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1.
Clin Transl Immunology ; 11(3): e1381, 2022.
Article in English | MEDLINE | ID: covidwho-1763220

ABSTRACT

Group 2 innate lymphoid cells (ILC2) are a relatively new class of innate immune cells. Lung ILC2 are early responders that secrete type 2 cytokines in response to danger 'alarmin' signals such as interleukin (IL)-33 and thymic stromal lymphopoietin. Being an early source of type 2 cytokines, ILC2 are a critical regulator of type 2 immune cells of both innate and adaptive immune responses. The immune regulatory functions of ILC2 were mostly investigated in diseases where T helper 2 inflammation predominates. However, in recent years, it has been appreciated that the role of ILC2 extends to other pathological conditions such as cancer and viral infections. In this review, we will focus on the potential role of lung ILC2 in the induction of mucosal immunity against influenza virus infection and discuss the potential utility of ILC2 as a target for mucosal vaccination.

2.
Lancet Infect Dis ; 21(10): 1383-1394, 2021 10.
Article in English | MEDLINE | ID: covidwho-1621119

ABSTRACT

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, 5526-13 920 in the two-dose 45 µg cohort; 8793, 5570-13 881 in the single-dose 45 µg cohort); 4 weeks after the second dose (day 57) with two 5 µg doses (102 400, 64 857-161 676), with two 15 µg doses (74 725, 51 300-108 847), with two 45 µg doses (79 586, 55 430-114 268), only a single 45 µg dose (4795, 2858-8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 µg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose: two 5 µg doses (GMT 228, 95% CI 146-356), two 15 µg doses (230, 170-312), and two 45 µg doses (239, 187-307). INTERPRETATION: This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike protein elicits strong immune responses with a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assay interference, a possible barrier to widespread use highlighting the criticality of potential non-spike directed immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response. FUNDING: Coalition for Epidemic Preparedness Innovations, National Health and Medical Research Council, Queensland Government, and further philanthropic sources listed in the acknowledgments.


Subject(s)
Adjuvants, Immunologic/pharmacology , COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus/immunology , Squalene/immunology , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Australia , Female , Healthy Volunteers , Humans , Male , Pandemics/prevention & control , Polysorbates , Vaccination/adverse effects , Young Adult
3.
Vaccines (Basel) ; 9(10)2021 Oct 18.
Article in English | MEDLINE | ID: covidwho-1572674

ABSTRACT

As influenza season was approaching in 2020, public health officials feared that influenza would worsen the COVID-19 situation [...].

4.
Clin Transl Immunology ; 10(4): e1269, 2021.
Article in English | MEDLINE | ID: covidwho-1162553

ABSTRACT

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.

6.
Vaccines (Basel) ; 9(2)2021 Jan 20.
Article in English | MEDLINE | ID: covidwho-1045356

ABSTRACT

Subunit vaccines exhibit favorable safety and immunogenicity profiles and can be designed to mimic native antigen structures. However, pairing with an appropriate adjuvant is imperative in order to elicit effective humoral and cellular immune responses. In this study, we aimed to determine an optimal adjuvant pairing with the prefusion form of influenza haemagglutinin (HA) or respiratory syncytial virus (RSV) fusion (F) subunit vaccines in BALB/c mice in order to inform future subunit vaccine adjuvant selection. We tested a panel of adjuvants, including aluminum hydroxide (alhydrogel), QS21, Addavax, Addavax with QS21 (AdQS21), and Army Liposome Formulation 55 with monophosphoryl lipid A and QS21 (ALF55). We found that all adjuvants elicited robust humoral responses in comparison to placebo, with the induction of potent neutralizing antibodies observed in all adjuvanted groups against influenza and in AdQS21, alhydrogel, and ALF55 against RSV. Upon HA vaccination, we observed that none of the adjuvants were able to significantly increase the frequency of CD4+ and CD8+ IFN-γ+ cells when compared to unadjuvanted antigen. The varying responses to antigens with each adjuvant highlights that those adjuvants most suited for pairing purposes can vary depending on the antigen used and/or the desired immune response. We therefore suggest that an adjuvant trial for different subunit vaccines in development would likely be necessary in preclinical studies.

7.
Front Immunol ; 11: 592370, 2020.
Article in English | MEDLINE | ID: covidwho-937449

ABSTRACT

Prior to 2020, the threat of a novel viral pandemic was omnipresent but largely ignored. Just 12 months prior to the Coronavirus disease 2019 (COVID-19) pandemic our team received funding from the Coalition for Epidemic Preparedness Innovations (CEPI) to establish and validate a rapid response pipeline for subunit vaccine development based on our proprietary Molecular Clamp platform. Throughout the course of 2019 we conducted two mock tests of our system for rapid antigen production against two potential, emerging viral pathogens, Achimota paramyxovirus and Wenzhou mammarenavirus. For each virus we expressed a small panel of recombinant variants of the membrane fusion protein and screened for expression level, product homogeneity, and the presence of the expected trimeric pre-fusion conformation. Lessons learned from this exercise paved the way for our response to COVID-19, for which our candidate antigen is currently in phase I clinical trial.


Subject(s)
Drug Design , Vaccines, Subunit , Animals , Arenaviridae , COVID-19 Vaccines , Civil Defense , Clinical Trials as Topic , Humans , Molecular Structure , Paramyxovirinae/immunology , Time Factors , Vaccines, Subunit/chemistry , Viral Vaccines
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