ; 30(5): 520-526, 2022 May 20.
Article in Chinese | MEDLINE | ID: covidwho-1911774

ABSTRACT

Objective: To analyze whether there are differences and related influencing factors in liver injury associated with different strains of 2019-nCoV/SARS-CoV-2 infection. Methods: Data of epidemiology, clinical symptoms, laboratory tests, and treatment outcomes of patients with COVID-19 infection confirmed with Alpha and Delta virus strain in Zhejiang Province were retrospectively collected. Statistical analysis was performed using independent samples t-test or Mann-Whitney U test, χ2 test or Fisher's exact test, and logistic regression analysis. Results: A total of 788 and 381 cases with Alpha and Delta virus strain were included. Vaccination ratio was 0% in Alpha and 85.30% in Delta group (P<0.001), The proportion of patients with fever (80.71% vs. 40.94%, P<0.001) was significantly higher in Alpha than Delta strain group. The proportion of critical ill patients was significantly higher in Delta group (9.90% vs. 1.57%, respectively, P<0.001). The virus negative conversion time was significantly longer in Delta than Alpha group (22 d vs. 11 d, P<0.001), but the incidence of liver injury was significantly higher in Alpha than Delta group (20.05% vs. 13.91%, P=0.011). Univariate analysis showed that Alpha virus strain infection, male sex, body mass index, chronic liver disease, fever, diarrhea, shortness of breath, severe/critical illness, elevated creatine kinase (CK), elevated international normalized ratio (INR) and an elevated neutrophil/lymphocyte ratio was significantly associated with an increased risk of liver injury occurrence, and in patients with pharyngeal pain the risk of liver injury occurrence was significantly reduced. Multivariate analysis showed that shortness of breath [OR, 2.667 (CI: 1.389-5.122); P=0.003], increased CK [OR, 2.544 (CI: 1.414-4.576); P=0.002] and increased INR [OR, 1.721] (CI: 1.074-2.758); P=0.024] was significantly associated with an increased risk of liver injury occurrence, and in patients with pharyngeal pain the risk of liver injury occurrence was significantly reduced [OR, 0.424 (CI: 0.254-0.709); P=0.001]. Conclusion: Although the virulence of the Delta is stronger than Alpha strain, most patients infected with Delta strain vaccinated against COVID-19 in Zhejiang province had milder clinical symptoms and a lower incidence and degree of liver injury. Notably, the infection risk even remains after vaccination; however, symptoms and the incidence of severe and critical illness can be significantly reduced.


Subject(s)
COVID-19 , Critical Illness , Dyspnea , Fever , Humans , Liver , Male , Pain , Retrospective Studies , SARS-CoV-2
4.
Nat Commun ; 13(1): 3556, 2022 06 21.
Article in English | MEDLINE | ID: covidwho-1900487

ABSTRACT

Coronaviruses can evolve and spread rapidly to cause severe disease morbidity and mortality, as exemplified by SARS-CoV-2 variants of the COVID-19 pandemic. Although currently available vaccines remain mostly effective against SARS-CoV-2 variants, additional treatment strategies are needed. Inhibitors that target essential viral enzymes, such as proteases and polymerases, represent key classes of antivirals. However, clinical use of antiviral therapies inevitably leads to emergence of drug resistance. In this study we implemented a strategy to pre-emptively address drug resistance to protease inhibitors targeting the main protease (Mpro) of SARS-CoV-2, an essential enzyme that promotes viral maturation. We solved nine high-resolution cocrystal structures of SARS-CoV-2 Mpro bound to substrate peptides and six structures with cleavage products. These structures enabled us to define the substrate envelope of Mpro, map the critical recognition elements, and identify evolutionarily vulnerable sites that may be susceptible to resistance mutations that would compromise binding of the newly developed Mpro inhibitors. Our results suggest strategies for developing robust inhibitors against SARS-CoV-2 that will retain longer-lasting efficacy against this evolving viral pathogen.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , COVID-19/drug therapy , Coronavirus 3C Proteases , Cysteine Endopeptidases/metabolism , Drug Resistance , Humans , Molecular Docking Simulation , Pandemics , Peptide Hydrolases , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/chemistry
5.
Chinese Journal of Biologicals ; 34(6):699-703, 2021.
Article in Chinese | EMBASE | ID: covidwho-1894085

