Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a … – Nature.com

The protocol was approved by the ethics committee (EC) of each of the 16 study centers and the Vietnam National EC in Biomedical Research and Ministry of Health. All participants provided informed consent before enrolment, and the study was conducted in accordance with the ethical principles of Good Clinical Practice, the Declaration of Helsinki and International Council for Harmonisation (ICH E6R2), and applicable local regulatory and bioethics requirements. Primary objectives of phase 1, 2, and 3a studies were to assess in comparison with placebo the safety and reactogenicity of two ARCT-154 doses administered four weeks apart, and the immunogenicity four weeks after the second dose. Primary objectives of the phase 3b study were to assess the safety and reactogenicity of two doses of ARCT-154 and their efficacy against COVID-19 disease from 7 (Day 36) to 63 (Day 92) days after the second vaccination. An exploratory assessment of efficacy from Day 1 to Day 92 was done in all participants who had received at least one dose of ARCT-154 in any phase of the study. An independent data and safety monitoring board (DSMB) had full oversight over the study, including assessment of blinded data on safety and confirmed COVID-19 cases, and made recommendations to continue enrolment or the study.

Study designs for individual study phases are illustrated in Fig.1. In phase 1 eligible participants were healthy adults > 18 to <60 years of age; in phases 2/3a/3b eligible participants were adults > 18 years of age. Enrolled volunteers in phases 1/2/3a were randomized 3:1 and those in phase 3b 1:1 to receive ARCT-154 or placebo. Phase 3b included volunteers at increased risk of severe COVID-19 due to their comorbidity status31 or being 60 years old, and randomization included stratification of these at-risk participants. Phase 1 participants were recruited and treated first, parallel enrolment for phases 2 and 3a was only allowed after the DSMB and Vietnam MoH had reviewed all safety data collected up to 7 days after the second vaccination (Day 36) in phase 1. Similarly, enrolment for phase 3b was only approved following review of all safety data collected through Day 7 following the first dose in phases 2 and 3a.

Other than the above age restrictions, eligible participants were male or female adults who could consent to participate, agreed to comply with all required study visits and procedures, and were willing to provide required blood and nasal swab samples. Major exclusion criteria were evidence of an acute infection at the time of enrolment, pregnancy or breastfeeding, previous COVID-19 infection (including a positive result of RT-PCR), close contact with a person known to be infected with SARS-CoV-2 or any known history of anaphylactic reactions to vaccines. Detailed exclusion criteria are shown in Supplementary Table2.

At enrolment volunteers were allocated to ARCT-154 or placebo groups using an interactive response technology (IRT) system which provided a unique identifying study code and the allocated study intervention for each participant. Codes were accessible only to unblinded study personnel who prepared and administered the vaccine/placebo but played no other role in the study. All other study personnel and participants were blinded to study allocation. A nasal swab was collected for SARS-CoV-2 testing by RT-PCR at screening on or within 5 days of Day 1. On Day 1, after a baseline blood draw for testing for SARS-CoV-2 nucleocapsid-specific antibodies and negative urine or blood pregnancy test for females of child-bearing potential, the first assigned vaccine or placebo injection was administered; a second dose was given in the same manner on Day 29. To ensure all participants received immunization against COVID-19 there was as switchover at Day 92 when placebo recipients from all phases were offered ARCT-154 as two doses four weeks apart. Vaccinees from the different phases received either a third dose of ARCT-154 or two doses of placebo. This report only presents data acquired up to Day 92, data from the switchover will be presented separately.

ARCT-154 consists of a replicon based upon Venezuela equine encephalitis virus in which RNA coding for the virus structural proteins has been replaced with RNA coding for the full-length spike (S) glycoprotein of the SARS-CoV-2 D614G variant, encapsulated in lipid nanoparticles. 100g active ingredient, stored in vials at -20C or lower, was dissolved in 10mL sterile saline immediately before use and 0.5mL doses containing 5g were administered by intramuscular injection in the deltoid. Placebo was sterile saline.

After 30minutes monitoring for any immediate reactions, all participants completed electronic or paper study diaries for 7 days starting on the day of each study injection. Diaries solicited local reactions (injection site erythema, pain, induration/swelling, and tenderness) and systemic adverse events (AEs; arthralgia, chills, diarrhea, dizziness, fatigue, headache, myalgia, nausea/vomiting and fever). Unsolicited AEs were recorded up to 28 days after each vaccination. Any adverse event leading to discontinuation or withdrawal from the study, any medically attended adverse event (MAAE) or serious adverse event (SAE) was to be documented for one year of follow-up after the completion of the initial vaccination series. Here we present general safety data including MAAEs, SAES and withdrawals up to six months (Day 210). Participants were contacted through weekly telephone calls to ensure compliance with completing the study diaries, which were collected on Days 8 and 36, 7 days after each vaccination, and at a follow-visit on Day 57. Adverse event data was entered into the case report form, and the causal relationship of events was established by the reporting investigator.

