First-in-human use of a modular capsid virus-like vaccine platform: an open-label, non-randomised, phase 1 clinical trial of the SARS-CoV-2 vaccine ABNCoV2.

BACKGROUND: Capsid virus-like particles (cVLP) have proven safe and immunogenic and can be a versatile platform to counter pandemics. We aimed to clinically test a modular cVLP COVID-19 vaccine in individuals who were naive to SARS-CoV-2. METHODS: In this phase 1, single-centre, dose-escalation, adjuvant-selection, open-label clinical trial, we recruited participants at the Radboud University Medical Center in Nijmegen, Netherlands, and sequentially assigned them to seven groups. Eligible participants were healthy, aged 18-55 years, and tested negative for SARS-CoV-2 and anti-SARS-CoV-2 antibodies. Participants were vaccinated intramuscularly on days 0 and 28 with 6 µg, 12 µg, 25 µg, 50 µg, or 70 µg of the cVLP-based COVID-19 vaccine (ABNCoV2). A subgroup received MF59-adjuvanted ABNCoV2. Follow-up was for 24 weeks after second vaccination. The primary objectives were to assess the safety and tolerability of ABNCoV2 and to identify a dose that optimises the tolerability-immunogenicity ratio 14 days after the first vaccination. The primary safety endpoint was the number of related grade 3 adverse events and serious adverse events in the intention-to-treat population. The primary immunogenicity endpoint was the concentration of ABNCoV2-specific antibodies. The trial is registered with ClinicalTrials.gov, NCT04839146. FINDINGS: 45 participants (six to nine per group) were enrolled between March 15 and July 15, 2021. Participants had a total of 249 at least possibly related solicited adverse events (185 grade 1, 63 grade 2, and one grade 3) within a week after vaccination. Two serious adverse events occurred; one was classified as a possible adverse reaction. Antibody titres were dose-dependent with levels plateauing at a vaccination dose of 25-70 µg ABNCoV2. After second vaccination, live virus neutralisation activity against major SARS-CoV-2 variants was high but was lower with an omicron (BA.1) variant. Vaccine-specific IFNγ+ CD4+ T cells were induced. INTERPRETATION: Immunisation with ABNCoV2 was well tolerated, safe, and resulted in a functional immune response. The data support the need for additional clinical development of ABNCoV2 as a second-generation SARS-CoV-2 vaccine. The modular cVLP platform will accelerate vaccine development, beyond SARS-CoV-2. FUNDING: EU, Carlsberg Foundation, and the Novo Nordisk Foundation.

Increased overall survival after introduction of structured bedside consultation in Staphylococcus aureus bacteraemia.

Staphylococcus aureus bacteraemia (SAB) is a common and severe disease. In 2012, a structured bedside consultation (SBC) was introduced at Rijnstate Hospital. We analysed the effect of this SBC on the overall survival of patients with SAB and the effect on the diagnostic workup. We performed a retrospective cohort study, including all patients over 18 years with SAB from 2009 until 2017. The cases preceding versus those after implementation of SBC in 2012 were compared. In total, 613 episodes of SAB were analysed: 234 cases before and 379 cases since SBC. In 484 patients at risk for a complicated course, there was no significant difference in the 30-day survival (77 versus 82%, p = 0.18); however, an increase in 365-day survival was seen (56 versus 64%, p = 0.05). Overall, more patients received adequate therapy, both in the first 2 weeks (67.8 versus 86.7%, p < 0.001), as in complicated SAB (70.5 versus 93.2%, p < 0.001). In 21% of patients with transoesophageal echocardiogram (TEE) following a negative or inconclusive TTE, endocarditis was diagnosed. In patients at risk for complicated SAB, the PET scan revealed a metastatic infection which was not clinically suspected in 65% of positive PET scans. Structured bedside consultation is associated with a better 365-day survival in patients at risk for complicated SAB. Moreover, the additional value of TEE and the PET scan was shown. We strongly advise compliance to SBC in all patients at risk for complicated SAB and the use of both TEE and PET scans in these patients. Even in uncomplicated SAB, TEE or PET scan can reveal metastatic infections.