Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study.

BACKGROUND: We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. METHODS: This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18-59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. FINDINGS: Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744-2746) for the low-dose group, 2269 (1792-2873) for the medium-dose group, and 2895 (2294-3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85-135) in the low-dose group, 110 (87-140) in the medium-dose group, and 141 (111-179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836-11 815) in the low-dose group, 2338 (593-9226) in the medium-dose group, and 7069 (1361-36 725) in the high-dose group. INTERPRETATION: Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, administered concomitantly with influenza vaccine in healthy adults aged ≥50 years: a randomized phase 3 trial (PNEU-FLU).

Streptococcus pneumoniae and influenza viruses are associated with significant morbidity and mortality in older adults. Concomitant vaccination against these agents reduces hospitalization and mortality rates. This phase 3 trial evaluated safety, tolerability, and immunogenicity of concomitant and non-concomitant administration of V114, a 15-valent pneumococcal conjugate vaccine containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 22F, 23F, 33F, and quadrivalent inactivated influenza vaccine (QIV), in healthy adults aged ≥50 years. Participants (N = 1,200) were randomized 1:1 to receive either V114 administered concomitantly with QIV (concomitant group) or QIV plus placebo (non-concomitant group) on Day 1, followed by placebo (concomitant group) or V114 (non-concomitant group) 30 days later. Randomization was stratified by age and history of pneumococcal polysaccharide vaccine receipt. Overall, 426 (71.0%) and 438 (73.5%) participants in the concomitant and non-concomitant groups experienced solicited injection-site adverse events (AEs); 278 (46.3%) and 300 (50.3%) reported solicited systemic AEs. Most solicited AEs were mild or moderate in severity and of short duration. Non-inferiority for pneumococcal- and influenza-specific antibody responses (lower bound 95% confidence interval of opsonophagocytic activity [OPA] and hemagglutination inhibition geometric mean titers [GMTs] ratios ≥0.5) was demonstrated for concomitant versus non-concomitant administration for all 15 pneumococcal serotypes and all four influenza strains. Consistent with previous studies, a trend was observed toward lower pneumococcal OPA GMTs in the concomitant versus the non-concomitant group. V114 administered concomitantly with QIV is generally well tolerated and immunologically non-inferior to non-concomitant administration, supporting coadministration of both vaccines.

Immunogenicity and safety of a second dose of a measles-mumps-rubella vaccine administered to healthy participants 7 years of age or older: A phase III, randomized study.

The introduction of vaccination programs against measles, mumps, and rubella (MMR) led to significant global reduction in morbidity and mortality from these diseases. The currently recommended MMR vaccination schedule in the United States of America comprises 2 vaccine doses typically administered at 12-15 months and 4-6 years, respectively. Considering recent outbreaks in the USA, catch-up vaccination with an additional dose of MMR vaccine could contribute to outbreak control and community protection. This phase III, observer-blind, randomized controlled trial (NCT02058563) assessed the immunogenicity and safety of a dose of the MMR-RIT vaccine (Priorix, GSK) compared to MMR II vaccine (control; M-M-R II, Merck&Co Inc.) in ≥7-year-olds who had received ≥1 previous dose of MMR vaccine. We assessed anti-measles, anti-mumps, and anti-rubella antibody geometric mean concentrations (GMCs; primary endpoint) and seroresponse rates (SRRs) at day 42 post-vaccination. Solicited, unsolicited, and serious adverse events (AEs) were recorded. The according-to-protocol cohort for immunogenicity included 869 participants (MMR-RIT: N = 433; MMR II: N = 436). We observed anti-measles, anti-mumps, and anti-rubella antibody GMCs of 1790.2 mIU/mL, 113.5 EU/mL, and 76.1 IU/mL, respectively, and SRRs of 98.8%, 98.4%, and 99.5%, respectively, after a dose of MMR-RIT; non-inferiority compared to MMR II was demonstrated. Both vaccines showed comparable reactogenicity profiles; the most common solicited AEs were injection site redness and pain, and fever (MMR-RIT: 12.2%, 11.8%, and 3.0%; MMR II: 11.7%, 11.5%, and 5.2%, respectively). The dose of MMR-RIT induced robust immune responses that were not inferior to those of MMR II, and was well tolerated.

Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial.

OBJECTIVE: To compare lipid-lowering efficacy of adding alirocumab to rosuvastatin versus other treatment strategies (NCT01730053). METHODS: Patients receiving baseline rosuvastatin regimens (10 or 20 mg) were randomized to: add-on alirocumab 75 mg every-2-weeks (Q2W) (1-mL subcutaneous injection via pre-filled pen); add-on ezetimibe 10 mg/day; or double-dose rosuvastatin. Patients had cardiovascular disease (CVD) and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dL (1.8 mmol/L) or CVD risk factors and LDL-C ≥100 mg/dL (2.6 mmol/L). In the alirocumab group, dose was blindly increased at Week 12 to 150 mg Q2W (also 1-mL volume) in patients not achieving their LDL-C target. Primary endpoint was percent change in calculated LDL-C from baseline to 24 weeks (intent-to-treat). RESULTS: 305 patients were randomized. In the baseline rosuvastatin 10 mg group, significantly greater LDL-C reductions were observed with add-on alirocumab (-50.6%) versus ezetimibe (-14.4%; p < 0.0001) and double-dose rosuvastatin (-16.3%; p < 0.0001). In the baseline rosuvastatin 20 mg group, LDL-C reduction with add-on alirocumab was -36.3% compared with -11.0% with ezetimibe and -15.9% with double-dose rosuvastatin (p = 0.0136 and 0.0453, respectively; pre-specified threshold for significance p < 0.0125). Overall, ∼80% alirocumab patients were maintained on 75 mg Q2W. Of alirocumab-treated patients, 84.9% and 66.7% in the baseline rosuvastatin 10 and 20 mg groups, respectively, achieved risk-based LDL-C targets. Treatment-emergent adverse events occurred in 56.3% of alirocumab patients versus 53.5% ezetimibe and 67.3% double-dose rosuvastatin (pooled data). CONCLUSIONS: The addition of alirocumab to rosuvastatin provided incremental LDL-C lowering versus adding ezetimibe or doubling the rosuvastatin dose.