Immunogenicity and safety of beta variant COVID-19 vaccine AZD2816 and AZD1222 (ChAdOx1 nCoV-19) as primary-series vaccination for previously unvaccinated adults in Brazil, South Africa, Poland, and the UK: a randomised, partly double-blinded, phase 2/3 non-inferiority immunobridging study.

BACKGROUND: AZD2816 is a variant-adapted COVID-19 vaccine that expresses the full-length SARS-CoV-2 beta variant spike protein but is otherwise similar to AZD1222 (ChAdOx1 nCoV-19). This study aimed to evaluate the safety and immunogenicity of AZD1222 or AZD2816 (or both) primary-series vaccination in a cohort of adult participants who were previously unvaccinated. METHODS: In this phase 2/3, randomised, multinational, active-controlled, non-inferiority, immunobridging study, adult participants previously unvaccinated for COVID-19 were enrolled at 16 study sites in Brazil, South Africa, Poland, and the UK. Participants were stratified by age, sex, and comorbidity and randomly assigned 5:5:5:2 to receive a primary series of AZD1222 (AZD1222 group), AZD2816 (AZD2816 [4-week] group), or AZD1222-AZD2816 (AZD1222-AZD2816 group) at 4-week dosing intervals, or AZD2816 at a 12-week interval (AZD2816 [12-week] group) and evaluated for safety and immunogenicity through 180 days after dose 2. Primary outcomes were safety (rates of solicited adverse events occurring during 7 days and unsolicited adverse events occurring during 28 days after each dose) and immunogenicity (non-inferiority of pseudovirus neutralising antibody geometric mean titre [GMT], GMT ratio margin of 0·67, and seroresponse rate, rate difference margin of -10%, recorded 28 days after dose 2 with AZD2816 [4-week interval] against beta vs AZD1222 against ancestral SARS-CoV-2) in participants who were seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04973449, and is completed. FINDINGS: Between July 7 and Nov 12, 2021, 1449 participants were assigned to the AZD1222 group (n=413), the AZD2816 (4-week) group (n=415), the AZD1222-AZD2816 group (n=412), and the AZD2816 (12-week) group (n=209). Ten (2·6%) of 378 participants who were seronegative at baseline in the AZD1222 group, nine (2·4%) of 379 in the AZD2816 (4-week) group, eight (2·1%) of 380 in the AZD1222-AZD2816 group, and 11 (5·8%) of 191 in the AZD2816 (12-week) group had vaccine-related unsolicited adverse events. Serious adverse events were recorded in one (0·3%) participant in the AZD1222 group, one (0·3%) in the AZD2816 (4-week) group, two (0·5%) in the AZD1222-AZD2816 group, and none in the AZD2816 (12-week) group. Co-primary immunogenicity endpoints were met: neutralising antibody GMT (ratio 1·19 [95% CI 1·08-1·32]; lower bound greater than 0·67) and seroresponse rate (difference 1·7% [-3·1 to 6·5]; lower bound greater than -10%) at 28 days after dose 2 were non-inferior in the AZD2816 (4-week) group against beta versus in the AZD1222 group against ancestral SARS-CoV-2. Seroresponse rates were highest with AZD2816 against beta (12-week interval 94·3% [95% CI 89·4-97·3]; 4-week interval 85·7% [81·5-89·2]) and with AZD1222 (84·6% [80·3-88·2]) against ancestral SARS-CoV-2. INTERPRETATION: Primary series of AZD1222 and AZD2816 were well tolerated, with no emergent safety concerns. Both vaccines elicited robust immunogenicity against beta and ancestral SARS-CoV-2 with greater responses demonstrated when testing against SARS-CoV-2 strains that matched those targeted by the respective vaccine. These findings demonstrate the continued importance of ancestral COVID-19 vaccines in protecting against severe COVID-19 and highlight the feasibility of using the ChAdOx1 platform to develop COVID-19 vaccines against future SARS-CoV-2 variants. FUNDING: AstraZeneca.

Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial.

GSK3532795 (formerly known as BMS-955176) is a second-generation maturation inhibitor targeting a specific Gag cleavage site between capsid p24 and spacer peptide 1 of HIV-1. Study 205891 (previously AI468038) investigated the efficacy, safety, and dose response of GSK3532795 in treatment-naive, HIV-1-infected participants. Study 205891 (NCT02415595) was a Phase IIb, randomized, active-controlled, double-blind, international trial. Participants were randomized 1:1:1:1 to one of three GSK3532795 arms at doses 60 mg, 120 mg or 180 mg once daily (QD), or to efavirenz (EFV) at 600 mg QD, each in combination with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) (300/200 mg QD). Primary endpoint was proportion of participants with plasma HIV-1 RNA <40 copies/mL at Week 24. Between May 2015 and May 2016, 206 participants received treatment. At Week 24, 76-83% participants receiving GSK3532795 and 77% receiving EFV achieved HIV-1 RNA <40 copies/mL. Fifteen participants receiving GSK3532795 and one receiving EFV met resistance testing criteria; 10/15 receiving GSK3532795 had emergent substitutions at reverse transcriptase positions M184, and one at position K65, while the participant receiving EFV did not have any nucleoside reverse transcriptase inhibitor (NRTI)/non-NRTI mutations. EFV, relative to GSK3532795, had more serious adverse events (9% versus 5%) and adverse events leading to discontinuation (17% versus 5%). However, 3-4-fold higher rates of gastrointestinal adverse events were observed with GSK3532795 relative to EFV. GSK3532795 combined with TDF/FTC is efficacious with 24 weeks of therapy. However, GSK3532795 showed a higher rate of gastrointestinal intolerability and treatment-emergent resistance to the NRTI backbone relative to EFV. Trial registration: ClinicalTrials.gov NCT02415595.