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Inflammatory parameters associated with systemic reactogenicity following vaccination with adjuvanted hepatitis B vaccines: a randomized phase II trial Table of contents: Supplementary information TOC \o "2-3" \h \z \t "Heading 1,1,NoNum:Head1,1,NoNum:Head2,2,NoNum:Head3,3" MAIN analysis PAGEREF _Toc516053366 \h 3Methods PAGEREF _Toc516053367 \h 3Inclusion and exclusion criteria PAGEREF _Toc516053368 \h 3Specific dietary and lifestyle recommendations PAGEREF _Toc516053369 \h 3List of potential immune-mediated diseases (pIMDs) PAGEREF _Toc516053370 \h 5Datasets for the multivariate analysis PAGEREF _Toc516053371 \h 5Multivariate analyses PAGEREF _Toc516053372 \h 6Results PAGEREF _Toc516053373 \h 7Local symptoms recorded by study staff PAGEREF _Toc516053374 \h 7Safety PAGEREF _Toc516053375 \h 7Sensitivity analysis for the multivariate analysis PAGEREF _Toc516053376 \h 8List of tables TOC \h \z \c "eTable" STable1Cytokines and chemokines measured in this study PAGEREF _Toc516053377 \h 9STable2Summary of demographic characteristics (Total vaccinated cohort) PAGEREF _Toc516053378 \h 10List of Figures TOC \h \z \c "eFigure" SFig 1Hematological and biochemical parameters showing no change over time after vaccination, geometric mean and 95% confidence interval (Total vaccinated cohort). PAGEREF _Toc516053381 \h 13SFig 2Median (interquartile range) heart rate and respiratory rate as measured by the investigator/study nurse after vaccination (Total vaccinated cohort) PAGEREF _Toc516053382 \h 14SFig 3Systemic and local reactogenicity score 1 day after dose 2 (D31) PAGEREF _Toc516053383 \h 15SFig 4Associations between the innate response and the solicited reactogenicity symptoms at 1 day after dose 2 in an independent cohort PAGEREF _Toc516053384 \h 16MAIN analysisMethodsInclusion and exclusion criteriaSubjects could not participate if they were positive for antibodies against hepatitis C virus or human immunodeficiency virus, if they had previously received MPL or QS-21, had received an investigational or non-registered product within the last 30 days or planned use during the study period, had significant dietary restrictions, or regularly used non-steroidal anti-inflammatories. Other exclusion criteria were administration/planned administration of a vaccine not foreseen by the study protocol within the last 30 days and ending 210 days after the first dose of vaccine, with the exception of the in?uenza vaccine which could be administered >21 days preceding or following each injection, chronic administration of immunosuppressants or other immune-modifying drugs within the last six months, administration of immunoglobulins and/or any blood products within the last three months, any con?rmed or suspected immunosuppressive or immunode?cient condition, known or suspected reaction or hypersensitivity likely to be exacerbated by vaccine components, a bleeding or coagulation disorder, any clinical condition including anemia that would preclude frequent blood drawings, poor venous access as assessed at screening by the investigator, blood loss, including blood donation, of >300 mL within 90 days before the first injection, and any hematological or biochemical level out of normal range before entering into the study. Women who were pregnant or lactating could not participate, nor could individuals with chronic alcohol consumption and/or drug abuse. Eligibility criteria were checked at the screening visit.Specific dietary and lifestyle recommendations In order to ensure subject comparability giving the significant impact of diet and of strenuous exercise on metabolite concentrations in plasma as well as on certain hematological/biochemistry parameters, the subjects are asked not to drink alcohol, to follow specific diet and lifestyle recommendations on the day of as well as on the day before sampling for innate response evaluation.List of Diet and Lifestyle RequirementsList of foods (allowed or not allowed)You can drink/eat :You cannot drink/eat:Drinks:WaterMost Teas & infusionsGreen tea CoffeeSoft drinks (Coca-Cola …)Most Fruit juicesGrape juice Alcohol including wine & beerFoods:Breads, Cereal, Rice, Potatoes & PastaAll cereals, all breads, rice, potatoes and pasta Vegetables & FruitsMost VegetablesTomatoes (including derived