Immunogenicity and Safety of a Newly Developed Live Attenuated Varicella Vaccine in Healthy Children: A Multi-National, Randomized, Double-Blinded, Active-Controlled, Phase 3 Study.

Korean manufacturers have developed a new varicella vaccine, NBP608. This phase 3, randomized, double-blind, multicenter study aimed to compare the immunogenicity and safety of NBP608 in healthy children to those of VarivaxTM (control). Children aged 12 months to 12 years were randomized in a ratio of 1:1 to receive either NBP608 or the control vaccine. Serum samples were obtained before vaccination and within six to eight weeks after vaccination. In total, 499 participants (NBP608, n = 251; control, n = 248) were enrolled. The seroconversion rate (SCR) measured using a FAMA assay was 99.53% in the NBP608 group, and the lower limit of the 95% confidence interval (95% LCL) for the SCR difference (NBP608 minus the control) was 0.52%. This 95% LCL for the difference was higher than the specified non-inferiority margin of -15%. In an assessment using gpELISA, the SCR was 99.53% in the NBP608 group, and the 95% LCL for the SCR difference was 6.5%, which was higher than the specified non-inferiority margin of -15%. There were no significant differences between the NBP608 and control group with respect to the proportions of participants who demonstrated local and systemic solicited AEs. This study indicated that NBP608 had a clinically acceptable safety profile and was not immunologically inferior to VarivaxTM.

Immunogenicity and safety of SARS-CoV-2 recombinant protein nanoparticle vaccine GBP510 adjuvanted with AS03: interim results of a randomised, active-controlled, observer-blinded, phase 3 trial.

Background: GBP510 vaccine contains self-assembling, recombinant nanoparticles displaying SARS-CoV-2 spike receptor-binding domains. We report interim phase 3 immunogenicity results for GBP510 adjuvanted with AS03 (GBP510/AS03) compared with ChAdOx1-S (Vaxzevria, AstraZeneca) in healthy adults aged ≥18 years, up to 6 months after the second dose. Methods: This was a randomised, active-controlled, observer-blinded, parallel group, phase 3 study, conducted at 38 sites across six countries (South Korea, Philippines, Thailand, Vietnam, Ukraine and New Zealand). Cohort 1 (no history of SARS-CoV-2 infection/COVID-19 vaccination) was randomised 2:1 to receive two doses of GBP510/AS03 or ChAdOx1-S (immunogenicity and safety), while Cohort 2 (regardless of baseline serostatus) was randomised 5:1 (safety). Primary objectives were to demonstrate superiority in geometric mean titre (GMT) and non-inferiority in seroconversion rate (SCR; ≥4-fold rise from baseline) of GBP510/AS03 vs. ChAdOx1-S for neutralising antibodies against the ancestral strain by live-virus neutralisation assay. Secondary objectives included assessment of safety and reactogenicity (long-term 6 months cut-off date: 09 August 2022). This study was registered on ClinicalTrials.gov (NCT05007951). Findings: Between 30 August 2021 and 11 January 2022, a total of 4913 participants were screened and 4036 participants (1956 in Cohort 1 and 2080 in Cohort 2) who met eligibility criteria were enrolled and randomised to receive 2 doses of GBP510/AS03 (n = 3039) or ChAdOx1-S (n = 997). Most participants were Southeast Asian (81.5%) and aged 18-64 years (94.7%). The primary objectives assessed in per-protocol set included 877 participants in GBP510/AS03 and 441 in ChAdOx1-S group: at 2 weeks after the second vaccination, the GMT ratio (GBP510/AS03/ChAdOx1-S) in per-protocol set was 2.93 (95% CI 2.63-3.27), demonstrating superiority (95% CI lower limit >1) of GBP510/AS03; the between-group SCR difference of 10.8% (95% CI 7.68-14.32) also satisfied the non-inferiority criterion (95% CI lower limit > -5%). Neutralizing antibody titres sustained higher for the GBP510/AS03 group compared to the ChAdOx1-S group through 6 months after the second vaccination. In Safety analysis (Cohort 1 & 2), the proportion of participants with adverse events (AEs) after any vaccination was higher with GBP510/AS03 vs. ChAdOx1-S for solicited local AEs (56.7% vs. 49.2%), but was similar for solicited systemic AEs (51.2% vs. 53.5%) and unsolicited AEs (13.3% vs. 14.6%) up to 28 days after the second vaccination. No safety concerns were identified during follow-up for 6 months after the second vaccination. Interpretation: Our interim findings suggested that GBP510/AS03 met the superiority criterion for neutralising antibodies and non-inferiority criterion for SCR compared with ChAdOx1-S, and showed a clinically acceptable safety profile. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investments INV-010680 and INV-006462. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

