1048. Double-Blind, Randomized, Placebo-Controlled Phase 2b Multicenter Trial of V160, a Replication-Defective Human Cytomegalovirus (CMV) Vaccine

Abstract Background Preventing congenital cytomegalovirus infection (CMVi) is an important unmet need. Natural maternal immunity to CMV acquired prior to pregnancy appears to reduce fetal transmission. In a Phase 1 trial, V160, a replication-defective CMV vaccine expressing the pentameric complex, induced humoral and cell-mediated immune (CMI) responses comparable to natural immunity. Methods Healthy, CMV-seronegative women aged 16–35 years were randomized 1:1:1 to receive double-blind V160 in a 3- or 2-dose regimen or placebo. Primary and secondary endpoints were efficacy in reducing the incidence of CMVi with 3-dose or 2-dose regimens of V160 vs placebo, respectively, using a fixed-event design. Monthly urine and saliva samples were collected to identify CMVi by polymerase chain reaction (PCR) with a single positive sample considered evidence of infection. Immunoglobulin G (IgG) binding to glycoprotein B (gB) and CMV-specific neutralizing antibody (NAb) were measured in all participants, and CMI responses were measured in a subset. Injection-site and systemic adverse events (AEs) were collected for 5 days and 14 days, respectively, after each vaccination and serious AEs were collected for the trial duration. Results 2200 women from 7 countries were enrolled (of 7458 screened). Over 80% of participants received all doses, and compliance with saliva and urine samples was > 95%. Vaccine efficacy (VE) of 42.4% (95% CI -13.5, 71.1%) was demonstrated in the 3-dose group vs placebo. In the 2-dose group, VE was -32.0% (95% CI -135.0, 25.0%). Both the quantity and duration of CMV shedding in urine and saliva among cases of CMVi decreased in the 3-dose, but not the 2-dose group vs placebo. Both V160 regimens elicited humoral and CMI responses detected by CMV-specific NAb, gB IgG, and ELISpot, which peaked at Month 7 and continued to be detectable at Month 24. Mild to moderate AEs were more frequently reported in V160 vs placebo recipients, but no vaccine-related serious AEs or deaths were reported. Conclusion V160 was well tolerated and immunogenic, but neither the 3-dose nor 2-dose regimen demonstrated significant efficacy against CMVi as defined in this trial. The quantity and duration of CMV shedding was reduced in the 3-dose group, suggesting V160 may improve immune control of viral replication after CMVi. Disclosures Rituparna Das, MD, Merck & Co, Inc. (Employee) Daniel Blazquez-Gamero, MD, MSD (Other Financial or Material Support, Fees for lectures in educational activities) Soren Gantt, MD, Altona Diagnostics (Research Grant or Support)Merck (Consultant, Grant/Research Support)Meridian Biosciences (Research Grant or Support)Moderna (Consultant, Research Grant or Support)VBI Vaccines Inc (Research Grant or Support) Oliver Bautista, PhD, Merck & Co, Inc. (Employee) Karen Beck, RN, BSN, Merck & Co, Inc. (Employee) Anthony Conlon, PhD, Merck & Co, Inc. (Employee) Daniel Rosenbloom, PhD, Merck & Co, Inc. (Employee) Dai Wang, PhD, Merck & Co, Inc. (Employee) Michael Ritter, BA, Merck & Co, Inc. (Employee) Beth Arnold, MS, Merck & Co, Inc. (Employee, Shareholder) Paula Annunziato, MD, Merck & Co, Inc. (Employee) Kevin Russell, MD, MTM&H, Merck & Co., Inc. (Employee, Shareholder)

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Immunogenicity and safety of a third dose, and immune persistence of CoronaVac vaccine in healthy adults aged 18-59 years: interim results from a double-blind, randomized, placebo-controlled phase 2 clinical trial

10.1101/2021.07.23.21261026 ◽

2021 ◽

Author(s):

Hongxing Pan ◽

Qianhui Wu ◽

Gang Zeng ◽

Juan Yang ◽

Deyu Jiang ◽

...

