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We performed a randomized, multicenter, observer-blind, placebo-controlled phase I clinical trial to determine safety and immunogenicity of cHA-based vaccines (ClinicalTrials.gov identifier NCT03300050). The interim findings of this study (including blinded aggregate vaccine safety) have been previously reported29. Of the 131 subjects screened, 66 were enrolled (1 ineligible subject was randomized in error but replaced before receiving study treatment, resulting in 65 randomized participants) into three different vaccine groups and two placebo control groups (Figs. 1 and 2).
Graphpad Prism 7 Trial
The induced antibody responses also showed functional activities. Fc-FcR-mediated effector functions are an important mechanism of protection of anti-stalk antibodies in vivo in animal models18. Antibodies induced in our trial showed strong activity in both ADCC and ADCP reporter bioassays, which correlate with functional ADCC assays45. Neutralizing and even HI activities were also induced by the cHA vaccines, albeit at a low level. However, these functions are a major contributor to traditional protection mediated by seasonal influenza virus vaccines and might also play a role in the protection provided by novel vaccination approaches. In addition, we could show both HA-stalk-based20 and NA-based NI. Finally, passive transfer of postvaccination serum protected mice from challenge as compared with prevaccination serum. These antiviral activities reflect the multi-functionality of the characterized anti-stalk monoclonal antibodies19,20.
In summary, we show that vaccination with inactivated adjuvanted split virion cHA vaccines induces strong, broad, long-lasting and functional anti-stalk antibodies and appears to have acceptable safety in adults. While this clinical trial represents a proof of principle in humans, it only focused on group 1 HAs. Development of group 2 cHA22,47 and influenza B mosaic HA48 vaccine candidates is currently ongoing. Combining these constructs into a trivalent vaccine may enable protection against all drifted seasonal, zoonotic and emerging pandemic influenza viruses. While much more work is needed to further develop this vaccine concept, this first-in-human study supports further development of truly universal influenza virus vaccines.
Two different vaccine platforms were utilized for this trial (ClinicalTrials.gov identifier NCT03300050). First, an LAIV carrying the cH8/1 HA (head domain from A/mallard/Sweden/24/02 (H8N4), stalk domain from A/California/04/09 (Cal09, H1N1)), an N1 NA from Cal09 and the internal genes of the A/Leningrad/134/17/57 (refs. 49,50,51) was rescued using reverse genetics as described24. This vaccine was manufactured in embryonated chicken eggs at Meridian Life Sciences in Memphis, Tennessee, and formulated in sterile saline. Two IIV vaccines, one carrying the same cH8/1 HA and one carrying a cH5/1 HA (head domain from A/Vietnam/1203/04 (H5N1), stalk domain from Cal09), were also rescued with the same N1 NA in the A/Puerto Rico/8/34 (PR8, H1N1) backbone and manufactured in embryonated chicken eggs by GSK as described elsewhere24,29.
Three different vaccination regimens as well as two placebo groups were included in the trial. Group 1 received cH8/1N1 LAIV on day 1 followed by AS03A-adjuvanted cH5/1N1 IIV on day 85 (LAIV8-IIV5/AS03). Group 2 received the same vaccination regimen but with the booster vaccination nonadjuvanted (LAIV8-IIV5). Group 3 was the inpatient control group and received normal saline intranasally followed by PBS intramuscularly (SALINE-PBS). Group 4 received adjuvanted cH8/1N1 IIV followed by adjuvanted cH5/1N1 IIV (IIV8/AS03-IIV5/AS03). Group 5 served as outpatient placebo group and received PBS intramuscularly twice (PBS-PBS). For many of the immunological assays, the SALINE-PBS and PBS-PBS groups were pooled and designated as placebo.
Subjects were also monitored during two influenza transmission seasons for any protocol-defined ILI and throughout the duration of the trial for any pIMD, AE leading to withdrawal from the study, medically attended AE or SAE. At each study visit, venous blood was collected for a complete blood count and to measure serum creatinine, urea nitrogen, and alanine and aspartate transaminase levels.
