128 results on '"Ledgerwood JE"'
Search Results
2. P15-17. Social media as a tool for engaging and educating audiences around HIV vaccine research and clinical trial participation
- Author
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Ledgerwood JE, Graham BS, Hartman BI, and Sitar S
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2009
- Full Text
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3. Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses
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Kanekiyo, M, Joyce, MG, Gillespie, RA, Gallagher, JR, Andrews, SF, Yassine, HM, Wheatley, AK, Fisher, BE, Ambrozak, DR, Creanga, A, Leung, K, Yang, ES, Boyoglu-Barnum, S, Georgiev, IS, Tsybovsky, Y, Prabhakaran, MS, Andersen, H, Kong, W-P, Baxa, U, Zephir, KL, Ledgerwood, JE, Koup, RA, Kwong, PD, Harris, AK, McDermott, AB, Mascola, JR, Graham, BS, Kanekiyo, M, Joyce, MG, Gillespie, RA, Gallagher, JR, Andrews, SF, Yassine, HM, Wheatley, AK, Fisher, BE, Ambrozak, DR, Creanga, A, Leung, K, Yang, ES, Boyoglu-Barnum, S, Georgiev, IS, Tsybovsky, Y, Prabhakaran, MS, Andersen, H, Kong, W-P, Baxa, U, Zephir, KL, Ledgerwood, JE, Koup, RA, Kwong, PD, Harris, AK, McDermott, AB, Mascola, JR, and Graham, BS
- Abstract
The present vaccine against influenza virus has the inevitable risk of antigenic discordance between the vaccine and the circulating strains, which diminishes vaccine efficacy. This necessitates new approaches that provide broader protection against influenza. Here we designed a vaccine using the hypervariable receptor-binding domain (RBD) of viral hemagglutinin displayed on a nanoparticle (np) able to elicit antibody responses that neutralize H1N1 influenza viruses spanning over 90 years. Co-display of RBDs from multiple strains across time, so that the adjacent RBDs are heterotypic, provides an avidity advantage to cross-reactive B cells. Immunization with the mosaic RBD-np elicited broader antibody responses than those induced by an admixture of nanoparticles encompassing the same set of RBDs as separate homotypic arrays. Furthermore, we identified a broadly neutralizing monoclonal antibody in a mouse immunized with mosaic RBD-np. The mosaic antigen array signifies a unique approach that subverts monotypic immunodominance and allows otherwise subdominant cross-reactive B cell responses to emerge.
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- 2019
4. A monovalent chimpanzee adenovirus Ebola vaccine — preliminary report
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Rampling, T, Ewer, K, Bowyer, G, Wright, D, Imoukhuede, EB, Payne, R, Hartnell, F, Gibani, M, Bliss, C, Minhinnick, A, Wilkie, M, Venkatraman, N, Poulton, I, Lella, N, Roberts, R, Sierra-Davidson, K, Krähling, V, Berrie, E, Roman, F, De Ryck, I, Nicosia, A, Sullivan, NJ, Stanley, DA, Ledgerwood, JE, Schwartz, RM, Siani, L, Colloca, S, Folgori, A, Di Marco, S, Cortese, R, Becker, S, Graham, BS, Koup, RA, Levine, MM, Moorthy, V, Pollard, AJ, Draper, SJ, Ballou, WR, Lawrie, A, Gilbert, SC, and Hill, AV
- Abstract
Background The West African outbreak of Ebola virus disease has caused more than 8500 deaths. A vaccine could contribute to outbreak control in the region. We assessed a monovalent formulation of a chimpanzee adenovirus 3 (ChAd3)-vectored vaccine encoding the surface glycoprotein of Zaire ebolavirus (EBOV), matched to the outbreak strain. Methods After expedited regulatory and ethics approvals, 60 healthy adult volunteers in Oxford, United Kingdom, received a single dose of the ChAd3 vaccine at one of three dose levels: 1×10(10) viral particles, 2.5×10(10) viral particles, and 5×10(10) viral particles (with 20 participants per group). Safety was assessed over the next 4 weeks. Antibodies were measured on enzyme-linked immunosorbent assay (ELISA) and T-cell responses on enzyme-linked immunospot (ELISpot) and flow-cytometry assays. Results No safety concerns were identified at any of the dose levels studied. Fever developed in 2 of the 59 participants who were evaluated. Prolonged activated partial-thromboplastin times and transient hyperbilirubinemia were observed in 4 and 8 participants, respectively. Geometric mean antibody responses on ELISA were highest (469 units; range, 58 to 4051; 68% response rate) at 4 weeks in the high-dose group, which had a 100% response rate for T cells on ELISpot, peaking at day 14 (median, 693 spot-forming cells per million peripheral-blood mononuclear cells). Flow cytometry revealed more CD4+ than CD8+ T-cell responses. At the vaccine doses tested, both antibody and T-cell responses were detected but at levels lower than those induced in macaques protected by the same vaccine. Conclusions The ChAd3 monovalent vaccine against EBOV was immunogenic at the doses tested. (Funded by the Wellcome Trust and others; ClinicalTrials.gov number, NCT02240875 .).
- Published
- 2016
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5. P15-17. Social media as a tool for engaging and educating audiences around HIV vaccine research and clinical trial participation
- Author
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Sitar, S, primary, Hartman, BI, additional, Graham, BS, additional, and Ledgerwood, JE, additional
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- 2009
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6. P14-10. Comparable immunogenicity of VRC DNA and rAd5 HIV-1 vaccines delivered by intramuscular, subcutaneous and intradermal routes in healthy adults (VRC 011)
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Ledgerwood, JE, primary, Novik, L, additional, Enama, ME, additional, Gordon, IJ, additional, Holman, LA, additional, Nason, MC, additional, Bailer, RT, additional, Roederer, M, additional, Koup, RA, additional, Mascola, JR, additional, Nabel, GJ, additional, and Graham, BS, additional
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- 2009
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7. P18-06. Increased HIV-specific immunity in HIV-infected individuals vaccinated with a DNA prime, rAd5 boost regimen
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Casazza, JP, primary, Bowman, K, additional, Adzaku, S, additional, Ambrozak, DA, additional, Roederer, M, additional, Bailer, RT, additional, Enama, M, additional, Nason, M, additional, Ledgerwood, JE, additional, Graham, BS, additional, and Koup, RA, additional
- Published
- 2009
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8. Phase 1 dose-escalation trial evaluating a group 2 influenza hemagglutinin stabilized stem nanoparticle vaccine.
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Casazza JP, Hofstetter AR, Costner PJM, Holman LA, Hendel CS, Widge AT, Wu RL, Whalen WR, Cunningham J, Arthur A, Wang X, Ola A, Saunders J, Mendoza F, Novik L, Burgos Florez MC, Ortega-Villa AM, Apte PJ, Strom L, Wang L, Imam M, Basappa M, Naisan M, Castro M, Trost JF, Narpala SR, Vanderven HA, Yamshchikov GV, Berkowitz NM, Gordon IJ, Plummer SH, Wycuff DL, Vazquez S, Gillespie RA, Creanga A, Adams WC, Carlton K, Gall JG, McDermott AB, Serebryannyy LA, Houser KV, Koup RA, Graham BS, Ledgerwood JE, Mascola JR, Pierson TC, Andrews SF, Kanekiyo M, and Dropulic LK
- Abstract
The relative conservation of the influenza hemagglutinin (HA) stem compared to that of the immunodominant HA head makes the HA stem an attractive target for broadly protective influenza vaccines. Here we report the first-in-human, dose-escalation, open-label trial (NCT04579250) evaluating an unadjuvanted group 2 stabilized stem ferritin nanoparticle vaccine based on the H10 A/Jiangxi-Donghu/346/2013 influenza HA, H10ssF, in healthy adults. Participants received a single 20 mcg dose (n = 3) or two 60 mcg doses 16 weeks apart (n = 22). Vaccination with H10ssF was safe and well tolerated with only mild systemic and local reactogenicity reported. No serious adverse events occurred. Vaccination significantly increased homologous H10 HA stem binding and neutralizing antibodies at 2 weeks after both first and second vaccinations, and these responses remained above baseline at 40 weeks. Heterologous H3 and H7 binding antibodies also significantly increased after each vaccination and remained elevated throughout the study. These data indicate that the group 2 HA stem nanoparticle vaccine is safe and induces stem-directed binding and neutralizing antibodies., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2024
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9. Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.
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Mayer BT, Zhang L, deCamp AC, Yu C, Sato A, Angier H, Seaton KE, Yates N, Ledgerwood JE, Mayer K, Caskey M, Nussenzweig M, Stephenson K, Julg B, Barouch DH, Sobieszczyk ME, Edupuganti S, Kelley CF, McElrath MJ, Gelderblom HC, Pensiero M, McDermott A, Gama L, Koup RA, Gilbert PB, Cohen MS, Corey L, Hyrien O, Tomaras GD, and Huang Y
- Abstract
Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.
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- 2024
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10. Phase 1 trial evaluating safety and pharmacokinetics of HIV-1 broadly neutralizing mAbs 10E8VLS and VRC07-523LS.
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Awan SF, Pegu A, Strom L, Carter CA, Hendel CS, Holman LA, Costner PJ, Trofymenko O, Dyer R, Gordon IJ, Rothwell RSS, Hickman SP, Conan-Cibotti M, Doria-Rose NA, Lin BC, O'Connell S, Narpala SR, Almasri CG, Liu C, Ko S, Kwon YD, Namboodiri AM, Pandey JP, Arnold FJ, Carlton K, Gall JG, Kwong PD, Capparelli EV, Bailer RT, McDermott AB, Chen GL, Koup RA, Mascola JR, Coates EE, Ledgerwood JE, and Gaudinski MR
- Subjects
- Humans, HIV Antibodies, Broadly Neutralizing Antibodies pharmacology, Antibodies, Monoclonal pharmacology, HIV Infections drug therapy, HIV Infections prevention & control, HIV-1, HIV Seropositivity
- Abstract
BACKGROUNDBroadly neutralizing monoclonal antibodies (bNAbs) represent a promising strategy for HIV-1 immunoprophylaxis and treatment. 10E8VLS and VRC07-523LS are bNAbs that target the highly conserved membrane-proximal external region (MPER) and the CD4-binding site of the HIV-1 viral envelope glycoprotein, respectively.METHODSIn this phase 1, open-label trial, we evaluated the safety and pharmacokinetics of 5 mg/kg 10E8VLS administered alone, or concurrently with 5 mg/kg VRC07-523LS, via s.c. injection to healthy non-HIV-infected individuals.RESULTSEight participants received either 10E8VLS alone (n = 6) or 10E8VLS and VRC07-523LS in combination (n = 2). Five (n = 5 of 8, 62.5%) participants who received 10E8VLS experienced moderate local reactogenicity, and 1 participant (n = 1/8, 12.5%) experienced severe local reactogenicity. Further trial enrollment was stopped, and no participant received repeat dosing. All local reactogenicity resolved without sequelae. 10E8VLS retained its neutralizing capacity, and no functional anti-drug antibodies were detected; however, a serum t1/2 of 8.1 days was shorter than expected. Therefore, the trial was voluntarily stopped per sponsor decision (Vaccine Research Center, National Institute of Allergy and Infectious Diseases [NIAID], NIH). Mechanistic studies performed to investigate the underlying reason for the reactogenicity suggest that multiple mechanisms may have contributed, including antibody aggregation and upregulation of local inflammatory markers.CONCLUSION10E8VLS resulted in unexpected reactogenicity and a shorter t1/2 in comparison with previously tested bNAbs. These studies may facilitate identification of nonreactogenic second-generation MPER-targeting bNAbs, which could be an effective strategy for HIV-1 immunoprophylaxis and treatment.TRIAL REGISTRATIONClinicaltrials.gov, accession no. NCT03565315.FUNDINGDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.
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- 2024
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11. Heterologous cAd3-Ebola and MVA-EbolaZ vaccines are safe and immunogenic in US and Uganda phase 1/1b trials.