Keyword(s):

Large Scale ◽

Dose Group ◽

Geometric Mean ◽

Development Program ◽

Neutralizing Antibody ◽

Immune Memory ◽

High Dose ◽

Phase 2 ◽

Serious Adverse Events ◽

Double Blind

Background Large-scale vaccination is being implemented globally with CoronaVac, an inactivated vaccine against coronavirus disease 2019 (COVID-19). Immunogenicity and safety profiles of homologous two-dose schedules have been published. We report interim results of immune persistence, and the immunogenicity and safety of a third dose of CoronaVac. Methods In this ongoing, placebo-controlled, double-blind phase 2 trial in 18-to-59-year-olds, we randomly assigned subjects, 1:1:1:1, to one of four schedules to receive a third dose, 28 days or 6 months after two two-dose regimens (14-day or 28-day apart): schedule 1: days 0, 14, 42; schedule 2: days 0, 14, 194; schedule 3: days 0, 28, 56; schedule 4: days 0, 28, 208. For each schedule, participants were randomly assigned to either a medium-dose group (3 μg per 0.5 mL of aluminum hydroxide diluent per dose), a high-dose group (6 μg), or a placebo group (2:2:1). The primary outcome was geometric mean titers (GMTs) of neutralizing antibody to live SARS-CoV-2. Results Overall, 540 participants received a third dose. In the 3 μg group, neutralizing antibody titers induced by the first two doses declined after 6-8 months to below the seropositive cutoff (GMT: 4.1 [95%CI 3.3-5.2] for Schedule 2 and 6.7 [95%CI 5.2-8.6] for Schedule 4). When a third dose was given 6-8 months after a second dose, GMTs assessed 14 days later increased to 137.9 [95%CI 99.9-190.4] for Schedule 2, and 143.1 [95%CI 110.8-184.7] for Schedule 4, approximately 3-fold above Schedule 1 and Schedule 3 GMTs after third doses. Similar patterns were observed for the 6 μg group. The severity of solicited local and systemic adverse reactions reported within 28 days after the third dose were grade 1 to grade 2 in all vaccination cohorts. None of the fourteen serious adverse events were considered to be related to vaccination. Conclusions A third dose of CoronaVac administered 6 or more months after a second dose effectively recalled specific immune response to SARS-CoV-2, resulting in a remarkable increase in antibody levels, and indicating that a two-dose schedule generates good immune memory. Optimizing the timing of a booster dose should take into account immunogenicity, vaccine efficacy/effectiveness, local epidemic situation, infection risk, and vaccine supply. (Funded by the National Key Research and Development Program, Beijing Science and Technology Program and National Science Fund for Distinguished Young Scholars; ClinicalTrials.gov number, NCT04352608.)

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Clinical utility of Elecsys Anti-SARS-CoV-2 S assay in COVID-19 vaccination: An exploratory analysis of the mRNA-1273 phase 1 trial

10.1101/2021.10.04.21264521 ◽

2021 ◽

Author(s):

Simon Jochum ◽

Imke Kirste ◽

Sayuri Hortsch ◽

Veit Peter Grunert ◽

Holly Legault ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Clinical Utility ◽

