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1.
Nat Commun ; 13(1): 5886, 2022 Oct 06.
Article in English | MEDLINE | ID: covidwho-2050378

ABSTRACT

Monoclonal antibody therapy has played an important role against SARS-CoV-2. Strategies to deliver functional, antibody-based therapeutics with improved in vivo durability are needed to supplement current efforts and reach underserved populations. Here, we compare recombinant mAbs COV2-2196 and COV2-2130, which compromise clinical cocktail Tixagevimab/Cilgavimab, with optimized nucleic acid-launched forms. Functional profiling of in vivo-expressed, DNA-encoded monoclonal antibodies (DMAbs) demonstrated similar specificity, broad antiviral potency and equivalent protective efficacy in multiple animal challenge models of SARS-CoV-2 prophylaxis compared to protein delivery. In PK studies, DNA-delivery drove significant serum antibody titers that were better maintained compared to protein administration. Furthermore, cryo-EM studies performed on serum-derived DMAbs provide the first high-resolution visualization of in vivo-launched antibodies, revealing new interactions that may promote cooperative binding to trimeric antigen and broad activity against VoC including Omicron lineages. These data support the further study of DMAb technology in the development and delivery of valuable biologics.


Subject(s)
Biological Products , COVID-19 , Nucleic Acids , Animals , Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/prevention & control , DNA , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics
2.
Clin Respir J ; 16(9): 618-622, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1968080

ABSTRACT

INTRODUCTION: In the management of acute hospital admissions during the COVID-19 pandemic, safe patient cohorting depends on robust admission diagnostic strategies. It is essential that screening strategies are sensitive and rapid, to prevent nosocomial transmission of COVID-19 and maintain patient flow. METHODS: We retrospectively identified all COVID-19 positive and suspected cases at our institution screened by reverse transcription polymerase chain reaction (RT-PCR) between 4 April and 28 June 2020. Using RT-PCR positivity within 7 days as our reference standard, we assessed sensitivity and net-benefit of three admission screening strategies: single admission RT-PCR, composite admission RT-PCR and CXR and repeat RT-PCR with 48 h. RESULTS: RT-PCR single-test sensitivity was 91.5% (87.8%-94.4%) versus 97.7% (95.4%-99.1%) (p = 0.025) for RT-PCR/CXR composite testing and 95.1% (92.1%-97.2%) (p = 0.03) for repeated RT-PCR. Net-benefit was 0.83 for single RT-PCR versus 0.89 for RT-PCR/CXR and 0.87 for repeated RT-PCR at 0.02% threshold probability. CONCLUSION: The RT-PCR/CXR composite testing strategy was highly sensitive when screening patients at the point of hospital admission. Real-world sensitivity of this approach was comparable to repeat RT-PCR testing within 48 h; however, faster facilitating improved patient flow.


Subject(s)
COVID-19 , Cross Infection , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19 Testing , Cross Infection/diagnosis , Cross Infection/epidemiology , Cross Infection/prevention & control , Hospitals , Humans , Pandemics/prevention & control , Retrospective Studies , SARS-CoV-2/genetics , Sensitivity and Specificity
3.
Cell Rep Med ; 3(7): 100693, 2022 07 19.
Article in English | MEDLINE | ID: covidwho-1946857

ABSTRACT

The global coronavirus disease 2019 (COVID-19) pandemic has claimed more than 5 million lives. Emerging variants of concern (VOCs) continually challenge viral control. Directing vaccine-induced humoral and cell-mediated responses to mucosal surfaces may enhance vaccine efficacy. Here we investigate the immunogenicity and protective efficacy of optimized synthetic DNA plasmids encoding wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (pS) co-formulated with the plasmid-encoded mucosal chemokine cutaneous T cell-attracting chemokine (pCTACK; CCL27). pCTACK-co-immunized animals exhibit increased spike-specific antibodies at the mucosal surface and increased frequencies of interferon gamma (IFNγ)+ CD8+ T cells in the respiratory mucosa. pCTACK co-immunization confers 100% protection from heterologous Delta VOC challenge. This study shows that mucosal chemokine adjuvants can direct vaccine-induced responses to specific immunological sites and have significant effects on heterologous challenge. Further study of this unique chemokine-adjuvanted vaccine approach in the context of SARS-CoV-2 vaccines is likely important.