- Author
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Happe M, Hofstetter AR, Wang J, Yamshchikov GV, Holman LA, Novik L, Strom L, Kiweewa F, Wakabi S, Millard M, Kelley CF, Kabbani S, Edupuganti S, Beck A, Kaltovich F, Murray T, Tsukerman S, Carr D, Ashman C, Stanley DA, Ploquin A, Bailer RT, Schwartz R, Cham F, Tindikahwa A, Hu Z, Gordon IJ, Rouphael N, Houser KV, Coates EE, Graham BS, Koup RA, Mascola JR, Sullivan NJ, Robb ML, Ake JA, Lyke KE, Mulligan MJ, Ledgerwood JE, and Kibuuka H
- Abstract
Ebola virus disease (EVD) is a filoviral infection caused by virus species of the Ebolavirus genus including Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV). We investigated the safety and immunogenicity of a heterologous prime-boost regimen involving a chimpanzee adenovirus 3 vectored Ebola vaccine [either monovalent (cAd3-EBOZ) or bivalent (cAd3-EBO)] prime followed by a recombinant modified vaccinia virus Ankara EBOV vaccine (MVA-EbolaZ) boost in two phase 1/1b randomized open-label clinical trials in healthy adults in the United States (US) and Uganda (UG). Trial US (NCT02408913) enrolled 140 participants, including 26 EVD vaccine-naïve and 114 cAd3-Ebola-experienced participants (April-November 2015). Trial UG (NCT02354404) enrolled 90 participants, including 60 EVD vaccine-naïve and 30 DNA Ebola vaccine-experienced participants (February-April 2015). All tested vaccines and regimens were safe and well tolerated with no serious adverse events reported related to study products. Solicited local and systemic reactogenicity was mostly mild to moderate in severity. The heterologous prime-boost regimen was immunogenic, including induction of durable antibody responses which peaked as early as two weeks and persisted up to one year after each vaccination. Different prime-boost intervals impacted the magnitude of humoral and cellular immune responses. The results from these studies demonstrate promising implications for use of these vaccines in both prophylactic and outbreak settings., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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12. Author Correction: High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials.
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Reeves DB, Mayer BT, deCamp AC, Huang Y, Zhang B, Carpp LN, Magaret CA, Juraska M, Gilbert PB, Montefiori DC, Bar KJ, Cardozo-Ojeda EF, Schiffer JT, Rossenkhan R, Edlefsen P, Morris L, Mkhize NN, Williamson C, Mullins JI, Seaton KE, Tomaras GD, Andrew P, Mgodi N, Ledgerwood JE, Cohen MS, Corey L, Naidoo L, Orrell C, Goepfert PA, Casapia M, Sobieszczyk ME, Karuna ST, and Edupuganti S
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- 2024
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13. High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials.
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Reeves DB, Mayer BT, deCamp AC, Huang Y, Zhang B, Carpp LN, Magaret CA, Juraska M, Gilbert PB, Montefiori DC, Bar KJ, Cardozo-Ojeda EF, Schiffer JT, Rossenkhan R, Edlefsen P, Morris L, Mkhize NN, Williamson C, Mullins JI, Seaton KE, Tomaras GD, Andrew P, Mgodi N, Ledgerwood JE, Cohen MS, Corey L, Naidoo L, Orrell C, Goepfert PA, Casapia M, Sobieszczyk ME, Karuna ST, and Edupuganti S
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- Humans, Antibodies, Neutralizing, Viral Load, HIV Antibodies, Models, Theoretical, HIV Infections, HIV-1
- Abstract
The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300-1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected., (© 2023. The Author(s).)
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- 2023
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14. Safety, tolerability, and immunogenicity of the Ebola Sudan chimpanzee adenovirus vector vaccine (cAd3-EBO S) in healthy Ugandan adults: a phase 1, open-label, dose-escalation clinical trial.
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Mwesigwa B, Houser KV, Hofstetter AR, Ortega-Villa AM, Naluyima P, Kiweewa F, Nakabuye I, Yamshchikov GV, Andrews C, O'Callahan M, Strom L, Schech S, Anne Eller L, Sondergaard EL, Scott PT, Amare MF, Modjarrad K, Wamala A, Tindikahwa A, Musingye E, Nanyondo J, Gaudinski MR, Gordon IJ, Holman LA, Saunders JG, Costner PJM, Mendoza FH, Happe M, Morgan P, Plummer SH, Hickman SP, Vazquez S, Murray T, Cordon J, Dulan CNM, Hunegnaw R, Basappa M, Padilla M, Gajjala SR, Swanson PA 2nd, Lin BC, Coates EE, Gall JG, McDermott AB, Koup RA, Mascola JR, Ploquin A, Sullivan NJ, Kibuuka H, Ake JA, and Ledgerwood JE
- Subjects
- Animals, Humans, Adult, Pan troglodytes, Uganda, Sudan, Antibodies, Viral, Adenoviridae genetics, Glycoproteins, Immunogenicity, Vaccine, Double-Blind Method, Hemorrhagic Fever, Ebola prevention & control, Ebola Vaccines, Ebolavirus genetics, Adenoviruses, Simian genetics
- Abstract
Background: Sudan Ebola virus can cause severe viral disease, with an average case fatality rate of 54%. A recent outbreak of Sudan Ebola virus in Uganda caused 55 deaths among 164 confirmed cases in the second half of 2022. Although vaccines and therapeutics specific for Zaire Ebola virus have been approved for use during outbreak situations, Sudan Ebola virus is an antigenically distinct virus with no approved vaccines available., Methods: In this phase 1, open-label, dose-escalation trial we evaluated the safety, tolerability, and immunogenicity of a monovalent chimpanzee adenovirus 3 vaccine against Sudan Ebola virus (cAd3-EBO S) at Makerere University Walter Reed Project in Kampala, Uganda. Study participants were recruited from the Kampala metropolitan area using International Review Board-approved written and electronic media explaining the trial intervention. Healthy adults without previous receipt of Ebola, Marburg, or cAd3 vectored-vaccines were enrolled to receive cAd3-EBO S at either 1 × 10
10 or 1 × 1011 particle units (PU) in a single intramuscular vaccination and were followed up for 48 weeks. Primary safety and tolerability endpoints were assessed in all vaccine recipients by reactogenicity for the first 7 days, adverse events for the first 28 days, and serious adverse events throughout the study. Secondary immunogenicity endpoints included evaluation of binding antibody and T-cell responses against the Sudan Ebola virus glycoprotein, and neutralising antibody responses against the cAd3 vector at 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT04041570, and is completed., Findings: 40 healthy adults were enrolled between July 22 and Oct 1, 2019, with 20 receiving 1 × 1010 PU and 20 receiving 1 × 1011 PU of cAd3-EBO S. 38 (95%) participants completed all follow-up visits. The cAd3-EBO S vaccine was well tolerated with no severe adverse events. The most common reactogenicity symptoms were pain or tenderness at the injection site (34 [85%] of 40), fatigue (29 [73%] of 40), and headache (26 [65%] of 40), and were mild to moderate in severity. Positive responses for glycoprotein-specific binding antibodies were induced by 2 weeks in 31 (78%) participants, increased to 34 (85%) participants by 4 weeks, and persisted to 48 weeks in 31 (82%) participants. Most participants developed glycoprotein-specific T-cell responses (20 [59%, 95% CI 41-75] of 34; six participants were removed from the T cell analysis after failing quality control parameters) by 4 weeks after vaccination, and neutralising titres against the cAd3 vector were also increased from baseline (90% inhibitory concentration of 47, 95% CI 30-73) to 4 weeks after vaccination (196, 125-308)., Interpretation: The cAd3-EBO S vaccine was safe at both doses, rapidly inducing immune responses in most participants after a single injection. The rapid onset and durability of the vaccine-induced antibodies make this vaccine a strong candidate for emergency deployment in Sudan Ebola virus outbreaks., Funding: National Institutes of Health via interagency agreement with Walter Reed Army Institute of Research., Competing Interests: Declaration of interests NJS is listed on patents involving cAd3-vectored vaccines. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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15. Chikungunya virus virus-like particle vaccine is well tolerated and immunogenic in chikungunya seropositive individuals.
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McCarty JM, Bedell L, Mendy J, Coates EE, Chen GL, Ledgerwood JE, Tredo SR, Warfield KL, and Richardson JS
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- Humans, Antibodies, Viral, Antibodies, Neutralizing, Immunogenicity, Vaccine, Double-Blind Method, Chikungunya virus, Chikungunya Fever prevention & control, Vaccines, Virus-Like Particle, Viral Vaccines
- Abstract
In a phase 2 safety and immunogenicity study of a chikungunya virus virus-like particle (CHIKV VLP) vaccine in an endemic region, of 400 total participants, 78 were found to be focus reduction neutralizing antibody seropositive at vaccination despite being ELISA seronegative at screening, of which 39 received vaccine. This post hoc analysis compared safety and immunogenicity of CHIKV VLP vaccine in seropositive (n = 39) versus seronegative (n = 155) vaccine recipients for 72 weeks post-vaccination. There were no differences in solicited adverse events, except injection site swelling in 10.3% of seropositive versus 0.6% of seronegative recipients (p = 0.006). Baseline seropositive vaccine recipients had stronger post-vaccination luciferase neutralizing antibody responses versus seronegative recipients (peak geometric mean titer of 3594 and 1728, respectively) persisting for 72 weeks, with geometric mean fold increases of 3.1 and 13.2, respectively. In this small study, CHIKV VLP vaccine was well-tolerated and immunogenic in individuals with pre-existing immunity. ClinicalTrials.gov Identifier: NCT02562482., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)
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- 2023
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16. Vaccine elicitation and structural basis for antibody protection against alphaviruses.
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Sutton MS, Pletnev S, Callahan V, Ko S, Tsybovsky Y, Bylund T, Casner RG, Cerutti G, Gardner CL, Guirguis V, Verardi R, Zhang B, Ambrozak D, Beddall M, Lei H, Yang ES, Liu T, Henry AR, Rawi R, Schön A, Schramm CA, Shen CH, Shi W, Stephens T, Yang Y, Florez MB, Ledgerwood JE, Burke CW, Shapiro L, Fox JM, Kwong PD, and Roederer M
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- Animals, Mice, Antibodies, Viral, Macaca, Alphavirus, Encephalitis Virus, Venezuelan Equine genetics, Viral Vaccines
- Abstract
Alphaviruses are RNA viruses that represent emerging public health threats. To identify protective antibodies, we immunized macaques with a mixture of western, eastern, and Venezuelan equine encephalitis virus-like particles (VLPs), a regimen that protects against aerosol challenge with all three viruses. Single- and triple-virus-specific antibodies were isolated, and we identified 21 unique binding groups. Cryo-EM structures revealed that broad VLP binding inversely correlated with sequence and conformational variability. One triple-specific antibody, SKT05, bound proximal to the fusion peptide and neutralized all three Env-pseudotyped encephalitic alphaviruses by using different symmetry elements for recognition across VLPs. Neutralization in other assays (e.g., chimeric Sindbis virus) yielded variable results. SKT05 bound backbone atoms of sequence-diverse residues, enabling broad recognition despite sequence variability; accordingly, SKT05 protected mice against Venezuelan equine encephalitis virus, chikungunya virus, and Ross River virus challenges. Thus, a single vaccine-elicited antibody can protect in vivo against a broad range of alphaviruses., Competing Interests: Declaration of interests NIH has submitted a provisional patent application for select antibodies described in this manuscript on which M.S.S., S.K., R.V., P.D.K., and M.R. are co-inventors., (Published by Elsevier Inc.)
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- 2023
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17. Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial.
- Author
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Lyke KE, Berry AA, Mason K, Idris AH, O'Callahan M, Happe M, Strom L, Berkowitz NM, Guech M, Hu Z, Castro M, Basappa M, Wang L, Low K, Holman LA, Mendoza F, Gordon IJ, Plummer SH, Trofymenko O, Strauss KS, Joshi S, Shrestha B, Adams M, Chagas AC, Murphy JR, Stein J, Hickman S, McDougal A, Lin B, Narpala SR, Vazquez S, Serebryannyy L, McDermott A, Gaudinski MR, Capparelli EV, Coates EE, Wu RL, Ledgerwood JE, Dropulic LK, and Seder RA
- Subjects
- Adult, Animals, Humans, Antibodies, Monoclonal therapeutic use, Plasmodium falciparum, Malaria, Falciparum drug therapy, Malaria, Falciparum prevention & control, Antimalarials, Malaria Vaccines therapeutic use
- Abstract
Background: Human monoclonal antibodies might offer an important new approach to reduce malaria morbidity and mortality. In the first two parts of a three-part clinical trial, the antimalarial monoclonal antibody CIS43LS conferred high protection against parasitaemia at doses of 20 mg/kg or 40 mg/kg administered intravenously followed by controlled human malaria infection. The ability of CIS43LS to confer protection at lower doses or by the subcutaneous route is unknown. We aimed to provide data on the safety and optimisation of dose and route for the human antimalaria monoclonal antibody CIS43LS., Methods: VRC 612 Part C was the third part of a three-part, first-in-human, phase 1, adaptive trial, conducted at the University of Maryland, Baltimore Center for Vaccine Development and Global Health, Baltimore, MD, USA. We enrolled adults aged 18-50 years with no previous malaria vaccinations or infections, in a sequential, dose-escalating manner. Eligible participants received the monoclonal antibody CIS43LS in a single, open-label dose of 1 mg/kg, 5 mg/kg, or 10 mg/kg intravenously, or 5 mg/kg or 10 mg/kg subcutaneously. Participants underwent controlled human malaria infection by the bites of five mosquitoes infected with Plasmodium falciparum 3D7 strain approximately 8 weeks after their monoclonal antibody inoculation. Six additional control participants who did not receive CIS43LS underwent controlled human malaria infection simultaneously. Participants were followed-up daily on days 7-18 and day 21, with qualitative PCR used for P falciparum detection. Participants who tested positive for P falciparum were treated with atovaquone-proguanil and those who remained negative were treated at day 21. Participants were followed-up until 24 weeks after dosing. The primary outcome was safety and tolerability of CIS43LS at each dose level, assessed in the as-treated population. Secondary outcomes included protective efficacy of CIS43LS after controlled human malaria infection. This trial is now complete and is registered with ClinicalTrials.gov, NCT04206332., Findings: Between Sept 1, 2021, and Oct 29, 2021, 47 people were assessed for eligibility and 31 were enrolled (one subsequently withdrew and was replaced) and assigned to receive doses of 1 mg/kg (n=7), 5 mg/kg (n=4), and 10 mg/kg (n=3) intravenously and 5 mg/kg (n=4) and 10 mg/kg (n=4) subcutaneously, or to the control group (n=8). CIS43LS administration was safe and well tolerated; no serious adverse events occurred. CIS43LS protected 18 (82%) of 22 participants who received a dose. No participants developed parasitaemia following dosing at 5 mg/kg intravenously or subcutaneously, or at 10 mg/kg intravenously or subcutaneously. All six control participants and four of seven participants dosed at 1 mg/kg intravenously developed parasitaemia after controlled human malaria infection., Interpretation: CIS43LS was safe and well tolerated, and conferred protection against P falciparum at low doses and by the subcutaneous route, providing evidence that this approach might be useful to prevent malaria across several clinical use cases., Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health., Competing Interests: Declaration of interests AHI and RAS are listed as inventors on a pending patent application describing CIS43 and related antibodies. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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18. An influenza H1 hemagglutinin stem-only immunogen elicits a broadly cross-reactive B cell response in humans.