ABSTRACT

Objective To explore the application and safety of apheresis technology in collection of Coronavirus Disease 2019 (COVID-19) convalescent plasma (CP), and to analyze the quality characteristics of the plasma. Methods The general data of COVID-19 convalescent plasma (CP) donors, including gender, age, date of discharge or release from medical isolation, were collected based on informed consent. After physical examination, the CP was collected by apheresis technology with plasma separator, inactivated with methylene blue, and determined for severe acute respiratory symptom Coronavirus 2 (SARS-CoV-2) nucleic acid and specific antibody (RBD-IgG) against SARS-CoV-2. Results The collection process went well, and no serious adverse events related to plasma collection were reported during or after the collection. The average age of COVID-19 CP donors was 38 years (n = 933). The distributions of blood groups A, B, AB and 0 in RhD (+) COVID-19 CP were 33. 4%, 29. 2%, 10% and 27. 2% respectively. The plasma donation date was 18 d from the discharge date in average. All the test results of SARS-CoV-2 nucleic acid in CP were negative, while the proportion of plasma samples at SARS-CoV-2 antibody titer of more than 1: 160 was 92. 60%. Conclusion Apheresis technology was safe and reliable. The COVID-19 CP contained high titer antibody. Large-scale collection and preparation of inactivated plasma against SARS-CoV-2 played an important role in the treatment of COVID-19.

6.
Topics in Antiviral Medicine ; 30(1 SUPPL):92-93, 2022.
Article in English | EMBASE | ID: covidwho-1881049

ABSTRACT

Background: SARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations;however no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Thus far, we assessed whether oral administration of live SARS-CoV-2 in non-human primates might offer prophylactic benefits. Methods: In this study, we assessed the immunogenicity of gastrointestinal (GI) delivery of SARS-CoV-2 and the protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge in rhesus macaques. Esophagogastroduodenoscopy (EGD) administration of 106 50% Tissue Culture Infectious Dose (TCID50) of SARS-CoV-2 elicited low levels of serum neutralizing antibodies (NAb), which correlated with modestly diminished viral loads in nasal swabs (NS) and Bronchoalveolar Lavage (BAL) post-challenge. In addition, mucosal NAb titers from the rectal swabs (RS), NS, and BAL and Spike-specific T-cell responses appear to be below the limit of detection post-vaccination. Replicating virus was only observed in 44% of macaques and on limited number of dates post vaccination, suggesting limited, if any, productive infection in the GI tract. Results: We demonstrate that GI delivery of live 1x106 TCID50 SARS-CoV-2 elicited modest immune responses and provided partial protection against intranasal and intratracheal challenge with SARS-CoV-2. Moreover, serum neutralizing antibody titers correlated with protective efficacy. Conclusion: These data provide proof-of-concept that an orally administered vaccine can protect against respiratory SARS-CoV-2 challenge, but the limited immunogenicity and protective efficacy observed here suggests that the oral vaccine approach will require optimization.

7.
Topics in Antiviral Medicine ; 30(1 SUPPL):92, 2022.
Article in English | EMBASE | ID: covidwho-1880330

ABSTRACT

Background: Ad26.COV2.S is a single-shot vaccine that has demonstrated clinical efficacy against symptomatic COVID-19. In this study, we report the durability of immune responses in 20 rhesus macaques received single-shot Ad26.COV2.S and the immunogenicity of a booster shot at 8-10 months following the initial immunization. Methods: Animals were immunized by intramuscular route with 1011 vp (N=10) or 5x1010 vp (N=10) Ad26.COV2.S and were followed for either 230 or 315 days. Animals were then boosted with 5x1010 vp Ad26.COV2.S (N=10). Humoral immune responses including RBD-specific Ig ELISA and pseudovirus-based virus neutralization response were monitored. Circulating RBD-specific memory B cells and bone marrow plasma cells were assessed by multiparameter flow cytometry. Results: Ad26.COV2.S elicited robust and comparable RBD-specific binding and neutralizing antibody responses in animals that received the 1011 vp and 5x1010 vp doses, which peaked on days 28-56, and then showed a biphasic decay. All animals showed binding antibody responses for the duration of follow-up, and 17 of 20 animals showed neutralizing antibody responses by day 230-315. RBD-specific memory B cell response peaked on day 14-28 followed by a gradual decline, and remained detectable in 17 of 20 animals by day 230-315. On day 315 following vaccination, bone marrow RBD-specific PCs were detected in the majority of vaccinated macaques, including in all animals that received the 1011 vp dose. Following Ad26.COV2.S boost immunization, RBD-specific binding antibody responses increased 31-69 fold compared with pre-boost levels against the ancestral (WA1/2020), alpha (B.1.1.7), beta (B.1.351), kappa (B.1.617.1), and delta (B.1.617.2) SARS-CoV-2 variants. Neutralizing antibody responses increased 23-43 fold compared with pre-boost levels against the ancestral, alpha, beta, gamma (P.1), kappa, and delta SARS-CoV-2 variants. Antigen-specific memory B cell response also increased 8 fold following the boost immunization. Conclusion: Ad26.COV2.S elicited durable antibody and B cell responses, and a late boost with Ad26.COV2.S resulted in a dramatic increase in humoral immunity that were highly cross-reactive across multiple SARS-CoV-2 variants in rhesus macaques. These data contribute to our understanding of Ad26.COV2.S durability and boostability, and provide important data to inform COVID-19 vaccine boosting strategies in humans.

