In animal, epidemiological, and human challenge studies, a pre-existing T-cell response to internal proteins of influenza A has been associated with improved virological and disease outcomes. The aim ...of this study was to assess whether inducing additional responses to conserved CD4 and CD8 T-cell antigens provides added benefit to standard influenza vaccination.
We designed a phase 2b, randomised, placebo-controlled, double-blind trial of a recombinant viral-vectored vaccine (modified vaccinia Ankara expressing virus nucleoprotein and matrix protein 1; MVA-NP+M1), which has been shown to induce both CD4 and CD8 T cells, at eight outpatient clinical trial sites in Australia over two consecutive influenza seasons. We recruited non-immunosuppressed adults (≥18 years) who had received the 2019 quadrivalent influenza vaccine (QIV) vaccine within 28 days before study enrolment and randomisation (day 0). Participants were randomly assigned (1:1) according to a computer-generated random sequence to receive one dose of 1·5 × 108 plaque-forming units of MVA-NP+M1 or saline (placebo) intramuscularly. Randomisation was stratified by age (<65 years or ≥65 years). The patients and trial assessors were masked to treatment assignment. During the subsequent influenza seasons, participants with symptoms related to respiratory illness or influenza-like illness were to attend the clinic within 72 h of symptom onset for two nasal swabs for influenza testing by quantitative RT-PCR. The primary endpoint was the incidence rate of laboratory-confirmed influenza in the intention-to-treat (ITT) population. Safety (solicited adverse events within 7 days and unsolicited adverse events within 28 days after study vaccination, and serious adverse events for the study duration) was assessed in all randomly assigned participants who received at least one vaccination (according to the treatment received). The trial is registered with ClinicalTrials.gov, NCT03880474.
Between April 2 and June 14, 2019, 2152 adults were randomly allocated and received MVA-NP+M1 (n=1077) or placebo (n=1075), comprising the efficacy (ITT) analysis set. Participants were followed up throughout the 2019 Australia influenza season (May 1 to Oct 15, 2019). 419 (19·5%) of 2152 participants were aged 65 years or older. The incidence of laboratory-confirmed influenza did not differ between the MVA-NP+M1 group (35 of 1077 participants; 3·25% 95% CI 2·31–4·44) and the placebo group (23 of 1075; 2·14% 1·39–3·14; Fisher's exact p=0·14). 23 severe solicited local injection site reactions were reported in 13 (0·6%) of 2152 participants, 22 of which were reported in the MVA-NP + M1 group (in 12 1·1% participants). 100 severe systemic events were reported in 45 (4·2%) MVA-NP + M1 recipients, and 20 were reported in 14 (1·3%) placebo recipients. Three unsolicited grade 3 events in three participants (two headache and one nausea, all in the MVA-NP+M1 group) were deemed vaccine related. 21 serious adverse events were reported in 18 (1·7%) of 1077 participants in the MVA-NP+M1 group and 25 serious adverse events were reported in 22 (2·0%) of 1075 participants in the placebo group; none were considered vaccine related. The trial was stopped after one season for futility on the recommendation of the data monitoring committee.
MVA-NP+M1 was well tolerated with no vaccine-associated serious adverse events. A vaccine designed to induce moderate T-cell responses to the cross-reactive internal proteins of influenza A did not lead to improved incidence when given within 28 days after standard QIV immunisation. A greater magnitude of T-cell response with a different vaccine or regimen, or localisation in the lungs via alternative delivery, such as intranasal or aerosol, might be successful and require further investigation.
Vaccitech.
Emerging SARS-CoV-2 variants and evidence of waning vaccine efficacy present substantial obstacles towards controlling the COVID-19 pandemic. Booster doses of SARS-CoV-2 vaccines might address these ...concerns by amplifying and broadening the immune responses seen with initial vaccination regimens. We aimed to assess the immunogenicity and safety of a homologous booster dose of a SARS-CoV-2 recombinant spike protein vaccine (NVX-CoV2373).
