scholarly journals Immunogenicity and Safety Following a Homologous Booster Dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373): A Phase 2 Randomized Placebo-Controlled Trial

2021 ◽  
Author(s):  
Raburn Mallory ◽  
Neil Formica ◽  
Susan Pfeiffer ◽  
Bethanie Wilkinson ◽  
Alex Marcheschi ◽  
...  
Keyword(s):  
Immune Responses ◽  
Receptor Binding ◽  
Booster Dose ◽  
Primary Vaccination ◽  
Spike Protein ◽  
Phase 2 ◽  
Protein Vaccine ◽  
Binding Inhibition ◽  
Grade 3 ◽  
Incremental Increase

Background Emerging SARS-CoV-2 variants and evidence of waning vaccine efficacy present significant obstacles toward controlling the COVID-19 pandemic. Booster doses of SARS-CoV-2 vaccines may address these concerns by both amplifying and broadening the immune responses seen with initial vaccination regimens. Methods In a phase 2 study, a single booster dose of a SARS-CoV-2 recombinant spike protein vaccine with Matrix-M adjuvant (NVX-CoV2373) was administered to healthy adult participants 18 to 84 years of age approximately 6 months following their primary two-dose vaccination series. Safety and immunogenicity parameters were assessed, including assays for IgG, MN50, and hACE2 receptor binding inhibition against the ancestral SARS-CoV-2 strain and select variants (B.1.351 [Beta], B.1.1.7 [Alpha], B.1.617.2 [Delta], and B.1.1.529 [Omicron]). This trial is registered with ClinicalTrials.gov, NCT04368988. Findings An incremental increase in the incidence of solicited local and systemic reactogenicity events was observed with subsequent vaccinations. Following the booster, incidence rates of local and systemic reactions were 82.5% (13.4% ≥ Grade 3) and 76.5% (15.3% ≥ Grade 3), respectively, compared to 70.0% (5.2% ≥ Grade 3) and 52.8% (5.6% ≥ Grade 3), respectively, following the primary vaccination series. Events were primarily mild or moderate in severity and transient in nature, with a median duration of 1.0 to 2.5 days. Immune responses seen 14 days following the primary vaccination series were compared with those observed 28 days following the booster (Day 35 and Day 217, respectively). For the ancestral SARS-CoV-2 strain, serum IgG geometric mean titers (GMTs) increased ~4.7-fold from 43,905 ELISA units (EU) at day 35 to 204,367 EU at Day 217. Neutralization (MN50) assay GMTs showed a similar increase of ~4.1-fold from 1,470 at day 35 to 6,023 at Day 217. A functional hACE2 receptor binding inhibition assay analyzing activity against ancestral and variant strains of SARS-CoV-2 at Day 189 vs Day 217 found 54.4-fold (Ancestral), 21.9 fold (Alpha), 24.5-fold (Beta), 24.4-fold (Delta), and 20.1-fold (Omicron) increases in titers. An anti-rS IgG activity assay comparing the same time points across the same SARS-CoV-2 strains found titers improved 61.2-fold, 85.9-fold, 65.0-fold, 92.5 fold, and 73.5 fold, respectively. Interpretation Administration of a booster dose of NVX-CoV2373 approximately 6 months following the primary vaccination series resulted in an incremental increase in reactogenicity along with enhanced immune responses. For both the prototype strain and all variants evaluated, immune responses following the booster were notably higher than those associated with high levels of efficacy in phase 3 studies of the vaccine.

scholarly journals 480 Preliminary evaluation of a novel coronavirus vaccine (CORVax) using electroporation of plasmid DNA encoding a stabilized prefusion SARS-CoV-2 spike protein alone or with transfection of plasmid IL-12

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A514-A514
Author(s):  
Shawn Jensen ◽  
Christopher Twitty ◽  
Christopher Paustian ◽  
Madelein Laws ◽  
Glenna McDonnell ◽  
...  
Keyword(s):  
Immune Responses ◽  
Receptor Binding ◽  
Binding Domain ◽  
Tumor Rejection ◽  
Spike Protein ◽  
Preliminary Evaluation ◽  
List Type ◽  
Receptor Binding Domain ◽  
Igg Antibodies ◽  
Viral Neutralization