Dose Group ◽

Phase 1 ◽

Geometric Mean ◽

Neutralizing Antibody ◽

High Specificity ◽

Live Virus ◽

Phase 1 Trial ◽

Antibody Levels

Background The ability to quantify an immune response after vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is essential. This study assessed the clinical utility of the quantitative Roche Elecsys® Anti-SARS-CoV-2 S assay (ACOV2S) using samples from the 2019-nCoV vaccine (mRNA-1273) phase 1 trial (NCT04283461). Methods Samples from 30 healthy participants, aged 18-55 years, who received two injections with mRNA-1273 at a dose of 25 μg (n=15) or 100 μg (n=15), were collected at Days 1 (first vaccination), 15, 29 (second vaccination), 43 and 57. ACOV2S results (shown in U/mL - equivalent to BAU/mL per the first WHO international standard) were compared with results from ELISAs specific to antibodies against the Spike protein (S-2P) and the receptor binding domain (RBD) as well as neutralization tests including nanoluciferase (nLUC80), live-virus (PRNT80), and a pseudovirus neutralizing antibody assay (PsVNA50). Results RBD-specific antibodies were already detectable by ACOV2S at the first time point of assessment (d15 after first vaccination), with seroconversion before in all but 2 participants (25 μg dose group); all had seroconverted by Day 29. Across all post-baseline visits, geometric mean concentration of antibody levels were 3.27-7.48-fold higher in the 100 μg compared with the 25 μg dose group. ACOV2S measurements were highly correlated with those from RBD ELISA (Pearson's r=0.938; p<0.0001) and S-2P ELISA (r=0.918; p<0.0001). For both ELISAs, heterogeneous baseline results and smaller increases in antibody levels following the second vs first vaccination compared with ACOV2S were observed. ACOV2S showed absence of any baseline noise indicating high specificity detecting vaccine-induced antibody response. Moderate-strong correlations were observed between ACOV2S and neutralization tests (nLUC80 r=0.933; PsVNA50, r=0.771; PRNT80, r=0.672; all p≤0.0001). Conclusion The Elecsys Anti-SARS-CoV-2 S assay (ACOV2S) can be regarded as a highly valuable method to assess and quantify the presence of RBD-directed antibodies against SARS-CoV-2 following vaccination, and may indicate the presence of neutralizing antibodies. As a fully automated and standardized method, ACOV2S could qualify as the method of choice for consistent quantification of vaccine-induced humoral response.

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Safety and immunogenicity trial of an inactivated SARS-CoV-2 vaccine-BBV152: a phase 1, double-blind, randomised control trial

10.1101/2020.12.11.20210419 ◽

2020 ◽

Author(s):

Raches Ella ◽

Krishna Mohan ◽

Harsh Jogdand ◽

Sai Prasad ◽

Siddharth Reddy ◽

...

Keyword(s):

Phase 1 ◽

Neutralizing Antibody ◽

Cold Chain ◽

Wild Type Virus ◽

Randomised Control Trial ◽

Enzyme Linked Immunosorbent Assay ◽

Double Blind ◽

Efficacy Trials ◽

National Immunization ◽

Antibody Titers

Background: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a TLR 7/8 agonist molecule adsorbed to alum (Algel-IMDG). Methods We conducted a double-blind randomized controlled phase 1 clinical trial to evaluate the safety and immunogenicity of BBV152. A total of 375 participants were randomized equally to receive three vaccine formulations (n=100 each) prepared with 3 μg with Algel-IMDG, 6 μg with Algel-IMDG, and 6 μg with Algel, and an Algel only control arm (n=75). Vaccines were administered on a two-dose intramuscular accelerated schedule on day 0 (baseline) and day 14. The primary outcomes were reactogenicity and safety. The secondary outcomes were immunogenicity based on the anti-IgG S1 response (detected with an enzyme-linked immunosorbent assay [ELISA] and wild-type virus neutralization [microneutralization and plaque reduction neutralization assays]). Cell-mediated responses were also evaluated. Results: Reactogenicity was absent in the majority of participants, with mild events. The majority of adverse events were mild and were resolved. One serious adverse event was reported, which was found to be unrelated to vaccination. All three vaccine formulations resulted in robust immune responses comparable to a panel of convalescent serum. No significant differences were observed between the 3-μg and 6-μg Algel-IMDG groups. Neutralizing responses to homologous and heterologous SARS-CoV-2 strains were detected in all vaccinated individuals. Cell-mediated responses were biased to a Th-1 phenotype. Conclusions BBV152 induced binding and neutralising antibody responses and with the inclusion of the Algel-IMDG adjuvant, this is the first inactivated SARS-CoV-2 vaccine that has been reported to induce a Th1-biased response. Vaccine-induced neutralizing antibody titers were reported with two divergent SARS-CoV-2 strains. BBV152 is stored between 2°C and 8°C, which is compatible with all national immunization program cold chain requirements. Both Algel-IMDG formulations were selected for the phase 2 immunogenicity trials. Further efficacy trials are underway.

