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2022 ◽  
Author(s):  
John Schrom ◽  
Carina Marquez ◽  
Genay Pilarowski ◽  
Grace Wang ◽  
Anthea Mitchell ◽  
...  

In 731 persons seeking COVID-19 testing at a walk-up San Francisco community site in January 2022, simultaneous nasal rapid antigen testing (BinaxNOWTM) and RT-PCR testing was performed. There were 296 (40.5%) positive tests by RT-PCR; 97% of a random sample were the omicron variant. Sensitivity of a single antigen test was 95.2% (95% CI 92-98%); 82.1% (95% CI 77-87%) and 65.2% (95% CI 60-70%) for Ct threshold of < 30, < 35 and no threshold, respectively. A single BinaxNowTM rapid antigen test detected 95% of high viral load omicron cases from nasal specimens. As currently recommended, repeat testing should be done for high- risk persons with an initial negative antigen test result.


2022 ◽  
Vol 12 ◽  
Author(s):  
Suzanne Bezstarosti ◽  
Cynthia S. M. Kramer ◽  
Marry E. I. Franke-van Dijk ◽  
Manon Vergunst ◽  
Kim H. Bakker ◽  
...  

HLA-DQ donor-specific antibodies (DSA) are the most prevalent type of DSA after renal transplantation and have been associated with eplet mismatches between donor and recipient HLA. Eplets are theoretically defined configurations of surface exposed amino acids on HLA molecules that require verification to confirm that they can be recognized by alloantibodies and are therefore clinically relevant. In this study, we isolated HLA-DQ specific memory B cells from immunized individuals by using biotinylated HLA-DQ monomers to generate 15 recombinant human HLA-DQ specific monoclonal antibodies (mAb) with six distinct specificities. Single antigen bead reactivity patterns were analyzed with HLA-EMMA to identify amino acids that were uniquely shared by the reactive HLA alleles to define functional epitopes which were mapped to known eplets. The HLA-DQB1*03:01-specific mAb LB_DQB0301_A and the HLA-DQB1*03-specific mAb LB_DQB0303_C supported the antibody-verification of eplets 45EV and 55PP respectively, while mAbs LB_DQB0402_A and LB_DQB0602_B verified eplet 55R on HLA-DQB1*04/05/06. For three mAbs, multiple uniquely shared amino acid configurations were identified, warranting further studies to define the inducing functional epitope and corresponding eplet. Our unique set of HLA-DQ specific mAbs will be further expanded and will facilitate the in-depth analysis of HLA-DQ epitopes, which is relevant for further studies of HLA-DQ alloantibody pathogenicity in transplantation.


npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Sudha Chivukula ◽  
Timothy Plitnik ◽  
Timothy Tibbitts ◽  
Shrirang Karve ◽  
Anusha Dias ◽  
...  

AbstractRecent approval of mRNA vaccines for emergency use against COVID-19 is likely to promote rapid development of mRNA-based vaccines targeting a wide range of infectious diseases. Compared to conventional approaches, this vaccine modality promises comparable potency while substantially accelerating the pace of development and deployment of vaccine doses. Already demonstrated successfully for single antigen vaccines such as for COVID-19, this technology could be optimized for complex multi-antigen vaccines. Herein, utilizing multiple influenza antigens, we demonstrated the suitability of the mRNA therapeutic (MRT) platform for such applications. Seasonal influenza vaccines have three or four hemagglutinin (HA) antigens of different viral subtypes. In addition, influenza neuraminidase (NA), a tetrameric membrane protein, is identified as an antigen that has been linked to protective immunity against severe viral disease. We detail the efforts in optimizing formulations of influenza candidates that use unmodified mRNA encoding full-length HA or full-length NA encapsulated in lipid nanoparticles (LNPs). HA and NA mRNA-LNP formulations, either as monovalent or as multivalent vaccines, induced strong functional antibody and cellular responses in non-human primates and such antigen-specific antibody responses were associated with protective efficacy against viral challenge in mice.