8.
American Journal of Respiratory and Critical Care Medicine ; 205:2, 2022.
Article in English | English Web of Science | ID: covidwho-1880311
9.
Topics in Antiviral Medicine ; 30(1 SUPPL):95, 2022.
Article in English | EMBASE | ID: covidwho-1880255

ABSTRACT

Background: The CVnCoV (CureVac) mRNA vaccine for SARS-CoV-2 has recently been evaluated in a Phase IIb/III efficacy trial in humans. CV2CoV is a second-generation mRNA vaccine with optimized non-coding regions and enhanced antigen expression. Methods: Here we report a head-to-head study of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in nonhuman primates. We immunized 18 cynomolgus macaques with two doses of 12 ug of lipid nanoparticle formulated CVnCoV, CV2CoV, or sham (N=6/group). Results: CV2CoV induced substantially higher binding and neutralizing antibodies, memory B cell responses, and T cell responses as compared with CVnCoV. CV2CoV also induced more potent neutralizing antibody responses against SARS-CoV-2 variants, including B.1.351 (beta), B.1.617.2 (delta), and C.37 (lambda). While CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded robust protection with markedly lower viral loads in the upper and lower respiratory tract. Antibody responses correlated with protective efficacy. Conclusion: These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of an mRNA SARS-CoV-2 vaccine in nonhuman primates.

10.
Topics in Antiviral Medicine ; 30(1 SUPPL):94, 2022.
Article in English | EMBASE | ID: covidwho-1880132

ABSTRACT

Background: It is imperative to investigate novel, broadly conserved coronavirus immunogens as new SARS-CoV-2 variants of concern are continually emerging. The goal of this study was to generate a broadly protective long-term vaccine candidate against potential new variants of SARS-CoV-2 and novel, outbreak coronaviruses. The vaccine immunogen spanned portions of the highly conserved RNA replication machinery (nsp12 and nsp13) (CoV.Con). The vaccine was packaged into a rhesus adenoviral vector (RhAd52.CoV.Con) with the goal of generating robust long-lived CD8+ T-cell responses. Methods: The CoV.Con immunogen was generated by aligning coronavirus sequences to determine the most conserved region. ACE2 carrier and BALB/c mice were immunized intramuscularly with 109 RhAd52.CoV.Con and boosted four weeks later. Splenocytes were harvested four weeks after boost. Cellular immunity was determined through ELIspot and intracellular cytokine stain (ICS). BALB/c mice were primed and boosted with RhAd52.CoV.Con. Four weeks post boost mice were challenged intranasally with mouse adapted SARS-CoV-2. Protection was measured by weight loss and plaque assay. Results: Four weeks post RhAd52.CoV.Con boost immunization, ACE2 carrier and BALB/c mice developed cellular immunity as shown by ELIspot (Fig 1a) and ICS. ACE2 carrier mice cellular immunity showed bias toward nsp12 while BALB/c mice showed nsp13 preference. BALB/c mice were primed and boosted with RhAd52.CoV.Con. Four weeks after boost mice were challenged with mouse adapted SARS-CoV-2. RhAd52.CoV.Con was compared against and combined with a suboptimal dose of RhAd52.S.pp at 4 and 8 weeks post injection. Protection against weight loss (Fig 1b) and viral load (Fig 1c) was minimal although increased RhAd52.S.pp protection was observed from 4 to 8 weeks post immunization. Increased RhAd52.S.pp protection corresponded to increased spike antibody binding and neutralizing titers. Conclusion: Our work investigates a highly conserved coronavirus immunogen, CoV.Con, demonstrating immunogenicity in two mouse strains. While RhAd52. CoV.Con protection in the mouse model was minimal it demonstrates a schema for generating coronavirus immunogens that can protect against multiple different viruses. This work takes the first steps towards generating a long-lived broadly protective T-cell coronavirus vaccine.