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16. A Randomized Phase 1 Study of a Novel Pneumococcal Conjugate Vaccine in Healthy Japanese Adults in the United States

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.061 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S30-S31

Author(s):

David Fitz-Patrick ◽

Mariano Young Jr. ◽

Daniel Scott ◽

Ingrid L Scully ◽

Gary Baugher ◽

...

Keyword(s):

United States ◽

Conjugate Vaccine ◽

Phase 1 ◽

Geometric Mean ◽

Age Groups ◽

Unmet Need ◽

The United States ◽

Double Blind Study ◽

Double Blind ◽

Japanese Adults

Abstract Background Because of the number and variability of serotypes causing pneumococcal disease among different geographic regions, age groups, and environmental backgrounds, expanding serotype coverage with pneumococcal conjugate vaccines (PCVs) is a continued unmet need. Methods This phase 1, randomized, double-blind study included healthy Japanese adults aged 18–49 years residing in the United States. Subjects were randomized 1:1:1 to receive a single dose of a 20-valent PCV (containing 13-valent PCV [PCV13] serotypes plus 8, 10A, 11A, 12F, 15B, 22F, 33F), a novel pneumococcal polysaccharide conjugate vaccine with extended coverage, or PCV13 (control). Safety was the primary endpoint and included reactogenicity events occurring ≤ 14 days after vaccination, adverse events (AEs) ≤ 1 month after vaccination, and serious AEs (SAEs) ≤ 6 months after vaccination. The secondary endpoint was pneumococcal serotype-specific immunogenicity as determined by opsonophagocytic activity (OPA) titers on sera collected before and 1 month after vaccination. Results Overall, 35 subjects received PCV20 and 35 subjects received PCV13. One subject withdrew before the 1-month follow-up. Local reactions and systemic events across groups were generally mild or moderate (Figure 1). Two vaccine-related AEs occurred (injection site erythema and swelling in the PCV20 group); no severe AEs, SAEs, or safety-related withdrawals were reported. OPA geometric mean titers increased for all 20 serotypes in the PCV20 group and all 13 serotypes in the PCV13 group 1 month after vaccination; corresponding OPA geometric mean fold rises from baseline to 1 month after vaccination are reported (Figure 2; Figure 3). Figure 1 Figure 2 Figure 3 Conclusion PCV20 was well tolerated and induced serotype-specific functional OPA immune responses that are anticipated to be associated with protection in Japanese adults. ClinicalTrials.gov: NCT03642847. Funding: Pfizer Inc. Disclosures David Fitz-Patrick, MD, Pfizer Inc (Grant/Research Support) Mariano Young Jr., MD, Pfizer Inc (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Ingrid L. Scully, PhD, Pfizer Inc (Employee, Shareholder) Gary Baugher, PharmD, Pfizer Inc (Employee, Shareholder) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)

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636. A Phase I Study to Evaluate the Safety, Tolerability, and Immunogenicity of a Live, Attenuated, Quadrivalent Dengue Vaccine (V181)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.833 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S420-S421

Author(s):

Kevin Russell ◽

Richard E Rupp ◽

Javier O Morales-Ramirez ◽

Clemente Diaz-Perez ◽

Charles P Andrews ◽

...