Subject(s)
COVID-19 , Viral Vaccines , Adjuvants, Immunologic/pharmacology , Animals , Antibodies, Viral , CD8-Positive T-Lymphocytes , COVID-19/prevention & control , COVID-19 Vaccines , Chemokines , Humans , SARS-CoV-2/genetics , Viral Vaccines/genetics
4.
J Immunol ; 209(1): 118-127, 2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1911834

ABSTRACT

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have demonstrated strong immunogenicity and protection against severe disease, concerns about the duration and breadth of these responses remain. In this study, we show that codelivery of plasmid-encoded adenosine deaminase-1 (pADA) with SARS-CoV-2 spike glycoprotein DNA enhances immune memory and durability in vivo. Coimmunized mice displayed increased spike-specific IgG of higher affinity and neutralizing capacity as compared with plasmid-encoded spike-only-immunized animals. Importantly, pADA significantly improved the longevity of these enhanced responses in vivo. This coincided with durable increases in frequencies of plasmablasts, receptor-binding domain-specific memory B cells, and SARS-CoV-2-specific T follicular helper cells. Increased spike-specific T cell polyfunctionality was also observed. Notably, animals coimmunized with pADA had significantly reduced viral loads compared with their nonadjuvanted counterparts in a SARS-CoV-2 infection model. These data suggest that pADA enhances immune memory and durability and supports further translational studies.


Subject(s)
COVID-19 , Viral Vaccines , Adenosine Deaminase/genetics , Adjuvants, Immunologic , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Mice , SARS-CoV-2
5.
J Infect ; 84(4): 558-565, 2022 04.
Article in English | MEDLINE | ID: covidwho-1783515

ABSTRACT

OBJECTIVES: Risk of hospital-acquired COVID-19 (HA-COVID-19) infection is increased by cohorting infected and non-infected patients together in assessment areas, whist awaiting laboratory PCR results. Molecular point-of-care tests (mPOCT) reduce time to results and improve patient flow but the impact on HA-COVID-19 is unknown. METHODS: In this pre and post implementation study patients were evaluated across two time periods: March 1st to August 13th 2020, prior to the introduction of mPOCT in medical admissions areas, and 14th August 2020 to 1st April 2021, after mPOCT introduction. The primary outcome was proportion of HA-COVID-19 infection among all COVID-19 positive patients. Secondary outcome measures included time to SARS-CoV-2 results, length of time spent in the medical assessment area and comparison of local, regional and national proportions of HA-COVID-19. RESULTS: 1988 patients were admitted through the acute medicine admission cohorting area and tested for SARS-CoV-2 prior to introducing mPOCT and 4640 afterwards. Median (IQR) time to SARS-CoV-2 result was 6.5 (2.1-17.9) hours prior to introducing mPOCT and 1.0 (0.8-1.3) hours afterwards (p < 0.0001). Median (IQR) duration in the assessment cohort area was 12.0 (4.8-20.6) hours prior to introduction of POCT and 3.2 (2.0-5.6) hours afterwards (p < 0.0001). The proportion of hospital-acquired COVID-19 cases was 108 (16.5%) of 654 prior to introducing mPOCT compared with 168 (9.4%) of 1782 afterwards, (HR 0.55, 95%CI 0.43-0.70; p < 0.0001). In the period following the introduction of mPOCT up to 1st April 2021 the median proportion of HA-COVID-19 was 13.6% (95%CI 8.2-18.9%) locally, compared with 43.8% (95%CI 37.8-49.9%) for all acute NHS trusts regionally and 30.9% (95%CI 28.4-33.5%) for all NHS trusts nationally. CONCLUSIONS: Routine mPOCT for SARS-CoV-2 was associated with reduced time to results, time spent in admission cohort areas, and hospital-acquired COVID-19, compared to laboratory PCR.