2021 ◽  
Author(s):  
Yiquan Wang ◽  
Meng Yuan ◽  
Jian Peng ◽  
Ian A. Wilson ◽  
Nicholas C. Wu

In the past two years, the global research in combating COVID-19 pandemic has led to isolation and characterization of numerous human antibodies to the SARS-CoV-2 spike. This enormous collection of antibodies provides an unprecedented opportunity to study the antibody response to a single antigen. Using information derived from 88 research publications and 13 patents, we have assembled a dataset of ~8,000 human antibodies to the SARS-CoV-2 spike from >200 donors. Analysis of antibodies that target different domains of the spike protein reveals a number of common (public) responses to SARS-CoV-2, exemplified via recurring IGHV/IGK(L)V pairs, CDR H3 sequences, IGHD usage, and somatic hypermutation. We further present a proof-of-concept for predicting antigen specificity by using deep learning to differentiate sequences of antibodies to SARS-CoV-2 spike and to influenza hemagglutinin. Overall, this study not only provides an informative resource for antibody research, but fundamentally advances our molecular understanding of public antibody responses.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2781-2781
Author(s):  
Laura Volta ◽  
Renier Myburgh ◽  
Christian Edoardo Pellegrino ◽  
Jan Müller ◽  
C. Matthias Wilk ◽  
...  

Abstract Chimeric antigen receptor (CAR) T-cells are genetically engineered T-cells with potent biocidal activity against respective target-expressing cells. Recently, CAR T-cells have been successfully used clinically to eradicate B cell-derived malignancies by targeting B-cell lineage specific surface antigens (e.g. CD19, BCMA). However, several limitations of current single-antigen targeting CAR T-cell therapies are becoming evident: a) low target tumor-antigen expression might lead to low CAR T-cell targeting efficacy; b) single antigen-targeting might lead to rapid selection of tumor cells with low or loss of antigen expression; c) single antigen-targeting does frequently not generate a high tumor-selectivity as tumor-antigens are frequently also expressed on healthy tissues; d) production of single-antigen CAR T-cells is time- and resource-consuming but results in effectors that target only one antigen; e) on-target off-tumor as well as off-target side-effects are difficult to control without terminally eliminating CAR T-cells in the recipient. While a-c) might be overcome by combinatorial tumor-antigen targeting, d-e) might be addressed by production of Universal CAR T-cells that recognize a specific tag on selective bridging molecules with short half-life. To address some of these limitations in principle, we have here developed universal CAR T-cells targeting fluorescein, as well as fluorescein-labeled antibody-constructs directed against several cell surface antigens, that would serve as versatile, combinatorial selective linkers and, upon target binding, also CAR T-cells activators. We then tested the system on human acute myeloid leukemia (AML) cell lines and primary patient AML blasts. Specifically, we engineered CAR T-cells, termed FluA-CAR T-cells, to display the anti-fluorescein engineered lipocalin FluA, which mediated recognition of randomly or site-specifically fluorescein-labeled antibodies in IgG or short half-life diabody (Db) format, directed against the frequently AML expressed antigens CD33, CD117 and CD371. Site-specific chemical modification methods and cysteine-tagged Db mediated the strongest AML killing results in vitro over a broad range of antibody concentrations. We then hypothesized that FluA-CAR T-cells, targeting AML cells via combinatorial use of linker molecules adapted to specific AML antigen-expression profiles, would allow to most efficiently eliminate AML cells in a dose- and timely-regulated fashion. To this end, we tested single and combinatorial use of fluoresceinated anti-CD117 Db and anti-CD371 Db on MOLM13 AML cell lines, engineered to be either CD117 highCD371 neg, CD117 negCD371 high, or CD117 highCD371 high. Indeed, combination of anti-CD117 and anti-CD371 Db-linkers, resulted in significantly improved MOLM13 cell lysis compared to equimolar concentrations of single agents in vitro (example figure). We then tested the same approach, targeting CD117 +CD371 + primary AML cells from two different patients, using either patient-derived or allogeneic FluA CAR T-cells. Again, the combinatorial use of linkers generated a significantly higher AML cell lysis than the use of single Db linkers. We thus here provide proof-of-concept for the generation of highly potent universal targeting FluA CAR T-cells from healthy donors and AML patients. By choosing suitable CAR-adaptors with respect to their conjugation chemistry and size, it is possible to tightly regulate CAR-T cell activity against CD33, CD117 and CD371 expressing AML cells and likely any tumor cell expressed antigen. Short half-life small molecule linkers will allow to control FluA CAR T-cell on-off activity and combinatorial use of linkers will allow to maximize anti-tumor activity and to minimize on-target off-tumor toxicity. Figure 1 Figure 1. Disclosures Myburgh: University of Zurich: Patents & Royalties: CD117xCD3 TEA. Neri: Philogen S.p.A.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Multiple patents on vascular targeting; ETH Zurich: Patents & Royalties: CD117xCD3 TEA. Manz: CDR-Life Inc: Consultancy, Current holder of stock options in a privately-held company; University of Zurich: Patents & Royalties: CD117xCD3 TEA.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 470-470
Author(s):  
Colleen Annesley ◽  
Corinne Summers ◽  
Michael A. Pulsipher ◽  
Jodi L. Skiles ◽  
Amanda M. Li ◽  
...  