Keyword(s):

Phase 1 ◽

Healthy Adults ◽

Controlled Study ◽

Dengue Vaccine ◽

Double Blind ◽

Denv Serotypes ◽

Medical Need ◽

Tetravalent Vaccine ◽

To Receive ◽

Research Grant

Abstract Background Dengue (DENV) is a mosquito-borne virus with four serotypes causing substantial morbidity in tropical and subtropical areas worldwide. A dengue vaccine that can be given to both seronegative and seropositive populations remains an important unmet medical need. V181 is an investigational live, attenuated, quadrivalent dengue vaccine. Methods In this phase 1 double-blind, placebo-controlled study, the safety, tolerability, and immunogenicity of V181 in healthy adults were evaluated in two formulations: TV003 and TV005. TV005 has a 10-fold higher DENV2 component as compared to TV003. Two-hundred participants [~ 50% baseline flavivirus-experienced (BFE) and 50% baseline flavivirus-naive (BFN)] were randomized 2:2:1 to receive TV003, TV005, or placebo on Days 1 and 180. Immunogenicity against each of the four DENV serotypes was measured using a Virus Reduction Neutralization Test (VRNT60) after each vaccination and out to 1 year after the second dose. Results There were no discontinuations due to adverse events (AEs) or vaccine-related serious AEs. The most common AEs Days 1-28 after any TV003 or TV005 vaccination were rash, headache, fatigue, and myalgia. DENV VRNT60 seropositivity to 3 or 4 serotypes (i.e. tri-or tetravalent) was demonstrated in 92.6% of BFN TV003 participants, 74.2% of BFN TV005 participants, and 100% of the BFE participants at 6 months postdose 1 (PD1). Vaccine viremia, a measure of vaccine infectivity, was transiently detected from all four DENV types after the first dose of TV003 and TV005. Tri- or tetravalent vaccine-viremia was detected in 63.9 % and 25.6 % of BFN TV003 and TV005 participants, respectively, PD1. Compared to baseline, robust increases in VRNT60 GMTs were observed after the first dose of TV003 and TV005 in both flavivirus subgroups for all DENV serotypes and minimal increases were observed PD2. GMTs in the TV003 and TV005 BFE and BFN subgroups remained above the respective baselines and placebo at 1-year PD2. Conclusion Both formulations of V181 were generally well tolerated in healthy adults. Overall, viremia and immunogenicity were higher after TV003 as compared to TV005. These data support the continued development of the V181 TV003 formulation as a single-dose vaccine for the prevention of DENV disease. Disclosures Kevin Russell, MD, MTM&H, Merck & Co., Inc. (Employee, Shareholder) Richard E. Rupp, MD, Merck & Co., Inc. (Research Grant or Support) Clemente Diaz-Perez, MD, Merck & Co., Inc. (Research Grant or Support) Charles P. Andrews, MD, Merck & Co., Inc. (Research Grant or Support) Andrew W. Lee, MD, Merck & Co., Inc. (Employee, Shareholder) Tyler S. Finn, BA, Merck & Co., Inc. (Employee, Shareholder) Kara Cox, MS, Merck & Co., Inc. (Employee, Shareholder) Amy Falk Russell, MS, Merck & Co., Inc. (Employee, Shareholder) Margaret M. Schaller, BS, Merck & Co., Inc. (Employee, Shareholder) Jason C. Martin, PhD, Merck & Co., Inc. (Employee, Shareholder) Donna M. Hyatt, BA, Merck & Co., Inc. (Employee, Shareholder) Sabrina Gozlan-Kelner, MS, Merck & Co., Inc. (Employee, Shareholder) Androniki Bili, MD, MPH, Merck & Co., Inc. (Employee, Shareholder) Beth-Ann Coller, PhD, Merck & Co., Inc. (Employee, Shareholder)

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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

10.1101/2021.08.03.21261544 ◽

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).

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Different dose regimens of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373) in younger and older adults: A phase 2 randomized placebo-controlled trial

PLoS Medicine ◽

10.1371/journal.pmed.1003769 ◽

2021 ◽

Vol 18 (10) ◽

pp. e1003769

Author(s):

Neil Formica ◽

Raburn Mallory ◽

Gary Albert ◽

Michelle Robinson ◽

Joyce S. Plested ◽

...