Subject(s)
COVID-19 , Cross Infection , COVID-19/diagnosis , Cohort Studies , Cross Infection/diagnosis , Hospitals , Humans , Point-of-Care Testing , SARS-CoV-2
6.
Vaccine ; 40(21): 2960-2969, 2022 05 09.
Article in English | MEDLINE | ID: covidwho-1773836

ABSTRACT

The enhanced transmissibility and immune evasion associated with emerging SARS-CoV-2 variants demands the development of next-generation vaccines capable of inducing superior protection amid a shifting pandemic landscape. Since a portion of the global population harbors some level of immunity from vaccines based on the original Wuhan-Hu-1 SARS-CoV-2 sequence or natural infection, an important question going forward is whether this immunity can be boosted by next-generation vaccines that target emerging variants while simultaneously maintaining long-term protection against existing strains. Here, we evaluated the immunogenicity of INO-4800, our synthetic DNA vaccine candidate for COVID-19 currently in clinical evaluation, and INO-4802, a next-generation DNA vaccine designed to broadly target emerging SARS-CoV-2 variants, as booster vaccines in nonhuman primates. Rhesus macaques primed over one year prior with the first-generation INO-4800 vaccine were boosted with either INO-4800 or INO-4802 in homologous or heterologous prime-boost regimens. Both boosting schedules led to an expansion of T cells and antibody responses which were characterized by improved neutralizing and ACE2 blocking activity across wild-type SARS-CoV-2 as well as multiple variants of concern. These data illustrate the durability of immunity following vaccination with INO-4800 and additionally support the use of either INO-4800 or INO-4802 in prime-boost regimens.


Subject(s)
COVID-19 , Vaccines, DNA , Viral Vaccines , Animals , Antibody Formation , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Macaca mulatta , Mice , Mice, Inbred BALB C , SARS-CoV-2 , Vaccination
8.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-321794

ABSTRACT

The coronavirus family member, SARS-CoV-2 has been identified as the causal agent for the outbreak of viral pneumonia disease, COVID-19 which first emerged in mid-December 2019 in the city of Wuhan in central China. As of February 25, 2020 there are 80,994 people infected and 2,760 deaths, and documented human-to-human transmission across multiple continents. At this time, no vaccine is available to control further dissemination of the disease. We have previously developed a synthetic DNA vaccine targeting the MERS coronavirus Spike (S) protein that was deployed in response to the MERS outbreak in South Korea. This vaccine induced potent antibody and CTL responses, and provided protection in a NHP challenge model. In the clinic, the vaccine generated humoral immunity including neutralizing antibody responses, as well as T cell immunity. Here we build on this prior work and report on the rapid development of a synthetic DNA-based vaccine targeting the major surface antigen Spike protein of SARS-CoV-2. The engineered construct, INO-4800 induced robust expression of the Spike protein in vitro, and generated antibody and T cell responses following a single immunization in mice and guinea pigs. This preliminary dataset identifies INO-4800 as a potential COVID-19 vaccine candidate, supporting further study for mobilization against this emerging disease threat.

9.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-311378

ABSTRACT

Safe and effective vaccines will provide essential medical countermeasures to tackle the COVID-19 pandemic. Here, we evaluate the safety, immunogenicity and efficacy of the intradermal delivery of INO-4800, a synthetic DNA vaccine candidate encoding the SARS-CoV-2 spike protein in the rhesus macaque model. Single and 2 dose vaccination regimens were evaluated. Vaccination induces both binding and neutralizing antibodies, along with IFN-γ-producing T cells against SARS-CoV-2. Upon administration of a high viral dose (5 x 10 6 pfu) via the intranasal and intratracheal routes we observe significantly reduced virus load in the lung and throat, in the vaccinated animals compared to controls. 2 doses of INO-4800 is associated with more robust vaccine-induced immune responses and improved viral protection. Importantly, histopathological examination of lung tissue provides no indication of vaccine-enhanced disease following SARS-CoV-2 challenge in INO-4800 immunized animals. This vaccine candidate is currently under clinical evaluation as a 2 dose regimen.

10.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-318350

ABSTRACT

We are developing a new research based assessment (RBA) focused on quantitative reasoning -- rather than conceptual understanding -- in physics contexts. We rapidly moved administration of the RBA online in Spring 2020 due to the COVID-19 pandemic. We present our experiences with online, unproctored administration of an RBA in development to students enrolled in a large-enrollment, calculus-based, introductory physics course. We describe our attempts to adhere to best practices on a limited time frame, and present a preliminary analysis of the results, comparing results from the online administration to earlier results from in-person, proctored administration. We include discussion of online administration of multiple-choice/multiple-response (MCMR) items, which we use on the instrument as a way to probe multiple facets of student reasoning. Our initial comparison indicates little difference between online and paper administrations of the RBA, consistent with previous work by other researchers.