Abstract Introduction: CAR T cells in B-ALL have recently focused on the dual targeting of CD19 and CD22 to enhance long term remissions and prevent antigen negative recurrence that is frequently encountered with single antigen targeting. However, a barrier to this approach has been the retention of dual specificity killing and ongoing persistence. PLAT-05 is a multisite phase 1 trial (NCT03330691) that was undertaken to evaluate the safety and feasibility of SCRI-CAR19x22v1, a dual transduced patient-derived product with lentiviral vectors encoding for either a CD19- or CD22-specific CAR, both with 4-1BB co-stimulation. Early results of the first 27 subjects infused demonstrated feasibility and a favorable safety profile with encouraging CR rates. Products were fractionated evenly between CD19 CAR, CD19+CD22 CAR and CD22 CAR. However, engraftment was predominated by the single CD19 CAR population, leading to unsuccessful eradication of CD19-CD22+ leukemia. This finding led to re-engineering the CD22 CAR construct for enhanced CD22 targeting, and re-initiation of dose finding with the new product, SCRI-CAR19v2. Methods: After enrollment, subjects undergo apheresis followed by a combined CD4/CD8 positive immunomagnetic selection and seeded at a prescribed ratio for co-culture in a closed-system G-Rex bioreactor. Following anti-CD3xCD28 bead stimulation, T cells are transduced with two lentiviral vectors that encode for either a CD19- or CD22-specific CAR. After flu/cy lymphodepletion, CAR T cells are infused at one of three dose levels: 0.5, 1 or 3 X 10 6 CAR T cells/kg. Toxicity is graded according to CTCAEv5 except for CRS and ICANS which are graded per ASTCT criteria. Leukemic response and CAR T cell persistence are evaluated by flow cytometry. Results: 14 subjects enrolled onto PLAT-05 for the SCRI-CAR19x22v2 dose escalation and products were successfully manufactured in all subjects with an average of 8.9 days in culture (range 7-12 days). In contrast to v1 products, the CAR composition of v2 products was skewed in favor of CD22 CAR expression, with median expression of each population as follows: 42% CD22 only, 33% CD19 and CD22, 3.2% CD19 only. Twelve subjects were infused (0.5x10 6/kg n=3, 1x10 6/kg n=3, 3x10 6/kg n=6), 11 of whom had prior exposure to CD19 or CD22 targeted therapies with diverse expression of CD19 and CD22 on the leukemic blasts. No dose limiting toxicities occurred in the 11 fully evaluable subjects (1 subject is pending) and the recommended phase 2 dose was determined as 3x10 6 CAR + cells/kg. CRS was present in 45% of subjects, all grade 1. Neurotoxicity occurred in 45% of subjects, all grade 1 except a single self-limited grade 3 ICANS event (due to a single time point CAPD score). 91% of infused subjects obtained a CR, of which 100% were MRD negative. The non-responder had persistent disease that was CD19-CD22-. The in vivo engraftment of CAR T cells peaked most frequently between day +7 and +14 and was predominated by the CD22 CAR T cells, with some minimal contribution of dual and CD19 CAR T cells. Of the 4 subjects who had previously received an FMC63 based CD19 CAR, expansion was due to solely to the CD22 CARs in all 4 subjects, with apparent rejection of the T cells expressing CD19 CAR. Conclusions: We demonstrate enhanced activity of SCRI-CAR19x22v2 compared to v1, now with dual activity against both CD19 and CD22 demonstrated by elimination of ALL with single antigen expression. We maintained encouraging CR rates with a favorable toxicity profile. Interestingly, the product is predominated by CD22 CAR and CD19/CD22 CAR populations, while in vivo engraftment is predominated by single CD22 CAR expressing T cells. Subjects exposed to prior CD19 murine based CAR rejected the CD19 CAR but engrafted the CD22 CAR with demonstratable activity, a potential advantage of a dual transduced product. The impact of lower CD19 CAR engraftment on durable remissions is unknown. While limited expansion of the CD19 CAR population could be protective against exhaustion, the uneven engraftment of the CAR populations may ultimately lead to single antigen targeting. Optimization of transduction may be required for a more balanced product to maintain dual targeting and give further insight into the behavior of dual-expressing CAR T cells. An expansion cohort is currently underway to further characterize engraftment kinetics and in vivo performance to best inform future development of this product. Figure 1 Figure 1. Disclosures Pulsipher: Jasper Therapeutics: Honoraria; Adaptive: Research Funding; Equillium: Membership on an entity's Board of Directors or advisory committees. Li: Novartis Canada: Membership on an entity's Board of Directors or advisory committees. Jensen: Bluebird Bio: Research Funding; Umoja Biopharma: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Patents & Royalties. Gardner: Novartis: Consultancy; BMS: Patents & Royalties. OffLabel Disclosure: investigational use of SCRI-CAR19x22 will be discussed


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi218-vi218
Author(s):  
Adam Swartz ◽  
Kendra Congdon ◽  
Smita Nair ◽  
Qi-Jing Li ◽  
James Herndon ◽  
...  