Correlation Between Computed Tomography Findings and the Laboratory Test-Derived Severity Score in Patients With Severe Acute Alcoholic Hepatitis.

OBJECTIVE: This study aimed to compare computed tomography (CT) findings between patients with severe and nonsevere acute alcoholic hepatitis (AAH). METHODS: We included 96 patients diagnosed with AAH between January 2011 and October 2021 who underwent 4-phase liver CT and laboratory blood tests. Two radiologists reviewed the initial CT images with respect to distribution and grade of hepatic steatosis; transient parenchymal arterial enhancement (TPAE); and presence of cirrhosis, ascites, and hepatosplenomegaly. A Maddrey discriminant function score (4.6 × [patient's prothrombin time - control] + total bilirubin [mg/mL]) was used as cutoff indicator for severity, with a score of 32 or higher indicating severe disease. The image findings were compared between the severe (n = 24) and nonsevere (n = 72) groups using the χ 2 test or Fisher exact test. After univariate analysis, the most significant factor was identified using a logistic regression analysis. RESULTS: In the univariate analysis, there were significant between-group differences in the TPAE, liver cirrhosis, splenomegaly, and ascites ( P < 0.0001, P < 0.0001, P = 0.0002, and P = 0.0163, respectively). Among them, TPAE was the only significant factor for severe AAH ( P < 0.0001; odds ratio, 48.1; 95% confidence interval, 8.3-280.6). Using this single indicator, the estimated accuracy, positive predictive, and negative predictive values were 86%, 67%, and 97%, respectively. CONCLUSIONS: Transient parenchymal arterial enhancement was the only significant CT finding in severe AAH.

Immune non-interference and safety study of Vi-DT typhoid conjugate vaccine with a measles, mumps and rubella containing vaccine in 9-15 months old Nepalese infants.

BACKGROUND: Typhoid fever is a common disease in developing countries especially in the Indian subcontinent and Africa. The available typhoid conjugate vaccines (TCV) have been found to be highly immunogenic in infants and children less than 2 years of age. Many countries are planning to adopt TCV in their routine EPI programs around 9 months of age when measles containing vaccines are given. Therefore, Vi-DT TCV was tested in 9-15 months aged healthy infants in Nepal to demonstrate non-interference with a measles containing vaccine. METHODS: This was a randomized, open label, phase III study to assess the immune non-interference, safety, and reactogenicity of Vi-DT typhoid conjugate vaccine when given concomitantly with measles, mumps and rubella (MMR) vaccine. A total of 360 participants aged 9-15 months were enrolled and randomized equally into Vi-DT + MMR (180 participants) or MMR alone (180 participants) group and were evaluated for immunogenicity and safety 28 days post vaccination. RESULTS: Using the immunogenicity set, difference between proportions (95% CI) of the Vi-DT + MMR group vs MMR alone group were -2.73% (-8.85, 3.38), -3.19% (-11.25, 4.88) and 2.91% (-3.36, 9.18) for sero-positivity rate of anti-measles, anti-mumps and anti- rubella, respectively. Only the lower bound of the range in difference of the proportions for sero-positivity rate of anti-mumps did not satisfy the non-inferiority criteria as it was above the -10% limit, which may not be of clinical significance. These results were confirmed in the per protocol set. There were no safety concerns reported from the study and both Vi-DT + MMR and MMR alone groups were comparable in terms of solicited and unsolicited adverse events . CONCLUSIONS: Results indicated that there is non-interference of MMR vaccine with Vi-DT and Vi-DT conjugate vaccine could be considered as an addition to the EPI schedule among children at risk of contracting typhoid.