products e.g. sauce on pizzas/pasta)Most FruitsGrapes Meat, Poultry, Fish and AlternativesWhite Meat (Chicken, turkey, veal & pork meat)Red Meat (Beef, mouton, horse, game, duck and goose )Delicatessen (ham, sausages, bacon…)FishBeans and lentilsNutsPeanuts(including derived products e.g. biscuits/chocolates)EggsTofu, corn, seitan tempehFats, Oils & SweetsFried foodPastry, biscuits, chips, sweets, chocolate Most OilsDairyMilk, Butter, Yogurt & CheeseOtherFood products that you suspect you may be allergic tooLifestyle (allowed or not allowed)You can:You cannot:Physical Activity:Do your normal daily activities (including usual work and home activities)Do non strenuous activities such as go for a one hour walkDo any sports: such as go to the gym to exercise or go running/jogging/ swimming. Do intense activities such as moving house, playing sports games on the Wii/?PlayStation. Smoking:Smoke as you usually wouldSmoke soft drugs (such as cannabis)Other:Get a good night sleep (follow your usual sleeping habits)List of potential immune-mediated diseases (pIMDs)Neuroinflammatory disordersMusculoskeletal disordersSkin disordersCranial nerve disorders, including paralyses/paresis (e.g. Bell’s palsy) Optic neuritisMultiple sclerosisTransverse myelitisGuillain-Barré syndrome, including Miller Fisher syndrome and other variantsAcute disseminated encephalomyelitis, including site specific variants: e.g. non-infectious encephalitis, encephalomyelitis, myelitis, myeloradiculomyelitisMyasthenia gravis, including Lambert-Eaton myasthenic syndrome Immune-mediated peripheral neuropathies and plexopathies, (including chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy and polyneuropathies associated with monoclonal gammopathy).NarcolepsySystemic lupus erythematosus Scleroderma, including diffuse systemic form and CREST syndromeSystemic sclerosisDermatomyositis Polymyositis Antisynthetase syndromeRheumatoid arthritis, Juvenile chronic arthritis, (including Still’s disease)Polymyalgia rheumaticSpondyloarthritis, including ankylosing spondylitis, reactive arthritis (Reiter's Syndrome) and undifferentiated spondyloarthritis Psoriatic arthropathyRelapsing polychondritisMixed connective tissue disorderPsoriasisVitiligoErythema nodosumAutoimmune bullous skin diseases (including pemphigus, pemphigoid and dermatitis herpetiformis)Cutaneous lupus erythematosusAlopecia areataLichen planusSweet’s syndromeMorphoeaLiver disordersGastrointestinal disordersMetabolic diseasesAutoimmune hepatitisPrimary biliary cirrhosisPrimary sclerosing cholangitisAutoimmune cholangitisCrohn’s disease Ulcerative colitis Ulcerative proctitis Celiac diseaseAutoimmune thyroiditis (including Hashimoto thyroiditis)Grave's or Basedow’s diseaseDiabetes mellitus type IAddison’s diseaseVasculitidesOthersLarge vessels vasculitis including: giant cell arteritis such as Takayasu's arteritis and temporal arteritis. Medium sized and/or small vessels vasculitis including: polyarteritis nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's granulomatosis, Churg–Strauss syndrome (allergic granulomatous angiitis), Buerger’s disease (thromboangiitis obliterans), necrotizing vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive vasculitis (type unspecified), Henoch-Schonlein purpura, Behcet's syndrome, leukocytoclastic vasculitis.Autoimmune hemolytic anemiaAutoimmune thrombocytopeniaAntiphospholipid syndromePernicious anemiaAutoimmune glomerulonephritis (including IgA nephropathy, glomerulonephritis rapidly progressive, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and mesangioproliferative glomerulonephritis)UveitisAutoimmune myocarditis/cardiomyopathySarcoidosisStevens-johnson syndromeSj?gren’s syndromeIdiopathic pulmonary fibrosisGoodpasture syndromeRaynaud’s phenomenonDatasets for the multivariate analysis Reactogenicity (as measured using standard procedures) the day after dose 2 (day 31 [D31]) and vital signs measured by the study nurse after dose 2 using the maximum absolute values of either day 30 at hour 18 (D30-H18) or D31, were modeled separately as a linear function of innate immune responses (cytokines, hematology and biochemical parameters) after the first dose (from D0 to D7) or after the second dose (from D30 to D31). Modeling was performed for 24 participants in the Alum group and 27 in the AS01B