No immunological interference or safety concerns when adjuvanted recombinant zoster vaccine is coadministered with a COVID-19 mRNA-1273 booster vaccine in adults aged 50 years and older: A randomized trial (preprint)

Background: There is growing consensus that COVID-19 booster vaccines may be coadministered with other age-appropriate vaccines. Adding to the limited available data supporting coadministration, especially with adjuvanted vaccines, could enhance vaccine coverage in adults. Methods: In this phase 3, randomized, open-label study, eligible adults aged [≥]50 years were randomly assigned (1:1) to receive mRNA-1273 (50g) booster vaccination and a first dose of recombinant zoster vaccine (RZV1) 2 weeks apart (Seq group) or concomitantly (Coad group). The second RZV dose (RZV2) was administered 2 months post RZV1 in both groups. Primary objectives were noninferiority of anti-glycoprotein E and anti-Spike protein antibody responses in the Coad group compared to the Seq group. Safety and further immunogenicity assessments were secondary objectives. Results: 273 participants were randomized to the Seq group, 272 to the Coad group. Protocol-specified non-inferiority criteria were met. The adjusted geometric mean concentration ratio (Seq/Coad) was 1.01 (95% confidence interval [CI], 0.89-1.13) for anti-gE antibodies 1-month post-RZV2, and 1.09 (95% CI 0.90-1.32) for anti-Spike antibodies 1-month post-mRNA-1273 booster. No clinically relevant differences were observed in overall frequency, intensity, or duration of adverse events between the 2 study groups. Most solicited adverse events were mild/moderate in intensity, each with median duration [≤]2.5 days. Administration site pain and myalgia were the most frequently reported in both groups. Conclusions: Coadministration of mRNA-1273 booster vaccine with RZV in adults aged [≥]50 years was immunologically noninferior to sequential administration and had a safety and reactogenicity profile consistent with both vaccines administered sequentially (clinicaltrials.gov NCT05047770).

Immunogenicity and safety of SARS-CoV-2 recombinant protein nanoparticle vaccine GBP510 adjuvanted with AS03: randomised, active-controlled, observer-blinded, phase 3 trial (preprint)

Background: GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) up to 2 weeks after the second dose, and safety data up to a median of 2.5 months follow-up. Methods: Randomised, active-controlled, observer-blinded, multinational study: Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination, n=1956) randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety); Cohort 2 (regardless of baseline serostatus; n=2080) randomised 5:1 (safety). Primary objectives: demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; [≥]4-fold rise from baseline) of GBP510/AS03 versus ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity. Findings: At 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03 / ChAdOx1-S) was 2.93 (95% CI 2.63 - 3.27), demonstrating superiority (95% CI lower limit >1). The between-group SCR difference of 10.76% (95% CI 7.68 - 14.32) satisfied the non-inferiority criterion (95% CI lower limit >5%).The proportion of subjects with adverse events (AEs) after any vaccination was higher with GBP510/AS03 versus ChAdOx1-S for solicited local AEs (56.69% vs 49.20%), but was similar for solicited systemic AEs (51.21% vs 53.51%) and unsolicited AEs (13.27% vs 14.56%). No safety concerns were identified during follow-up for a median 2.5-months after the second vaccination. Interpretation: GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

Efficacy and Safety of a Plant-Based Virus-Like Particle Vaccine for COVID-19 Adjuvanted with AS03 (preprint)