11.
Cell Rep ; 38(5): 110318, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1654152

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may target epitopes that reduce durability or increase the potential for escape from vaccine-induced immunity. Using synthetic vaccinology, we have developed rationally immune-focused SARS-CoV-2 Spike-based vaccines. Glycans can be employed to alter antibody responses to infection and vaccines. Utilizing computational modeling and in vitro screening, we have incorporated glycans into the receptor-binding domain (RBD) and assessed antigenic profiles. We demonstrate that glycan-coated RBD immunogens elicit stronger neutralizing antibodies and have engineered seven multivalent configurations. Advanced DNA delivery of engineered nanoparticle vaccines rapidly elicits potent neutralizing antibodies in guinea pigs, hamsters, and multiple mouse models, including human ACE2 and human antibody repertoire transgenics. RBD nanoparticles induce high levels of cross-neutralizing antibodies against variants of concern with durable titers beyond 6 months. Single, low-dose immunization protects against a lethal SARS-CoV-2 challenge. Single-dose coronavirus vaccines via DNA-launched nanoparticles provide a platform for rapid clinical translation of potent and durable coronavirus vaccines.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Nanoparticles/administration & dosage , SARS-CoV-2/immunology , Animals , Antibodies, Neutralizing/immunology , Binding Sites , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/genetics , Cricetinae , Epitopes , Guinea Pigs , Immunogenicity, Vaccine , Mice , Nanoparticles/chemistry , Nucleic Acid-Based Vaccines/administration & dosage , Nucleic Acid-Based Vaccines/chemistry , Nucleic Acid-Based Vaccines/genetics , Nucleic Acid-Based Vaccines/immunology , Polysaccharides/chemistry , Polysaccharides/genetics , Polysaccharides/immunology , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccine Potency
12.
Front Med Technol ; 3: 729658, 2021.
Article in English | MEDLINE | ID: covidwho-1635765

ABSTRACT

Objectives: The provision of high-quality personal protective equipment (PPE) has been a critical challenge during the COVID-19 pandemic. We evaluated an alternative strategy, mass deployment of a powered air-purifying respirator (PeRSo), in a large university hospital. Methods: We performed prospective user feedback via questionnaires sent to healthcare workers (HCWs) issued PeRSos, economic analysis, and evaluated the real-world impact. Results: Where paired responses were available, PeRSo was preferred over droplet precautions for comfort, patient response, overall experience, and subjective feeling of safety. For all responses, more participants reported the overall experience being rated "Very good" more frequently for PeRSo. The primary limitation identified was impairment of hearing. Economic simulation exercises revealed that the adoption of PeRSo within ICU is associated with net cost savings in the majority of scenarios and savings increased progressively with greater ITU occupancy. In evaluation during the second UK wave, over 3,600 respirators were deployed, all requested by staff, which were associated with a low staff absence relative to most comparator hospitals. Conclusions: Health services should consider a widespread implementation of powered reusable respirators as a safe and sustainable solution for the protection of HCWs as SARS-CoV-2 becomes an endemic viral illness.