This secondary analysis of a phase 2, randomised study assessed a single booster dose of a SARS-CoV-2 recombinant spike protein vaccine with Matrix-M adjuvant (NVX-CoV2373) in healthy adults aged 18–84 years, recruited from 17 clinical centres in the USA and Australia. Eligible participants had a BMI of 17–35 kg/m2 and, for women, were heterosexually inactive or using contraception. Participants who had a history of SARS-CoV or SARS-CoV-2, confirmed diagnosis of COVID-19, serious chronic medical conditions, or were pregnant or breastfeeding were excluded. Approximately 6 months following their primary two-dose vaccination series (administered day 0 and day 21), participants who received placebo for their primary vaccination series received a placebo booster (group A) and participants who received NVX-CoV2373 for their primary vaccination series (group B) were randomly assigned (1:1) again, via centralised interactive response technology system, to receive either placebo (group B1) or a single booster dose of NVX-CoV2373 (5 μg SARS-CoV-2 rS with 50 μg Matrix-M adjuvant; group B2) via intramuscular injection; randomisation was stratified by age and study site. Vaccinations were administered by designated site personnel who were masked to treatment assignment, and participants and other site staff were also masked. Administration personnel also assessed the outcome. The primary endpoints are safety (unsolicited adverse events) and reactogenicity (solicited local and systemic) events and immunogenicity (serum IgG antibody concentrations for the SARS-CoV-2 rS protein antigen) assessed 14 days after the primary vaccination series (day 35) and 28 days following booster (day 217). Safety was analysed in all participants in groups A, B1, and B2, according to the treatment received; immunogenicity was analysed in the per-protocol population (ie, participants in groups A, B1, and B2) who received all assigned doses and who did not test SARS-CoV-2-positive or received an authorised vaccine, analysed according to treatment assignment). This trial is registered with ClinicalTrials.gov, NCT04368988.
1610 participants were screened from Aug 24, 2020, to Sept 25, 2020. 1282 participants were enrolled, of whom 173 were assigned again to placebo (group A), 106 were re-randomised to NVX-CoV2373–placebo (group B1), and 104 were re-randomised to NVX-CoV2373–NVX-CoV2373 (group B2); after accounting for exclusions and incorrect administration, 172 participants in group A, 102 in group B1, and 105 in group B2 were analysed for safety. Following the active booster, the proportion of participants with available data reporting local (80 82% of 97 participants had any adverse event; 13 13% had a grade ≥3 event) and systemic (75 77% of 98 participants had any adverse event; 15 15% had a grade ≥3 event) reactions was higher than after primary vaccination (175 70% of 250 participants had any local adverse event, 13 5% had a grade ≥3 event; 132 53% of 250 had any systemic adverse event, 14 6% had a grade ≥3 event). Local and systemic events were transient in nature (median duration 1·0–2·5 days). In the per-protocol immunogenicity population at day 217 (167 participants in group A, 101 participants in group B1, 101 participants in group B2), IgG geometric mean titres (GMT) had increased by 4·7-fold and MN50 GMT by 4·1-fold for the ancestral SARS-CoV-2 strain compared with the day 35 titres.
Administration of a booster dose of NVX-CoV2373 resulted in an incremental increase in reactogenicity. For both the prototype strain and all variants evaluated, immune responses following the booster were similar to or higher than those associated with high levels of efficacy in phase 3 studies of the vaccine. These data support the use of NVX-CoV2373 in booster programmes.
Novavax and the Coalition for Epidemic Preparedness Innovations.
