Background COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. Methods We conducted a global Phase 3, multi-stage efficacy study (NCT04904549) among adults aged [≥]18 years. Participants were randomized 1:1 to receive two intramuscular injections 21 days apart of a bivalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (5 g of ancestral (D614) and 5 g of B.1.351 [beta] variant spike protein) or placebo. Symptomatic COVID-19 was defined as laboratory-confirmed COVID-19 with COVID-19-like illness (CLI) symptoms. The primary efficacy endpoint was the prevention of symptomatic COVID-19 [≥]14 days after the second injection. Results Between 19 Oct 2021 and 15 Feb 2022, 12,924 participants received [≥]1 study injection. 75% of participants were SARS-CoV-2 non-naive. 11,416 participants received both study injections (efficacy-evaluable population [vaccine, n=5,736; placebo, n=5,680]). Up to 15 March 2022, 121 symptomatic COVID-19 cases were reported (32 in the vaccine group and 89 in the placebo group) [≥]14 days after the second injection with a vaccine efficacy (VE) of 64.7% (95% confidence interval [CI] 46.6; 77.2%). VE was 75.1% (95% CI 56.3; 86.6%) in non-naive and 30.9% (95% CI -39.3; 66.7%) in naive participants. Viral genome sequencing identified the infecting strain in 68 cases (Omicron [BA.1 and BA.2 subvariants]: 63; Delta: 4; Omicron and Delta: 1). The vaccine was well-tolerated and had an acceptable safety profile. Conclusions A bivalent vaccine conferred heterologous protection against symptomatic infection with newly emergent Omicron (BA.1 and BA.2) in non-naive adults 18-59 years of age. ClinicalTrials.gov: NCT04904549
BackgroundBooster vaccines providing protection against emergent SARS-CoV-2 variants are needed. In an international phase 3 study, we evaluated booster vaccines containing prototype (D614) and/or Beta (B.1.351) variant recombinant spike proteins and AS03 adjuvant (CoV2 preS dTM-AS03). MethodsAdults, primed 4-10 months earlier with mRNA (BNT162b2, mRNA-1273]), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or adjuvanted protein (CoV2 preS dTM-AS03 [D614]) vaccines and stratified by age (18-55 and [≥]56 years), were boosted with monovalent (MV) D614 (5g, n=1285), MV (B.1351) (5g, n=707) or bivalent (BiV) (2.5g D614 plus 2.5g B.1.351, n=625) CoV2 preS dTM-AS03. SARS-CoV-2-naive adults (controls, n=479) received a primary series (two injections, 21 days apart) of CoV2 preS dTM-AS03 containing 10g D614. Antibodies to D614G, B.1.351 and Omicron BA.2 and BA.1 variants were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay. D614G or B.1.351 PsVN titers 14 days (D15) post-booster were compared with pre-booster (D1) titers in BNT162b2-primed participants (18-55 years old) and controls (D36), for each booster formulation (co-primary objectives). Safety was evaluated throughout the trial. Results of a planned interim analysis are presented. ResultsAmong BNT162b2-primed adults (18-55 years old), PsVN titers against D614G or B.1.351 were significantly higher post-booster than anti-D614G titers post-primary vaccination in controls, for all booster formulations, with an anti-D614G GMT ratio (98.3% CI) of 2.16 (1.69; 2.75) for MV(D614), an anti-B.1.351 ratio of 1.96 (1.54; 2.50) for MV (B.1.351) and anti-D614G and anti-B.1.351 ratios of 2.34 (1.84; 2.96) and 1.39 (1.09; 1.77), respectively, for BiV. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 across vaccine priming subgroups and against Omicron BA.1 (evaluated in BNT162b2-primed participants). Similar patterns in antibody responses were observed for participants aged [≥]56 years. No safety concerns were identified. ConclusionCoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. ClinicalTrials.govNCT04762680 FundingSanofi and federal funds from the Biomedical Advanced Research and Development Authority (BARDA), part of the office of the Administration for Strategic Preparedness and Response at the U.S. Department of Health and Human Services under Contract # HHSO100201600005I, and in collaboration with the U.S. Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense under Contract # W15QKN-16-9-1002.
