Impact of Pre-Exposure History and Host Genetics on Antibody Avidity Following Norovirus Vaccination

Background: Development of high avidity, broadly neutralizing antibodies (Abs) is a priority after vaccination against rapidly evolving, widely disseminated viruses like human norovirus. After vaccination with a multivalent GI.1 and GII.4c norovirus virus-like particle (VLP) vaccine candidate adjuvanted with alum and monophosphoryl lipid A (MPL), blockade Ab titers peaked early, with no increase in titer following a second vaccine dose. Methods: Blockade Ab relative avidity was evaluated by measuring the slope of blockade Ab neutralization curves. Results: Blockade Ab avidity to the GI.1 vaccine component peaked at day 35 (7 days after dose 2). Avidities to heterotypic genogroup I VLPs were not sustained at day 35 after vaccination or GI.1 infection, as measured from archived sera. Only secretor-positive participants maintained high avidity blockade Ab to GI.1 at day 180. Avidity to the GII.4c vaccine component peaked at day 7, remained elevated through day 180, and was not secretor dependent. Avidity to an immunologically novel GII.4 strain VLP correlated with preexisting Ab titer to an ancestral strain Epitope A. Conclusions: Host genetics and pre-exposure history shape norovirus vaccine Ab responses, including blockade Ab avidity. Avidity of potentially neutralizing Ab may be an important metric for evaluating vaccine responses to highly penetrant viruses with cross-reactive serotypes

Spesolimab efficacy and safety in patients with moderate-to-severe palmoplantar pustulosis: a multicentre, double-blind, randomised, placebo-controlled, phase IIb, dose-finding study

Introduction: We evaluated the anti-interleukin-36 receptor antibody spesolimab in patients with moderate-to-severe palmoplantar pustulosis (PPP). Methods: This phase IIb trial comprised a loading dose period to week (W) 4, then maintenance dosing to W52. Patients were randomised 2:1:1:1:2 to subcutaneous spesolimab 3000 mg to W4 then 600 mg every 4 weeks (q4w), spesolimab 3000 mg to W4 then 300 mg q4w, spesolimab 1500 mg to W4 then 600 mg q4w, spesolimab 1500 mg to W4, 300 mg q4w to W16 then 300 mg every 8 weeks (q8w), or placebo switching to spesolimab 600 mg q4w at W16. The primary efficacy endpoint was percentage change from baseline in Palmoplantar Pustular Area and Severity Index (PPP ASI) at W16. Secondary endpoints included a Palmoplantar Pustular Physician’s Global Assessment (PPP PGA) score of 0/1. Safety (including adverse events [AEs], local tolerability) was assessed. Results: 152 patients were treated. The primary endpoint was not met; mean differences for spesolimab versus placebo ranged from − 14.6% (95% confidence interval [CI]: − 31.5%, 2.2%) to − 5.3% (95% CI: − 19.1%, 8.6%); none reached significance. At W16, 23 (21.1%) and two (4.7%) patients in the combined spesolimab and placebo groups, respectively, achieved PPP PGA 0/1 (mean difference 16.4%; 95% CI: 3.8%, 25.7%), increasing to 59 (54.1%; combined spesolimab) and 12 (27.9%; placebo switch to spesolimab) patients at W52. Non-Asian patients had significant improvements in the primary endpoint (mean difference − 17.7%; nominal P = 0.0394) and PPP PGA 0/1 at W16 with spesolimab versus placebo. Rates of AEs and AE-related discontinuations were similar for spesolimab and placebo. Local tolerability events and injection-site reactions were more frequent with spesolimab than placebo. Conclusion: The primary objective to demonstrate a non-flat dose–response relationship and proof-of-concept was not achieved; improvements with spesolimab occurred in secondary endpoints and in non-Asian patients, indicating potential modest benefits. Spesolimab was generally well tolerated (ClinicalTrials.gov NCT04015518)

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Spesolimab Efficacy and Safety in Patients with Moderate-to-Severe Palmoplantar Pustulosis: A Multicentre, Double-Blind, Randomised, Placebo-Controlled, Phase IIb, Dose-Finding Study

Abstract Introduction We evaluated the anti-interleukin-36 receptor antibody spesolimab in patients with moderate-to-severe palmoplantar pustulosis (PPP). Methods This phase IIb trial comprised a loading dose period to week (W) 4, then maintenance dosing to W52. Patients were randomised 2:1:1:1:2 to subcutaneous spesolimab 3000 mg to W4 then 600 mg every 4 weeks (q4w), spesolimab 3000 mg to W4 then 300 mg q4w, spesolimab 1500 mg to W4 then 600 mg q4w, spesolimab 1500 mg to W4, 300 mg q4w to W16 then 300 mg every 8 weeks (q8w), or placebo switching to spesolimab 600 mg q4w at W16. The primary efficacy endpoint was percentage change from baseline in Palmoplantar Pustular Area and Severity Index (PPP ASI) at W16. Secondary endpoints included a Palmoplantar Pustular Physician’s Global Assessment (PPP PGA) score of 0/1. Safety (including adverse events [AEs], local tolerability) was assessed. Results 152 patients were treated. The primary endpoint was not met; mean differences for spesolimab versus placebo ranged from − 14.6% (95% confidence interval [CI]: − 31.5%, 2.2%) to − 5.3% (95% CI: − 19.1%, 8.6%); none reached significance. At W16, 23 (21.1%) and two (4.7%) patients in the combined spesolimab and placebo groups, respectively, achieved PPP PGA 0/1 (mean difference 16.4%; 95% CI: 3.8%, 25.7%), increasing to 59 (54.1%; combined spesolimab) and 12 (27.9%; placebo switch to spesolimab) patients at W52. Non-Asian patients had significant improvements in the primary endpoint (mean difference − 17.7%; nominal P = 0.0394) and PPP PGA 0/1 at W16 with spesolimab versus placebo. Rates of AEs and AE-related discontinuations were similar for spesolimab and placebo. Local tolerability events and injection-site reactions were more frequent with spesolimab than placebo. Conclusion The primary objective to demonstrate a non-flat dose–response relationship and proof-of-concept was not achieved; improvements with spesolimab occurred in secondary endpoints and in non-Asian patients, indicating potential modest benefits. Spesolimab was generally well tolerated (ClinicalTrials.gov NCT04015518)