Abstract INTRODUCTION Cancer vaccines involve the administration of tumor-associated antigens into the host to generate anti-tumor T cell responses. Glioblastoma (GBM) is a disease with poor prognosis. GBM has a limited number of immunotherapeutic targets due to low mutational load, and is also highly heterogeneous; targeting a single antigen leads to antigen escape and tumor growth. METHODS VMDK mice were subcutaneously implanted with 750,000 SMA560 cells and on days 1 and 8 post implantation, mice were treated with 15 nmol of the universal helper epitope, P30, conjoined to the MHCI-restricted neoepitopes Odc1MHCI-P30 or Topbp1MHCI-P30. Human CD27 (hCD27) transgenic mice were intracranially implanted with CT2A-Odc1, followed by anti-CD27 and 15 nmol of Odc1MHCI-P30. B16.OVA or B16.F10 tumor cells were intracranially implanted in hCD27 mice and received SIINFEKL-P30 or Trp2-P30 conjoined peptides. Tumor growth, survival, or IFNγ secretion of splenic or tumor-infiltrating cells was assessed. RESULTS Unlike Odc1MHCI mixed with P30, conjoined Odc1MHCI-P30 had equivalent immunogenicity and anti-tumor efficacy to that observed with native long Odc1 peptide. Native long peptide of Topbp1 did not elicit an antitumor response, yet Topbp1MHCI-P30 caused an increase in numbers of IFNγ-secreting splenocytes and a decrease in tumor growth and similar to that seen with Odc1MHCI-P30 . Anti-CD27 treatment significantly increased numbers of IFNγ secreting splenocytes in Odc1MHCI-P30 vaccinated hCD27 mice, and the use of anti-CD27 with Odc1MHCI-P30 achieved long-term survival in 90% of tumor bearing hCD27 mice. Anti-CD27 synergized with SIINFEKL-P30 and Trp2-P30 to significantly improve survival after administration of these peptides. CONCLUSIONS Our work shows that poorly immunogenic neoantigens can be conjoined to P30 and used to generate an anti-tumor response in mouse models of GBM, and anti-tumor responses of conjoined peptides can be enhanced with anti-CD27 treatment. Together, these data demonstrate the efficacy of neoantigen vaccines for the treatment of heterogeneous GBM.


2021 ◽  
Vol 4 (10) ◽  
pp. e2128652
Author(s):  
Timo Vesikari ◽  
Adam Finn ◽  
Pierre van Damme ◽  
Isabel Leroux-Roels ◽  
Geert Leroux-Roels ◽  
...  

2021 ◽  
pp. 101482
Author(s):  
Mepur H. Ravindranath ◽  
Edward J. Filippone ◽  
Carly J. Amato-Menker ◽  
Fernando A. Arosa ◽  
Ballabh Das ◽  
...  

Vaccines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 964
Author(s):  
Kelsey A. Pilewski ◽  
Kevin J. Kramer ◽  
Ivelin S. Georgiev

Vaccination remains one of the most successful medical interventions in history, significantly decreasing morbidity and mortality associated with, or even eradicating, numerous infectious diseases. Although traditional immunization strategies have recently proven insufficient in the face of many highly mutable and emerging pathogens, modern strategies aim to rationally engineer a single antigen or cocktail of antigens to generate a focused, protective immune response. However, the effect of cocktail vaccination (simultaneous immunization with multiple immunogens) on the antibody response to each individual antigen within the combination, remains largely unstudied. To investigate whether immunization with a cocktail of diverse antigens would result in decreased antibody titer against each unique antigen in the cocktail compared to immunization with each antigen alone, we immunized mice with surface proteins from uropathogenic Escherichia coli, Mycobacterium tuberculosis, and Neisseria meningitides, and monitored the development of antigen-specific IgG antibody responses. We found that antigen-specific endpoint antibody titers were comparable across immunization groups by study conclusion (day 70). Further, we discovered that although cocktail-immunized mice initially elicited more robust antibody responses, the rate of titer development decreases significantly over time compared to single antigen-immunized mice. Investigating the basic properties that govern the development of antigen-specific antibody responses will help inform the design of future combination immunization regimens.


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