13.
J Crohns Colitis ; 16(6): 911-921, 2022 Jul 14.
Article in English | MEDLINE | ID: covidwho-1598968

ABSTRACT

BACKGROUND AND AIMS: Subcutaneous [SC] vedolizumab presents the opportunity for inflammatory bowel disease [IBD] patients to manage their treatment at home. There are currently no data on the process of transitioning patients established on intravenous [IV] to SC vedolizumab as part of routine clinical care. The aim of this programme is to evaluate the clinical and biochemical outcomes of switching a cohort of IBD patients established on IV vedolizumab to SC, at 12 weeks following the transition. METHODS: In all, 178 adult patients were offered the opportunity to transition to SC vedolizumab. Patients who agreed were reviewed prior to switching and at Week 12 [W12] after their first SC dose. Evaluation outcomes included disease activity scores, the IBD-Control Patient-Reported Outcome Measures [PROMs], and faecal calprotectin [FCP]. Reasons for patients declining or accepting transitioning, pharmacokinetics, adverse drug reactions, and risk factors for a poor outcome in SARS-CoV-2 infection were also assessed. RESULTS: A total of 124 patients agreed to transition, of whom 106 patients had been on IV vedolizumab for at least 4 months. There were no statistically significant differences in disease activity scores or IBD-Control PROMs between baseline and W12. A statistically significant increase in FCP was observed [31 µg/g vs. 47 µg/g; p = 0.008], although this was unlikely to be clinically relevant. The most common adverse drug reaction reported was injection site reactions [15%]. Based on this cohort of patients, an expected reduction of £572,000 per annum is likely to be achieved. CONCLUSIONS: Transitioning patients established on IV vedolizumab to SC appears to be safe and effective, with high patient satisfaction and multiple benefits for the health service.


Subject(s)
COVID-19 , Colitis, Ulcerative , Inflammatory Bowel Diseases , Adult , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Colitis, Ulcerative/drug therapy , Gastrointestinal Agents/administration & dosage , Gastrointestinal Agents/adverse effects , Gastrointestinal Agents/therapeutic use , Humans , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/drug therapy , Leukocyte L1 Antigen Complex , SARS-CoV-2 , Treatment Outcome
14.
Open Forum Infectious Diseases ; 8(Supplement_1):S391-S392, 2021.
Article in English | PMC | ID: covidwho-1570006

ABSTRACT

First generation COVID-19 vaccines matched to the original Wuhan-Hu-1 (WT) strain are showing reduced efficacy against emerging SARS-CoV-2 variants of concern (VOC). In response, next generation vaccines either matched to a single variant or designed to provide broader coverage across the VOC group are being developed. The latter pan-SARS-CoV-2 approach may offer substantial advantages in terms of cross-strain protection, immune coverage, reduced susceptibility to escape mutants, and non-restricted geographical use. Here we have employed our SynCon® design technology to construct a DNA vaccine expressing a pan-Spike immunogen (INO-4802) to induce broad immunity across SARS-CoV-2 variants. Compared to WT and VOC-matched vaccines which showed limited cross-neutralizing activity, INO-4802 induced potent neutralizing antibodies and T cell responses against WT as well as B.1.1.7, P.1, and B.1.351 VOCs in a murine model. In addition, a hamster vaccination model showed enhanced humoral responses against VOCs in a heterologous pWT prime/INO-4802 boost setting. These results demonstrate the potential of the pan-SARS-CoV-2 vaccine, INO-4802 to induce cross-reactive immune responses against emerging VOCs as either a standalone vaccine, or as a potential boost for individuals previously immunized with WT-matched vaccines.Competing Interest StatementC.C.R., V.M.A., R.K., K.S., J.T., B.S., D.E., J.W., I.M., A.D., Z.E., P.P., D.A. M.Y., J.F., R.F., M.V., J.J.K., L.M.H., S.J.R., T.R.F.S., K.E.B. are employees of Inovio Pharmaceuticals and as such receive salary and benefits, including ownership of stock and stock options, from the company. D.B.W. has received grant funding, participates in industry collaborations, has received speaking honoraria, and has received fees for consulting, including serving on scientific review committees and board services. Remuneration received by D.B.W. includes direct payments or stock or stock options, and in the interest of disclosure he notes potential conflicts associated with this work with Inovio and possibly others. In addition, he has a patent DNA vaccine delivery pending to Inovio. All other authors report there are no competing interests.