Safety and immunogenicity of a SARS-CoV-2 recombinant protein nanoparticle vaccine (GBP510) adjuvanted with AS03: A randomised, placebo-controlled, observer-blinded phase 1/2 trial.

Background: Vaccination has helped to mitigate the COVID-19 pandemic. Ten traditional and novel vaccines have been listed by the World Health Organization for emergency use. Additional alternative approaches may better address ongoing vaccination globally, where there remains an inequity in vaccine distribution. GBP510 is a recombinant protein vaccine, which consists of self-assembling, two-component nanoparticles, displaying the receptor-binding domain (RBD) in a highly immunogenic array. Methods: This randomised, placebo-controlled, observer-blinded phase 1/2 study was conducted to evaluate the safety and immunogenicity of GBP510 (2-doses at a 28-day interval) adjuvanted with or without AS03 in adults aged 19-85 years at 14 hospital sites in Korea. This study was consisted of two stages (stage I, healthy adults aged 19-55 years; stage II, 240 healthy adults aged 19-85 years). Healthy participants who did not previously receive any vaccine within 4 weeks (2 weeks for flu vaccine) prior to the study, no history of COVID-19 vaccination/medication, and were naïve to SARS-CoV-2 infection at screening were eligible for the study enrollment. Participants were block-randomized in a 2:2:1 ratio to receive 2 doses of 10 µg GBP510 adjuvanted with AS03 (group 1), 10 µg unadjuvanted GBP510 (group 2) or placebo intramuscularly in stage I, while they were block-randomized in a 2:2:1:1 ratio to receive 10 µg GBP510 adjuvanted with AS03 (group 1), 25 µg GBP510 adjuvanted with AS03 (group 3), 25 µg unadjuvanted GBP510 (group 4) or placebo in stage II. The primary safety outcomes were solicited and unsolicited adverse events, while primary immunogenicity outcomes included anti-SARS-CoV-2 RBD IgG antibodies; neutralizing antibody responses; and T-cell immune responses. Safety assessment included all participants who received at least 1 dose of study intervention (safety set). Immunogenicity assessment included all participants who completed the vaccination schedule and had valid immunogenicity assessment results without any major protocol deviations (per-protocol set). This study was registered with ClinicalTrials.gov (NCT04750343). Findings: Of 328 participants who were enrolled between February 1 and May 28, 2021, 327 participants received at least 1 dose of vaccine. Each received either 10 µg GBP510 adjuvanted with AS03 (Group 1, n = 101), 10 µg unadjuvanted GBP510 (Group 2, n = 10), 25 µg GBP510 adjuvanted with AS03 (Group 3, n = 104), 25 µg unadjuvanted GBP510 (Group 4, n = 51), or placebo (n = 61). Higher reactogenicity was observed in the GBP510 adjuvanted with AS03 groups compared to the non-adjuvanted and placebo groups. The most frequently reported solicited local adverse event (AE) was injection site pain after any vaccination: (88·1% in group 1; 50·0% in group 2; 92·3% in group 3; 66·7% in group 4). Fatigue and myalgia were two most frequently reported systemic AEs and more frequently reported in GBP510 adjuvanted with AS03 recipients (79·2% and 78·2% in group 1; 75·0% and 79·8% in group 3, respectively) than in the unadjuvanted vaccine recipients (40·0% and of 40·0% in group 2; 60·8% and 47·1% in group 4) after any vaccination. Reactogenicity was higher post-dose 2 compared to post-dose 1, particularly for systemic AEs. The geometric mean concentrations of anti-SARS-CoV-2-RBD IgG antibody reached 2163·6/2599·2 BAU/mL in GBP510 adjuvanted with AS03 recipients (10 µg/25 µg) by 14 days after the second dose. Two-dose vaccination of 10 µg or 25 µg GBP510 adjuvanted with AS03 induced high titres of neutralizing antibody via pseudovirus (1369·0/1431·5 IU/mL) and wild-type virus (949·8/861·0 IU/mL) assay. Interpretation: GBP510 adjuvanted with AS03 was well tolerated and highly immunogenic. These results support further development of the vaccine candidate, which is currently being evaluated in Phase 3. Funding: This work was supported, in whole or in part, by funding from CEPI and the Bill & Melinda Gates Foundation Investment ID OPP1148601. The Bill & Melinda Gates Foundation supported this project for the generation of IND-enabling data and CEPI supported this clinical study.