11.
Mbio ; 12(5):21, 2021.
Article in English | Web of Science | ID: covidwho-1854240

ABSTRACT

Newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic with astonishing mortality and morbidity. The high replication and transmission of SARS-CoV-2 are remarkably distinct from those of previous closely related coronaviruses, and the underlying molecular mechanisms remain unclear. The innate immune defense is a physical barrier that restricts viral replication. We report here that the SARS-CoV-2 Nsp5 main protease targets RIG-I and mitochondrial antiviral signaling (MAVS) protein via two distinct mechanisms for inhibition. Specifically, Nsp5 cleaves off the 10 most-N-terminal amino acids from RIG-I and deprives it of the ability to activate MAVS, whereas Nsp5 promotes the ubiquitination and proteosome-mediated degradation of MAVS. As such, Nsp5 potently inhibits interferon (IFN) induction by double-stranded RNA (dsRNA) in an enzyme-dependent manner. A synthetic small-molecule inhibitor blunts the Nsp5mediated destruction of cellular RIG-I and MAVS and processing of SARS-CoV-2 nonstructural proteins, thus restoring the innate immune response and impeding SARSCoV-2 replication. This work offers new insight into the immune evasion strategy of SARS-CoV-2 and provides a potential antiviral agent to treat CoV disease 2019 (COVID-19) patients. IMPORTANCE The ongoing COVID-19 pandemic is caused by SARS-CoV-2, which is rapidly evolving with better transmissibility. Understanding the molecular basis of the SARS-CoV-2 interaction with host cells is of paramount significance, and development of antiviral agents provides new avenues to prevent and treat COVID-19 diseases. This study describes a molecular characterization of innate immune evasion mediated by the SARS-CoV-2 Nsp5 main protease and subsequent development of a small-molecule inhibitor.

12.
12th International Conference on ICT Convergence (ICTC) - Beyond the Pandemic Era with ICT Convergence Innovation ; : 1649-1654, 2021.
Article in English | Web of Science | ID: covidwho-1853458

ABSTRACT

Due to the increasing use of the Internet, the development of the information society, and public awareness about health, many patients are using the Internet to find health information. In addition, medical field information retrieval is exploding to retrieve specific medical knowledge about diseases due to the current corona pandemic and the prevalence of mobile handsets such as smartphones. Currently, much of the knowledge information in the medical field is provided in ontology, a method of expressing knowledge information. However, medical knowledge built in this ontology form requires the general user to know basic logic-based representations of ontology, such as the web ontology language OWL and semantic web technologies, for searching. Furthermore, the usage and understanding of the SPARQL protocol and RDF query language (SPARQL), a formalized query language in the form of ontology, is essential. To overcome the limitations of this ontology form of knowledge retrieval, this paper proposes the stroke medical ontology question and answering (QA) system that can analyze user medical knowledge in natural language form for medical knowledge curation services and automatically convert it to the structured query language, SPARQL. The proposed system analyzes questions and answers through query analysis, s each syntax word through top-level medical ontology, and deduces the structured query template for ed questions and answers based on SWRL to complete the structured query template.

13.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333823

ABSTRACT

Antibodies that potently neutralize SARS-CoV-2 target mainly the receptor-binding domain or the N-terminal domain (NTD). Over a dozen potently neutralizing NTD-directed antibodies have been studied structurally, and all target a single antigenic supersite in NTD (site 1). Here we report the 3.7 A resolution cryo-EM structure of a potent NTD-directed neutralizing antibody 5-7, which recognizes a site distinct from other potently neutralizing antibodies, inserting a binding loop into an exposed hydrophobic pocket between the two sheets of the NTD beta-sandwich. Interestingly, this pocket has been previously identified as the binding site for hydrophobic molecules including heme metabolites, but we observe their presence to not substantially impede 5-7 recognition. Mirroring its distinctive binding, antibody 5-7 retains a distinctive neutralization potency with variants of concern (VOC). Overall, we reveal a hydrophobic pocket in NTD proposed for immune evasion can actually be used by the immune system for recognition. HIGHLIGHTS: Cryo-EM structure of neutralizing antibody 5-7 in complex with SARS CoV-2 spike5-7 recognizes NTD outside of the previously identified antigenic supersite5-7 binds to a site known to accommodate numerous hydrophobic ligandsStructural basis of 5-7 neutralization tolerance to some variants of concern.