Interleukin (IL)-17A underlies the pathogenesis of chronic plaque psoriasis (CPP). Well-tolerated, effective IL-17A inhibitors for mild-to-moderate CPP are needed. ZL-1102 is a novel antibody ...fragment targeting IL-17A. To assess the safety, tolerability, preliminary efficacy and skin penetration of a topical 1% ZL-1102 hydrogel in patients with mild-to-moderate CPP, a two-part, Phase Ib study was conducted. Open-label Part A: six patients received a single topical application of ZL-1102 onto a psoriatic plaque; double-blind Part B: 53 patients were randomised 1:1 to twice-daily ZL-1102 or vehicle for 4 weeks. Key primary endpoints included treatment-emergent adverse events (TEAEs), tolerability and changes in local psoriasis area and severity index (PASI). TEAEs occurred in two (33.3%) patients in Part A and in 16 (59.3%) and 13 (50.0%) patients in the ZL-1102 and vehicle arms, respectively, in Part B. No grade ≥3 TEAEs were seen with ZL-1102. ZL-1102 led to numerically greater changes in local PASI versus vehicle (-28.8% vs. -17.2%), with good local tolerability. The trend towards local PASI improvement was accompanied by biomarker changes based on RNA sequencing, indicative of ZL-1102 penetration into psoriatic plaques. Topical ZL-1102 showed good safety, local tolerability and a trend towards improved local PASI; skin penetration was observed without measurable systemic exposure. ACTRN12620000700932.
Abstract
Background
NVX-CoV2373 is an efficacious coronavirus disease 2019 (COVID-19) vaccine comprising full-length recombinant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ...(rS) glycoprotein and Matrix-M adjuvant. Phase 2 of a randomized, placebo-controlled, phase 1/2 trial in healthy adults (18–84 years of age) previously reported good safety/tolerability and robust humoral immunogenicity.
Methods
Participants were randomized to placebo or 1 or 2 doses of 5-µg or 25-µg rS with 50 µg Matrix-M adjuvant 21 days apart. CD4+ T-cell responses to SARS-CoV-2 intact S or pooled peptide stimulation (with ancestral or variant S sequences) were measured via enzyme-linked immunosorbent spot assay and intracellular cytokine staining.
Results
A clearly discernable spike antigen-specific CD4+ T-cell response was induced after 1 dose, but markedly enhanced after 2 doses. Counts and fold increases in cells producing Th1 cytokines exceeded those secreting Th2 cytokines, although both phenotypes were clearly present. Interferon-γ responses to rS were detected in 93.5% of 2-dose 5-µg recipients. A polyfunctional CD4+ T-cell response was cross-reactive and of equivalent magnitude to all tested variants, including Omicron BA.1/BA.5.
Conclusions
NVX-CoV2373 elicits a moderately Th1-biased CD4+ T-cell response that is cross-reactive with ancestral and variant S proteins after 2 doses.
Clinical Trials Registration
NCT04368988.
Primary series of NVX-CoV2373 vaccine with Matrix-M adjuvant induces polyfunctional CD4+ T-cell responses of balanced to moderately Th1-biased phenotype. Essentially equivalent cytokine production by vaccinee cells can be stimulated by spike proteins of ancestral or multiple variant sequences.
Abstract
Background
COVID-19 continues to cause substantial morbidity and mortality globally. It is likely that booster vaccinations will be needed in future years to protect older adults and those ...with chronic medical conditions. We present interim topline results of a phase 1/2 study of IVX-411 ACTRN12621000738820.; ACTRN12621000882820, an investigational VLP protein subunit SARS-CoV-2 vaccine, in adults aged 18–69 years (Figure 1).
Methods
In Part 1, 84 SARS-CoV-2-naïve adults were randomized to receive two doses on Days 0 and 28 of either IVX-411 (5, 25, or 125µg) ± adjuvant, or placebo (Figure 2a). In Part 2, 84 subjects received a single dose of either IVX-411 ± adjuvant or placebo 3–6 months after completion of a primary licensed vaccine regimen (Figure 2b). Solicited adverse events (AEs) were collected for 7 days after each dose, with immunogenicity assessed on Days 0, 28, and 49 (Part 1) and on Days 0, 7 and 28 (Part 2). Primary outcomes in both parts were solicited and unsolicited AEs, neutralizing antibody titers, and spike protein-specific IgG antibody titers.