BackgroundSARS-CoV-2 (CoV2) has precipitated a global pandemic and the effectiveness of standard vaccine strategies to induce potent and persistent immunity to CoV2 is in question, particularly for the elderly. This problem is not dissimilar to what we have struggled with in our quest to induce immunity to cancer antigens, where vaccine-induced anti-cancer immune responses can be weak. Here, we describe a novel vaccine approach which leverages electroporation (EP) of a plasmid encoding a prefusion stabilized CoV2 spike protein (CORVax). As IL-12 has been shown to augment the efficacy of immunotherapy in aged mice,1 we have initiated studies to evaluate if plasmid IL-12 (TAVO™) can similarly augment anti-CoV2 immune responses in young mice and have planned studies in aged animals.MethodsA prefusion stabilized CoV2 spike plasmid expression vector was constructed, a master cell bank generated and clinical-grade plasmid manufactured. C57BL/6 and BALB/c were vaccinated via intramuscular (IM) and/or intradermal (ID) injection followed immediately by EP of plasmids encoding the CoV2 spike protein with or without plasmid-encoded murine IL-12 on days 1 and 14 or 21. Mice were followed for >120 days to assess safety. Splenocytes and serum were harvested at different time points to interrogate virus-specific cellular responses as well anti-spike IgG1/IgG2 antibody titers. A surrogate viral neutralization test (sVNT) assessed serum blockade of soluble hACE2R binding to immobilized CoV2 spike.ResultsPreliminary data shows that EP of CORVax alone or combined with IL-12 was safe. EP of CORVax was able to elicit anti-Spike IgG antibodies (IC50 = 1/2112), as well as IgG antibodies targeting the receptor binding domain of the Spike protein (IC50 = 1/965) approximately 40 days after the booster vaccination. In 2 of 2 experiments, CORVax combined with IL-12 significantly (P<0.0001) increased the sVNT titers at 2 months, but this benefit was lost by 3 months.ConclusionsEarly preclinical data shows that EP of CORVax can induce IgG responses to CoV2 Spike and the receptor binding domain (RBD) as well as apparent viral neutralizing activity. The addition of IL-12, at least transiently, increased sVNT titer. We plan to investigate alternate vaccine boosting strategies while extending these studies into aged animals and initiate a clinical trial in the near future.ReferencesRuby CE, Weinberg AD. OX40-Enhanced tumor rejection and effector T cell differentiation decreases with age. J Immunol2009;182:1481–9. https://doi.org/10.4049/jimmunol.182.3.1481.

scholarly journals Conjugation of Human β-Defensin 2 to Spike Protein Receptor-Binding Domain Induces Antigen-Specific Protective Immunity against Middle East Respiratory Syndrome Coronavirus Infection in Human Dipeptidyl Peptidase 4 Transgenic Mice

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 635
Author(s):  
Ju Kim ◽  
Ye Lin Yang ◽  
Yongsu Jeong ◽  
Yong-Suk Jang
Keyword(s):  
Middle East ◽  
Immune Responses ◽  
Receptor Binding ◽  
Dipeptidyl Peptidase ◽  
Binding Domain ◽  
Middle East Respiratory Syndrome ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Dipeptidyl Peptidase 4 ◽  
Protein Receptor

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe acute respiratory symptoms. Due to the lack of medical countermeasures, effective and safe vaccines against MERS-CoV infection are urgently required. Although different types of candidate vaccines have been developed, their immunogenicity is limited, and the dose and administration route need optimization to achieve optimal protection. We here investigated the potential use of human β-defensin 2 (HBD 2) as an adjuvant to enhance the protection provided by MERS-CoV vaccination. We found that immunization of human dipeptidyl peptidase 4 (hDPP4)-transgenic (hDPP4-Tg) mice with spike protein receptor-binding domain (S RBD) conjugated with HBD 2 (S RBD-HBD 2) induced potent antigen (Ag)-specific adaptive immune responses and protected against MERS-CoV infection. In addition, immunization with S RBD-HBD 2 alleviated progressive pulmonary fibrosis in the lungs of MERS-CoV-infected hDPP4-Tg mice and suppressed endoplasmic reticulum stress signaling activation upon viral infection. Compared to intramuscular administration, intranasal administration of S RBD-HBD 2 induced more potent mucosal IgA responses and was more effective for protecting against intranasal MERS-CoV infection. In conclusion, our findings suggest that HBD 2 potentiates Ag-specific immune responses against viral Ag and can be used as an adjuvant enhancing the immunogenicity of subunit vaccine candidates against MERS-CoV.