17.
Open forum infectious diseases ; 8(Suppl 1):387-388, 2021.
Article in English | EuropePMC | ID: covidwho-1564905

ABSTRACT

Background DNA vaccines are safe, tolerable, elicit humoral and cellular responses, allow for repeated dosing over time, are thermostable at room temperature, and are easy to manufacture. We present a compilation of Phase 1 and Phase 2 data of Inovio’s US COVID-19 DNA Vaccine (INO-4800) targeting the full-length Spike antigen of SARS-CoV-2. A South Korean Phase 2 study is ongoing. Methods Participants in the open-label Phase 1 trial received 0.5 mg, 1.0 mg or 2.0 mg intradermally (ID) followed by electroporation (EP) at Days 0 and 28. An optional booster dose was administered >6 months post-dose 2. The Phase 2 further compared the 1.0 mg and 2.0 mg doses against placebo in a total of 401 participants randomized at a 3:3:1:1 ratio. ClinicalTrials.gov identifiers: NCT04336410 and NCT04642638 Results The majority of adverse events (AEs) related to INO-4800 across both trials were mild in severity and did not increase in frequency with age and subsequent doses. In Phase 1, 78% (14/18) and 84% (16/19) of subjects generated neutralizing antibody responses with geometric mean titers (GMTs) of 17.4 (95%CI 8.3, 36.5) and 62.3 (95% CI 36.4, 106.7) in the 1.0 and 2.0 groups, respectively (Figure 1). By week 8, 74% (14/19) and 100% (19/19) subjects generated T cell responses by Th1- associated IFNγ ELISPOT assay . Following a booster dose, neutralizing GMTs rose to 82.2 (95% CI 38.2, 176.9) and 124.7 (95% CI 62.8, 247.7) in the 1.0 mg and 2.0 mg groups, respectively, demonstrating the ability of INO-4800 to boost (Figure 2). In Phase 2, neutralizing antibody responses demonstrated GMTs of 93.6 (95%CI 77.3, 113.4) in the 1.0 mg dose group and 150.6 (95%CI 123.8, 183.1) in the 2.0 mg dose group (Figure 3). Conclusion INO-4800 appears safe and tolerable as a primary series and as a booster with the induction of both humoral and cellular immune responses. In addition to eliciting neutralizing antibodies, INO-4800 also induced T cell immune responses as demonstrated by IFNγ ELISpot. Finally, as a homologous booster, INO-4800, when administered 6-10.5 months following the primary series, resulted in an increased immune response without increase in reactogenicity. The 2.0 mg dose was selected for Phase 3 evaluation. Disclosures Joseph Agnes, PhD, Inovio (Employee, Shareholder) Mary Giffear, BS, Inovio Pharmaceuticals, Inc. (Employee) Kimberly A. Kraynyak, PhD, Inovio Pharmaceuticals (Employee, Other Financial or Material Support, Stock options) Dinah Amante, BS, Inovio (Employee) Emma Reuschel, PhD, Inovio Pharmaceuticals (Employee) Aaron Christensen-Quick, PhD, Inovio Pharmaceuticals, Inc (Employee) Viviane M. Andrade, PhD, Inovio Pharmaceuticals Inc. (Employee) Gabriella Garufi, PhD, Inovio Pharmaceuticals, Inc. (Employee) Albert Sylvester, MS, Inovio (Employee, Shareholder) Matthew P. Morrow, PhD, Inovio Pharmaceuticals (Employee) Patrick P. Pezzoli, BS, Inovio Pharmaceuticals, Inc. (Employee) Jan Pawlicki, PhD, Inovio Pharmaceuticals (Employee) Elisabeth Gillespie, PhD, Inovio Pharmaceuticals, Inc. (Employee) Katherine Schultheis, MSc, Inovio Pharmaceuticals (Employee) Hedieh Badie, PhD, INOVIO Pharmaceuticals (Employee) Timothy A. Herring, MPH, Inovio Pharmaceuticals, Inc. (Employee, Other Financial or Material Support, Own stock in the company) Keiko O. Simon, PhD, Inovio Pharmaceuticals (Employee) Trevor R. F. Smith, PhD, Inovio (Employee, Shareholder) Stephanie Ramos, PhD, Inovio Pharmaceuticals (Employee) Jessica Lee, MPH, Inovio Pharmaceuticals (Employee) Michael Dallas, PhD, Inovio Pharmaceuticals, Inc. (Employee, Shareholder) Ami Shah Brown, PhD, Abbot Laboratories (Shareholder)IBB Biotech ETF (Shareholder)Inovio Pharmaceuticals (Employee)J & J (Shareholder)Moderna (Shareholder) Jacqueline E. Shea, PhD, Inovio Pharmaceuticals (Employee, Shareholder) J Joseph Kim, PhD, Inovio (Employee) David Weiner, PhD, Inovio (Board Member, Grant/Research Support, Shareholder, I serve on the SAB in addition to the above activities) Kate Broderick, PhD, Inovio (Employee) Trevor Mc ullan, MSc, Inovio (Shareholder) Jean Boyer, PhD, Inovio (Employee) Laurent Humeau, PhD, Inovio Pharmaceuticals (Employee) Mammen P. Mammen Jr., MD, Inovio Pharmaceuticals (Employee)