A Phase 3, Multicenter, Randomized, Controlled Trial to Evaluate Immune Equivalence and Safety of Multidose and Single-dose Formulations of Vi-DT Typhoid Conjugate Vaccine in Healthy Filipino Individuals 6 Months to 45 Years of Age.

Trial Design: Phase 3, randomized, controlled, multicenter, equivalence trial. Methods: Recruitment of participants occurred between 04Februray2020 and 15July2020 at four centers in the Philippines: University of the East - Ramon Magsaysay Memorial Medical Center Inc., Quezon City; University of Philippines Manila - National Institute of Health, Ermita Manila; Asian Hospital and Medical Center, Metro Manila, Philippines Study; and Medical Research Unit, Tropical Disease Foundation, Makati City, Metro Manila, Philippines. Participants: 1800 adults and children 6-months to 45-years of age. Interventions: Participants received a single injection of multidose (MD) or single dose (SD) Vi-DT as test vaccines or meningococcal conjugate vaccine as a comparator. Objective: To evaluate immune equivalence of SD and MD formulations of Vi-DT, and to assess the safety of both formulations compared with comparator vaccine. Outcome Measurement: Blood draw for immunogenicity was performed at baseline prior to vaccine receipt and at four weeks after vaccination for a subset of participants to determine anti-Vi IgG geometric mean titers (GMT) and seroconversion rates. The primary outcome was comparison of anti Vi-IgG seroconversion and GMT between the two formulations of Vi-DT at 4 weeks following vaccine administration. Immune equivalence of MD and SD formulations was confirmed when the two-tailed 95% confidence interval (CI) of the GMT ratio is within [0.67, 1.5] at a two-sided significance level of 0.05. All participants were followed for safety events for six months after vaccine administration. Randomization: Participants were randomized to receive SD Vi-DT, MD Vi-DT, or meningococcal conjugate vaccines in 2.5:2.5:1 allocation ratio. Blinding: Study participants and observers were blinded to treatment assignment. Findings: Immune equivalence of SD (n=252) and MD (n=247) formulations was confirmed by anti-Vi IgG GMT ratio of 1.14 (95%CI: 0.91, 1.43) with respective GMTs in the MD and SD groups of 640.62 IU/mL (95%CI: 546.39, 751.11) and 562.57 IU/mL (95%CI: 478.80, 661.00) (p=0.259). Similarly, anti-Vi IgG seroconversion rate difference between the two formulations of ‒0.43% (95%CI: -4.42, 3.56) confirmed immune equivalence with corresponding seroconversion rates of 98.38% (95%CI: 95.91, 99.37) and 98.81% (95%CI: 96.56, 99.59) in MD and SD Vi-DT formulations, respectively (p=0.722). Both formulations of Vi-DT had a satisfactory safety profile - all five serious adverse events reported during the study were unrelated to the investigational product. Interpretation: The MD and SD formulations of Vi-DT elicited robust and equivalent immune responses following one dose vaccination, and both formulations demonstrated a favorable safety profile. Trial Registration: ClinicalTrials.gov: NCT04204096. Funding: This study was funded by the Bill & Melinda Gates Foundation (OPP 1115556).

Immune persistence and response to booster dose of Vi-DT vaccine at 27.5 months post-first dose.