scholarly journals 476 First-in-human phase 1/2 study of the first-in-class SUMO-activating enzyme inhibitor TAK-981 in patients with advanced or metastatic solid tumors or relapsed/refractory lymphoma: phase 1 results

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A505-A506
Author(s):  
Arkadiusz Dudek ◽  
Dejan Juric ◽  
Afshin Dowlati ◽  
Ulka Vaishampayan ◽  
Hadeel Assad ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Immune Responses ◽  
Solid Tumors ◽  
Cell Activation ◽  
Nk Cell ◽  
Phase 1 ◽  
Phase 2 ◽  
Target Engagement ◽  
Grade 3

BackgroundSUMOylation is a post-translational modification that serves as an important modulator of immune responses via its role in constraining the type I interferon (IFN-1) response. TAK-981 is a small molecule that inhibits SUMOylation and increases IFN-1-dependent innate immune responses with the potential to enhance adaptive immunity. Here, we report dose-escalation data from a TAK-981 Phase 1/2 clinical study (NCT03648372), the first clinical data for a SUMOylation inhibitor.MethodsAdults with advanced/metastatic solid tumors or relapsed/refractory lymphomas received TAK-981 IV twice-weekly (BIW; days 1, 4, 8, 11) or once-weekly (QW; days 1, 8) in 21-day cycles. Dose escalation was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control, plus available pharmacokinetic/pharmacodynamic (PK/PD) data. Phase 1 objectives were to determine TAK-981 safety/tolerability and establish the recommended phase 2 dose (RP2D).ResultsSeventy-six patients received TAK-981 at 10 dose levels (3–40 mg BIW; 60–120 mg QW/BIW). Median age was 61 years (range, 38–79); 42 (55.3%) patients were female. Four dose-limiting toxicities were seen in 62 evaluable patients (transient grade 3 ALT/AST elevation, 60 mg BIW; grade 3 pneumonitis, 90 mg BIW; grade 3 stomatitis and grade 3 cognitive disturbance, 120 mg BIW). Per BLRM, 120 mg BIW was determined to be the maximum tolerated dose. At data cut-off, median treatment duration was 2 cycles (range, 1–12); 13 (17.1%) patients were ongoing. table 1 summarizes TAK-981 safety. The most common (≥20%) treatment-emergent adverse events (TEAEs) were fatigue (42.1%), nausea (39.5%), headache (31.6%), diarrhea (28.9%), pyrexia (27.6%), vomiting (23.7%), decreased appetite (22.4%). Common (≥5%) grade ≥3 TEAEs were hypokalemia (9.2%), anemia (7.9%), lymphocyte count decreased (6.6%), abdominal pain (5.3%). Grade 2 cytokine release syndrome was reported in 4 (5.2%) patients; symptoms resolved within 12–24 hours with supportive oxygen and/or IV fluids. One partial response was observed at 40 mg TAK-981 BIW in a patient with relapsed/refractory HER2-negative, hormone receptor-positive breast cancer. TAK-981 exhibited linear PK, with approximately dose-proportional exposure and a mean terminal half-life of 3.8–10.8 hours at ≥60 mg. Evidence of dose-dependent target engagement (figure 1), and PD (figures 2–4) in blood were observed. The single-agent TAK-981 RP2D was 90 mg BIW.Abstract 476 Table 1Summary of TAK-981 safety profileAbstract 476 Figure 1PD in patients receiving TAK-981 on the BIW schedule: target engagement.Blood samples were collected on Cycle 1 Day 1 pre-dose and at multiple timepoints after TAK-981 administration. Target engagement in T cells was detected by flow cytometry with an antibody recognizing the TAK-981-SUMO adduct formed during the inhibition of the SUMO-activating enzyme by TAK-981; Cycle 1 Day 1 signal increased at 1 hour post-end-of-infusion compared to the background level observed pre-dose.Abstract 476 Figure 2PD in patients receiving TAK-981 on the BIW schedule: SUMOylation.SUMOylation in T cells, detected by flow cytometry with an antibody recognizing SUMO2/3, decreased at 1 hour post-end-of-infusion on Cycle 1 Day 1 compared to pre-dose, indicating that fewer SUMO2/3 chains are formed when the SUMO-activating enzyme is inhibited.Abstract 476 Figure 3PD in patients receiving TAK-981 on the BIW schedule: upregulation of CXCL10 expression.Upregulation of mRNA levels of CXCL10, an IFN-I-regulated gene, in peripheral blood. Gene expression was measured using Nanostring nCounter at Cycle 1 Day 1 pre-dose and at several timepoints post-dose. Data for maximum increase at 8 or 24 hours, relative to pre-dose, is shown.Abstract 476 Figure 4PD in patients receiving TAK-981 on the BIW schedule: NK cell activation.NK cell activation in peripheral blood measured by flow cytometry. Percentage of CD69-positive NK cells at Cycle 1 Day 1 pre-dose and at 24 hours post-end-of-infusion is shown by patient for each dose.ConclusionsThe data generated in this study support continued TAK-981 development for treatment of solid tumors and lymphoma. The Phase 2 study expansion is ongoing in patients with advanced/metastatic non-small-cell lung, cervical, and colorectal cancer, and in relapsed/refractory non-Hodgkin lymphoma.Trial RegistrationClinical Trial identification: ClinicalTrials.gov. Identifier: NCT03648372Ethics ApprovalThe study was approved by the Institutional Review Board or Institutional Ethics Committee of all participating institutions