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Andrews SF, Cominsky LY, Shimberg GD, Gillespie RA, Gorman J, Raab JE, Brand J, Creanga A, Gajjala SR, Narpala S, Cheung CSF, Harris DR, Zhou T, Gordon I, Holman L, Mendoza F, Houser KV, Chen GL, Mascola JR, Graham BS, Kwong PD, Widge A, Dropulic LK, Ledgerwood JE, Kanekiyo M, and McDermott AB
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- Adolescent, Adult, Aged, Humans, Middle Aged, Young Adult, Antibodies, Neutralizing, Antibodies, Viral, Epitopes, Hemagglutinin Glycoproteins, Influenza Virus, Hemagglutinins, Influenza Vaccines, Influenza, Human
- Abstract
Current yearly seasonal influenza vaccines primarily induce an antibody response directed against the immunodominant but continually diversifying hemagglutinin (HA) head region. These antibody responses provide protection against the vaccinating strain but little cross-protection against other influenza strains or subtypes. To focus the immune response on subdominant but more conserved epitopes on the HA stem that might protect against a broad range of influenza strains, we developed a stabilized H1 stem immunogen lacking the immunodominant head displayed on a ferritin nanoparticle (H1ssF). Here, we evaluated the B cell response to H1ssF in healthy adults ages 18 to 70 in a phase 1 clinical trial (NCT03814720). We observed both a strong plasmablast response and sustained elicitation of cross-reactive HA stem-specific memory B cells after vaccination with H1ssF in individuals of all ages. The B cell response was focused on two conserved epitopes on the H1 stem, with a highly restricted immunoglobulin repertoire unique to each epitope. On average, two-thirds of the B cell and serological antibody response recognized a central epitope on the H1 stem and exhibited broad neutralization across group 1 influenza virus subtypes. The remaining third recognized an epitope near the viral membrane anchor and was largely limited to H1 strains. Together, we demonstrate that an H1 HA immunogen lacking the immunodominant HA head produces a robust and broadly neutralizing HA stem-directed B cell response.
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- 2023
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19. An influenza hemagglutinin stem nanoparticle vaccine induces cross-group 1 neutralizing antibodies in healthy adults.
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Widge AT, Hofstetter AR, Houser KV, Awan SF, Chen GL, Burgos Florez MC, Berkowitz NM, Mendoza F, Hendel CS, Holman LA, Gordon IJ, Apte P, Liang CJ, Gaudinski MR, Coates EE, Strom L, Wycuff D, Vazquez S, Stein JA, Gall JG, Adams WC, Carlton K, Gillespie RA, Creanga A, Crank MC, Andrews SF, Castro M, Serebryannyy LA, Narpala SR, Hatcher C, Lin BC, O'Connell S, Freyn AW, Rosado VC, Nachbagauer R, Palese P, Kanekiyo M, McDermott AB, Koup RA, Dropulic LK, Graham BS, Mascola JR, and Ledgerwood JE
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- Adolescent, Adult, Aged, Humans, Middle Aged, Young Adult, Antibodies, Neutralizing, Antibodies, Viral, Broadly Neutralizing Antibodies, Hemagglutinin Glycoproteins, Influenza Virus, Hemagglutinins, Pandemics, COVID-19, Influenza Vaccines, Influenza, Human
- Abstract
Influenza vaccines could be improved by platforms inducing cross-reactive immunity. Immunodominance of the influenza hemagglutinin (HA) head in currently licensed vaccines impedes induction of cross-reactive neutralizing stem-directed antibodies. A vaccine without the variable HA head domain has the potential to focus the immune response on the conserved HA stem. This first-in-human dose-escalation open-label phase 1 clinical trial (NCT03814720) tested an HA stabilized stem ferritin nanoparticle vaccine (H1ssF) based on the H1 HA stem of A/New Caledonia/20/1999. Fifty-two healthy adults aged 18 to 70 years old enrolled to receive either 20 μg of H1ssF once ( n = 5) or 60 μg of H1ssF twice ( n = 47) with a prime-boost interval of 16 weeks. Thirty-five (74%) 60-μg dose participants received the boost, whereas 11 (23%) boost vaccinations were missed because of public health restrictions in the early stages of the COVID-19 pandemic. The primary objective of this trial was to evaluate the safety and tolerability of H1ssF, and the secondary objective was to evaluate antibody responses after vaccination. H1ssF was safe and well tolerated, with mild solicited local and systemic reactogenicity. The most common symptoms included pain or tenderness at the injection site ( n = 10, 19%), headache ( n = 10, 19%), and malaise ( n = 6, 12%). We found that H1ssF elicited cross-reactive neutralizing antibodies against the conserved HA stem of group 1 influenza viruses, despite previous H1 subtype head-specific immunity. These responses were durable, with neutralizing antibodies observed more than 1 year after vaccination. Our results support this platform as a step forward in the development of a universal influenza vaccine.
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- 2023
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20. Safety, tolerability, and immunogenicity of the chimpanzee adenovirus type 3-vectored Marburg virus (cAd3-Marburg) vaccine in healthy adults in the USA: a first-in-human, phase 1, open-label, dose-escalation trial.
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Hamer MJ, Houser KV, Hofstetter AR, Ortega-Villa AM, Lee C, Preston A, Augustine B, Andrews C, Yamshchikov GV, Hickman S, Schech S, Hutter JN, Scott PT, Waterman PE, Amare MF, Kioko V, Storme C, Modjarrad K, McCauley MD, Robb ML, Gaudinski MR, Gordon IJ, Holman LA, Widge AT, Strom L, Happe M, Cox JH, Vazquez S, Stanley DA, Murray T, Dulan CNM, Hunegnaw R, Narpala SR, Swanson PA 2nd, Basappa M, Thillainathan J, Padilla M, Flach B, O'Connell S, Trofymenko O, Morgan P, Coates EE, Gall JG, McDermott AB, Koup RA, Mascola JR, Ploquin A, Sullivan NJ, Ake JA, and Ledgerwood JE
- Subjects
- Animals, Adult, Humans, Pan troglodytes, Antibodies, Viral, Vaccines, Synthetic adverse effects, Adenoviridae, Glycoproteins, Double-Blind Method, Marburgvirus, Adenoviruses, Simian
- Abstract
Background: WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy adults., Methods: We did a first-in-human, phase 1, open-label, dose-escalation trial of the cAd3-Marburg vaccine at the Walter Reed Army Institute of Research Clinical Trials Center in the USA. Healthy adults aged 18-50 years were assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10
10 or 1 × 1011 particle units (pu). Primary safety endpoints included reactogenicity assessed for the first 7 days and all adverse events assessed for 28 days after vaccination. Secondary immunogenicity endpoints were assessment of binding antibody responses and T-cell responses against the Marburg virus glycoprotein insert, and assessment of neutralising antibody responses against the cAd3 vector 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT03475056., Findings: Between Oct 9, 2018, and Jan 31, 2019, 40 healthy adults were enrolled and assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 1010 pu (n=20) or 1 × 1011 pu (n=20). The cAd3-Marburg vaccine was safe, well tolerated, and immunogenic. All enrolled participants received cAd3-Marburg vaccine, with 37 (93%) participants completing follow-up visits; two (5%) participants moved from the area and one (3%) was lost to follow-up. No serious adverse events related to vaccination occurred. Mild to moderate reactogenicity was observed after vaccination, with symptoms of injection site pain and tenderness (27 [68%] of 40 participants), malaise (18 [45%] of 40 participants), headache (17 [43%] of 40 participants), and myalgia (14 [35%] of 40 participants) most commonly reported. Glycoprotein-specific antibodies were induced in 38 (95%) of 40 participants 4 weeks after vaccination, with geometric mean titres of 421 [95% CI 209-846] in the 1 × 1010 pu group and 545 [276-1078] in the 1 × 1011 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13-119] in the 1 ×1010 pu group and 27 [95-156] in the 1 ×1011 pu group; both p<0·0001). T-cell responses to the glycoprotein insert and neutralising responses against the cAd3 vector were also increased at 4 weeks after vaccination., Interpretation: This first-in-human trial of this cAd3-Marburg vaccine showed the agent is safe and immunogenic, with a safety profile similar to previously tested cAd3-vectored filovirus vaccines. 95% of participants produced a glycoprotein-specific antibody response at 4 weeks after a single vaccination, which remained in 70% of participants at 48 weeks. These findings represent a crucial step in the development of a vaccine for emergency deployment against a re-emerging pathogen that has recently expanded its reach to new regions., Funding: National Institutes of Health., Competing Interests: Declaration of interests NJS is listed on patents involving cAd3-vectored vaccines. All other authors declare no competing interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2023
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21. Application of B cell immortalization for the isolation of antibodies and B cell clones from vaccine and infection settings.
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Boswell KL, Watkins TA, Cale EM, Samsel J, Andrews SF, Ambrozak DR, Driscoll JI, Messina MA, Narpala S, Hopp CS, Cagigi A, Casazza JP, Yamamoto T, Zhou T, Schief WR, Crompton PD, Ledgerwood JE, Connors M, Gama L, Kwong PD, McDermott A, Mascola JR, and Koup RA
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- Humans, B-Lymphocytes, Antibodies, Neutralizing, Cell Line, Clone Cells, HIV Seropositivity, Vaccines
- Abstract
The isolation and characterization of neutralizing antibodies from infection and vaccine settings informs future vaccine design, and methodologies that streamline the isolation of antibodies and the generation of B cell clones are of great interest. Retroviral transduction to express Bcl-6 and Bcl-xL and transform primary B cells has been shown to promote long-term B cell survival and antibody secretion in vitro , and can be used to isolate antibodies from memory B cells. However, application of this methodology to B cell subsets from different tissues and B cells from chronically infected individuals has not been well characterized. Here, we characterize Bcl-6/Bcl-xL B cell immortalization across multiple tissue types and B cell subsets in healthy and HIV-1 infected individuals, as well as individuals recovering from malaria. In healthy individuals, naïve and memory B cell subsets from PBMCs and tonsil tissue transformed with similar efficiencies, and displayed similar characteristics with respect to their longevity and immunoglobulin secretion. In HIV-1-viremic individuals or in individuals with recent malaria infections, the exhausted CD27
- CD21- memory B cells transformed with lower efficiency, but the transformed B cells expanded and secreted IgG with similar efficiency. Importantly, we show that this methodology can be used to isolate broadly neutralizing antibodies from HIV-infected individuals. Overall, we demonstrate that Bcl-6/Bcl-xL B cell immortalization can be used to isolate antibodies and generate B cell clones from different B cell populations, albeit with varying efficiencies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Boswell, Watkins, Cale, Samsel, Andrews, Ambrozak, Driscoll, Messina, Narpala, Hopp, Cagigi, Casazza, Yamamoto, Zhou, Schief, Crompton, Ledgerwood, Connors, Gama, Kwong, McDermott, Mascola and Koup.)- Published
- 2022
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22. Safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted chikungunya virus-like particle vaccine: a randomised, double-blind, parallel-group, phase 2 trial.