BackgroundSeveral COVID-19 vaccines are currently being deployed but supply constraints, concerns over durability of immune responses, solidifying vaccine hesitancy/resistance and vaccine efficacy in the face of emerging variants mean that new vaccines continue to be needed to fight the ongoing pandemic. The vaccine described here is an enveloped, coronavirus-like particle produced in plants (CoVLP) that displays the prefusion-stabilized spike (S) glycoprotein of SARS-CoV-2 (ancestral Wuhan strain) and is adjuvanted with AS03 (CoVLP+AS03). MethodsThis Phase 3 randomized, observer-blind, placebo-controlled trial was conducted at 85 centers in Argentina, Brazil, Canada, Mexico, the UK, and the USA. Adults [≥]18 years of age including those at high risk for COVID-19 complications were randomly assigned 1:1 to receive two intramuscular injections of CoVLP (3.75 g) adjuvanted with AS03 or placebo, 21 days apart. The primary efficacy endpoint was prevention of symptomatic ([≥] 1 symptom), PCR-confirmed SARS-CoV-2 infection with onset at least 7 days after the second injection and was triggered by the identification of [≥]160 virologically-confirmed cases. Tolerability and safety of CoVLP+AS03 were also determined. ResultsA total of 24,141 volunteers were randomly assigned 1:1 to receive vaccine or placebo (N= 12,074 and 12,067, respectively: median age 29, range 18 to 86 years). Overall, 83% received both doses. 14.8% were SARS-CoV-2 seropositive at baseline. Symptomatic SARS-CoV-2 infection was confirmed in 165 study participants in the intention to treat (ITT) set and 157 in the per-protocol population (PP) set. Of the 157 in the PP set, 118 COVID-19 cases were in the placebo group and 39 COVID-19 cases were in the CoVLP+AS03 group for an overall vaccine efficacy (VE) of 71.0% (95% confidence interval (CI) 58.6, 80.0). Moderate-to-severe COVID-19 occurred in 8 and 32 participants in the CoVLP+AS03 and placebo groups, respectively: VE 78.1% (95% CI: 53.9, 90.5) in the PP set overall and 84.5% (95% CI: 62.0, 94.7) in those seronegative at recruitment. To date, 100% of the sequenced strains (122/165 cases: 73.39%) were variants, dominated by Delta (45.9%) and Gamma (43.4%) strains. Vaccine efficacy by variant was 75.3% (95% CI 52.8, 87.9) against Delta and 88.6% (95% CI 74.6, 95.6) against Gamma. Cross-protection was also observed against Alpha, Lambda and Mu variants; although fewer cases were identified, all were in the placebo group. At diagnosis, viral loads in the CoVLP+AS03 breakthrough cases were >100-fold lower than in the placebo cases. Reactogenicity data for solicited adverse events (AEs) was analysed for a subset (N=4,136 in vaccine arm and N=3,683 for placebo) of participants. Reactogenicity was mostly mild to moderate, and transient, and occurred more frequently in the CoVLP+AS03 group. The safety analysis set used for unsolicited AE assessment comprised 24,076 participants who received at least one study injection: 12,036 received CoVLP+AS03 and 12,040 received placebo. All serious adverse events were assessed as unrelated, except two events reported in the same subject in the placebo group. No significant imbalance or safety concern was noted in medically attended AEs (MAAEs), adverse event of special interest (AESIs), AEs leading to withdrawal, deaths, or adverse events potentially associated with currently authorized vaccines. ConclusionsThe CoVLP+AS03 vaccine candidate conferred an efficacy of 71.0% in preventing symptomatic SARS-CoV-2 infection caused by a spectrum of variants. Vaccine efficacy of 78.1% was observed against moderate and severe disease, while variant-specific efficacy ranged from 75.3% to 100%. Markedly lower viral loads in the CoVLP+AS03 group at the time of diagnosis suggests a significant virologic impact of vaccination even in the breakthrough cases. CoVLP+AS03 vaccine candidate was well tolerated, and no safety concerns were identified during the study. If approved by regulators, this more traditional protein+adjuvant vaccine produced using the novel plant-based platform may be able to make an important contribution to the global struggle against the increasingly complex family of SARS-CoV-2 viruses (Funded by Medicago with grants from the governments of Quebec and Canada; NCT04636697).

Recombinant adjuvanted zoster vaccine and reduced risk of COVID-19 diagnosis and hospitalization in older adults (preprint)

BackgroundVaccines may elicit long-term boosting of innate immune responses that can help protect against COVID-19. We evaluated the association between recombinant adjuvanted zoster vaccine (RZV) and COVID-19 outcomes at Kaiser Permanente Southern California. MethodsIn a cohort design, adults aged [≥]50 years who received [≥]1 RZV dose prior to 3/1/2020 were matched 1:2 to unvaccinated individuals and followed until 12/31/2020. Adjusted hazard ratios (aHR) and 95% confidence intervals (CIs) for COVID-19 outcomes were estimated using Cox proportional hazards regression. In a test-negative design, cases had a positive SARS-CoV-2 test and controls had only negative tests, from 3/1/2020-12/31/2020. Adjusted odds ratios (aOR) and 95% CIs for prior receipt of RZV were estimated using logistic regression. ResultsIn the cohort design, 149,244 RZV recipients were matched to 298,488 unvaccinated individuals. The aHRs (95% CI) for COVID-19 diagnosis and hospitalization were 0.84 (0.81-0.87) and 0.68 (0.64-0.74), respectively. In the test-negative design, 8.4% of 75,726 test-positive cases and 13.1% of 340,898 test-negative controls had received [≥]1 RZV dose. The aOR (95% CI) was 0.84 (0.81-0.86). ConclusionRZV vaccination was associated with a 16% lower risk of COVID-19 diagnosis and 32% lower risk of hospitalization, suggesting RZV elicits heterologous protection, possibly through trained immunity.