scholarly journals Persistence of Bactericidal Activity at 4 Years After 2 Primary Doses of a Recombinant, 4-Component, Meningococcal Serogroup B Vaccine (4CMenB) and Response to a Booster Dose in Adolescents and Young Adults

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S322-S322 ◽  
Author(s):  
Terry Nolan ◽  
Hartley Garfield ◽  
Anil Gupta ◽  
Murdo Ferguson ◽  
Helen Marshall ◽  
...  
Keyword(s):  
Young Adults ◽  
Immune Responses ◽  
Bactericidal Activity ◽  
Booster Dose ◽  
Geometric Mean ◽  
Primary Vaccination ◽  
Adolescents And Young Adults ◽  
Open Label ◽  
Antibody Levels ◽  
Research Grant

Abstract Background This phase 3b, open label, controlled, multi-center, extension study (NCT02446743) assessed the persistence of bactericidal activity at 4 years post-primary vaccination with a recombinant, 4-component, meningococcal serogroup B vaccine (4CMenB) in adolescents who participated in the parent study NCT01423084 and their response to a booster dose, compared with that in vaccine-naïve healthy controls. Methods Adolescents and young adults previously primed with 4CMenB (2 doses; following a 0,1-month schedule) in study NCT01423084 (group 3B) and vaccine-naïve 15–22 year olds (group B0_1) were enrolled. Group 3B received a booster dose of 4CMenB at 4 years post-primary vaccination; group B0_1 received 2 catch-up doses of 4CMenB (following a 0,1-month schedule). Antibody persistence (primary objective) was evaluated at 4 years post-primary vaccination (in group 3B) vs. baseline (in group B0_1) using human serum bactericidal assay (hSBA), in terms of geometric mean titer (GMT) and percentage (%) of individuals with hSBA titer at least 4. Immune responses at 1 month after booster dose (in group 3B) vs. those at 1 month after first dose (in group B0_1) were also assessed. Results In group 3B, antibody levels declined from 1 month to 4 years post-primary vaccination against all antigens except NHBA, but were higher than in group B0_1 at baseline (Table), with a GMT ratio ≥1.3 and a difference in % of individuals with hSBA titer at least 4 of ≥9%. After one dose of 4CMenB (booster in 3B or first dose in B0_1), GMTs increased (≥4.6-fold in group 3B; ≥2.3-fold in group B0_1), and ≥94% of participants in group 3B and ≥41% of participants in group B0_1 had hSBA titer at least 4 (Table). Conclusion Antibody levels in adolescents and young adults primed with 4CMenB waned over time but were higher at 4 years post-primary vaccination than for vaccine-naïve individuals at baseline. A booster dose of 4CMenB in vaccine-primed individuals elicited higher immune responses than one dose of 4CMenB in vaccine-naïve individuals. The research was supported by GlaxoSmithKline Biologicals SA. Disclosures T. Nolan, GSK group of companies: Research Contractor and Scientific Advisor, Research grant. Pfizer: Research Contractor, Research grant. H. Garfield, Novartis/GSK group of companies: Investigator, Research support. A. Gupta, Novartis/GSK group of companies: Investigator, payment for research-related activities; M. Ferguson, GSK group of companies: Investigator, I receive salary from CRG. CRG has contracts with GSK. H. Marshall, GSK group of companies: Grant Investigator and Investigator, Research grant. Pfizer: Grant Investigator and Investigator, Research grant; sanofi pasteur: Grant Investigator, Research grant. Novavax: Investigator, Research grant. D. D’Agostino, GSK group of companies: Consultant, Consulting fee. D. Toneatto, GSK group of companies: Employee, Salary.

