Background Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]). Methods We did a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclamp subunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 days apart of either placebo, sclamp vaccine at 5 μg, 15 μg, or 45 μg, or one dose of sclamp vaccine at 45 μg followed by placebo. Participants and study personnel, except the dose administration personnel, were masked to treatment. The primary safety endpoints included solicited local and systemic adverse events in the 7 days after each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up until day 57. Primary immunogenicity endpoints were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation assays assessed at 28 days after each dose. The study is ongoing and registered with ClinicalTrials.gov , NCT04495933 . Findings Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose: 4 weeks after the initial dose (day 29) with 5 μg dose (geometric mean titre [GMT] 6400, 95% CI 3683–11 122), with 15 μg dose (7492, 4959–11 319), and the two 45 μg dose cohorts (8770, 5526–13...

XLGB over 1-year treatment at the conventional dose demonstrated safe and only a statistically significant increase in BMD at lumbar spine at 6 months in postmenopausal women.

Objectives Efforts to develop and deploy effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) continue at pace. Here, we describe rational antigen design through to manufacturability and vaccine efficacy of a prefusion‐stabilised spike (S) protein, Sclamp, in combination with the licensed adjuvant MF59 ‘MF59C.1’ (Seqirus, Parkville, Australia). Methods A panel recombinant Sclamp proteins were produced in Chinese hamster ovary and screened in vitro to select a lead vaccine candidate. The structure of this antigen was determined by cryo‐electron microscopy and assessed in mouse immunogenicity studies, hamster challenge studies and safety and toxicology studies in rat. Results In mice, the Sclamp vaccine elicits high levels of neutralising antibodies, as well as broadly reactive and polyfunctional S‐specific CD4 + and cytotoxic CD8 + T cells in vivo . In the Syrian hamster challenge model ( n = 70), vaccination results in reduced viral load within the lung, protection from pulmonary disease and decreased viral shedding in daily throat swabs which correlated strongly with the neutralising antibody level. Conclusion The SARS‐CoV‐2 Sclamp vaccine candidate is compatible with large‐scale commercial manufacture, stable at 2–8°C. When formulated with MF59 adjuvant, it elicits neutralising antibodies and T‐cell responses and provides protection in animal challenge models.

This study demonstrates that the fate of a vaccine is influenced by the cytokines produced by the innate lymphoid cells (ILC) recruited to the vaccination site, and it is vaccine route and adjuvant dependent. Intranasal virus vaccination induced ST2/IL-33R+ ILC2 in lung, while intramuscular vaccination induced exclusively IL-25R+ ILC2 in muscle. Interestingly, a larger proportion of IL-13+ ILC2s were detected in muscle following i.m. viral vector vaccination compared to lung post i.n. delivery. These observations revealed that ILC2 were the main source of IL-13 at the vaccination site (24 h post vaccination) responsible for inducing T cells of varying avidities. Moreover, recombinant fowlpox viral vector-based vaccines expressing adjuvants that transiently block IL-13 signalling at the vaccination site using different mechanisms (IL-4R antagonist or IL-13Rα2 adjuvants), revealed that the level of IL-13 present in the milieu also significantly influenced IFN-γ, IL-22 or IL-17A expression by ILC1/ILC3. Specifically, an early IL-13 and IFN-γ co-dependency at the ILC level may also be associated with shaping the downstream antibody responses, supporting the notion that differentially regulating IL-13 signalling via STAT6 or IL-13Rα2 pathways can modify ILC function and the resulting adaptive T- and B-cell immune outcomes reported previously. Moreover, unlike chronic inflammatory or experimentally induced conditions, viral vector vaccination induced uniquely different ILC profiles (i.e., expression of CD127 only on ILC2 not ILC1/ILC3; expression of IFN-γ in both NKP46+ and NKp46− ILCs). Collectively, our data highlight that tailoring a vaccine vector/adjuvant to modulate the ILC cytokine profile according to the target pathogen, may help design more efficacious vaccines in the future.

Host genetic factors and environment factors including hepatitis B virus (HBV) genotypes are widely studied for the different outcomes of HBV infection. Recent studies suggest that tumour necrosis factor-alpha (TNF-alpha) plays a pivotal role in the viral clearance and host immune response to HBV, and the capacity for TNF-alpha production in individuals is influenced by a major genetic component. In this study, we aimed to explore whether the single-nucleotide polymorphisms (SNPs) of TNF-alpha promoter are associated with the outcomes of HBV infection in the Chinese Han population. One hundred and forty-three spontaneously recovered HBV subjects and 196 chronic hepatitis B patients were recruited in this case-control study in the Beijing area of China. Polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) and sequence-specific primer-PCR (SSP-PCR) were used to detect the SNPs of five sites in the TNF-alpha promoter (-238G/A, -308G/A, -857C/T, -863C/A, -1031T/C). The frequency distributions of genotypes and haplotypes in two groups were analysed by EPI and EH programs. The presence of the -238GG genotype was significantly correlated with persistence of HBV infection (OR = 4.08, P = 0.02), and -857TT genotype appeared in relation to the spontaneous clearance of HBV (OR = 0.47, P = 0.03). Frequency of haplotype GGCCT (-238/-308/-857/-863/-1031) in the chronic HB group was significantly lower than that in spontaneously recovered group (P = 0.03), and frequencies of haplotypes GGCAT and GGTAT in the chronic HB group were significantly higher than those in the spontaneously recovered group (P = 0.0001, P = 0.0004). In conclusion, TNF-alpha promoter polymorphisms are independently associated with different outcomes of HBV infection.