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Bennett SR, McCarty JM, Ramanathan R, Mendy J, Richardson JS, Smith J, Alexander J, Ledgerwood JE, de Lame PA, Royalty Tredo S, Warfield KL, and Bedell L
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- Adjuvants, Immunologic, Adult, Aluminum Hydroxide, Antibodies, Neutralizing, Antibodies, Viral, Double-Blind Method, Humans, Immunogenicity, Vaccine, Chikungunya Fever, Vaccines, Virus-Like Particle
- Abstract
Background: Chikungunya virus (CHIKV) disease is an ongoing public health threat. We aimed to evaluate the safety and immunogenicity of PXVX0317, an aluminium hydroxide-adjuvanted formulation of a CHIKV virus-like particle (VLP) vaccine., Methods: This randomised, double-blind, parallel-group, phase 2 trial was conducted at three clinical trial centres in the USA. Eligible participants were healthy CHIKV-naïve adults aged 18-45 years. Participants were stratified by site and randomly assigned (1:1:1:1:1:1:1:1) to one of the eight vaccination groups using a block size of 16. Group 1 received two doses of unadjuvanted PXVX0317 28 days apart (2 × 20 μg; standard); all other groups received adjuvanted PXVX0317: groups 2-4 received two doses 28 days apart (2 × 6 μg [group 2], 2 × 10 μg [group 3], or 2 × 20 μg [group 4]; standard); group 4 also received a booster dose 18 months after the first active injection (40 μg; standard plus booster); groups 5-7 received two doses 14 days apart (2 × 6 μg [group 5], 2 × 10 μg [group 6], or 2 × 20 μg [group 7]; accelerated); and group 8 received one dose (1 × 40 μg; single). The primary endpoint was the geometric mean titre of anti-CHIKV neutralising antibody on day 57 (28 days after the last vaccination), assessed in the immunogenicity-evaluable population. Additionally, we assessed safety. This trial is registered at ClinicalTrials.gov, NCT03483961., Findings: This trial was conducted from April 18, 2018, to Sept 21, 2020; 468 participants were assessed for eligibility. Of these, 415 participants were randomly assigned to eight groups (n=53 in groups 1, 5, and 6; n=52 in groups 2 and 8; n=51 in groups 3 and 7; and n=50 in group 4) and 373 were evaluable for immunogenicity. On day 57, serum neutralising antibody geometric mean titres were 2057·0 (95% CI 1584·8-2670·0) in group 1, 1116·2 (852·5-1461·4; p=0·0015 vs group 1 used as a reference) in group 2, 1465·3 (1119·1-1918·4; p=0·076) in group 3, 2023·8 (1550·5-2641·7; p=0·93) in group 4, 920·1 (710·9-1190·9; p<0·0001) in group 5, 1206·9 (932·4-1562·2; p=0·0045) in group 6, 1562·8 (1204·1-2028·3; p=0·14) in group 7, and 1712·5 (1330·0-2205·0; p=0·32) in group 8. In group 4, a booster dose increased serum neutralising antibody geometric mean titres from 215·7 (95% CI 160·9-289·1) on day 547 to 10 941·1 (7378·0-16 225·1) on day 575. Durability of the immune response (evaluated in groups 1, 4, and 8) was shown up to 2 years. The most common solicited adverse event was pain at the injection site, reported in 12 (23%) of 53 participants who received the unadjuvanted vaccine (group 1) and 111 (31%) of 356 who received the adjuvanted vaccine. No vaccine-related serious adverse events were reported., Interpretation: PXVX0317 was well tolerated and induced a robust and durable serum neutralising antibody immune response against CHIKV up to 2 years. A single 40 μg injection of adjuvanted PXVX0317 is being further investigated in phase 3 clinical trials (NCT05072080 and NCT05349617)., Funding: Emergent BioSolutions., Competing Interests: Declaration of interests SRB, RR, JM, JSR, JS, LB, JA, KLW, and SRT were employees of Emergent BioSolutions. LB, JM, SRT, RR, JSR, and KLW own stock in Emergent BioSolutions. P-AL and JMM were consultants and received consulting fees from Emergent BioSolutions. SRB received consulting fees from Emergent BioSolutions. JA and JS are inventors on an international patent application submitted by Emergent BioSolutions for the chikungunya virus-like particle vaccine. JEL declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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23. Safety and Pharmacokinetics of Monoclonal Antibodies VRC07-523LS and PGT121 Administered Subcutaneously for Human Immunodeficiency Virus Prevention.
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Mahomed S, Garrett N, Capparelli EV, Osman F, Harkoo I, Yende-Zuma N, Gengiah TN, Archary D, Samsunder N, Baxter C, Mkhize NN, Modise T, Carlton K, McDermott A, Moore PL, Karim QA, Barouch DH, Fast PE, Mascola JR, Ledgerwood JE, Morris L, and Abdool Karim SS
- Subjects
- Antibodies, Monoclonal, Antibodies, Neutralizing, Female, HIV, HIV Antibodies, Humans, Immunization, Passive, Antineoplastic Agents, Immunological, HIV Infections
- Abstract
Background: Effective, long-acting prevention approaches are needed to reduce human immunodeficiency virus (HIV) incidence. We evaluated the safety and pharmacokinetics of VRC07-523LS and PGT121 administered subcutaneously alone and in combination as passive immunization for young women in South Africa., Methods: CAPRISA 012A was a randomized, double-blinded, placebo-controlled, dose-escalation phase 1 trial. We enrolled 45 HIV-negative women into 9 groups and assessed safety, tolerability, pharmacokinetics, neutralization activity, and antidrug antibody levels. Pharmacokinetic modeling was conducted to predict steady-state concentrations for 12- and 24-weekly dosing intervals., Results: VRC07-523LS and PGT121, administered subcutaneously, were safe and well tolerated. Most common reactogenicity events were injection site tenderness and headaches. Nine product-related adverse events were mild and transient. Median VRC07-523LS concentrations after 20 mg/kg doses were 9.65 μg/mL and 3.86 μg/mL at 16 and 24 weeks. The median week 8 concentration after the 10 mg/kg PGT121 dose was 8.26 μg/mL. Modeling of PGT121 at 20 mg/kg showed median concentrations of 1.37 μg/mL and 0.22 μg/mL at 16 and 24 weeks. Half-lives of VRC07-523LS and PGT121 were 29 and 20 days. Both antibodies retained neutralizing activity postadministration and no antidrug antibodies were detected., Conclusions: Subcutaneous administration of VRC07-523LS in combination with optimized versions of PGT121 or other antibodies should be further assessed for HIV prevention., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.)
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- 2022
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24. Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria.
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Wu RL, Idris AH, Berkowitz NM, Happe M, Gaudinski MR, Buettner C, Strom L, Awan SF, Holman LA, Mendoza F, Gordon IJ, Hu Z, Campos Chagas A, Wang LT, Da Silva Pereira L, Francica JR, Kisalu NK, Flynn BJ, Shi W, Kong WP, O'Connell S, Plummer SH, Beck A, McDermott A, Narpala SR, Serebryannyy L, Castro M, Silva R, Imam M, Pittman I, Hickman SP, McDougal AJ, Lukoskie AE, Murphy JR, Gall JG, Carlton K, Morgan P, Seo E, Stein JA, Vazquez S, Telscher S, Capparelli EV, Coates EE, Mascola JR, Ledgerwood JE, Dropulic LK, and Seder RA
- Subjects
- Administration, Cutaneous, Administration, Intravenous, Adult, Animals, Child, Child, Preschool, Humans, Malaria, Falciparum drug therapy, Malaria, Falciparum prevention & control, Parasitemia parasitology, Plasmodium falciparum, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal pharmacokinetics, Malaria prevention & control
- Abstract
Background: New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed., Methods: We conducted a phase 1 clinical trial to assess the safety and pharmacokinetics of L9LS, a next-generation antimalarial monoclonal antibody, and its protective efficacy against controlled human malaria infection in healthy adults who had never had malaria or received a vaccine for malaria. The participants received L9LS either intravenously or subcutaneously at a dose of 1 mg, 5 mg, or 20 mg per kilogram of body weight. Within 2 to 6 weeks after the administration of L9LS, both the participants who received L9LS and the control participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying Plasmodium falciparum (3D7 strain)., Results: No safety concerns were identified. L9LS had an estimated half-life of 56 days, and it had dose linearity, with the highest mean (±SD) maximum serum concentration (C
max ) of 914.2±146.5 μg per milliliter observed in participants who had received 20 mg per kilogram intravenously and the lowest mean Cmax of 41.5±4.7 μg per milliliter observed in those who had received 1 mg per kilogram intravenously; the mean Cmax was 164.8±31.1 in the participants who had received 5 mg per kilogram intravenously and 68.9±22.3 in those who had received 5 mg per kilogram subcutaneously. A total of 17 L9LS recipients and 6 control participants underwent controlled human malaria infection. Of the 17 participants who received a single dose of L9LS, 15 (88%) were protected after controlled human malaria infection. Parasitemia did not develop in any of the participants who received 5 or 20 mg per kilogram of intravenous L9LS. Parasitemia developed in 1 of 5 participants who received 1 mg per kilogram intravenously, 1 of 5 participants who received 5 mg per kilogram subcutaneously, and all 6 control participants through 21 days after the controlled human malaria infection. Protection conferred by L9LS was seen at serum concentrations as low as 9.2 μg per milliliter., Conclusions: In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729.)., (Copyright © 2022 Massachusetts Medical Society.)- Published
- 2022
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25. Safety and immunogenicity of a trivalent virus-like particle vaccine against western, eastern, and Venezuelan equine encephalitis viruses: a phase 1, open-label, dose-escalation, randomised clinical trial.
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Coates EE, Edupuganti S, Chen GL, Happe M, Strom L, Widge A, Florez MB, Cox JH, Gordon I, Plummer S, Ola A, Yamshchikov G, Andrews C, Curate-Ingram S, Morgan P, Nagar S, Collins MH, Bray A, Nguyen T, Stein J, Case CL, Kaltovich F, Wycuff D, Liang CJ, Carlton K, Vazquez S, Mascola JR, and Ledgerwood JE
- Subjects
- Adjuvants, Immunologic, Adult, Animals, Antibodies, Neutralizing, Antibodies, Viral, Double-Blind Method, Female, Horses, Humans, Immunogenicity, Vaccine, Male, Middle Aged, Pain, Young Adult, Alphavirus, Encephalitis Virus, Venezuelan Equine, Vaccines, Virus-Like Particle
- Abstract
Background: Western (WEEV), eastern (EEEV), and Venezuelan (VEEV) equine encephalitis viruses are mosquito-borne pathogens classified as potential biological warfare agents for which there are currently no approved human vaccines or therapies. We aimed to evaluate the safety, tolerability, and immunogenicity of an investigational trivalent virus-like particle (VLP) vaccine, western, eastern, and Venezuelan equine encephalitis (WEVEE) VLP, composed of WEEV, EEEV, and VEEV VLPs., Methods: The WEVEE VLP vaccine was evaluated in a phase 1, randomised, open-label, dose-escalation trial at the Hope Clinic of the Emory Vaccine Center at Emory University, Atlanta, GA, USA. Eligible participants were healthy adults aged 18-50 years with no previous vaccination history with an investigational alphavirus vaccine. Participants were assigned to a dose group of 6 μg, 30 μg, or 60 μg vaccine product and were randomly assigned (1:1) to receive the WEVEE VLP vaccine with or without aluminium hydroxide suspension (alum) adjuvant by intramuscular injection at study day 0 and at week 8. The primary outcomes were the safety and tolerability of the vaccine (assessed in all participants who received at least one administration of study product) and the secondary outcome was immune response measured as neutralising titres by plaque reduction neutralisation test (PRNT) 4 weeks after the second vaccination. This trial is registered at ClinicalTrials.gov, NCT03879603., Findings: Between April 2, 2019, and June 13, 2019, 30 trial participants were enrolled (mean age 32 years, range 21-48; 16 [53%] female participants and 14 [47%] male participants). Six groups of five participants each received 6 μg, 30 μg, or 60 μg vaccine doses with or without adjuvant, and all 30 participants completed study follow-up. Vaccinations were safe and well tolerated. The most frequently reported symptoms were mild injection-site pain and tenderness (22 [73%] of 30) and malaise (15 [50%] of 30). Dose-dependent differences in the frequency of pain and tenderness were found between the 6 μg, 30 μg, and 60 μg groups (p=0·0217). No significant differences were observed between dosing groups for any other reactogenicity symptom. Two adverse events (mild elevated blood pressure and moderate asymptomatic neutropenia) were assessed as possibly related to the study product in one trial participant (60 μg dose with alum); both resolved without clinical sequelae. 4 weeks after second vaccine administration, neutralising antibodies were induced in all study groups with the highest response seen against all three vaccine antigens in the 30 μg plus alum group (PRNT
80 geometric mean titre for EEEV 60·8, 95% CI 29·9-124·0; for VEEV 111·5, 49·8-249·8; and for WEEV 187·9, 90·0-392·2). Finally, 4 weeks after second vaccine administration, for all doses, the majority of trial participants developed an immune response to all three vaccine components (24 [83%] of 29 for EEEV; 26 [90%] of 29 for VEEV; 27 [93%] of 29 for WEEV; and 22 [76%] of 29 for EEEV, VEEV, and WEEV combined)., Interpretation: The favourable safety profile and neutralising antibody responses, along with pressing public health need, support further evaluation of the WEVEE VLP vaccine in advanced-phase clinical trials., Funding: The Vaccine Research Center of the National Institute of Allergy and Infectious Diseases, National Institutes of Health funded the clinical trial. The US Department of Defense contributed funding for manufacturing of the study product., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2022
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26. Safety and immunogenicity of an HIV-1 prefusion-stabilized envelope trimer (Trimer 4571) vaccine in healthy adults: A first-in-human open-label, randomized, dose-escalation, phase 1 clinical trial.