scholarly journals 1478. Efficacy and Safety of a Booster Dose of the MenACWY-TT Vaccine Administered 10 Years After Primary Vaccination with MenACWY-TT or MenACWY-PS

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S539-S539
Author(s):  
Beatriz Quiambao ◽  
Paula Peyrani ◽  
Chris Webber ◽  
Marie Van Der Wielen ◽  
Veronique Bianco ◽  
...  
Keyword(s):  
Immune Responses ◽  
Booster Dose ◽  
Geometric Mean ◽  
Primary Vaccination ◽  
The Philippines ◽  
Primary Dose ◽  
Serum Bactericidal Activity ◽  
Antibody Persistence ◽  
Rabbit Complement

Abstract Background The quadrivalent meningococcal ACWY polysaccharide tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix) is licensed in various countries to prevent disease caused by meningococcal serogroups A, C, W, and Y. In a previous study (NCT00464815), subjects aged 11‒17 years received a primary dose of MenACWY-TT or a quadrivalent polysaccharide vaccine (MenACWY-PS). Here, we report the long-term antibody persistence of the primary dose and the immunogenicity and safety of a booster dose given 10 years after primary vaccination of subjects. Methods Participants were enrolled from the Philippines and received a booster dose of MenACWY-TT at 10 years postvaccination. Antibody persistence 10 years postprimary vaccination and immunogenicity 1 month after the booster dose were evaluated by serum bactericidal activity assays using rabbit complement (rSBA) to assess the percentages of subjects with titers ≥1:8 and ≥1:128 and geometric mean titers (GMTs) for each serogroup. Safety was assessed for the booster dose. Results Of 229 subjects enrolled in this extension study, 169 and 58 subjects in the MenACWY-TT and MenACWY-PS groups, respectively, completed the booster phase. The percentages of primary MenACWY-TT recipients with prebooster rSBA titers ≥ 1:8 and ≥ 1:128 at year 10 ranged from 71.6%‒90.7% and 64.8%‒85.2% for all serogroups, respectively, compared with 43.1%‒82.4% and 25.5%‒76.5% of primary MenACWY-PS recipients; rSBA GMTs for all serogroups were higher in the MenACWY-TT group than in the MenACWY-PS group at year 10. For the MenACWY-TT and MenACWY-PS groups, respectively, the MenACWY-TT booster dose elicited rSBA titers ≥1:8 in 100% and ≥98.0% of subjects (figure); 100% and ≥96.1% of all subjects had titers ≥1:128. For all serogroups, rSBA GMTs at 1 month after the booster dose were higher than before the booster dose. No new safety signals were observed during the booster phase. Conclusion Functional antibody responses elicited by MenACWY-TT persisted 10 years after primary vaccination; the booster dose was well tolerated and elicited robust immune responses. ClinicalTrials.gov: NCT03189745, EudraCT # 2013-001512-29. Funded by Pfizer. Disclosures All authors: No reported disclosures.

