Interim results from a phase I randomized, placebo-controlled trial of novel SARS-CoV-2 beta variant receptor-binding domain recombinant protein and mRNA vaccines as a 4th dose booster.

BACKGROUND: SARS-CoV-2 booster vaccination should ideally enhance protection against variants and minimise immune imprinting. This Phase I trial evaluated two vaccines targeting SARS-CoV-2 beta-variant receptor-binding domain (RBD): a recombinant dimeric RBD-human IgG1 Fc-fusion protein, and an mRNA encoding a membrane-anchored RBD. METHODS: 76 healthy adults aged 18-64 y, previously triple vaccinated with licensed SARS-CoV-2 vaccines, were randomised to receive a 4th dose of either an adjuvanted (MF59®, CSL Seqirus) protein vaccine (5, 15 or 45 µg, N = 32), mRNA vaccine (10, 20, or 50 µg, N = 32), or placebo (saline, N = 12) at least 90 days after a 3rd boost vaccination or SARS-CoV-2 infection. Bleeds occurred on days 1 (prior to vaccination), 8, and 29. CLINICALTRIALS: govNCT05272605. FINDINGS: No vaccine-related serious or medically-attended adverse events occurred. The protein vaccine reactogenicity was mild, whereas the mRNA vaccine was moderately reactogenic at higher dose levels. Best anti-RBD antibody responses resulted from the higher doses of each vaccine. A similar pattern was seen with live virus neutralisation and surrogate, and pseudovirus neutralisation assays. Breadth of immune response was demonstrated against BA.5 and more recent omicron subvariants (XBB, XBB.1.5 and BQ.1.1). Binding antibody titres for both vaccines were comparable to those of a licensed bivalent mRNA vaccine. Both vaccines enhanced CD4+ and CD8+ T cell activation. INTERPRETATION: There were no safety concerns and the reactogenicity profile was mild and similar to licensed SARS-CoV-2 vaccines. Both vaccines showed strong immune boosting against beta, ancestral and omicron strains. FUNDING: Australian Government Medical Research Future Fund, and philanthropies Jack Ma Foundation and IFM investors.

A protocol for prospective observational study to determine if non-anaemic iron deficiency worsens postoperative outcome in adult patients undergoing elective cardiac surgery: the IDOCS study.

BACKGROUND: Pre-operative anaemia has been associated independently with worse outcomes after cardiac surgery in adults and is often caused by absolute or functional iron deficiency. Iron deficiency is a continuum ending with anaemia, and therefore it is plausible that pre-operative early or 'non-anaemic' iron deficiency may also be associated with worse outcomes in patients undergoing cardiac surgery. METHODS: We have designed a prospective, observational study to determine if there is an association between non-anaemic iron deficiency and worse outcomes after cardiac surgery in adults. Patients without anaemia undergoing elective cardiac surgery will be allocated to an iron-deficient and an iron-replete group based on standard pre-operative blood tests (ferritin, transferrin saturation and C-reactive protein). The primary outcome is days alive and at home on postoperative day 30. The key secondary outcomes are days alive and at home on postoperative day 90 and readmission to acute care. Other secondary outcomes include health-related quality of life questionnaires, quality of postoperative recovery, postoperative complications, changes in haemoglobin concentration, and requirement for allogeneic blood products. The planned study sample size is 240 patients per group, which has 83% power to detect a median difference of 1.25 days in the primary outcome. The study commenced in March 2018, and recently completed recruitment, with data audit and cleaning ongoing. DISCUSSION: This study will be conducted using a rigorous, prospective observational design; it will provide peak bodies and clinicians with high-quality evidence concerning the associations between non-anaemic iron deficiency and patient-centred outcomes after elective cardiac surgery. Our primary and key secondary outcomes are known to have great importance to clinicians and patients alike and align with the recommendations of the StEP-COMPAC group for outcomes in prospective peri-operative research. The definition used for iron deficiency accounts for both absolute and functional iron deficiency and make use of standard pre-operative blood tests to make this determination, easing the transition of results into clinical practice. The study will be conducted in two relatively high-volume centres in a single high-income country. This limits the generalisability of study results to similar centres. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12618000185268 ). Registered 5 February 2018.