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Houser KV, Gaudinski MR, Happe M, Narpala S, Verardi R, Sarfo EK, Corrigan AR, Wu R, Rothwell RS, Novik L, Hendel CS, Gordon IJ, Berkowitz NM, Cartagena CT, Widge AT, Coates EE, Strom L, Hickman S, Conan-Cibotti M, Vazquez S, Trofymenko O, Plummer S, Stein J, Case CL, Nason M, Biju A, Parchment DK, Changela A, Cheng C, Duan H, Geng H, Teng IT, Zhou T, O'Connell S, Barry C, Carlton K, Gall JG, Flach B, Doria-Rose NA, Graham BS, Koup RA, McDermott AB, Mascola JR, Kwong PD, and Ledgerwood JE
- Abstract
Background: Advances in therapeutic drugs have increased life-expectancies for HIV-infected individuals, but the need for an effective vaccine remains. We assessed safety and immunogenicity of HIV-1 vaccine, Trimer 4571 (BG505 DS-SOSIP.664) adjuvanted with aluminum hydroxide (alum), in HIV-negative adults., Methods: We conducted a phase I, randomized, open-label, dose-escalation trial at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Eligible participants were HIV-negative, healthy adults between 18-50 years. Participants were randomized 1:1 to receive Trimer 4571 adjuvanted with 500 mcg alum by either the subcutaneous (SC) or intramuscular (IM) route at weeks 0, 8, and 20 in escalating doses of 100 mcg or 500 mcg. The primary objectives were to evaluate the safety and tolerability of Trimer 4571 with a secondary objective of evaluating vaccine-induced antibody responses. The primary and safety endpoints were evaluated in all participants who received at least one dose of Trimer 4571. Trial results were summarized using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03783130., Findings: Between March 7 and September 11, 2019, 16 HIV-negative participants were enrolled, including six (38%) males and ten (62%) females. All participants received three doses of Trimer 4571. Solicited reactogenicity was mild to moderate in severity, with one isolated instance of severe injection site redness (6%) following a third 500 mcg SC administration. The most commonly reported solicited symptoms included mild injection site tenderness in 14 (88%) and mild myalgia in six (38%) participants. The most frequent unsolicited adverse event attributed to vaccination was mild injection site pruritus in six (38%) participants. Vaccine-induced seropositivity occurred in seven (44%) participants and resolved in all but one (6%). No serious adverse events occurred. Trimer 4571-specific binding antibodies were detected in all groups two weeks after regimen completion, primarily focused on the glycan-free trimer base. Neutralizing antibody activity was limited to the 500 mcg dose groups., Interpretation: Trimer 4571 was safe, well tolerated, and immunogenic in this first-in-human trial. While this phase 1 trial is limited in size, our results inform and support further evaluation of prefusion-stabilized HIV-1 envelope trimers as a component of vaccine design strategies to generate broadly neutralizing antibodies against HIV-1., Funding: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health., Competing Interests: CC, HG, JRM, and PDK are listed on patent applications involving Trimer 4571. All other authors declare no competing interests., (© 2022 The Authors.)
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- 2022
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27. Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial.
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Casazza JP, Cale EM, Narpala S, Yamshchikov GV, Coates EE, Hendel CS, Novik L, Holman LA, Widge AT, Apte P, Gordon I, Gaudinski MR, Conan-Cibotti M, Lin BC, Nason MC, Trofymenko O, Telscher S, Plummer SH, Wycuff D, Adams WC, Pandey JP, McDermott A, Roederer M, Sukienik AN, O'Dell S, Gall JG, Flach B, Terry TL, Choe M, Shi W, Chen X, Kaltovich F, Saunders KO, Stein JA, Doria-Rose NA, Schwartz RM, Balazs AB, Baltimore D, Nabel GJ, Koup RA, Graham BS, Ledgerwood JE, and Mascola JR
- Subjects
- Adult, Antibodies, Neutralizing, Broadly Neutralizing Antibodies, Dependovirus genetics, HIV Antibodies, Humans, HIV Infections drug therapy, HIV-1
- Abstract
Adeno-associated viral vector-mediated transfer of DNA coding for broadly neutralizing anti-HIV antibodies (bnAbs) offers an alternative to attempting to induce protection by vaccination or by repeated infusions of bnAbs. In this study, we administered a recombinant bicistronic adeno-associated virus (AAV8) vector coding for both the light and heavy chains of the potent broadly neutralizing HIV-1 antibody VRC07 (AAV8-VRC07) to eight adults living with HIV. All participants remained on effective anti-retroviral therapy (viral load (VL) <50 copies per milliliter) throughout this phase 1, dose-escalation clinical trial ( NCT03374202 ). AAV8-VRC07 was given at doses of 5 × 10
10 , 5 × 1011 and 2.5 × 1012 vector genomes per kilogram by intramuscular (IM) injection. Primary endpoints of this study were to assess the safety and tolerability of AAV8-VRC07; to determine the pharmacokinetics and immunogenicity of in vivo VRC07 production; and to describe the immune response directed against AAV8-VRC07 vector and its products. Secondary endpoints were to assess the clinical effects of AAV8-VRC07 on CD4 T cell count and VL and to assess the persistence of VRC07 produced in participants. In this cohort, IM injection of AAV8-VRC07 was safe and well tolerated. No clinically significant change in CD4 T cell count or VL occurred during the 1-3 years of follow-up reported here. In participants who received AAV8-VRC07, concentrations of VRC07 were increased 6 weeks (P = 0.008) and 52 weeks (P = 0.016) after IM injection of the product. All eight individuals produced measurable amounts of serum VRC07, with maximal VRC07 concentrations >1 µg ml-1 in three individuals. In four individuals, VRC07 serum concentrations remained stable near maximal concentration for up to 3 years of follow-up. In exploratory analyses, neutralizing activity of in vivo produced VRC07 was similar to that of in vitro produced VRC07. Three of eight participants showed a non-idiotypic anti-drug antibody (ADA) response directed against the Fab portion of VRC07. This ADA response appeared to decrease the production of serum VRC07 in two of these three participants. These data represent a proof of concept that adeno-associated viral vectors can durably produce biologically active, difficult-to-induce bnAbs in vivo, which could add valuable new tools to the fight against infectious diseases., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)- Published
- 2022
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28. SARS-CoV-2 Omicron Variant Neutralization after mRNA-1273 Booster Vaccination.
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Pajon R, Doria-Rose NA, Shen X, Schmidt SD, O'Dell S, McDanal C, Feng W, Tong J, Eaton A, Maglinao M, Tang H, Manning KE, Edara VV, Lai L, Ellis M, Moore KM, Floyd K, Foster SL, Posavad CM, Atmar RL, Lyke KE, Zhou T, Wang L, Zhang Y, Gaudinski MR, Black WP, Gordon I, Guech M, Ledgerwood JE, Misasi JN, Widge A, Sullivan NJ, Roberts PC, Beigel JH, Korber B, Baden LR, El Sahly H, Chalkias S, Zhou H, Feng J, Girard B, Das R, Aunins A, Edwards DK, Suthar MS, Mascola JR, and Montefiori DC
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- 2022
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29. A single residue in influenza virus H2 hemagglutinin enhances the breadth of the B cell response elicited by H2 vaccination.
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Andrews SF, Raab JE, Gorman J, Gillespie RA, Cheung CSF, Rawi R, Cominsky LY, Boyington JC, Creanga A, Shen CH, Harris DR, Olia AS, Nazzari AF, Zhou T, Houser KV, Chen GL, Mascola JR, Graham BS, Kanekiyo M, Ledgerwood JE, Kwong PD, and McDermott AB
- Subjects
- Antibodies, Neutralizing, Antibodies, Viral, Child, Clinical Trials, Phase I as Topic, Epitopes, Hemagglutinin Glycoproteins, Influenza Virus, Hemagglutinins, Humans, Vaccination, Influenza A Virus, H5N1 Subtype, Influenza Vaccines, Influenza, Human
- Abstract
Conserved epitopes on the influenza hemagglutinin (HA) stem are an attractive target for universal vaccine strategies as they elicit broadly neutralizing antibodies. Such antibody responses to stem-specific epitopes have been extensively characterized for HA subtypes H1 and H5 in humans. H2N2 influenza virus circulated 50 years ago and represents a pandemic threat due to the lack of widespread immunity, but, unlike H1 and H5, the H2 HA stem contains Phe45
HA2 predicted to sterically clash with HA stem-binding antibodies characterized to date. To understand the effect of Phe45HA2 , we compared the HA stem-specific B cell response in post hoc analyses of two phase 1 clinical trials, one testing vaccination with an H2 ferritin nanoparticle immunogen ( NCT03186781 ) and one with an inactivated H5N1 vaccine ( NCT01086657 ). In H2-naive individuals, the magnitude of the B cell response was equivalent, but H2-elicited HA stem-binding B cells displayed greater cross-reactivity than those elicited by H5. However, in individuals with childhood H2 exposure, H5-elicited HA stem-binding B cells also displayed high cross-reactivity, suggesting recall of memory B cells formed 50 years ago. Overall, we propose that a one-residue difference on an HA immunogen can alter establishment and expansion of broadly neutralizing memory B cells. These data have implications for stem-based universal influenza vaccination strategies., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)- Published
- 2022
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30. Safety and immunogenicity of a ferritin nanoparticle H2 influenza vaccine in healthy adults: a phase 1 trial.
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Houser KV, Chen GL, Carter C, Crank MC, Nguyen TA, Burgos Florez MC, Berkowitz NM, Mendoza F, Hendel CS, Gordon IJ, Coates EE, Vazquez S, Stein J, Case CL, Lawlor H, Carlton K, Gaudinski MR, Strom L, Hofstetter AR, Liang CJ, Narpala S, Hatcher C, Gillespie RA, Creanga A, Kanekiyo M, Raab JE, Andrews SF, Zhang Y, Yang ES, Wang L, Leung K, Kong WP, Freyn AW, Nachbagauer R, Palese P, Bailer RT, McDermott AB, Koup RA, Gall JG, Arnold F, Mascola JR, Graham BS, and Ledgerwood JE
- Subjects
- Adult, Antibodies, Viral, Ferritins, Humans, Immunogenicity, Vaccine, Vaccination adverse effects, Influenza Vaccines, Influenza, Human, Nanoparticles, Orthomyxoviridae
- Abstract
Currently, licensed seasonal influenza vaccines display variable vaccine effectiveness, and there remains a need for novel vaccine platforms capable of inducing broader responses against viral protein domains conserved among influenza subtypes. We conducted a first-in-human, randomized, open-label, phase 1 clinical trial ( NCT03186781 ) to evaluate a novel ferritin (H2HA-Ferritin) nanoparticle influenza vaccine platform. The H2 subtype has not circulated in humans since 1968. Adults born after 1968 have been exposed to only the H1 subtype of group 1 influenza viruses, which shares a conserved stem with H2. Including both H2-naive and H2-exposed adults in the trial allowed us to evaluate memory responses against the conserved stem domain in the presence or absence of pre-existing responses against the immunodominant HA head domain. Fifty healthy participants 18-70 years of age received H2HA-Ferritin intramuscularly as a single 20-μg dose (n = 5) or a 60-μg dose either twice in a homologous (n = 25) prime-boost regimen or once in a heterologous (n = 20) prime-boost regimen after a matched H2 DNA vaccine prime. The primary objective of this trial was to evaluate the safety and tolerability of H2HA-Ferritin either alone or in prime-boost regimens. The secondary objective was to evaluate antibody responses after vaccination. Both vaccines were safe and well tolerated, with the most common solicited symptom being mild headache after both H2HA-Ferritin (n = 15, 22%) and H2 DNA (n = 5, 25%). Exploratory analyses identified neutralizing antibody responses elicited by the H2HA-Ferritin vaccine in both H2-naive and H2-exposed populations. Furthermore, broadly neutralizing antibody responses against group 1 influenza viruses, including both seasonal H1 and avian H5 subtypes, were induced in the H2-naive population through targeting the HA stem. This ferritin nanoparticle vaccine technology represents a novel, safe and immunogenic platform with potential application for pandemic preparedness and universal influenza vaccine development., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)
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- 2022
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31. Booster of mRNA-1273 Strengthens SARS-CoV-2 Omicron Neutralization.