scholarly journals 4. MenACWY-TT Long-Term Antibody Persistence Following Adolescent Vaccination and Evaluation of a Booster Dose: A Review of Clinical Data

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S24-S24
Author(s):  
Paula Peyrani ◽  
Chris Webber ◽  
Cindy Burman ◽  
Paul Balmer ◽  
John L Perez
Keyword(s):  
Immune Responses ◽  
Conjugate Vaccine ◽  
Booster Dose ◽  
Geometric Mean ◽  
Booster Vaccination ◽  
Primary Vaccination ◽  
The United States ◽  
The European Union ◽  
Adolescent Vaccination

Abstract Background A peak in meningococcal carriage and invasive meningococcal disease (IMD) occurs during adolescence and young adulthood. In the United States, preventive vaccination with a quadrivalent meningococcal (MenACWY) conjugate vaccine is recommended at age 11–12 years, with a booster dose given at age 16 years. MenACWY-TT (Nimenrix®), a MenACWY tetanus toxoid conjugate vaccine, was first licensed in 2012 and is available in the European Union and 50 other countries. Immune responses to other MenACWY conjugate vaccines decline over several years following vaccination. Here, we review 2 recent studies evaluating the long-term persistence of MenACWY-TT immune responses in adolescents as well as safety and immunogenicity of a booster dose given 10 years after primary vaccination. Methods Both studies (ClinicalTrials.gov NCT01934140, NCT03189745) were extensions of phase 2 or 3 studies of subjects 11–17 years of age given a single dose of MenACWY-TT or MenACWY polysaccharide vaccine (MenACWY-PS). Immune responses through 10 years after primary vaccination and after a Year 10 MenACWY-TT booster dose were measured by serum bactericidal antibody assays using baby rabbit complement (rSBA). Specific endpoints included percentages of subjects with rSBA titers ≥1:8 and ≥1:128 and geometric mean titers (GMTs). Booster dose safety and tolerability were also evaluated. Results In both studies, the percentages of subjects with rSBA titers ≥1:8 through 10 years postvaccination were generally higher or similar among MenACWY-TT (69.3%–91.2% at Year 10; n=137–163) compared with MenACWY-PS (24.4%–88.9%; n=45–53) recipients for all 4 serogroups (Figure); similar results were observed for GMTs (146.0–446.9 vs 12.9–191.0 at Year 10). One month after a MenACWY-TT booster dose, 97.7%–100% of subjects across groups had titers ≥1:8 (Figure), and GMTs were markedly higher than prebooster values. No new safety signals were identified following the booster dose. Figure 1. Subjects in each of the 2 studies with rSBA titers ≥1:8 before and at 1 month, 5 years, and 10 years after primary vaccination with MenACWY-TT or MenACWY-PS at 11–17 years of age and 1 month after booster vaccination with MenACWY-TT at 10 years following primary vaccination. Conclusion Functional antibodies for all 4 serogroups persisted through 10 years after MenACWY-TT adolescent vaccination, suggesting that this vaccine may help prevent IMD throughout the lengthy risk period in this group. A MenACWY-TT booster dose may further extend protection regardless of the primary vaccine received. Funded by Pfizer. Disclosures Paula Peyrani, MD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Paul Balmer, PhD, Pfizer Inc (Employee, Shareholder) John L. Perez, MD, MA, Pfizer Inc (Employee, Shareholder)

scholarly journals A booster dose is immunogenic and will be needed for older adults who have completed two doses vaccination with CoronaVac: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial

2021 ◽  
Author(s):  
Minjie Li ◽  
Juan Yang ◽  
Lin Wang ◽  
Qianhui Wu ◽  
Zhiwei Wu ◽  
...  
Keyword(s):  
Older Adults ◽  
Immune Responses ◽  
Booster Dose ◽  
Phase 1 ◽  
Neutralizing Antibody ◽  
Healthy Adults ◽  
Phase 2 ◽  
Double Blind ◽  
Phase 2 Trial ◽  
Antibody Titres