Results
Demographics were similar in the IVX-411 groups vs placebo. In Part 1 and Part 2, local reactogenicity was mild-to-moderate, with higher rates of AEs with increasing doses and addition of adjuvant (Figure 3a). Rates of systemic AEs were similar to placebo across groups (Figure 3b). No vaccine-related severe or serious AEs were noted. IVX-411 was immunogenic in both primary and booster vaccination: in SARS-CoV-2-naïve subjects, a limited dose effect was seen, with significantly higher antibody titers in the groups receiving adjuvanted IVX-411 vaccine (p< 0.01; Figure 4a). The magnitude of antibody responses was similar to, or below, Human Convalescent Sera levels. In previously vaccinated subjects, IVX-411 boosted baseline antibody titers, with no conclusive dose or adjuvant effect (Figure 4b). Immunogenicity was observed across all variants of concern (beta, delta, and omicron) in both parts, with up to 7- fold rises from baseline (Figure 5).
Conclusion
The study met all primary safety and immunogenicity objectives, with acceptable tolerability profiles in primary and booster vaccination. A clear adjuvant effect was observed in SARS-CoV-2-naïve subjects.
Disclosures
All Authors: No reported disclosures.
Abstract only Background: Familial chylomicronemia syndrome (FCS) is an ultrarare condition caused by biallelic pathogenic DNA variants in lipolysis-associated genes, resulting in severe ...hypertriglyceridemia (HTG) and associated with high risk of acute pancreatitis with few therapeutic options. In a 16-week Phase 1 study (NCT03783377), subcutaneously administered ARO-APOC3 reduced serum apolipoprotein C3 (APOC3) and TG in healthy volunteers and participants (pts) with HTG and was well tolerated. Purpose: To report on the safety/pharmacodynamic (PD) effects of ARO-APOC3 in both FCS pts with biallelic pathogenic variants and pts with severely elevated TG at screening (>880 mg/dL) but without biallelic pathogenic variants (chylomicronemia (MCM)). Methods: Four genetically confirmed FCS pts received 50 mg ARO-APOC3 and 26 MCM pts received 10, 25, 50, or 100 mg ARO-APOC3 on Days 1 and 29. Since similar PD responses were observed among MCM pts, results were pooled across dose levels. Safety and PD responses were examined. Maximal mean/median changes from baseline for APOC3, TG, non-HDL-C, and HDL-C were reported. Results: Baseline/demographics were comparable between groups, except for mean BMI (22.1 FCS and 30.5 MCM kg/m 2 ), and mean baseline HDL-C , which were lower in FCS pts (Table 1) (p<0.0001 for both). Mean APOC3 was reduced by 98% and 96% in FCS and MCM pts, respectively. Both groups also showed similar maximum median reductions in TG of 91% and 90%, respectively. Similar to the full study, non-HDL-C was reduced and HDL-C increased with treatment in both groups (Table 1). AEs were similar between groups, suggesting a comparable safety profile. Conclusions: In patients with severe HTG, ARO-APOC3 was safe, and consistently decreased APOC3, TG, and non-HDL-C, and increased HDL-C, regardless of underlying genetic cause of HTG, and may represent a promising RNAi therapeutic for the treatment of severe HTG.