Vaccination with typhoid conjugate vaccines (TCV) is a major part of typhoid prevention. However, little is known about long-term immune persistence following vaccination with TCVs. In this phase-2, randomized double-blind trial (NCT03527355), 285 children aged 6-23 months were randomized to one of three groups: (1) the group that received a first dose of Vi polysaccharide conjugated to diphtheria-toxoid (Vi-DT) vaccine followed by an "early booster" at 24 weeks, (2) the group that which received a first dose of Vi-DT followed by a "late booster" at 96 or 110 weeks, and (3) comparator group. Safety and immunogenicity of anti-Vi IgG GMTs were assessed at weeks 0, 4, 24, 28, 60, 96, 110, and 114 since the first dose. Here, we describe persistence of immune responses at weeks 60, 96, 110, and 114 post first dose. The anti-Vi IgG seroconversion rate after 27.5 months of follow-up was 88.16% (95% CI: 79.00, 93.64) in late-booster and 94.76% (95% CI: 86.91, 97.88) in early booster Vi-DT groups (p = 0.081). Whereas anti-Vi IgG GMTs were significantly higher in the early booster group (11.95 [95% CI: 9.65, 14.81]) than prebooster GMTs in the late booster group (5.50 [95% CI: 4.44, 6.80], p < 0.0001). GMT in the late booster group significantly increased to 351.76 (95% CI: 265.01, 466.93) (p < 0.0001) when measured 4 weeks after they received their "late-booster" shot. In conclusion, late booster dosing with Vi-DT at 27.5 months post first dose was safe and elicited robust anti-Vi IgG immune responses. Anti-Vi IgG seroconversion rates were persistently comparable in early and late-booster Vi-DT groups.

Safety and immunogenicity of the Vi-DT typhoid conjugate vaccine in healthy volunteers in Nepal: an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial.