Sera for immunogenicity analyses were collected on Days 1, 29 and 57. The primary immunogenicity objective was the response at Day 57 in all sera available from eligible phase 1/2/3a participants as measured at the Vietnamese National Institute of Hygiene and Epidemiology Laboratory using the SARS-CoV-2 Surrogate Virus Neutralization Test (sVNT) kit (GenScript, Piscataway, NJ, USA). This kit is a functional enzyme-linked immunosorbent assay for qualitative or semiquantitative detection of antibodies (Nabs) that block the binding of SARS-CoV-2 to the human ACE2 receptor of host cells. Antibodies were expressed as group geometric mean concentrations (GMC), seroconversion rates (SCR), and geometric mean fold rises (GMFR) from Day 1. Results were expressed in units per mL (U/mL) calibrated with the WHO standard serum.

To confirm observations from the exploratory assay, immunogenicity was also assessed in a validated 293T-ACE2 cell-based microneutralization assay by the Pharmaceutical Product Development Bioanalytical Laboratory (PPD, Richmond, VA, USA). This measured neutralizing antibodies against SARS-CoV-2 in sera from Days 1 and 57 from all phase 1 participants, the first 150 samples from phase 2, and randomly selected samples from the other participants in phase 2, and all available samples from phase 3a.

For efficacy assessments, participants with suspected COVID-19 were evaluated for the presence of potential symptoms and clinical signs of COVID-19 including fever, chills, cough, shortness of breath or difficulty breathing, fatigue, muscle or body aches, headache, new loss of taste or smell, sore throat, congestion or runny nose, nausea, vomiting or diarrhea. Any of these symptoms occurring after 3 days post-vaccination triggered COVID-19 diagnostic testing. Where possible, participants visited their respective study clinic where nasal swabs were taken for RT-PCR, with documentation of medical history and medications taken. A protocol-defined COVID-19 case had to have virological confirmation (by RT-PCR) of SARS-CoV-2 and at least one of the symptoms or clinical findings listed above.

Case definitions for evaluations of COVID-19 and severe COVID-19 were based on US FDA recommendations in line with similar clinical trials, which for severe COVID-19 included any of the following: acute pulmonary, cardiac, renal, hepatic, or neurologic dysfunction; shock; death; or admission to an intensive care unit (Supplementary table3). All suspected COVID-19 cases underwent blinded tiered review by an independent Event Adjudication Committee (EAC) composed of clinical experts experienced in the diagnosis, care, and treatment of COVID-19. The EAC reviewed blinded data from each case and concluded on whether the case met the protocol-defined COVID-19 case criteria, and severity according to the US FDA and WHO classifications. Only virologically confirmed, protocol-defined cases adjudicated by the EAC are included in the primary vaccine efficacy (VE).

Primary safety endpoints were evaluated in the Safety Analysis Set (SAS; all participants who received any study injection) and Reactogenicity Analysis Set (RAS; all participants who received any study injection and provide at least one diary report). Statistical analysis of safety and reactogenicity data was descriptive with frequency and percentage for participants analyzed according to study group.

Primary immunogenicity analysis in the Immunogenicity Analysis Set (IAS) included all participants who received both assigned study injections by the evaluated timepoint with no evidence of prior SARS-CoV-2 infection at Day 1 (i.e., were seronegative for N-antibody) and at least one valid post-vaccination immunogenicity assay result. GMCs were calculated as the mean of log-transformed results and then exponentiating the mean (in order to present the results on the original scale). GMFR was calculated as the mean of the difference after log-transformed results (post baseline minus baseline) and exponentiating the mean. Two-sided 95% CI for GMCs and GMFRs were obtained by taking log-transformation of the antibody results; the 95% CI was calculated based on Students t-distribution for the mean difference, then exponentiating the confidence limits. Seroconversion was defined as 4-fold increase in titer from baseline and its two-sided 95% CI was calculated using the Clopper-Pearson method.

The primary efficacy objective was assessed in the modified Intention to Treat (mITT) set composed of all participants who received both assigned study injections and had no evidence of SARS-CoV-2 infection on Day 1 and up to Day 36, 7 days after the second study injection. The first primary endpoint was defined as the first occurrence of confirmed, protocol-defined COVID-19 with onset between Days 36 and 92 inclusive. For the overall primary efficacy objective of the study, the null hypothesis was that the vaccine efficacy (VE) of ARCT-154 to prevent COVID-19 was 30% (i.e., H0efficacy: VE 0.3). Vaccine efficacy was calculated from 1-hazard ratio, where the hazard ratio (HR) and 95% CI are estimated by Cox proportional hazard regression. The primary efficacy objective would be met if the lower limit of the 95% CI for VE exceeded 30%; a total of 372 COVID-19 cases were needed to provide approximately 90% power to detect a 50% reduction in hazard rate (50% VE). Factors used as covariates in Cox proportional hazard regression included: Risk group: 18 to <60 years and healthy, 18 and <60 years and at risk and 60 years and study site region. If the primary efficacy objective was met, following a hierarchical approach, the null hypothesis that the vaccine efficacy to prevent occurrence of confirmed severe COVID-19 was 0% (i.e., H0efficacy: VEsevere0) was also tested. A secondary efficacy assessment was done in the ITT set, comprising all participants who received at least one study injection, in which the secondary endpoint was the occurrence of confirmed, protocol-defined COVID-19 with onset at any time after the Dose 1 up to Day 92, inclusive.

Further information on research design is available in theNature Portfolio Reporting Summary linked to this article.

See more here:

Safety, immunogenicity and efficacy of the self-amplifying mRNA ARCT-154 COVID-19 vaccine: pooled phase 1, 2, 3a ... - Nature.com