Immunogenicity and tolerability of a bivalent virus-like particle norovirus vaccine candidate in children from 6 months up to 4 years of age: A phase 2 randomized, double-blind trial

We conducted a dose-finding phase 2 study of the HilleVax bivalent virus-like particle (VLP) vaccine candidate (HIL-214) in two cohorts of children, 6–≤12 months and 1–≤4 years of age (N = 120 per cohort), in Panama and Colombia (ClinicalTrials.gov, identifier NCT02153112). On Day 1, children randomized to one of the four equal groups received intramuscular injections of four different HIL-214 formulations containing 15/15, 15/50, 50/50, or 50/150 μg of GI.1/GII.4c genotype VLPs and 0.5 mg Al(OH)3. On Day 29, half the children in each group received a second vaccination (N = 60), while the other half received saline placebo injections to maintain the blind. VLP-specific ELISA Pan-Ig and histo-blood group binding antigen-blocking antibodies (HBGA) were measured on Days 1, 29, 57 and 210. On Day 29, after one dose, there were large Pan-Ig and HBGA responses in both age cohorts with some indication of dose-dependence, and higher geometric mean titers (GMT) in the older children. A further increase in titers was observed 28 days after a second dose in the 6–≤12-month-old groups, but less so in the 1–≤4-year-old groups; GMTs at Day 57 were broadly similar across doses and in both age groups. GMTs of Pan-Ig and HBGA persisted above baseline up to Day 210. All formulations were well tolerated with mostly mild-to-moderate transient solicited adverse events reported by parents/guardians, and no vaccine-related serious adverse events occurred. Further development of HIL-214 is warranted to protect the most susceptible young children against norovirus

Immunogenicity of a bivalent virus-like particle norovirus vaccine in children from 1 to 8 years of age : A phase 2 randomized, double-blind study

Background: Young children can suffer severe consequences of norovirus gastroenteritis. We performed a dose-finding study of a bivalent virus-like particle (VLP) vaccine candidate (TAK-214) in healthy 1–8-year-old children. Methods: In this phase 2 study two age cohorts (1–3 and 4–8 years of age inclusive, N = 120 per cohort) of children enrolled from Finland, Panama and Colombia were initially randomized 1:1:1:1 to four groups which were further split into two equal subgroups, to receive one or two intramuscular doses of four TAK-214 formulations containing 15/15, 15/50, 50/50 or 50/150 μg of GI.1/GII.4c genotype VLPs and 0.5 mg Al(OH)3 at 28 days interval. ELISA Pan-Ig and histoblood group antigen-blocking (HBGA) antibodies against each VLP were measured on days 1, 29, 57 and 210. Parents/guardians recorded solicited local and systemic adverse events (AE) and any unsolicited or serious AEs (SAE). Results: All formulations were well-tolerated across both age cohorts and dosage groups with no vaccine-related SAEs reported. Solicited AEs were mostly mild-to-moderate, resolved quickly, and did not increase after the second dose. Pan-Ig and HBGA responses induced after one dose were only slightly increased by the second dose. Across dose groups at Day 29 after one dose GI.1 Pan Ig seroresponse rates (SRR) were 82–97% and 81–96% and GII.4c SRR were 79–97% and 80–91% in 1–3 and 4–8 year-olds, respectively. Respective rates were to 92–93% and 73–92% for GI.1, and 77–100% and 62–83% for GII.4c at Day 57 following two doses. HBGA responses had similar profiles. Both Pan Ig and HBGA geometric mean titers persisted above baseline up to Day 210. Conclusions: All dosages of TAK-214 displayed acceptable reactogenicity in 1–8-year-old children and induced robust, durable immune responses after one dose which are further increased after two doses.publishedVersionPeer reviewe

Broad Blockade Antibody Responses in Human Volunteers after Immunization with a Multivalent Norovirus VLP Candidate Vaccine: Immunological Analyses from a Phase I Clinical Trial

<div><p>Background</p><p>Human noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP) candidate vaccine in human volunteers.</p><p>Methods and Findings</p><p>Sera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated.</p><p>Conclusions</p><p>Vaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential feasibility of an efficacious multivalent NoV VLP vaccine for future use in human populations.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/show/NCT01168401" target="_blank">NCT01168401</a></p></div

Day 0 blockade antibody titers below the assay limit of detection for any norovirus virus-like particle are predictive of a ≥4-fold increase, but not overall blockade Ab titer, at day 7.

<p>Day 0 blockade Ab titers for all of the NoV VLPs studied were compared to the corresponding day 7 fold increase (A) and titer of blockade Ab (B) using GEEs (<i>n</i> = 10 participants, 82 samples). The likelihood of responding to vaccination with a ≥4-fold increase in blockade Ab titer to any NoV VLP was 3-fold greater if the day 0 titer was below the assay limit of detection. Day 0 blockade Ab titer did not correspond with day 7 titer. The dotted lines mark the lower limit of detection of the blockade Ab assay. The solid grey line marks a 4-fold increase in blockade titer at day 7. RR, relative risk.</p