Keyword(s):

Dose Regimen ◽

Phase 1 ◽

Late Phase ◽

Age Groups ◽

Neutralizing Antibody ◽

Spike Protein ◽

Wild Type Virus ◽

Phase 2 ◽

Type Virus ◽

Wild Type

Background NVX-CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant. Methods and findings The phase 2 component of our randomized, placebo-controlled, phase 1 to 2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late-phase studies and was based on immunogenicity and safety data through Day 35 (14 days after the second dose). The trial was conducted at 9 sites in Australia and 8 sites in the United States. Participants in 2 age groups (aged 18 to 59 and 60 to 84 years) were randomly assigned to receive either 1 or 2 intramuscular doses of 5-μg or 25-μg NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7-day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild-type virus neutralizing antibody response. After enrollment, 1,288 participants were randomly assigned to 1 of 4 vaccine groups or placebo, with 1,283 participants administered at least 1 study treatment. Of these, 45% were older participants 60 to 84 years. Reactogenicity was predominantly mild to moderate in severity and of short duration (median <3 days) after first and second vaccination with NVX-CoV2373, with higher frequencies and intensity after second vaccination and with the higher dose. Reactogenicity occurred less frequently and was of lower intensity in older participants. Both 2-dose regimens of 5-μg and 25-μg NVX-CoV2373 induced robust immune responses in younger and older participants. For the 2-dose regimen of 5 μg, geometric mean titers (GMTs) for IgG anti-spike protein were 65,019 (95% confidence interval (CI) 55,485 to 76,192) and 28,137 (95% CI 21,617 to 36,623) EU/mL and for wild-type virus neutralizing antibody (with an inhibitory concentration of 50%—MN50%) were 2,201 (95% CI 1,343 to 3,608) and 981 (95% CI 560 to 1,717) titers for younger and older participants, respectively, with seroconversion rates of 100% in both age groups. Neutralizing antibody responses exceeded those seen in a panel of convalescent sera for both age groups. Study limitations include the relatively short duration of safety follow-up to date and current lack of immune persistence data beyond the primary vaccination regimen time point assessments, but these data will accumulate over time. Conclusions The study confirmed the phase 1 findings that the 2-dose regimen of 5-μg NVX-CoV2373 is highly immunogenic and well tolerated in younger adults. In addition, in older adults, the 2-dose regimen of 5 μg was also well tolerated and showed sufficient immunogenicity to support its use in late-phase efficacy studies. Trial registration ClinicalTrials.gov NCT04368988.

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Safety and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older: two single-center, randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00692-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Fan-Yue Meng ◽

Fan Gao ◽

Si-Yue Jia ◽

Xiang-Hong Wu ◽

Jing-Xin Li ◽

...

Keyword(s):

Dose Group ◽

Low Dose ◽

Phase 1 ◽

High Dose ◽

Healthy Population ◽

Phase 2 ◽

Double Blind ◽

Double Blind Placebo ◽

To Receive ◽

Dose Vaccine

AbstractCOVID-19 vaccines from multiple manufacturers are needed to cope with the problem of insufficient supply. We did two single-center, randomised, double-blind, placebo-controlled phase 1 and phase 2 trials to assess the safety, tolerability and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older in China. Eligible participants were enrolled, the ratio of candidate vaccine and placebo within each dose group was 3:1 (phase 1) or 5:1 (phase 2). From August 28, 2020, 168 participants were sequentially enrolled and randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 28 days or 0, 14, 28 days in phase 1 trial. From November 18, 2020, 960 participants were randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 21 days or 0, 14, 28 days in phase 2 trial. The most common solicited injection site adverse reaction within 7 days in both trials was pain. The most common solicited systematic adverse reactions within 7 days were fatigue, cough, sore throat, fever and headache. ELISA antibodies and neutralising antibodies increased at 14 days, and peaked at 28 days (phase 1) or 30 days (phase 2) after the last dose vaccination. The GMTs of neutralising antibody against live SARS-CoV-2 at 28 days or 30 days after the last dose vaccination were highest in the adult high dose group (0, 14, 28 days), with 102.9 (95% CI 61.9–171.2) and 102.6 (95% CI 75.2–140.1) in phase 1 and phase 2 trials, respectively. Specific T-cell response peaked at 14 days after the last dose vaccination in phase 1 trial. This vaccine is safe, and induced significant immune responses after three doses of vaccination.