BackgroundHypertriglyceridemia (HTG) increases the risk of acute pancreatitis and atherosclerosis. In a Phase 1 study (NCT03783377), single subcutaneous doses of investigational RNA interference ...(RNAi) therapeutic ARO-APOC3 (10, 25, 50, and 100 mg; N=24) demonstrated deep and prolonged reductions in apolipoprotein C3 (APOC3) and triglycerides (TG) and increases in HDL-C in healthy volunteers with good tolerability, compared with placebo (N=16).PurposeWe report initial results of the effects of ARO-APOC3 in patients with HTG (fasting TG ≥ 300 mg/dL) or multifactorial chylomicronemia (MCM; fasting TG ≥ 880 mg/dL).MethodsUp to 40 subjects with HTG and 20 subjects with MCM will receive ARO-APOC3 or placebo on days 1 and 29. Pharmacodynamic responses include serum APOC3, TG, and other lipid parameters reported up to week 4 prior to the 2 dose.ResultsAt the data cutoff (16 March 2020), the first 4 enrolled patients with HTG and 6 enrolled patients with MCM were administered ARO-APOC3 50 mg. ARO-APOC3 substantially reduced mean (range) APOC3 levels by 96% (88-99%) in both patient groups at Week 4 (Table). ARO-APOC3 substantially reduced mean (range) TG by 78% (67-87%) in HTG patients and by 92% (90-95%) in MCM patients at Week 4. Three of 4 HTG patients and 3 of 6 MCM patients had TG levels below 150 mg/dL. All MCM patients had TG ≤ 500 mg/dL. To date, ARO-APOC3 has been generally well tolerated with no reports of treatment-related serious or severe adverse events. Two of the 6 unblinded MCM patients experienced a transient ALT elevation to >3X ULN that returned to approximate pre-dose baseline by Day 113.ConclusionsPreliminary results indicate that a single dose of ARO-APOC3 reduces APOC3 levels by >90% and TG by ~80% 4 weeks after treatment in patients with HTG and MCM. The magnitude of treatment effect was similar in both populations and ARO-APOC3 had a favorable safety profile. Using RNAi to silence expression of APOC3 appears promising for treating patients with HTG and MCM.
BACKGROUND: Apolipoprotein C-III (APOC3) inhibits triglyceride clearance by reducing lipoprotein lipase–mediated hydrolysis and hepatocyte uptake of triglyceride-rich lipoproteins. ARO-APOC3, a ...hepatocyte-targeting RNA interference therapeutic, inhibits APOC3 messenger ribonucleic acid expression, lowering triglyceride levels. The objective of this trial was to assess the safety, pharmacodynamic variables, and pharmacokinetic variables of ARO-APOC3 treatment. METHODS: Healthy participants and adults with hypertriglyceridemia were randomly assigned to receive escalating single (day 1) or repeat (days 1 and 29) doses, respectively, of subcutaneous injections of ARO-APOC3 10, 25, 50, or 100 mg or placebo; they were followed up until day 113. Additional cohorts of healthy participants and adults with chylomicronemia received repeat doses of open-label ARO-APOC3. The primary objective was to evaluate the safety and side effect profile of ARO-APOC3. Key secondary and exploratory objectives included pharmacokinetic variables and changes in serum APOC3, triglyceride, and cholesterol levels. RESULTS: Eighty-eight participants received ARO-APOC3 and 24 participants received placebo across double-blind and open-label cohorts. Treatment-emergent adverse events (AEs) of transient, mild to moderate liver transaminase changes occurred in 10 participants: 1 patient receiving ARO-APOC3 25 mg, 5 patients receiving ARO-APOC3 50 mg, and 4 participants receiving ARO-APOC3 100 mg (1 healthy participant and 3 patients with hypertriglyceridemia). These events were asymptomatic, and transaminase levels returned to near baseline by the end of the trial. No AEs related to thrombocytopenia or platelet declines were reported. In the hypertriglyceridemia cohorts, the day 113 mean changes from baseline in APOC3 at the 10-, 25-, 50-, and 100-mg doses were −62.0%, −81.7%, −90.1%, and −94.4%, respectively, compared with −1.6% with placebo. This corresponded to median changes in triglyceride levels of −65.6%, −69.9%, −81.2%, and −81.0% compared with −2.8% with placebo. CONCLUSIONS: In this small trial of short duration, ARO-APOC3 was associated with few AEs and reduced serum levels of APOC3 and triglycerides in healthy participants and patients with hypertriglyceridemia. (Funded by Arrowhead Pharmaceuticals, Inc.; ClinicalTrials.gov number, NCT03783377.)