18.
Open forum infectious diseases ; 8(Suppl 1):S391-S392, 2021.
Article in English | EuropePMC | ID: covidwho-1564784

ABSTRACT

Background First-generation COVID-19 vaccines are matched to spike protein of the Wuhan-H1 (WT) strain. Convalescent and vaccinee samples show reduced neutralization of SARS-CoV-2 variants of concern (VOC). Next generation DNA vaccines could be matched to single variants or synthetically designed for broader coverage of multiple VOCs. Methods The synthetic consensus (SynCon®) sequence for INO-4802 SARS-CoV-2 spike with focused RBD changes and dual proline mutations was codon-optimized (Figure 1). Sequences for wild-type (pWT) and B.1.351 (pB.1.351) were similarly optimized. Immunogenicity was evaluated in BALB/c mice. Pre-clinical efficacy was assessed in the Syrian Hamster model. Figure 1. Design Strategy for INO-4802 Results INO-4802 induced potent neutralizing antibody responses against WT, B.1.1.7, P.1, and B.1.351 VOC in a murine model. pWT vaccinated animals showed a 3-fold reduction in mean neutralizing ID50 for the B.1.351 pseudotyped virus. INO-4802 immunized animals had significantly higher (p = 0.0408) neutralizing capacity (mean ID50 816.16). ID50 of pB.1.351 serum was reduced 7-fold for B.1.1.7 and significantly lower (p = 0.0068) than INO-4802 (317.44). INO-4802 neutralized WT (548.28) comparable to pWT. INO-4802 also neutralized P.1 (1026.6) (Figure 2). pWT, pB.1.351 or INO-4802 induced similar T-cell responses against all variants. INO-4802 skewed towards a TH1-response. All hamsters vaccinated with INO-4802 or pB.1.351 were protected from weight loss after B.1.351 live virus challenge. 4/6 pWT immunized hamsters were completely protected. pWT immunized hamsters neutralized WT (1090) but not B.1.351 (39.16). INO-4802 neutralized both WT (672.2) and B.1.351 (1121) (Figure 3). We observed higher increase of binding titers following heterologous boost with INO-4802 (3.6 – 4.4 log2-fold change) than homologous boost with pWT (2.0 – 2.4 log2 fold change) (Figure 4). Figure 2. INO-4802 Induces Functional Humoral Immune Response Against SARS-CoV-2 Variants of Concern Figure 3. INO-4802 Protects Hamsters Against Challenge With B.1.351 Live Virus Figure 4. Heterologous Boost with INO-4802 Induces Humoral Immune Response Against SARS-CoV-2 Variants Conclusion Vaccines matching single VOCs, like pB.1.351 and pWT, elicit responses against the matched antigen but have reduced cross-reactivity. Presenting a pan-SARS-CoV-2 approach, INO-4802 may offer substantial advantages in terms of cross-strain protection, reduced susceptibility to escape mutants and non-restricted geographical use. Disclosures Katherine Schultheis, MSc, Inovio Pharmaceuticals (Employee) Charles C. Reed, PhD, Inovio Pharmaceuticals (Employee, Shareholder) Viviane M. Andrade, PhD, Inovio Pharmaceuticals Inc. (Employee) Richa Kalia, MS, Inovio Pharmaceuticals (Employee, Other Financial or Material Support, I have stock options with Inovio Pharmaceuticals as an employee.) Jared Tur, PhD, Inovio (Employee) Blake Schouest, PhD, Inovio Pharmaceuticals (Employee) Dustin Elwood, PhD, Inovio Pharmaceuticals (Employee) Arthur Doan, n/a, Inovio (Employee) Patrick Pezzoli, BS, Inovio (Employee) Dinah Amante, BS, Inovio (Employee) David Weiner, PhD, Inovio (Board Member, Grant/Research Support, Shareholder, I serve on the SAB in addition to the above activities) J Joseph Kim, PhD, Inovio (Employee) Laurent Humeau, PhD, Inovio Pharmaceuticals (Employee) Stephanie Ramos, PhD, Inovio Pharmaceuticals (Employee) Trevor R. F. Smith, PhD, Inovio (Employee, Shareholder) Kate Broderick, PhD, Inovio (Employee).

