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.

Despite the availability of several effective SARS-CoV-2 vaccines, additional vaccines will be required for optimal global vaccination. In this study, we investigate the immunogenicity and protective efficacy of the GBP510 protein subunit vaccine adjuvanted with AS03, which has recently been authorized for marketing in South Korea under the trade name SKYCovione^TM. The antigen in GBP510/AS03 is a two-part recombinant nanoparticle, which displays 60 receptor binding domain (RBD) proteins of SARS-CoV-2 Spike on its surface. In this study we show that GBP510/AS03 induced robust immune responses in rhesus macaques and protected against a high-dose SARS-CoV-2 Delta challenge. We vaccinated macaques with two or three doses of GBP510/AS03 matched to the ancestral Wuhan strain of SARS-CoV-2 or with two doses of GBP510/AS03 matched to the ancestral strain and one dose matched to the Beta strain. Following the challenge with Delta, the vaccinated macaques rapidly controlled the virus in bronchoalveolar lavage and nasal swabs. Binding and neutralizing antibody responses prior to challenge correlated with protection against viral replication postchallenge. These data are consistent with data with this vaccine from the phase 3 clinical trial.

This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investment ID OPP1148601. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

A homologous GBP510/AS03 booster was well tolerated and induced robust, durable neutralizing antibody responses against SARS-CoV-2, including Omicron variant.

ABSTRACT 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. RESEARCH IN CONTEXT Evidence before this study Immunobridging has been proposed as an approach for assessing new COVID-19 vaccines by comparing the immunogenicity of candidate vaccines with an active comparator with demonstrated clinical efficacy. We searched PubMed up to 26 October 2022 for immunobridging clinical trials comparing a candidate vaccine with an approved vaccine, using the terms “immunobridging”, “SARS-CoV-2”, “COVID-19”, and “vaccine”. A phase 2/3 study showed that the ChAdOx1 vaccine, manufactured by the Serum Institute of India after technology transfer from Oxford University/AstraZeneca, had a non-inferior immune response compared to the original ChAdOx1 (AZD1222) vaccine. A post hoc analysis of phase 2 data found that MVC-COV1901 vaccine (a protein subunit vaccine developed by Medigen Vaccine Biologics Corporation, Taiwan) was non-inferior to ChAdOx1 (AZD1222) with respect to neutralising antibody titres. A phase 3 study found that VLA2001 (an adjuvanted, inactivated whole-virus vaccine developed by Valneva, Austria) was superior to ChAdOx1 with respect to neutralising antibody titres and non-inferior with respect to seroconversion rates. Added value of this study This is the first study comparing the immunogenicity of recombinant SARS-CoV-2 protein nanoparticle vaccine GBP510 adjuvanted with AS03 versus ChAdOx1-S. Interim analysis found that two-dose vaccination with GBP510/AS03 induced stronger neutralising antibody immune responses compared with ChAdOx1-S against the ancestral D614G strain at 2 weeks after the second dose. GBP510/AS03 had an acceptable safety profile during a median 2.5 months of follow-up. Implications of the available evidence This interim analysis suggests that GBP510/AS03 induces strong neutralising antibody responses against SARS-CoV-2 ancestral strain and has an acceptable safety profile.