BackgroundVaccination has helped to mitigate the COVID-19 pandemic. Ten traditional and novel vaccines have been listed by the World Health Organization for emergency use. Additional alternative approaches may better address ongoing vaccination globally, where there remains an inequity in vaccine distribution. GBP510 is a recombinant protein vaccine, which consists of self-assembling, two-component nanoparticles displaying the receptor-binding domain (RBD) in a highly immunogenic array. MethodsWe conducted a randomized, placebo-controlled, observer-blinded, phase 1/2 trial to evaluate the safety and immunogenicity of GBP510 (2-doses at a 28-day interval) adjuvanted with or without AS03 in adults aged 19-85 years. The main outcomes included solicited and unsolicited adverse events; anti-SARS-CoV-2 RBD IgG antibody and neutralizing antibody responses; T-cell immune responses. FindingsOf 328 participants who underwent randomization, 327 participants received at least 1 dose of vaccine. Each received either 10 g GBP510 adjuvanted with AS03 (n = 101), 10 g unadjuvanted GBP510 (n = 10), 25 g GBP510 adjuvanted with AS03 (n = 104), 25 g unadjuvanted GBP510 (n = 51), or placebo (n = 61). Most solicited adverse events were mild-to-moderate in severity and transient. Higher reactogenicity was observed in the GBP510 adjuvanted with AS03 groups compared to the non-adjuvanted and placebo groups. Reactogenicity was higher post-dose 2 compared to post-dose 1, particularly for systemic adverse events. The geometric mean concentrations of anti-SARS-CoV-2-RBD IgG antibody reached 2163.6/2599.2 BAU/mL in GBP510 adjuvanted with AS03 recipients (10 g/25 g) by 14 days after the second dose. Two-dose vaccination with 10 g or 25 g GBP510 adjuvanted with AS03 induced high titers of neutralizing antibody via pseudovirus (1369.0/1431.5 IU/mL) and wild-type virus (949.8/861.0 IU/mL) assays. InterpretationGBP510 adjuvanted with AS03 was well tolerated and highly immunogenic. These results support further development of the vaccine candidate, which is currently being evaluated in Phase 3. FundingCoalition for Epidemic Preparedness Innovations RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for research articles published by December 31, 2021, using the terms "COVID-19" or "SARS-CoV-2," "vaccine," and "clinical trial." In previously reported randomized clinical trials, we found that mRNA vaccines were more immunogenic than adenovirus-vectored vaccines. Solicited adverse events were more frequent and more severe in intensity after the first dose compared to the second dose for adenovirus-vectored vaccines, whereas they increased after the second dose of mRNA or recombinant spike-protein nanoparticle vaccines. Added value of this studyThis is the first human study evaluating the immunogenicity and safety of recombinant SARS-CoV-2 protein nanoparticle with and without adjuvant AS03, designed to elicit functional cross-protective responses via receptor-binding domain (RBD). Both 10 and 25 g of GBP510 with AS03 formulations were well tolerated with an acceptable safety profile. Potent humoral immune responses against the SARS-CoV-2 RBD were induced and peaked by day 42 (14 days after the second dose). In addition, GBP510 adjuvanted with AS03 elicited a noticeable Th1 response, with production of IFN-{gamma}, TNF-, and IL-2. IL-4 was inconsistent and IL-5 nearly inexistent response across all groups. Implications of the available evidenceThe results from this phase 1/2 trial indicate that GBP510 adjuvanted with AS03 has an acceptable safety profile with no vaccine-related serious adverse events. Two-dose immunization with GBP510 adjuvanted with AS03 induced potent humoral and cellular immune responses against SARS-CoV-2.
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).
BackgroundThis study evaluated the safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein candidate vaccine, CoV2 preS dTM. MethodsThis Phase 2, modified double-blind, parallel-group study (NCT04762680) was conducted in adults, including those at increased risk of severe COVID-19. Participants were randomised 1:1:1, stratified by age (18-59/[≥]60 years), rapid serodiagnostic test (positive/negative) and high-risk medical conditions (yes/no), to receive two injections (day [D]1 and D22) of 5g, 10g or 15g of CoV2 preS dTM antigen with fixed AS03 content. Interim safety and reactogenicity results (to D43) and neutralising antibodies (NAbs) against the D614G variant are presented (primary objectives). FindingsOf 722 participants enrolled and randomised between 24 February and 8 March 2021, 721 received [≥]1 injections (5g, n=240; 10g, n=239; 15g, n=242). Four participants reported unsolicited immediate adverse events (AEs), two were vaccine-related (investigator assessment). Five participants reported seven vaccine-related medically-attended AEs. No vaccine-related serious AEs and no AEs of special interest were reported. Solicited reactions (local and systemic) were reported at similar frequencies between study groups; these were mostly mild to moderate and transient, with higher frequency and intensity post-injection 2 than post-injection 1. In SARS-CoV-2 naive participants at D36, 96{middle dot}9%, 97.0% and 97{middle dot}6% of participants had [≥]4-fold-rise in NAb titres from baseline in the 5g-, 10g- and 15g-dose groups, respectively. NAb titres increased with antigen dose in younger (GMTs: 2954, 3951 and 5142 for 5g-, 10g- and 15g-dose groups) but not older adults (GMTs: 1628, 1393 and 1736, respectively). NAb titres in non-naive adults after one injection were higher than titres after two injections in naive adults. InterpretationTwo injections of CoV2 preS dTM-AS03 demonstrated acceptable safety and reactogenicity, and robust immunogenicity in SARS-CoV-2 naive and non-naive adults. These results informed antigen dose selection for progression to Phase 3 evaluation of primary and booster vaccination.
The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and the needs of specific populations. We report herein a pre-specified interim analysis of the phase 2 portion of an ongoing Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein adjuvanted with AS03 (NCT04636697). A total of 753 subjects were recruited between 25 November 2020 and 24 March 2021 into three groups: Healthy Adults (18-64 years: N=306), Older Adults ([≥] 65 years: N=282) and Adults with Comorbidities ([≥]18 years: N=165) and randomized 5:1 to receive two intramuscular doses of either vaccine CoVLP (3.75 g/dose + AS03) or placebo 21 days apart. This report presents safety, tolerability and immunogenicity data collected up to 21 days after the second dose. The immune outcomes presented include neutralizing antibody (NAb) titres and cellular (IFN-{gamma} and IL-4 ELISpot) responses. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults. CoVLP+AS03 induced seroconversion in >35% of subjects in each group after the first dose and in [~]98% of subjects 21 days after the second dose. In all treatment groups, NAb levels were [~]10-fold higher than those in a panel of convalescent sera. A significant minority ([~]20%) of subjects had evidence of a pre-existing IFN-{gamma} response to the S protein and almost all subjects in all groups (>88%) had detectable cellular responses (IFN-{gamma}, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after dose two. These data demonstrated that CoVLP+AS03 will likely be well-tolerated and highly immunogenic in adults [≥]18 years of age with and without comorbidities.