19.
2021.
Preprint in English | Other preprints | ID: ppcovidwho-295818

ABSTRACT

Here we have employed SynCon ® design technology to construct a DNA vaccine expressing a pan-Spike immunogen (INO-4802) to induce broad immunity across SARS-CoV-2 variants of concern (VOC). Compared to WT and VOC-matched vaccines which showed reduced cross-neutralizing activity, INO-4802 induced potent neutralizing antibodies and T cell responses against WT as well as B.1.1.7, P.1, and B.1.351 VOCs in a murine model. In addition, a hamster challenge model demonstrated that INO-4802 conferred superior protection following intranasal B.1.351 challenge. Protection against weight loss associated with WT, B.1.1.7, P.1 and B.1.617.2 challenge was also demonstrated. Vaccinated hamsters showed enhanced humoral responses against VOC in a heterologous WT vaccine prime and INO-4802 boost setting. These results demonstrate the potential of the pan-SARS-CoV-2 vaccine, INO-4802 to induce cross-reactive immune responses against emerging VOC as either a standalone vaccine, or as a potential boost for individuals previously immunized with WT-matched vaccines.

20.
Gut ; 70(Suppl 4):A83-A84, 2021.
Article in English | ProQuest Central | ID: covidwho-1504946

ABSTRACT

IntroductionIn May 2020, subcutaneous (SC) vedolizumab was approved for use in Inflammatory Bowel Disease (IBD). Patients with IBD have a number of risk factors for a poor outcome from SARS-CoV-2 infection and managing this risk by reducing hospital visits is crucial. Currently there is no information on the process or outcomes of transitioning patients established on intravenous (IV) vedolizumab to SC.MethodsThis is a prospective service evaluation of adult patients who are either stable on IV vedolizumab or have been newly started and opted for SC administration. Between October and December 2020, all suitable patients attending our infusion centre for vedolizumab were offered the option to switch to SC. Initially, the aim was to offer a SC dose to patients in place of their IV infusion with injection training by IBD specialists. This proved to be a challenge as it left a narrow window of time for homecare deliveries to be arranged for subsequent doses. Therefore, the remaining patients who agreed to the switch received an IV infusion at their baseline review, with the aim of administering the first SC dose in place of the next scheduled IV dose.Outcomes include reasons for consenting or declining to switch, patient experience with using SC injections and time saved by not needing to travel to the infusion centre. Data on factors associated with poor outcomes from SARS-CoV-2 infection were collected, including co-morbidities, smoking status, concomitant medication and age.Clinical baseline data collected as part of routine care included disease activity (modified Harvey-Bradshaw Index or Simple Clinical Colitis Activity Index), biochemical results including C-reactive protein, albumin, haemoglobin and platelet count, faecal calprotectin and quality of life using IBD-Control. Trough vedolizumab levels were measured in patients who had had at least 3 IV doses previously. Patients will be reviewed after 12 weeks as part of the switching programme.Results179 patients were offered the opportunity to change to SC vedolizumab (54.2% CD, 44.1% UC, 1.7% IBDU), of which 125 (70%) (64 (51.2%) CD, 58 (46.4%) UC and 3 (2.4%) IBDU) agreed to the switch. The mean age (SD) was 55 (19.4). 11 patients were new to vedolizumab or reloading. The median time taken by patients (leaving home to returning home) to receive their infusions was 180 minutes (IQR 45 to 360).The main reasons for agreeing to switch were patient preference to manage their treatment at home (70.4%), concerns about contracting an infection at the infusion centre (15.7%) and difficulty attending the infusion centre (15.7%). Reasons for patients declining included not wanting to self-inject (28.3%), needle phobia (15.2%), and current instability of symptoms (15.2%). There have been no major adverse events to date.ConclusionsThis is a description of a service evaluation design to monitor outcomes in patients who have consented to transition from IV to SC vedolizumab at one IBD tertiary referral centre.

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