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Doria-Rose NA, Shen X, Schmidt SD, O'Dell S, McDanal C, Feng W, Tong J, Eaton A, Maglinao M, Tang H, Manning KE, Edara VV, Lai L, Ellis M, Moore K, Floyd K, Foster SL, Atmar RL, Lyke KE, Zhou T, Wang L, Zhang Y, Gaudinski MR, Black WP, Gordon I, Guech M, Ledgerwood JE, Misasi JN, Widge A, Roberts PC, Beigel J, Korber B, Pajon R, Mascola JR, Suthar MS, and Montefiori DC
- Abstract
The Omicron variant of SARS-CoV-2 is raising concerns because of its increased transmissibility and potential for reduced susceptibility to antibody neutralization. To assess the potential risk of this variant to existing vaccines, serum samples from mRNA-1273 vaccine recipients were tested for neutralizing activity against Omicron and compared to neutralization titers against D614G and Beta in live virus and pseudovirus assays. Omicron was 41-84-fold less sensitive to neutralization than D614G and 5.3-7.4-fold less sensitive than Beta when assayed with serum samples obtained 4 weeks after 2 standard inoculations with 100 μg mRNA-1273. A 50 μg boost increased Omicron neutralization titers and may substantially reduce the risk of symptomatic vaccine breakthrough infections.
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- 2021
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32. Limited Flavivirus Cross-Reactive Antibody Responses Elicited by a Zika Virus Deoxyribonucleic Acid Vaccine Candidate in Humans.
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Burgomaster KE, Foreman BM, Aleshnick MA, Larman BC, Gordon DN, Maciejewski S, Morabito KM, Ledgerwood JE, Gaudinski MR, Chen GL, Mascola JR, Debbink K, Dowd KA, Graham BS, and Pierson TC
- Subjects
- Antibodies, Viral, Antibody Formation, Cross Reactions, Humans, Neutralization Tests, Plasmids, Vaccines, Antibodies, Neutralizing, Flavivirus genetics, Flavivirus immunology, Vaccines, DNA, Zika Virus genetics, Zika Virus immunology, Zika Virus Infection prevention & control
- Abstract
Zika virus (ZIKV) deoxyribonucleic acid vaccine VRC5283 encoding viral structural genes has been shown to be immunogenic in humans. Recognizing that antigenically related flaviviruses cocirculate in regions with ZIKV activity, we explored the degree of antibody cross-reactivity elicited by this vaccine candidate using genetically diverse flaviviruses. The antibody response of vaccinated individuals with no evidence of prior flavivirus infection or vaccine experience had a limited capacity to bind heterologous viruses. In contrast, vaccine-elicited antibodies from individuals with prior flavivirus experience had a greater capacity to bind, but not neutralize, distantly related flaviviruses. These findings suggest that prior flavivirus exposure shapes the humoral immune response to vaccination., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)
- Published
- 2021
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33. Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase.
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El Sahly HM, Baden LR, Essink B, Doblecki-Lewis S, Martin JM, Anderson EJ, Campbell TB, Clark J, Jackson LA, Fichtenbaum CJ, Zervos M, Rankin B, Eder F, Feldman G, Kennelly C, Han-Conrad L, Levin M, Neuzil KM, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Polakowski L, Mascola JR, Ledgerwood JE, Graham BS, August A, Clouting H, Deng W, Han S, Leav B, Manzo D, Pajon R, Schödel F, Tomassini JE, Zhou H, and Miller J
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Adolescent, Adult, Aged, COVID-19 epidemiology, COVID-19 Vaccines adverse effects, Follow-Up Studies, Humans, Immunization, Secondary, Incidence, Intention to Treat Analysis, Male, Middle Aged, Patient Acuity, Single-Blind Method, Treatment Outcome, Young Adult, COVID-19 prevention & control, COVID-19 Vaccines immunology, Immunogenicity, Vaccine
- Abstract
Background: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported., Methods: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021., Results: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified., Conclusions: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)., (Copyright © 2021 Massachusetts Medical Society.)
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- 2021
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34. Durability of mRNA-1273 vaccine-induced antibodies against SARS-CoV-2 variants.
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Pegu A, O'Connell SE, Schmidt SD, O'Dell S, Talana CA, Lai L, Albert J, Anderson E, Bennett H, Corbett KS, Flach B, Jackson L, Leav B, Ledgerwood JE, Luke CJ, Makowski M, Nason MC, Roberts PC, Roederer M, Rebolledo PA, Rostad CA, Rouphael NG, Shi W, Wang L, Widge AT, Yang ES, Beigel JH, Graham BS, Mascola JR, Suthar MS, McDermott AB, Doria-Rose NA, Arega J, Beigel JH, Buchanan W, Elsafy M, Hoang B, Lampley R, Kolhekar A, Koo H, Luke C, Makhene M, Nayak S, Pikaart-Tautges R, Roberts PC, Russell J, Sindall E, Albert J, Kunwar P, Makowski M, Anderson EJ, Bechnak A, Bower M, Camacho-Gonzalez AF, Collins M, Drobeniuc A, Edara VV, Edupuganti S, Floyd K, Gibson T, Ackerley CMG, Johnson B, Kamidani S, Kao C, Kelley C, Lai L, Macenczak H, McCullough MP, Peters E, Phadke VK, Rebolledo PA, Rostad CA, Rouphael N, Scherer E, Sherman A, Stephens K, Suthar MS, Teherani M, Traenkner J, Winston J, Yildirim I, Barr L, Benoit J, Carste B, Choe J, Dunstan M, Erolin R, Ffitch J, Fields C, Jackson LA, Kiniry E, Lasicka S, Lee S, Nguyen M, Pimienta S, Suyehira J, Witte M, Bennett H, Altaras NE, Carfi A, Hurley M, Leav B, Pajon R, Sun W, Zaks T, Coler RN, Larsen SE, Neuzil KM, Lindesmith LC, Martinez DR, Munt J, Mallory M, Edwards C, Baric RS, Berkowitz NM, Boritz EA, Carlton K, Corbett KS, Costner P, Creanga A, Doria-Rose NA, Douek DC, Flach B, Gaudinski M, Gordon I, Graham BS, Holman L, Ledgerwood JE, Leung K, Lin BC, Louder MK, Mascola JR, McDermott AB, Morabito KM, Novik L, O'Connell S, O'Dell S, Padilla M, Pegu A, Schmidt SD, Shi W, Swanson PA 2nd, Talana CA, Wang L, Widge AT, Yang ES, Zhang Y, Chappell JD, Denison MR, Hughes T, Lu X, Pruijssers AJ, Stevens LJ, Posavad CM, Gale M Jr, Menachery V, and Shi PY
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Adolescent, Adult, Aged, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 prevention & control, COVID-19 Vaccines administration & dosage, Cross Reactions, Humans, Immune Evasion, Immunization, Secondary, Immunogenicity, Vaccine, Middle Aged, Time Factors, Young Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 Vaccines immunology, SARS-CoV-2 immunology
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations may diminish vaccine-induced protective immune responses, particularly as antibody titers wane over time. Here, we assess the effect of SARS-CoV-2 variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.429 (Epsilon), B.1.526 (Iota), and B.1.617.2 (Delta) on binding, neutralizing, and angiotensin-converting enzyme 2 (ACE2)–competing antibodies elicited by the messenger RNA (mRNA) vaccine mRNA-1273 over 7 months. Cross-reactive neutralizing responses were rare after a single dose. At the peak of response to the second vaccine dose, all individuals had responses to all variants. Binding and functional antibodies against variants persisted in most subjects, albeit at low levels, for 6 months after the primary series of the mRNA-1273 vaccine. Across all assays, B.1.351 had the lowest antibody recognition. These data complement ongoing studies to inform the potential need for additional boost vaccinations.
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- 2021
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35. A Monoclonal Antibody for Malaria Prevention.
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Gaudinski MR, Berkowitz NM, Idris AH, Coates EE, Holman LA, Mendoza F, Gordon IJ, Plummer SH, Trofymenko O, Hu Z, Campos Chagas A, O'Connell S, Basappa M, Douek N, Narpala SR, Barry CR, Widge AT, Hicks R, Awan SF, Wu RL, Hickman S, Wycuff D, Stein JA, Case C, Evans BP, Carlton K, Gall JG, Vazquez S, Flach B, Chen GL, Francica JR, Flynn BJ, Kisalu NK, Capparelli EV, McDermott A, Mascola JR, Ledgerwood JE, and Seder RA
- Subjects
- Adult, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal, Humanized administration & dosage, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Antibodies, Protozoan blood, Antimalarials administration & dosage, Antimalarials adverse effects, Antimalarials pharmacokinetics, Dose-Response Relationship, Drug, Healthy Volunteers, Humans, Infusions, Intravenous adverse effects, Injections, Subcutaneous adverse effects, Middle Aged, Plasmodium falciparum immunology, Plasmodium falciparum isolation & purification, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Antimalarials therapeutic use, Malaria, Falciparum prevention & control
- Abstract
Background: Additional interventions are needed to reduce the morbidity and mortality caused by malaria., Methods: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum . Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS., Results: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 μg per milliliter at the time of controlled human malaria infection., Conclusions: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.)., (Copyright © 2021 Massachusetts Medical Society.)
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- 2021
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36. Rectal tissue and vaginal tissue from intravenous VRC01 recipients show protection against ex vivo HIV-1 challenge.
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Astronomo RD, Lemos MP, Narpala SR, Czartoski J, Fleming LB, Seaton KE, Prabhakaran M, Huang Y, Lu Y, Westerberg K, Zhang L, Gross MK, Hural J, Tieu HV, Baden LR, Hammer S, Frank I, Ochsenbauer C, Grunenberg N, Ledgerwood JE, Mayer K, Tomaras G, McDermott AB, and McElrath MJ
- Subjects
- Adult, Antibodies, Monoclonal pharmacokinetics, Female, HIV Infections immunology, HIV Infections virology, Humans, In Vitro Techniques, Infusions, Intravenous, Male, Middle Aged, Mucous Membrane immunology, Mucous Membrane virology, Rectum virology, Vagina virology, Young Adult, Antibodies, Monoclonal administration & dosage, Broadly Neutralizing Antibodies administration & dosage, HIV Antibodies administration & dosage, HIV Infections prevention & control, HIV-1 immunology, HIV-1 pathogenicity, Rectum immunology, Vagina immunology
- Abstract
BackgroundVRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and pharmacokinetics of VRC01 in humans. We extend the clinical evaluation to determine intravenously infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry.MethodsHealthy, HIV-1-uninfected men (n = 7) and women (n = 5) receiving VRC01 every 2 months provided mucosal and serum samples once, 4-13 days after infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions, and tissue, and HIV-1 inhibition was determined in tissue explants.ResultsMedian VRC01 levels were quantifiable in serum (96.2 μg/mL or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein), and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r = 0.893, P = 0.012) and rectal secretions (r = 0.9643, P = 0.003). Ex vivo HIV-1Bal26 challenge infected 4 of 21 rectal explants from VRC01 recipients versus 20 of 22 from controls (P = 0.005); HIV-1Du422.1 infected 20 of 21 rectal explants from VRC01 recipients and 12 of 12 from controls (P = 0.639). HIV-1Bal26 infected 0 of 14 vaginal explants of VRC01 recipients compared with 23 of 28 control explants (P = 0.003).ConclusionIntravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective on in vivo protective efficacy.FundingNational Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation.
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- 2021
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37. Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants.
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Wang L, Zhou T, Zhang Y, Yang ES, Schramm CA, Shi W, Pegu A, Oloniniyi OK, Henry AR, Darko S, Narpala SR, Hatcher C, Martinez DR, Tsybovsky Y, Phung E, Abiona OM, Antia A, Cale EM, Chang LA, Choe M, Corbett KS, Davis RL, DiPiazza AT, Gordon IJ, Hait SH, Hermanus T, Kgagudi P, Laboune F, Leung K, Liu T, Mason RD, Nazzari AF, Novik L, O'Connell S, O'Dell S, Olia AS, Schmidt SD, Stephens T, Stringham CD, Talana CA, Teng IT, Wagner DA, Widge AT, Zhang B, Roederer M, Ledgerwood JE, Ruckwardt TJ, Gaudinski MR, Moore PL, Doria-Rose NA, Baric RS, Graham BS, McDermott AB, Douek DC, Kwong PD, Mascola JR, Sullivan NJ, and Misasi J
- Subjects
- Angiotensin-Converting Enzyme 2 antagonists & inhibitors, Angiotensin-Converting Enzyme 2 metabolism, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing metabolism, Antibodies, Viral chemistry, Antibodies, Viral metabolism, Antibody Affinity, Antigen-Antibody Reactions, COVID-19 virology, Humans, Immune Evasion, Immunoglobulin Fab Fragments immunology, Immunoglobulin Fab Fragments metabolism, Mutation, Neutralization Tests, Protein Domains, Receptors, Coronavirus antagonists & inhibitors, Receptors, Coronavirus metabolism, SARS-CoV-2 genetics, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus metabolism, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 immunology, SARS-CoV-2 immunology, SARS-CoV-2 pathogenicity, Spike Glycoprotein, Coronavirus immunology
- Abstract
The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain-targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC
50 ) 0.3 to 11.1 nanograms per milliliter; IC80 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2021
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38. Cross-reactive coronavirus antibodies with diverse epitope specificities and Fc effector functions.