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P655 Pharmacokinetics of ustekinumab in children and adolescents with moderately to severely active Crohn’s disease: Results from UniStar, a phase 1 study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.783 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S539-S540

Author(s):

O Adedokun ◽

J Hyams ◽

D Turner ◽

A Griffiths ◽

N Terry ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Dose Group ◽

Activity Index ◽

Phase 1 ◽

Double Blind Study ◽

Double Blind ◽

Faecal Calprotectin ◽

Adequate Treatment ◽

The Impact

Abstract Background Ustekinumab (UST) is approved for the treatment of adults with moderate to severe Crohn’s disease (CD) or ulcerative colitis. In the UniStar study, the pharmacokinetics (PK) of UST and its relationship with efficacy was evaluated in children who failed prior therapy. UniStar consisted of a PK portion (week 0–16) and extension (week 16–216); we report data through week 16. Methods UniStar is a multicentre, double-blind study (NCT02968108) designed to assess the PK, safety, and efficacy of UST in children (2–<18 years) with moderately to severely active CD, Paediatric CD Activity Index (PCDAI) score >30, and evidence of inflammation as measured by C-reactive protein >3.0 mg/l or faecal calprotectin >250 µg/g or ulcerations on ileocolonoscopy despite adequate treatment with corticosteroids and/or immunomodulators and/or anti-TNF therapies. Patients were randomised (1:1) and stratified by body weight (BW) and prior anti-TNF use for induction to one of 2 weight range-based IV doses: 130mg vs. 390 mg if BW ≥40 kg and 3mg/kg vs. 9 mg/kg if BW <40 kg. At week 8, all patients received a single subcutaneous (SC) UST maintenance dose of 90mg if BW ≥40 kg or 2 mg/kg if BW <40 kg. UST PK outcomes were assessed and compared with adult Phase 3 CD trials. Results 44 patients (59% ≥40 kg; >90% anti-TNF exposed) were randomised and treated with UST (n = 23 lower dose; n = 21 higher dose). Baseline demographics were generally similar between treatment groups. Most patients (67%) had a severe CD (PCDAI >40). At weeks 0 (1 h after infusion), 3, 6, and 8, mean serum UST concentrations (SUC) in the lower- (51.3, 7.7, 3.0, 1.6 μg/ml) and higher-dose groups (149.0, 23.7, 9.1, 4.8 μg/ml) were generally dose proportional (Figure 1a). Following SC UST at week 8, the impact of the difference in induction doses had diminished by week 16 when mean SUC was 1.5 µg/ml in the lower-dose group vs. 1.8 µg/ml in the higher-dose group. In the overall paediatric population (combined doses), serum UST concentrations were comparable to those in the reference adult CD studies (Figure 1b and c). In the higher dose group, we observed a pattern toward lower mean serum UST concentrations in patients weighing <40 kg vs. those weighing ≥40 kg; thus, UST should be dosed higher in patients <40 kg. Overall at week 8 and week 16, more patients achieved clinical response (PCDAI reduction ≥15) and biomarker improvement with higher UST concentrations, although this pattern was not observed for clinical remission (PCDAI ≤10; Figure 2). Conclusion Overall, UST PK was generally comparable between paediatric and adult patients with CD. A trend towards better efficacy outcomes with higher UST concentrations was observed in children similar to adults with CD.