group for whom data were available for each time-point and variable (n=51 in the first and second dose datasets). In the first analysis, solicited symptoms were split into two sub-groups: local reactogenicity (pain, redness and swelling) and systemic reactogenicity (fatigue, fever, gastrointestinal symptoms, headache, malaise, myalgia and shivering). Each sub-group was represented in the model by the sum of all individual scores (the grading reported by the participant for each local or systemic symptom) on D31. The sum of all individual scores at D31 is a random variable which can be assumed to follow a Poisson distribution.In the second analysis, modeling was performed using eight parameters: diastolic blood pressure, heart rate, respiratory rate, systolic blood pressure, temperature, redness, swelling and pain. For each parameter, the maximum value from either D30-H18 or D31 was retained. All parameters approximately followed a normal distribution with the exception of redness and swelling, which were binary random variables with two modalities: ‘1’ the subject presented with either redness or swelling; or ‘0’, otherwise. The pain score was an ordered categorical random variable.Data were organized in a matrix with n rows (one per subject) and P*T columns, where P is the number of variables and T is the number of post-vaccination time-points. All columns with zero-variance and near-zero-variance (meaning no or very few differences over time for a given parameter) were not considered in the analysis as suggested by Kuhn et al ADDIN EN.CITE <EndNote><Cite><Author>Kuhn</Author><Year>2013</Year><RecNum>5586</RecNum><DisplayText>[11]</DisplayText><record><rec-number>5586</rec-number><foreign-keys><key app="EN" db-id="rzsrdz0tj5vtt2e0dvl5xrpd5fetvf9zpz9f">5586</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Kuhn, M.</author><author>Johnson, K</author></authors></contributors><titles><title>Applied Predictive Modeling</title></titles><dates><year>2013</year></dates><pub-location>New York</pub-location><publisher>Springer Nature</publisher><urls></urls></record></Cite></EndNote>[11]. This approach allowed removal of parameters at post-vaccination time points that were not relevant to be associated with reactogenicity.As a result, data were organized in a matrix with n rows and K columns, where K is the remaining number of columns after removing columns with zero-variance and near-zero-variance. Data were then split in two datasets: innate data post-dose 1 with baseline at D0, and innate data post-dose 2 with baseline at D30. All variables in each datasets were expressed as fold change according to baseline.Multivariate analysesFour different models were used according to the nature of the response variable, as previously described ADDIN EN.CITE <EndNote><Cite><Author>Burny</Author><Year>2017</Year><RecNum>5441</RecNum><DisplayText>[12]</DisplayText><record><rec-number>5441</rec-number><foreign-keys><key app="EN" db-id="rzsrdz0tj5vtt2e0dvl5xrpd5fetvf9zpz9f">5441</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Burny, W.</author><author>Callegaro, A.</author><author>Bechtold, V.</author><author>Clément, F</author><author>Fissette, F</author><author>Janssens, Michel</author><author>Leroux-Roels, Geert</author><author>Delhaye, Sophie</author><author>Marchant, Arnaud</author><author>van den Berg, RA</author><author>Gar?on, N</author><author>van der Most, R</author><author>Didierlaurent, AM</author><author>on behalf of the ECR-002 study group, </author></authors></contributors><titles><title>Inter-relationship Between Innate and Adaptive Immune Responses Induced by Adjuvanted Vaccines in Humans: A Multivariate Analysis </title><secondary-title>Frontiers in Immunology. Accepted</secondary-title></titles><periodical><full-title>Frontiers in Immunology. Accepted</full-title></periodical><dates><year>2017</year></dates><urls></urls></record></Cite></EndNote>[12]. In each model, the response variable was modeled as a function of the regression coefficient β for the treatment effect on the innate variables (AS01B versus Alum group), and the individual innate variables pI and pII (INpI,i and INpII,i) summarized by their PCs. The Alum group was the primary comparator as displaying the lowest overall responses among groups, and the β of its intercept (β0) was considered