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Shiakolas AR, Kramer KJ, Wrapp D, Richardson SI, Schäfer A, Wall S, Wang N, Janowska K, Pilewski KA, Venkat R, Parks R, Manamela NP, Raju N, Fechter EF, Holt CM, Suryadevara N, Chen RE, Martinez DR, Nargi RS, Sutton RE, Ledgerwood JE, Graham BS, Diamond MS, Haynes BF, Acharya P, Carnahan RH, Crowe JE Jr, Baric RS, Morris L, McLellan JS, and Georgiev IS
- Subjects
- Animals, Antigen-Antibody Reactions, B-Lymphocytes cytology, B-Lymphocytes metabolism, COVID-19 pathology, COVID-19 virology, Cell Line, Cross Reactions immunology, Epitope Mapping, Female, Humans, Immunoglobulin Fc Fragments immunology, Mice, Mice, Inbred BALB C, Phagocytosis, Protein Subunits immunology, Severe acute respiratory syndrome-related coronavirus immunology, Severe acute respiratory syndrome-related coronavirus metabolism, SARS-CoV-2 isolation & purification, SARS-CoV-2 metabolism, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus metabolism, Antibodies, Monoclonal immunology, Epitopes immunology, Immunoglobulin Fc Fragments metabolism, Spike Glycoprotein, Coronavirus immunology
- Abstract
The continual emergence of novel coronaviruses (CoV), such as severe acute respiratory syndrome-(SARS)-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. From a recovered SARS-CoV donor sample, we identify and characterize a panel of six monoclonal antibodies that cross-react with CoV spike (S) proteins from the highly pathogenic SARS-CoV and SARS-CoV-2, and demonstrate a spectrum of reactivity against other CoVs. Epitope mapping reveals that these antibodies recognize multiple epitopes on SARS-CoV-2 S, including the receptor-binding domain, the N-terminal domain, and the S2 subunit. Functional characterization demonstrates that the antibodies mediate phagocytosis-and in some cases trogocytosis-but not neutralization in vitro . When tested in vivo in murine models, two of the antibodies demonstrate a reduction in hemorrhagic pathology in the lungs. The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies., Competing Interests: A.R.S. and I.S.G. are co-founders of AbSeek Bio. A.R.S., K.J.K., I.S.G., D.W., N.W., and J.S.M. are listed as inventors on patents filed describing the antibodies mentioned here. D.W., J.S.M., B.S.G., and N.W. are also listed as inventors on US patent application no. 62/972,886 (2019-nCoV vaccine). M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM Biopharmaceuticals, and Carnival Corporation and is on the Scientific Advisory Boards of Moderna and Immunome. The Diamond laboratory has unrelated sponsored research agreements from Emergent BioSolutions, Moderna, and Vir Biotechnology. J.E.C. has served as a consultant for Eli Lilly, GlaxoSmithKline, and Luna Biologics; is a member of the Scientific Advisory Boards of CompuVax and Meissa Vaccines; and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from IDBiologics and AstraZeneca. R.S.B. has competing interests associated with Eli Lily, Takeda Pharmaceuticals, and Pfizer. The Georgiev laboratory at Vanderbilt University Medical Center has received unrelated funding from Takeda Pharmaceuticals., (© 2021 The Author(s).)
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- 2021
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39. Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19.
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Doria-Rose N, Suthar MS, Makowski M, O'Connell S, McDermott AB, Flach B, Ledgerwood JE, Mascola JR, Graham BS, Lin BC, O'Dell S, Schmidt SD, Widge AT, Edara VV, Anderson EJ, Lai L, Floyd K, Rouphael NG, Zarnitsyna V, Roberts PC, Makhene M, Buchanan W, Luke CJ, Beigel JH, Jackson LA, Neuzil KM, Bennett H, Leav B, Albert J, and Kunwar P
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Adult, Aged, Antibodies, Neutralizing blood, Half-Life, Humans, Middle Aged, Antibodies, Viral blood, COVID-19 immunology, COVID-19 Vaccines immunology, SARS-CoV-2 immunology
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- 2021
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40. Durability of mRNA-1273-induced antibodies against SARS-CoV-2 variants.
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Pegu A, O'Connell S, Schmidt SD, O'Dell S, Talana CA, Lai L, Albert J, Anderson E, Bennett H, Corbett KS, Flach B, Jackson L, Leav B, Ledgerwood JE, Luke CJ, Makowski M, Roberts PC, Roederer M, Rebolledo PA, Rostad CA, Rouphael NG, Shi W, Wang L, Widge AT, Yang ES, Beigel JH, Graham BS, Mascola JR, Suthar MS, McDermott A, and Doria-Rose NA
- Abstract
SARS-CoV-2 mutations may diminish vaccine-induced protective immune responses, and the durability of such responses has not been previously reported. Here, we present a comprehensive assessment of the impact of variants B.1.1.7, B.1.351, P.1, B.1.429, and B.1.526 on binding, neutralizing, and ACE2-blocking antibodies elicited by the vaccine mRNA-1273 over seven months. Cross-reactive neutralizing responses were rare after a single dose of mRNA-1273. At the peak of response to the second dose, all subjects had robust responses to all variants. Binding and functional antibodies against variants persisted in most subjects, albeit at low levels, for 6 months after the primary series of mRNA-1273. Across all assays, B.1.351 had the greatest impact on antibody recognition, and B.1.1.7 the least. These data complement ongoing studies of clinical protection to inform the potential need for additional boost vaccinations., One-Sentence Summary: Most mRNA-1273 vaccinated individuals maintained binding and functional antibodies against SARS-CoV-2 variants for 6 months.
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- 2021
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41. A sensitive method to quantify HIV-1 antibodies in mucosal samples.
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Prabhakaran M, Narpala S, Andrews SF, O'Connell S, Lin CL, Coates EE, Flach B, Ledgerwood JE, and McDermott AB
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- Broadly Neutralizing Antibodies analysis, Cervix Uteri virology, Female, Humans, Immunoassay, Intestinal Mucosa virology, Limit of Detection, Mouth Mucosa virology, HIV Antibodies analysis, HIV-1 immunology, Mucous Membrane virology
- Abstract
Human immunodeficiency virus (HIV) remains a significant public health issue. In recent years, passive immunization with broadly neutralizing antibodies (bNabs) is being considered as a potentially efficacious approach for fighting HIV. One candidate that holds great promise is represented by the CD4-binding site targeted bNab capable of neutralizing over 90% of circulating HIV strains, VRC01. VRC01 along with its variants and clonal relatives - VRC01-LS and VRC07-523LS are currently being evaluated as vaccines in a number of clinical trials for HIV treatment and prevention. While mucosal areas of the body serve as major ports of HIV entry, reliable quantification of bNabs for pharmacokinetic and bioavailability analyses has been challenging due to low antibody concentrations in these samples. We developed an immunoassay on the Singulex platform which enables ultra-sensitive quantification of VRC01, VRC07, VRC01-LS and VRC07-523LS with a greater than 4-log linear dynamic range (LDR) and less than 120 pg/mL lower limit of quantitation (LLOQ). We implemented this assay to quantify VRC01 levels in rectal, cervical and oral mucosal samples in two passive immunization studies conducted with VRC01 - VRC 601 and VRC 602. Our assay was able to successfully quantify VRC01 levels in mucosal samples from all dosage groups (5 - -40 mg/kg) in these trials. VRC01 levels in a significant proportion of these samples (37% in oral and 25% in rectal mucosa) were below the lower limits of quantitation of other traditional immunoassays used for VRC01 quantification. We also measured VRC01 levels in sera from these trials and found that VRC01 measurements made using our assay exhibited excellent correlation (r
2 = 0.9509) with measurements made previously using Enzyme-linked immunosorbent assay (ELISA). Our assay provides a reliable, sensitive and accurate method for quantification of clinically relevant bNabs and will help delineate antibody infiltration and bioavailability characteristics in complex biological matrices (CBM) such as mucosal tissues. This will in turn help determine clinical antibody threshold concentrations required to mediate protection against HIV acquisition and serve to inform dosing regimens and clinical trial design for future efficacy trials with these bNabs., (Published by Elsevier B.V.)- Published
- 2021
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42. A comprehensive influenza reporter virus panel for high-throughput deep profiling of neutralizing antibodies.
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Creanga A, Gillespie RA, Fisher BE, Andrews SF, Lederhofer J, Yap C, Hatch L, Stephens T, Tsybovsky Y, Crank MC, Ledgerwood JE, McDermott AB, Mascola JR, Graham BS, and Kanekiyo M
- Subjects
- Antigens, Viral immunology, Gene Expression Profiling, Hemagglutinin Glycoproteins, Influenza Virus genetics, Hemagglutinin Glycoproteins, Influenza Virus immunology, Hemagglutinins, Humans, Immunity, Influenza A Virus, H1N1 Subtype immunology, Influenza A Virus, H3N2 Subtype immunology, Influenza A virus genetics, Influenza Vaccines immunology, Orthomyxoviridae Infections virology, Phylogeny, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Influenza A virus immunology, Influenza, Human virology
- Abstract
Broadly neutralizing antibodies (bnAbs) have been developed as potential countermeasures for seasonal and pandemic influenza. Deep characterization of these bnAbs and polyclonal sera provides pivotal understanding for influenza immunity and informs effective vaccine design. However, conventional virus neutralization assays require high-containment laboratories and are difficult to standardize and roboticize. Here, we build a panel of engineered influenza viruses carrying a reporter gene to replace an essential viral gene, and develop an assay using the panel for in-depth profiling of neutralizing antibodies. Replication of these viruses is restricted to cells expressing the missing viral gene, allowing it to be manipulated in a biosafety level 2 environment. We generate the neutralization profile of 24 bnAbs using a 55-virus panel encompassing the near-complete diversity of human H1N1 and H3N2, as well as pandemic subtype viruses. Our system offers in-depth profiling of influenza immunity, including the antibodies against the hemagglutinin stem, a major target of universal influenza vaccines.
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- 2021
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43. Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition.