A gluten-free diet is insufficient to treat coeliac disease because intestinal injury persists and acute reactions with cytokine release follow gluten exposure. Nexvax2 is a specific immunotherapy ...using immunodominant peptides recognised by gluten-specific CD4
T cells that might modify gluten-induced disease in coeliac disease. We aimed to assess the effects of Nexvax2 on gluten-induced symptoms and immune activation in patients with coeliac disease.
This was a randomised, double-blind, placebo-controlled phase 2 trial done at 41 sites (29 community, one secondary, and 11 tertiary centres) in the USA, Australia, and New Zealand. Patients with coeliac disease aged 18-70 years who had excluded gluten for at least 1 year, were HLA-DQ2.5 positive, and had a worsening of symptoms after an unmasked 10 g vital gluten challenge were eligible for inclusion. Patients were stratified by HLA-DQ2.5 status (HLA-DQ2.5 non-homozygous vs homozygous). Patients who were non-homozygous were centrally (ICON; Dublin, Ireland) randomly assigned (1:1) to receive subcutaneous Nexvax2 (non-homozygous Nexvax2 group) or saline (0·9% sodium chloride; non-homozygous placebo group) twice a week escalating from 1 μg to 750 μg during the first 5 weeks followed by 11 weeks of maintenance therapy at 900 μg per dose. The exploratory homozygous group was centrally randomly assigned (2:1) to receive Nexvax2 (homozygous Nexvax2 group) or placebo (homozygous placebo group); patients who were homozygous received the same dosage as those who were non-homozygous. The primary endpoint was change in coeliac disease patient reported outcomes (total gastrointestinal domain) from pretreatment baseline to the day of masked bolus 10 g vital gluten challenge given in week 14 analysed in the non-homozygous intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT03644069.
Between Sept 21, 2018, and April 24, 2019, 383 volunteers were screened for inclusion, of whom 179 (47%; 133 74% women, 46 26% men; median age 41 years IQR 33-55) were randomly assigned. One (1%) of 179 patients was excluded from analysis due to misassignment of genotype. The non-homozygous Nexvax2 group included 76 patients, the non-homozygous placebo group included 78 patients, the homozygous Nexvax2 group included 16 patients, and the homozygous placebo group included eight patients. The study was discontinued after planned interim analysis of 66 patients who were non-homozygous. We report an unmasked post-hoc analysis of all available data for the primary endpoint and secondary symptom-based endpoints combining data from 67 (66 were assessed in the planned interim analysis for the primary endpoint). Mean change from baseline to day of first masked gluten challenge in total gastrointestinal score for the non-homozygous Nexvax2 group was 2·86 (SD 2·28) compared with 2·63 (2·07) for the non-homozygous placebo group (p=0·43). Adverse events were similar between all patients who received Nexvax2 and those who received placebo. Serious adverse events were reported in five (3%) of 178 patients (two 2% of 92 who received Nexvax2 and three 4% of 82 who received placebo). One patient in the non-homozygous Nexvax2 group had a serious adverse event that occurred during gluten challenge (left-sided mid-back muscle strain with imaging suggestive of partial left kidney infarction). Serious adverse events were reported for three (4%) of 78 patients in the non-homozygous placebo group (one each with exacerbation of asthma and appendicitis, and one who had forehead abscess, conjunctivitis, and folliculitis) and one (1%) patient in the non-homozygous Nexvax2 group developed a pulmonary embolism. The most frequent adverse events in all 92 patients who received Nexvax2 compared with all 86 patients who received placebo were nausea (44 48% of 92 patients who received Nexvax2 vs 29 (34%) of 86 patients who received placebo), diarrhoea (32 35% vs 25 29%), abdominal pain (31 34% vs 27 31%), headache 32 35% vs 20 23%), and fatigue (24 26% vs 31 36%).
Nexvax2 did not reduce acute gluten-induced symptoms. Masked bolus vital gluten challenge provides an alternative to extended gluten challenge in efficacy studies for coeliac disease.
ImmusanT.