Background: This study aims to evaluate the results and the safety of a novel fixation method we developed for syndesmosis injuries that we call the “embrace” technique. Methods: Between March 2018 and October 2020, a total of 67 patients with ankle fractures and syndesmotic injuries underwent syndesmosis fixation with the embrace technique at our institute. Plain radiographs and computed tomographic (CT) scans were obtained preoperatively. Postoperative radiographic assessment included anteroposterior (AP) and lateral radiographs and CT scans of both ankles. Additionally, the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Score, Olerud-Molander Ankle Score, and visual analog scale (VAS) score were used for postoperative assessment. Results: The mean age was 27.6 ± 10.9 (range, 14-56) years. The mean follow-up time was 30.3 ± 6.2 (range, 24-48) months. There were no malreductions indicated by any CT parameter except fibular rotation in a postoperative comparison between 2 sides. We found significant preoperative-postoperative changes in anterior difference, posterior difference, and fibular rotation but no significant preoperative-postoperative difference in fibular translation. There was no significant postoperative difference between the affected-side and normal-side measurements of any parameter. Complications included delayed wound healing, lateral pain because of wire knot irritation (11.9%), and medial fiber wire irritation (7.5%). The mean AOFAS, Olerud-Molander, and VAS scores at the last follow-up were 94.4 ± 6.8 (range, 84-100), 95.4 ± 6.1 (range, 80-100), and 0.68 ± 1.0 (range, 0-3) points, respectively. Conclusion: In our cohort, this novel technique proved to be an effective method for syndesmosis fixation in patients with ankle fractures associated with very good radiologic and patient-reported outcomes. Level of Evidence: Level IV, case series.

SUMMARY Background Vaccination 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. Methods We 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. Findings Of 328 participants who underwent randomization, 327 participants received at least 1 dose of vaccine. Each received either 10 μg GBP510 adjuvanted with AS03 (n = 101), 10 μg unadjuvanted GBP510 (n = 10), 25 μg GBP510 adjuvanted with AS03 (n = 104), 25 μg 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 μg/25 μg) by 14 days after the second dose. Two-dose vaccination with 10 μg or 25 μg 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. Interpretation GBP510 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. Funding Coalition for Epidemic Preparedness Innovations RESEARCH IN CONTEXT Evidence before this study We 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 study This 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 μg 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-γ, TNF-α, and IL-2. IL-4 was inconsistent and IL-5 nearly inexistent response across all groups. Implications of the available evidence The 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.

Since the emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), various vaccines are being developed, with most vaccine candidates focusing on the viral spike protein. Here, we developed a previously unknown subunit vaccine comprising the receptor binding domain (RBD) of the spike protein fused with the tetanus toxoid epitope P2 (RBD-P2) and tested its efficacy in rodents and nonhuman primates (NHPs). We also investigated whether the SARS-CoV-2 nucleocapsid protein (N) could increase vaccine efficacy. Immunization with N and RBD-P2 (RBDP2/N) + alum increased T cell responses in mice and neutralizing antibody levels in rats compared with those obtained using RBD-P2 + alum. Furthermore, in NHPs, RBD-P2/N + alum induced slightly faster SARS-CoV-2 clearance than that induced by RBD-P2 + alum, albeit without statistical significance. Our study supports further development of RBD-P2 as a vaccine candidate against SARS-CoV-2. Also, it provides insights regarding the use of N in protein-based vaccines against SARS-CoV-2.

Because epithelioid AML has the potential for malignancy, clinicians must be aware of the knowledge of the characteristics and natural history of epithelioid AML.

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.

Despite the availability of several effective SARS-CoV-2 vaccines, additional vaccines will be required for optimal global vaccination. In this study, we investigate the immunogenicity and protective efficacy of the GBP510 protein subunit vaccine adjuvanted with AS03, which has recently been authorized for marketing in South Korea under the trade name SKYCovione^TM. The antigen in GBP510/AS03 is a two-part recombinant nanoparticle, which displays 60 receptor binding domain (RBD) proteins of SARS-CoV-2 Spike on its surface. In this study we show that GBP510/AS03 induced robust immune responses in rhesus macaques and protected against a high-dose SARS-CoV-2 Delta challenge. We vaccinated macaques with two or three doses of GBP510/AS03 matched to the ancestral Wuhan strain of SARS-CoV-2 or with two doses of GBP510/AS03 matched to the ancestral strain and one dose matched to the Beta strain. Following the challenge with Delta, the vaccinated macaques rapidly controlled the virus in bronchoalveolar lavage and nasal swabs. Binding and neutralizing antibody responses prior to challenge correlated with protection against viral replication postchallenge. These data are consistent with data with this vaccine from the phase 3 clinical trial.