Importance: Whether herd immunity through mass vaccination is sufficient to curb SARS-CoV-2 transmission requires an understanding of the duration of vaccine-induced immunity, and the necessity and timing of booster doses. Objective: To evaluate immune persistence of two priming doses of CoronaVac, and immunogenicity and safety of a third dose in healthy adults ≥60 years. Design, setting, and participants: We conducted a vaccine booster study built on a single-center, randomized, double-blind phase 1/2 trial of the two-dose schedule of CoronaVac among healthy adults≥60 years in Hebei, China. We examined neutralizing antibody titres six months or more after the second dose in all participants. We provided a third dose to 303 participants recruited in phase 2 trial to assess their immune responses. Interventions: Two formulations (3 μg, and 6 μg) were used in phase 1 trial, and an additional formulation of 1.5 μg was used in phase 2 trial. All participants were given two doses 28 days apart and followed up 6 months after the second dose. Participants in phase 2 received a third dose 8 months after the second dose. Main outcomes and measures: Geometric mean titres (GMT) of neutralizing antibodies to live SARS-CoV-2 and adverse events were assessed at multiple time points following vaccination. Results: Neutralizing antibody titres dropped below the seropositive cutoff of 8 at 6 months after the primary vaccination in all vaccine groups in the phase 1/2 trial. A third dose given 8 months or more after the second dose significantly increased neutralizing antibody levels. In the 3 μg group (the licensed formulation), GMT increased to 305 [95%CI 215.3-432.0] on day 7 following the third dose, an approximately 7-fold increase compared with the GMT 28 days after the second dose. All solicited adverse reactions reported within 28 days after a booster dose were of grade 1 or 2 severity. Conclusion and relevance: Neutralizing antibody titres declined substantially six months after two doses of CoronaVac among older adults. A booster dose rapidly induces robust immune responses. This evidence could help policymakers determine the necessity and the timing of a booster dose for older adults. Trial registration: ClinicalTrials.gov (NCT04383574).

Peptide Antidotes to SARS-CoV-2 (COVID-19)

2020 ◽  
Author(s):  
Andre Watson ◽  
Leonardo Ferreira ◽  
Peter Hwang ◽  
Jinbo Xu ◽  
Robert Stroud
Keyword(s):  
Immune Responses ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Spike Protein ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Specificity And Sensitivity ◽  
Peptide Scaffolds

ABSTRACTThe design of an immunogenic scaffold that serves a role in treating a pathogen, and can be rapidly and predictively modeled, has remained an elusive feat. Here, we demonstrate that SARS-BLOCK™ synthetic peptide scaffolds act as antidotes to SARS-CoV-2 spike protein-mediated infection of human ACE2-expressing cells. Critically, SARS-BLOCK™ peptides are able to potently and competitively inhibit SARS-CoV-2 S1 spike protein receptor binding domain (RBD) binding to ACE2, the main cellular entry pathway for SARS-CoV-2, while also binding to neutralizing antibodies against SARS-CoV-2. In order to create this potential therapeutic antidote-vaccine, we designed, simulated, synthesized, modeled epitopes, predicted peptide folding, and characterized behavior of a novel set of synthetic peptides. The biomimetic technology is modeled off the receptor binding motif of the SARS-CoV-2 coronavirus, and modified to provide enhanced stability and folding versus the truncated wildtype sequence. These novel peptides attain single-micromolar binding affinities for ACE2 and a neutralizing antibody against the SARS-CoV-2 receptor binding domain (RBD), and demonstrate significant reduction of infection in nanomolar doses. We also demonstrate that soluble ACE2 abrogates binding of RBD to neutralizing antibodies, which we posit is an essential immune-evasive mechanism of the virus. SARS-BLOCK™ is designed to “uncloak” the viral ACE2 coating mechanism, while also binding to neutralizing antibodies with the intention of stimulating a specific neutralizing antibody response. Our peptide scaffolds demonstrate promise for future studies evaluating specificity and sensitivity of immune responses to our antidote-vaccine. In summary, SARS-BLOCK™ peptides are a promising COVID-19 antidote designed to combine the benefits of a therapeutic and vaccine, effectively creating a new generation of prophylactic and reactive antiviral therapeutics whereby immune responses can be enhanced rather than blunted.

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