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A Single Dose Monoclonal Antibody (mAb) Immunoprophylaxis Strategy to Prevent RSV Disease in All Infants: Results of the First in Infant Study with MEDI8897

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx162.089 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S37-S37 ◽

Cited By ~ 1

Author(s):

Joseph B Domachowske ◽

Anis Khan ◽

Mark T Esser ◽

Kathryn M Jensen ◽

Therese Takas ◽

...

Keyword(s):

Preterm Infants ◽

Safety Profile ◽

Unmet Need ◽

Neutralizing Antibody ◽

Febrile Seizures ◽

10Mg Dose ◽

Healthy Infants ◽

Antibody Titers ◽

The One ◽

Research Grant

Abstract Background RSV is the most common cause of lower respiratory tract infection (LRTI) among infants making prevention of RSV disease a public health priority. A significant unmet need exists for RSV prevention in healthy infants. Our goal is to develop a mAb with an extended half-life (t½) capable of protecting infants for an entire RSV season by using a single intramuscular (IM) dose. This study was conducted to evaluate the safety profile, pharmacokinetics (PK), RSV neutralizing antibody titers, and anti-drug antibody (ADA) responses for MEDI8897 in healthy preterm infants born between 32 and 35 weeks gestational age. Methods Infants were randomized 4:1 to receive a single IM injection of MEDI8897 10mg (n = 8), 25mg (n = 31), 50mg (n = 32) or placebo (n = 18) and followed for 360 days. Enrollment occurred during the 2,015 RSV seasons in the US, South Africa, and Chile. Blood was collected at multiple timepoints. Infants who met criteria for a medically-attended (MA) LRTI had nasal swabs obtained for RSV testing by RT-PCR. Results A total of 85/89 (95.5%) infants completed the study. Adverse events (AEs) were reported in 17/18 (94.4%) placebo and 66/71 (93.0%) MEDI8897 recipients. Five serious AEs (three LRTIs, two febrile seizures) were reported in three MEDI8897 recipients. No events were consistent with hypersensitivity reactions. The estimated MEDI8897 serum t½ ranged from 62.5 to 72.9 days. On day 151, 87% of the infants who received the 50mg dose of MEDI8897 had serum concentrations above the target EC90 level of 6.8 µg/ml, and 93.3% showed a ≥3-fold rise from baseline in serum anti-RSV neutralizing antibody titers. ADA was detected in 28.2% of MEDI8897 recipients, but when present was not associated with any safety findings. ADA was detected at day 361 only in 26.5% of subjects. MA-LRTI was reported in 5 (7%) MEDI8897 recipients through 150 days after dosing. The one subject with an MA-LRTI caused by RSV had received a 10mg dose of MEDI8897. Conclusion In healthy preterm infants, the safety profile of MEDI8897 was favorable. The extended t½ of MEDI8897 with the corresponding increase in RSV neutralizing antibody levels was confirmed and supports protection from RSV disease during a typical 5-month season with a single 50mg IM dose. This study was sponsored by MedImmune. Disclosures J. B. Domachowske, Medimmune: Investigator, Research grant; Regeneron: Investigator, Research grant; Pfizer: Investigator, Research grant; Glaxo Smith Kline: Investigator, Research grant; Novavax: Investigator, Research grant; Janssen: Investigator, Research grant; A. Khan, MedImmune: Employee and Shareholder, Salary and stock; M. T. Esser, MedImmune: Employee and Shareholder, Salary and stock; K. M. Jensen, MedImmune: Employee and Shareholder, Salary and stock; T. Takas, MedImmune: Employee and Shareholder, Salary and stock; T. Villafana, MedImmune: Employee and Shareholder, Salary and stock; F. Dubovsky, MedImmune: Employee and Shareholder, Salary and stock; M. P. Griffin, MedImmune: Employee and Shareholder, Salary and stock

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