14.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333816

ABSTRACT

The global COVID-19 pandemic has sparked intense interest in the rapid development of vaccines as well as animal models to evaluate vaccine candidates and to define immune correlates of protection. We recently reported a mouse-adapted SARS-CoV-2 virus strain (MA10) with the potential to infect wild-type laboratory mice, driving high levels of viral replication in respiratory tract tissues as well as severe clinical and respiratory symptoms, aspects of COVID-19 disease in humans that are important to capture in model systems. We evaluated the immunogenicity and protective efficacy of novel rhesus adenovirus serotype 52 (RhAd52) vaccines against MA10 challenge in mice. Baseline seroprevalence is lower for rhesus adenovirus vectors than for human or chimpanzee adenovirus vectors, making these vectors attractive candidates for vaccine development. We observed that RhAd52 vaccines elicited robust binding and neutralizing antibody titers, which inversely correlated with viral replication after challenge. These data support the development of RhAd52 vaccines and the use of the MA10 challenge virus to screen novel vaccine candidates and to study the immunologic mechanisms that underscore protection from SARS-CoV-2 challenge in wild-type mice. IMPORTANCE: We have developed a series of SARS-CoV-2 vaccines using rhesus adenovirus serotype 52 (RhAd52) vectors, which exhibits a lower seroprevalence than human and chimpanzee vectors, supporting their development as novel vaccine vectors or as an alternative Ad vector for boosting. We sought to test these vaccines using a recently reported mouse-adapted SARS-CoV-2 (MA10) virus to i) evaluate the protective efficacy of RhAd52 vaccines and ii) further characterize this mouse-adapted challenge model and probe immune correlates of protection. We demonstrate RhAd52 vaccines elicit robust SARS-CoV-2-specific antibody responses and protect against clinical disease and viral replication in the lungs. Further, binding and neutralizing antibody titers correlated with protective efficacy. These data validate the MA10 mouse model as a useful tool to screen and study novel vaccine candidates, as well as the development of RhAd52 vaccines for COVID-19.

15.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333814

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer patients are usually immunocompromised and thus are particularly susceptible to SARS-CoV-2 infection resulting in COVID-19. Although many vaccines against COVID-19 are being preclinically or clinically tested or approved, none have yet been specifically developed for cancer patients or reported as having potential dual functions to prevent COVID-19 and treat cancer. Here, we confirmed that COVID-19 patients with cancer have low levels of antibodies against the spike (S) protein, a viral surface protein mediating the entry of SARS-CoV-2 into host cells, compared with COVID-19 patients without cancer. We developed an oncolytic herpes simplex virus-1 vector-based vaccine named oncolytic virus (OV)-spike. OV-spike induced abundant anti-S protein neutralization antibodies in both tumor-free and tumor-bearing mice, which inhibit infection of VSV-SARS-CoV-2 and wild-type (WT) live SARS-CoV-2 as well as the B.1.1.7 variant in vitro. In the tumor-bearing mice, OV-spike also inhibited tumor growth, leading to better survival in multiple preclinical tumor models than the untreated control. Furthermore, OV-spike induced anti-tumor immune response and SARS-CoV-2-specific T cell response without causing serious adverse events. Thus, OV-spike is a promising vaccine candidate for both preventing COVID-19 and enhancing the anti-tumor response. ONE SENTENCE SUMMARY: A herpes oncolytic viral vector-based vaccine is a promising vaccine with dual roles in preventing COVID-19 and treating tumor progression.