as the baseline. The four models used for this analysis were:1. A generalized linear Poisson-regression model for the systemic and local reactogenicity scores D31 of each participant (SRD31,i and LRD31,i). The following equations were used:log(E(SRD31,i)) = β0 + βAS01B,i INpI,AS01B,i + βPC1PC1[INpI,i] + βPC2PC2[INpI,i] + βPC3PC3[INpI,i] + βPC4PC4[INpI,i] + βPC5PC5[INpI,i] log(E(SRD31,i)) = β0 + βAS01B,i INpII,AS01B,i + βPC1PC1[INpII,i] + βPC2PC2[INpII,i] + βPC3PC3[INpII,i]log(E(LRD31,i)) = β0 + βAS01B,i INpI,AS01B,i + βPC1PC1[INpI,i] + βPC2PC2[INpI,i] + βPC3PC3[INpI,i] + βPC4PC4[INpI,i] + βPC5PC5[INpI,i] log(E(LRD31,i)) = β0 + βAS01B,i INpII,AS01B,i + βPC1PC1[INpII,i] + βPC2PC2[INpII,i] + βPC3PC3[INpII,i]where E = expected 2. A linear regression model for the maximum individual values on D30H18 or D31 for diastolic blood pressure, heart rate, respiratory rate, systolic blood pressure and body temperature (DBP(D30H18,D31),i ,HR(D30H18,D31),i ,RR(D30H18,D31),i ,SBP(D30H18,D31),i and TE(D30H18,D31),i ).3. A logistic regression model for the maximum individual grade on D30H18 and D31 of swelling and redness (SWE(D30H18,D31),i and RED(D30H18,D31),i). 4. An ordered logistic regression model for the maximum individual grade between D30H18 and D31 of pain (PAS(D30H18,D31),i).Eight multi-parametric models (one for each viral sign) were performed. For each model we used partial Fisher-test (when the response variable followed a normal distribution) or a likelihood ratio chi-square test (for binary random response variables or an ordered categorical random response variable), to test whether or not a subset of regression coefficients = zero. Z-tests were used to test whether or not individual regression coefficients = zero.The study included a second step to evaluate additional time-points and immune parameters. The design and the results of this second step are available at the GSK clinical registry @ Local symptoms recorded by study staffThe median injection site pain score as assessed by study staff 5 minutes-post vaccination was 0 in both groups after each injection (range 0-4).After dose 2, pain was reported by 70.4% of HBsAg-AS01B recipients and 28.6% of HBsAg-Alum recipients, and muscle stiffness by 55.6% and 14.3% of subjects, respectively. There were 7/27 participants in the AS01B group and 0/28 participants in the Alum group who had redness >20mm recorded after dose 2, and 4/27 versus 1/28 who had swelling >20mm after dose 2. Injection site induration >20mm was only reported by one participant after dose 2 of HBsAg-AS01B. There was minimal change in the circumference of the injected arm in either group after any injection (data not shown).Safety Most participants (>98%) were compliant in returning diary cards.Post-placeboThe percentage of participants in the total vaccinated cohort reporting any unsolicited adverse event within 28 days after injection with placebo was 40% in the AS01B group and 53.3% in the Alum group, of which 10.0% and 16.7% respectively, were considered to be of Grade 3 severity. No Grade 3 unsolicited AEs were considered by the investigator to be related to vaccination Post-vaccination The percentage of participants reporting unsolicited adverse events within 28 days after any vaccine dose was 50.0% (14/28, 95% CI 30.6-69.4) in the AS01B group and 51.7% (15/29, 95% CI 32.5-70.6) in the Alum group. Of these, four participants in the AS01B group and no participants in the Alum group had at least one event considered by the investigator to be vaccine related (influenza like illness, injection site pruritus, oral herpes, decreased appetite, musculoskeletal stiffness). None of the vaccine-related symptoms were grade 3 in intensity. There were no grade 3 increases in hematological or biochemical parameters observed in AS01B recipients. Grade 3 abnormal laboratory parameters were reported by 10.3% of subjects (3/29) in the Alum group (two hemoglobin changes from baseline and one platelet decrease). There was one serious adverse event during the study; a case of cholecystitis in the Alum group with onset 132 days after dose 3 and considered by the investigator to be unrelated to vaccination. No potential immune-mediated diseases or fatal serious adverse events were reported.Sensitivity analysis for the multivariate analysisThe potential impact