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Corey L, Gilbert PB, Juraska M, Montefiori DC, Morris L, Karuna ST, Edupuganti S, Mgodi NM, deCamp AC, Rudnicki E, Huang Y, Gonzales P, Cabello R, Orrell C, Lama JR, Laher F, Lazarus EM, Sanchez J, Frank I, Hinojosa J, Sobieszczyk ME, Marshall KE, Mukwekwerere PG, Makhema J, Baden LR, Mullins JI, Williamson C, Hural J, McElrath MJ, Bentley C, Takuva S, Gomez Lorenzo MM, Burns DN, Espy N, Randhawa AK, Kochar N, Piwowar-Manning E, Donnell DJ, Sista N, Andrew P, Kublin JG, Gray G, Ledgerwood JE, Mascola JR, and Cohen MS
- Subjects
- Adolescent, Adult, Africa South of the Sahara epidemiology, Americas epidemiology, Antibodies, Monoclonal adverse effects, Broadly Neutralizing Antibodies adverse effects, Double-Blind Method, Europe epidemiology, Female, HIV Antibodies adverse effects, HIV Infections epidemiology, Humans, Incidence, Male, Proof of Concept Study, Young Adult, Antibodies, Monoclonal therapeutic use, Broadly Neutralizing Antibodies therapeutic use, HIV Antibodies therapeutic use, HIV Infections prevention & control, HIV-1 drug effects
- Abstract
Background: Whether a broadly neutralizing antibody (bnAb) can be used to prevent human immunodeficiency virus type 1 (HIV-1) acquisition is unclear., Methods: We enrolled at-risk cisgender men and transgender persons in the Americas and Europe in the HVTN 704/HPTN 085 trial and at-risk women in sub-Saharan Africa in the HVTN 703/HPTN 081 trial. Participants were randomly assigned to receive, every 8 weeks, infusions of a bnAb (VRC01) at a dose of either 10 or 30 mg per kilogram (low-dose group and high-dose group, respectively) or placebo, for 10 infusions in total. HIV-1 testing was performed every 4 weeks. The VRC01 80% inhibitory concentration (IC
80 ) of acquired isolates was measured with the TZM-bl assay., Results: Adverse events were similar in number and severity among the treatment groups within each trial. Among the 2699 participants in HVTN 704/HPTN 085, HIV-1 infection occurred in 32 in the low-dose group, 28 in the high-dose group, and 38 in the placebo group. Among the 1924 participants in HVTN 703/HPTN 081, infection occurred in 28 in the low-dose group, 19 in the high-dose group, and 29 in the placebo group. The incidence of HIV-1 infection per 100 person-years in HVTN 704/HPTN 085 was 2.35 in the pooled VRC01 groups and 2.98 in the placebo group (estimated prevention efficacy, 26.6%; 95% confidence interval [CI], -11.7 to 51.8; P = 0.15), and the incidence per 100 person-years in HVTN 703/HPTN 081 was 2.49 in the pooled VRC01 groups and 3.10 in the placebo group (estimated prevention efficacy, 8.8%; 95% CI, -45.1 to 42.6; P = 0.70). In prespecified analyses pooling data across the trials, the incidence of infection with VRC01-sensitive isolates (IC80 <1 μg per milliliter) per 100 person-years was 0.20 among VRC01 recipients and 0.86 among placebo recipients (estimated prevention efficacy, 75.4%; 95% CI, 45.5 to 88.9). The prevention efficacy against sensitive isolates was similar for each VRC01 dose and trial; VRC01 did not prevent acquisition of other HIV-1 isolates., Conclusions: VRC01 did not prevent overall HIV-1 acquisition more effectively than placebo, but analyses of VRC01-sensitive HIV-1 isolates provided proof-of-concept that bnAb prophylaxis can be effective. (Supported by the National Institute of Allergy and Infectious Diseases; HVTN 704/HPTN 085 and HVTN 703/HPTN 081 ClinicalTrials.gov numbers, NCT02716675 and NCT02568215.)., (Copyright © 2021 Massachusetts Medical Society.)- Published
- 2021
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44. Antibodies with potent and broad neutralizing activity against antigenically diverse and highly transmissible SARS-CoV-2 variants.
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Wang L, Zhou T, Zhang Y, Yang ES, Schramm CA, Shi W, Pegu A, Oloninyi OK, Ransier A, Darko S, Narpala SR, Hatcher C, Martinez DR, Tsybovsky Y, Phung E, Abiona OM, Cale EM, Chang LA, Corbett KS, DiPiazza AT, Gordon IJ, Leung K, Liu T, Mason RD, Nazzari A, Novik L, Olia AS, Doria-Rose NA, Stephens T, Stringham CD, Talana CA, Teng IT, Wagner D, Widge AT, Zhang B, Roederer M, Ledgerwood JE, Ruckwardt TJ, Gaudinski MR, Baric RS, Graham BS, McDermott AB, Douek DC, Kwong PD, Mascola JR, Sullivan NJ, and Misasi J
- Abstract
The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.1.7 and B.1.351 VOCs. Two of them are ultrapotent, with sub-nanomolar neutralization titers (IC50 <0.0006 to 0.0102 μ g/mL; IC80 < 0.0006 to 0.0251 μ g/mL). We define the structural and functional determinants of binding for all four VOC-targeting antibodies, and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting potential means to mitigate resistance development. These results define the basis of therapeutic cocktails against VOCs and suggest that targeted boosting of existing immunity may increase vaccine breadth against VOCs.
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- 2021
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45. Functional Profiling of Antibody Immune Repertoires in Convalescent Zika Virus Disease Patients.
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Fahad AS, Timm MR, Madan B, Burgomaster KE, Dowd KA, Normandin E, Gutiérrez-González MF, Pennington JM, De Souza MO, Henry AR, Laboune F, Wang L, Ambrozak DR, Gordon IJ, Douek DC, Ledgerwood JE, Graham BS, Castilho LR, Pierson TC, Mascola JR, and DeKosky BJ
- Subjects
- Antibodies, Neutralizing genetics, Antibodies, Neutralizing immunology, Antibodies, Viral genetics, Antibody Formation genetics, B-Lymphocytes immunology, B-Lymphocytes metabolism, Computational Biology methods, Flow Cytometry, High-Throughput Nucleotide Sequencing, Humans, Neutralization Tests, Peptide Library, Antibodies, Viral immunology, Antibody Formation immunology, Host-Pathogen Interactions immunology, Zika Virus immunology, Zika Virus Infection immunology, Zika Virus Infection virology
- Abstract
The re-emergence of Zika virus (ZIKV) caused widespread infections that were linked to Guillain-Barré syndrome in adults and congenital malformation in fetuses, and epidemiological data suggest that ZIKV infection can induce protective antibody responses. A more detailed understanding of anti-ZIKV antibody responses may lead to enhanced antibody discovery and improved vaccine designs against ZIKV and related flaviviruses. Here, we applied recently-invented library-scale antibody screening technologies to determine comprehensive functional molecular and genetic profiles of naturally elicited human anti-ZIKV antibodies in three convalescent individuals. We leveraged natively paired antibody yeast display and NGS to predict antibody cross-reactivities and coarse-grain antibody affinities, to perform in-depth immune profiling of IgM, IgG, and IgA antibody repertoires in peripheral blood, and to reveal virus maturation state-dependent antibody interactions. Repertoire-scale comparison of ZIKV VLP-specific and non-specific antibodies in the same individuals also showed that mean antibody somatic hypermutation levels were substantially influenced by donor-intrinsic characteristics. These data provide insights into antiviral antibody responses to ZIKV disease and outline systems-level strategies to track human antibody immune responses to emergent viral infections., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fahad, Timm, Madan, Burgomaster, Dowd, Normandin, Gutiérrez-González, Pennington, De Souza, Henry, Laboune, Wang, Ambrozak, Gordon, Douek, Ledgerwood, Graham, Castilho, Pierson, Mascola and DeKosky.)
- Published
- 2021
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46. Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination.
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Widge AT, Rouphael NG, Jackson LA, Anderson EJ, Roberts PC, Makhene M, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott AB, Flach B, Lin BC, Doria-Rose NA, O'Dell S, Schmidt SD, Neuzil KM, Bennett H, Leav B, Makowski M, Albert J, Cross K, Edara VV, Floyd K, Suthar MS, Buchanan W, Luke CJ, Ledgerwood JE, Mascola JR, Graham BS, and Beigel JH
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Adolescent, Adult, Aged, COVID-19 prevention & control, COVID-19 Vaccines administration & dosage, Humans, Immunization, Secondary, Middle Aged, Spike Glycoprotein, Coronavirus immunology, Th1 Cells physiology, Young Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 immunology, COVID-19 Vaccines immunology, SARS-CoV-2 immunology
- Published
- 2021
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47. Model Informed Development of VRC01 in Newborn Infants Using a Population Pharmacokinetics Approach.
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Li J, Nikanjam M, Cunningham CK, McFarland EJ, Coates EE, Houser KV, Lin BC, McDermott AB, Flach B, Gama L, Koup RA, Graham BS, Mascola JR, Ledgerwood JE, and Capparelli EV
- Subjects
- Adult, Female, HIV Infections drug therapy, HIV Infections metabolism, HIV-1 drug effects, Humans, Infant, Infant, Newborn, Male, Middle Aged, Young Adult, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal therapeutic use, Broadly Neutralizing Antibodies pharmacology, Broadly Neutralizing Antibodies therapeutic use, HIV Antibodies therapeutic use
- Abstract
VRC01 is a first-in-class, potent, broadly neutralizing antibody that targets the CD4 binding site of gp120 on HIV-1 viruses, and is under development as a novel HIV therapeutic. This study utilized population pharmacokinetic (PK) modeling to characterize VRC01 PK to guide dosing selection for ongoing phase II clinical trials in pediatric patients. Combining VRC01 PK data from 3 adult and 1 infant clinical trials, a total of 1,475 VRC01 serum concentrations from 100 participants were used in the analysis (40 infants and 60 adults). VRC01 was administered either i.v. or s.c. (1-40 mg/kg). All infants received s.c. doses as compared with 13% s.c. and 87% i.v. in adults. The data were well-described by a two-compartment model. Clearance was 37% higher in adults with HIV infection and 83% lower in infants than adults. Subcutaneous bioavailability was 55% in adults. Rapid absorption was seen in infants indicating therapeutic levels could be achieved quickly. Monte Carlo simulations were used to determine optimal dosing and demonstrated 40 mg/kg s.c. at weeks 0, 2, 6, and 10 would maintain VRC01 levels at the suppressive target concentration of 50 μg/mL for the first 14 weeks of life in infants. The current analysis provides new insight into differences in monoclonal antibody PK between infants and adults and demonstrates the utility of a population PK approach in informing drug development for infant populations., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)
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- 2021
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48. Cross-reactive coronavirus antibodies with diverse epitope specificities and extra-neutralization functions.
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Shiakolas AR, Kramer KJ, Wrapp D, Richardson SI, Schäfer A, Wall S, Wang N, Janowska K, Pilewski KA, Venkat R, Parks R, Manamela NP, Raju N, Fechter EF, Holt CM, Suryadevara N, Chen RE, Martinez DR, Nargi RS, Sutton RE, Ledgerwood JE, Graham BS, Diamond MS, Haynes BF, Acharya P, Carnahan RH, Crowe JE, Baric RS, Morris L, McLellan JS, and Georgiev IS
- Abstract
The continual emergence of novel coronavirus (CoV) strains, like SARS-CoV-2, highlights the critical need for broadly reactive therapeutics and vaccines against this family of viruses. Coronavirus spike (S) proteins share common structural motifs that could be vulnerable to cross-reactive antibody responses. To study this phenomenon in human coronavirus infection, we applied a high-throughput sequencing method called LIBRA-seq (Linking B cell receptor to antigen specificity through sequencing) to a SARS-CoV-1 convalescent donor sample. We identified and characterized a panel of six monoclonal antibodies that cross-reacted with S proteins from the highly pathogenic SARS-CoV-1 and SARS-CoV-2 and demonstrated a spectrum of reactivity against other coronaviruses. Epitope mapping revealed that these antibodies recognized multiple epitopes on SARS-CoV-2 S, including the receptor binding domain (RBD), N-terminal domain (NTD), and S2 subunit. Functional characterization demonstrated that the antibodies mediated a variety of Fc effector functions in vitro and mitigated pathological burden in vivo . The identification of cross-reactive epitopes recognized by functional antibodies expands the repertoire of targets for pan-coronavirus vaccine design strategies that may be useful for preventing potential future coronavirus outbreaks.
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- 2020
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49. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults.
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Anderson EJ, Rouphael NG, Widge AT, Jackson LA, Roberts PC, Makhene M, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott AB, Flach B, Lin BC, Doria-Rose NA, O'Dell S, Schmidt SD, Corbett KS, Swanson PA 2nd, Padilla M, Neuzil KM, Bennett H, Leav B, Makowski M, Albert J, Cross K, Edara VV, Floyd K, Suthar MS, Martinez DR, Baric R, Buchanan W, Luke CJ, Phadke VK, Rostad CA, Ledgerwood JE, Graham BS, and Beigel JH
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Aged, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 immunology, COVID-19 Vaccines administration & dosage, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Neutralization Tests, Spike Glycoprotein, Coronavirus, T-Lymphocytes physiology, COVID-19 prevention & control, COVID-19 Vaccines adverse effects, COVID-19 Vaccines immunology, SARS-CoV-2 immunology
- Abstract
Background: Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age., Methods: We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 μg or 100 μg of vaccine administered 28 days apart., Results: Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-μg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-μg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells., Conclusions: In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, which supports the use of the 100-μg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.)., (Copyright © 2020 Massachusetts Medical Society.)
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- 2020
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50. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report.
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Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott A, Flach B, Doria-Rose NA, Corbett KS, Morabito KM, O'Dell S, Schmidt SD, Swanson PA 2nd, Padilla M, Mascola JR, Neuzil KM, Bennett H, Sun W, Peters E, Makowski M, Albert J, Cross K, Buchanan W, Pikaart-Tautges R, Ledgerwood JE, Graham BS, and Beigel JH
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, Antibody Formation, Betacoronavirus, COVID-19, COVID-19 Vaccines, Female, Humans, Immunization, Secondary, Male, SARS-CoV-2, T-Lymphocytes immunology, Viral Vaccines adverse effects, Young Adult, Coronavirus Infections prevention & control, Pandemics prevention & control, Pneumonia, Viral prevention & control, RNA, Messenger immunology, Spike Glycoprotein, Coronavirus immunology, Viral Vaccines therapeutic use
- Abstract
Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein., Methods: We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group., Results: After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events., Conclusions: The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461)., (Copyright © 2020 Massachusetts Medical Society.)
- Published
- 2020
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