16.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333803

ABSTRACT

Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic especially for low- and middle-income countries. While vaccines against SARS-CoV-2 based on mRNA and adenoviral-vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are needed to meet global demand. In this context, protein subunit vaccines formulated with appropriate adjuvants represent a promising approach to address this urgent need. Receptor-binding domain (RBD) is a key target of neutralizing antibodies (Abs) but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists, including those activating STING, TLR3, TLR4 and TLR9, alone or formulated with aluminum hydroxide (AH), and benchmarked them to AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that the AH and CpG adjuvant formulation (AH:CpG) demonstrated the highest enhancement of anti-RBD neutralizing Ab titers in both age groups (~80-fold over AH), and protected aged mice from the SARS-CoV-2 challenge. Notably, AH:CpG-adjuvanted RBD vaccine elicited neutralizing Abs against both wild-type SARS-CoV-2 and B.1.351 variant at serum concentrations comparable to those induced by the authorized mRNA BNT162b2 vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and synergistically enhanced cytokine and chemokine production in human young adult and elderly mononuclear cells. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups. ONE SENTENCE SUMMARY: Alum and CpG enhance SARS-CoV-2 RBD protective immunity, variant neutralization in aged mice and Th1-polarizing cytokine production by human elder leukocytes.

17.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-333657

ABSTRACT

Understanding protective mechanisms of antibody recognition can inform vaccine and therapeutic strategies against SARS-CoV-2. We discovered a new antibody, 910-30, that targets the SARS-CoV-2 ACE2 receptor binding site as a member of a public antibody response encoded by IGHV3-53/IGHV3-66 genes. We performed sequence and structural analyses to explore how antibody features correlate with SARS-CoV-2 neutralization. Cryo-EM structures of 910-30 bound to the SARS-CoV-2 spike trimer revealed its binding interactions and ability to disassemble spike. Despite heavy chain sequence similarity, biophysical analyses of IGHV3-53/3-66 antibodies highlighted the importance of native heavy:light pairings for ACE2 binding competition and for SARS-CoV-2 neutralization. We defined paired heavy:light sequence signatures and determined antibody precursor prevalence to be ~1 in 44,000 human B cells, consistent with public antibody identification in several convalescent COVID-19 patients. These data reveal key structural and functional neutralization features in the IGHV3-53/3-66 public antibody class to accelerate antibody-based medical interventions against SARS-CoV-2. HIGHLIGHTS: A molecular study of IGHV3-53/3-66 public antibody responses reveals critical heavy and light chain features for potent neutralizationCryo-EM analyses detail the structure of a novel public antibody class member, antibody 910-30, in complex with SARS-CoV-2 spike trimerCryo-EM data reveal that 910-30 can both bind assembled trimer and can disassemble the SARS-CoV-2 spikeSequence-structure-function signatures defined for IGHV3-53/3-66 class antibodies including both heavy and light chainsIGHV3-53/3-66 class precursors have a prevalence of 1:44,000 B cells in healthy human antibody repertoires.

18.
IEEE International Conference on Robotics and Automation (ICRA) ; : 8600-8606, 2021.
Article in English | Web of Science | ID: covidwho-1799303

ABSTRACT

We carry out a structural and algorithmic study of a mobile sensor coverage optimization problem targeting 2D surfaces embedded in a 3D workspace. The investigated settings model multiple important applications including camera network deployment for surveillance, geological monitoring/survey of 3D terrains, and UVC-based surface disinfection for the prevention of the spread of disease agents (e.g., SARS-CoV-2). Under a unified general "sensor coverage" problem, three concrete formulations are examined, focusing on optimizing visibility, single-best coverage quality, and cumulative quality, respectively. After demonstrating the computational intractability of all these formulations, we describe approximation schemes and mathematical programming models for near-optimally solving them. The effectiveness of our methods is thoroughly evaluated under realistic and practical scenarios.

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Proc Mach Learn Res ; 146:159-170, 2021.
Article in English | PubMed | ID: covidwho-1772436

ABSTRACT

Dynamic survival analysis is a variant of traditional survival analysis where time-to-event predictions are updated as new information arrives about an individual over time. In this paper we propose a new approach to dynamic survival analysis based on learning a global parametric distribution, followed by individualization via truncating and renormalizing that distribution at different locations over time. We combine this approach with a likelihood-based loss that includes predictions at every time step within an individual's history, rather than just including one term per individual. The combination of this loss and model results in an interpretable approach to dynamic survival, requiring less fine tuning than existing methods, while still achieving good predictive performance. We evaluate the approach on the problem of predicting hospital mortality for a dataset with over 6900 COVID-19 patients.

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