of the difference in the reactogenicity profile of HBsAg-AS01B and HBsAg-Alum in the analyses was explored in a sensitivity analysis using only data from AS01B recipients. Consistent results were obtained: the analyses revealed no associations with vital signs (p ≥ 0.06; F-test), but did identify associations between the innate response after each dose and systemic reactogenicity (p<0.001; partial Fisher test). Accordingly, the largest separations on the PC1 were observed for CRP at H18 and D1 after the first dose and for IFN-?, IP-10 and MCP-2 at the same two time points after the second dose (data not shown).STable SEQ eTable \* ARABIC 1Cytokines and chemokines measured in this studyAbbreviationDescriptionMultiplexGM-CSFGranulocyte-macrophage colony stimulating factor HMPCORE1INFInterferon-gammaHMPCORE1IL10Interleukin-10HMPCORE1IL18Interleukin-18HMPCORE1IL2Interleukin-2HMPCORE1IL3Interleukin-3HMPCORE1IL4Interleukin-4HMPCORE1IL5Interleukin-5HMPCORE1IL6Interleukin-6HMPCORE1IL6rInterleukin-6 receptorHMPC42IL7Interleukin-7HMPCORE1IL8Interleukin-8HMPCORE1MIP1Macrophage inflammatory protein 1-alphaHMPCORE1MIP-1 Macrophage inflammatory protein 1-betaHMPCORE1MIP3Macrophage inflammatory protein 3-alphaHMPC42MCP-1Monocyte chemotactic protein-1HMPCORE1MCP-2Monocyte chemotactic protein-2HMPC42MCP-4Monocyte chemotactic protein-4HMPC42TNFTumor necrosis factor alphaHMPCORE1TNFTumor necrosis factor betaHMPCORE1SELEE-selectin HMPC42IP-10 Inducible protein (Interferon-gamma-induced protein)HMPC42MIG Monokine-induced by Interferon-gammaHMPC42MPIF-1Myeloid progenitor inhibitory factors 1HMPC42STable SEQ eTable \* ARABIC 2Summary of demographic characteristics (Total vaccinated cohort) CharacteristicsCategoriesAS01BN = 30AlumN = 30TotalN = 60Age (years) at dose 1 (placebo)Mean (SD)39.0 (4.2)37.2 (6.5)38.1 (5.5)Range 28-4523-4523-45Gender n (%)Female 17 (56.7)18 (60.0)35 (58.3)Male13 (43.3)12 (40.0)25 (41.7)Geographic Ancestry n (%)African/African American1 (3.3)0 (0.0)1 (1.7)White Arabic/North African Heritage0 (0)1 (3.3)1 (1.7)White Caucasian/European Heritage29 (96.7)29 (96.7)58 (96.7)AS01B = Placebo followed by 2 doses of HBsAg-AS01BAlum = Placebo followed by 3 doses of HBsAg-AlumN = total number of subjectsn/% = number / percentage of subjects in a given categorySD = standard deviationSFig 1Hematological and biochemical parameters showing no change over time after vaccination, geometric mean and 95% confidence interval (Total vaccinated cohort).SFig 2Median (interquartile range) heart rate and respiratory rate as measured by the investigator/study nurse after vaccination (Total vaccinated cohort) Red lines show the physiological normal rangeSFig 3Systemic and local reactogenicity score 1 day after dose 2 (D31) Figure represents the local and systemic reactogenicity scores for the AS01B and Alum groups of the current study cohort (N=27 and 24, respectively; A) and of an independent cohort (N=52 and 43, respectively; B), for the pooled time-points of the reporting period after the second dose. SFig 4Associations between the innate response and the solicited reactogenicity symptoms at 1 day after dose 2 in an independent cohortTop panels: Multi-parametric analyses of solicited systemic reactogenicity symptoms recorded at 1 day post-dose 2 (day 31) performed for each coefficient (β) of the listed model input parameters are presented in terms of the estimate of the effect size, standard error (SE) and p-value (derived using a Z-test [P(>|Z|)] or partial Fisher test [P (>F)]). Input parameters included the blood parameters measured post-dose 1 (A) or post-dose 2 (B), as represented by their first 3 principal components (PC1-3). PCs that were associated (p<0.05) with reactogenicity are indicated by bold font. Bottom left panels: PC1 and PC3 of the innate response dataset post-dose 1 (A) or post-dose 2 (B) are presented by subject and treatment group and visualized in a bivariate plot. Each dot represents the expression profile of an individual subject. Bottom right panels: PC1 and PC3 represent the variables at the post-vaccination time-points post-dose 1 (A) or post-dose 2 (B) indicated by the color coding at the bottom of each plot. LYM: lymphocytes. NEU: neutrophils. WBC: White blood cells. MON: monocytes. ................
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