J.F., A.N., D.I.B., J.G., E.B.W., F.B.-S., C. Claeys, C.G., C.M., M.M.N., A.S., M.V.d.W. and B.L.I. are responsible for conducting, managing and coordinating the clinical trial. Laboratory experiments were performed by R.N., D.S., T.A., M.A.B., D.B., C.B., C. Capuano, J.M.C., V.C., L.C., A.W.F., A.J., K.J., M.M.M., M.M.N., S.S. and W.S. Resources and methods were provided by L.C., T.A., W.S., A.W.F., V.C., S.S., P.C.W. and F.K. All authors are responsible for writing, reviewing and editing the manuscript. Data analysis was performed by R.N., J.F., A.N., F.B.-S., D.S., J.M.C., V.C., C.G., C.M., A.S., B.L.I., A.G.-S., P.P. and F.K. Quality assurance on assays was performed at ISMMS by C.M.
The Icahn School of Medicine at Mount Sinai (ISMMS) has issued patents and filed patent applications covering the use of chimeric hemagglutinin antigens as vaccines. R.N., A.G.-S., P.P. and F.K. are named as inventors on these patents and applications. The ISMMS and the inventors have received payments as consideration for these rights. The laboratories of A.G.-S., P.P. and F.K. were also engaged in a research program that was funded by GlaxoSmithKline Biologicals SA. M.V.d.W. declares that she is employed by the GSK group of companies and declares no nonfinancial conflicts of interest. C. Claeys was an employee of the GSK group of companies at the time the study was performed. B.L.I. was an employee of the GSK group of companies until 2017 and held shares from this group of companies at the time the study was performed. He is also named as inventor on a patent family regarding influenza virus vaccine constructs filed by the ISMMS and the GSK group of companies. E.B.W. is a coinvestigator for a clinical trial supported by Pfizer. All other authors declare no competing interests.
Methods: PubMed, Web of Science, and Embase were searched up to May 1, 2020. Randomized controlled trials on PAE were collected according to specific inclusion and exclusion criteria. Meta-analyses were performed using RevMan 5.3, STATA 14, and GraphPad Prism 8. Pooled patient-reported scores and functional outcomes were calculated by using a fixed or random-effect model.
Whilst CM214 has established the superior efficacy of combination nivolumab with ipilimumab over sunitinib in patients with intermediate- and poor-risk mRCC, optimal scheduling of these drugs has not been explored in this disease area. Additionally, improving our current understanding of why some patients respond to immunotherapy whilst many others derive no benefit is recognised as a research priority and translational studies focusing on predictive biomarkers forms a further important exploratory objective of the trial.
PRISM is a Phase II, open label, multi-centre, parallel group, randomised controlled trial. Our trial was designed before CM214 results were available and seeks to establish whether less frequent scheduling of ipilimumab is associated with improved tolerability in patients with mRCC in comparison to the schedule used in CM214, without adversely impacting activity (in comparison with historic control data).
It was not feasible to design the study for an internal comparison of efficacy given the phase II nature of the trial and the required sample size for such a comparison. As the trial was designed prior to CM214 results being available, PRISM is powered to compare activity of the modified schedule with historic sunitinib control data, however ancillary analyses will explore results in relation to CM214.
The study protocol and this manuscript have been written in accordance with standard protocol items: recommendations for interventional trials (SPIRIT) guidelines [14]. We have included a SPIRIT checklist as supplementary material (Additional file 1: Table S1).
The PRISM trial is an open label, multi-centre, phase II, randomised controlled trial to explore the efficacy and safety of alternative reduced intensity scheduling of ipilimumab, when given in combination with nivolumab as first-line therapy, in patients with locally advanced or metastatic RCC. The trial will recruit 189 participants with individual randomisation on a 2:1 basis in favour of the modified schedule (see Fig. 1). The two arms of the trial are as follows (see Fig. 2):
The PRISM trial incorporates a strong translational element that seeks to explore circulating and tissue based predictive biomarkers of response to immunotherapy in patients with mRCC. The identification of such markers represents a research priority. Samples of plasma, serum and cell-free DNA will be collected in all consenting patients at baseline, weeks 7, 13 (selected to coincide with clinic visits) and at disease progression. Samples will be processed according to strict standard operating procedures (SOPs) defined within an associated trial-specific translational manual and all storage kit materials supplied centrally including barcoded blood tubes. In select centres, peripheral blood mononuclear cells (PBMCs) will also be collected from participants at the same time-points. Where available, an archival formalin-fixed paraffin embedded tissue block from nephrectomised participants will also be requested. 2ff7e9595c
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