BACKGROUND: Typhoid fever is an endemic disease in many low-income and middle-income countries. The 2018 WHO position paper recommends that countries should consider typhoid vaccination in high-risk groups and for outbreak control. To address the typhoid vaccine supply and demand gap, a typhoid Vi polysaccharide-diphtheria toxoid (Vi-DT) conjugate vaccine development effort was undertaken to achieve WHO prequalification and contribute to the global supply of typhoid conjugate vaccine. The main aim of this study was to show immune non-inferiority of the Vi-DT vaccine compared with the WHO prequalified Vi polysaccharide-tetanus toxoid (Vi-TT) conjugate vaccine (Typbar TCV; Bharat Biotech India, Hyderabad, India) in participants of various ages from an endemic country. METHODS: We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Kathmandu, Dhulikhel, Dharan, and Nepalgunj in Nepal. Eligible participants were healthy individuals aged 6 months to 45 years for whom informed consent was obtained, were willing to follow the study procedures and were available for the duration of the study. Patients with an acute or chronic illness that could interfere with interpretation of the study endpoints, or who were involved in any other clinical trial were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block size of four and eight), stratified by age (6 months to <2 years, 2 years to <18 years, and 18 years to 45 years), into one of four groups (A-D). Participants in groups A-C received a single dose (25 µg; 0·5 mL) of Vi-DT test vaccine via intramuscular injection from one of three good manufacturing practice lots (group A received lot 1, group B received lot 2, and group C received lot 3), and those in group D received a single dose (25 µg; 0·5 mL) of the Vi-TT vaccine via intramuscular injection. All participants, site staff (except for those who administered the study vaccines), and those assessing the outcomes were masked to group assignment. The co-primary endpoints were: (1) non-inferiority of immunogenicity of the Vi-DT vaccine (pooled groups A-C) versus the Vi-TT vaccine (group D), measured by the anti-Vi IgG seroconversion rate at 4 weeks after vaccination; and (2) the lot-to-lot consistency of the Vi-DT vaccine, measured by immune equivalence of the anti-Vi IgG geometric mean titre (GMT) at 4 weeks after receipt of the three Vi-DT vaccine lots (lot 1 vs lot 2, lot 1 vs lot 3, and lot 2 vs lot 3). Non-inferiority of the Vi-DT vaccine compared with the Vi-TT vaccine was shown if the lower limit of the 97·5% CI for the difference between the seroconversion rates in Vi-DT vaccine groups A-C combined versus Vi-TT vaccine group D was above the predefined non-inferiority margin of -10%. Lot-to-lot immune equivalence was shown if the upper and lower bounds of the two-sided 99·17% CI around the GMT ratio for each pairwise lot-to-lot comparison was between 0·67 and 1·50, which is the predefined equivalence margin recommended by WHO. The co-primary immunogenicity endpoints were assessed in all randomised participants who had received their assigned vaccine and had completed at least one post-baseline immunogenicity assessment. Safety was descriptively summarised by group and age strata, and was assessed in all participants who had received one dose of the investigational vaccine. The trial is registered with ClinicalTrials.gov, NCT03933098. FINDINGS: Between Nov 20, 2019, and March 10, 2020, 1854 individuals were screened, of whom 1800 were enrolled and randomly assigned to groups A-D (450 participants in each group). 1786 (99·2%; 443 in group A, 450 in group B, 447 in group C, and 446 in group D) were included in the immunogenicity assessments at 4 weeks post vaccination, and all 1800 participants were included in the safety analysis. In the immunogenicity analysis, the anti-Vi-IgG seroconversion rate in all age strata was 99·33% (97·5% CI 98·61 to 99·68; 1331 of 1340 participants) in Vi-DT vaccine groups A-C and 98·88% (97·10 to 99·57; 441 of 446) in Vi-TT vaccine group D. The difference in seroconversion rates between Vi-DT vaccine groups A-C combined versus Vi-TT group D was 0·47% (97·5% CI -0·68 to 1·61), indicating non-inferiority of the Vi-DT vaccine. Anti-Vi-IgG GMT ratios at 4 weeks post-vaccination were 1·02 (99·17% CI 0·85 to 1·22) for lot 1 versus lot 2, 1·02 (0·85 to 1·23) for lot 1 versus lot 3, and 1·01 (0·84 to 1·21) for lot 2 versus lot 3, indicating lot-to-lot equivalence according to the predefined, WHO-recommended equivalence margin. The proportion of participants reporting adverse events was similar between Vi-DT vaccine groups A-C and Vi-TT vaccine group D; 260 (19·3%) of 1350 participants in Vi-DT vaccine groups A-C and 115 (25·6%) of 450 in Vi-TT vaccine group D reported solicited adverse events within 7 days after vaccination, and 208 (15·4%) in Vi-DT vaccine groups A-C and 76 (16·9%) in Vi-TT vaccine group D reported unsolicited adverse events within 4 weeks after vaccination. Seven serious adverse events (four [0·3%] participants in Vi-DT vaccine groups A-C and three [0·7%] in Vi-TT vaccine group D), including one death in the Vi-TT vaccine group, were reported during the 24-week follow-up period, none of which were considered related to the investigational product. INTERPRETATION: When administered as a single dose, the Vi-DT test vaccine was safe, immunogenic, and non-inferior to the Vi-TT vaccine at 4 weeks post vaccination. Equivalent immunogenicity of the three lots of Vi-DT vaccine was also shown, supporting the manufacturing process of this vaccine. Once prequalified by WHO, this vaccine could be an option for purchase by UN agencies. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATION: For the Nepali translation of the abstract see Supplementary Materials section.

Clinically amyopathic dermatomyositis presenting with isolated facial edema complicated by acute respiratory failure: a case report.

BACKGROUND: In clinically amyopathic dermatomyositis, the hallmark cutaneous manifestations are the key to diagnosis. We report a case of clinically amyopathic dermatomyositis which presented with facial edema as the sole cutaneous manifestation and was later complicated by acute respiratory failure leading to death. CASE PRESENTATION: A 58-year-old woman presented with edema of the face that had developed approximately one year ago. There was no weakness in the extremities, and the serum creatine kinase level was within normal range. On MRI, there was diffuse edematous change in the bilateral masticator and extra-ocular muscles, accompanied by subcutaneous fat infiltration in the face. A shared decision was made to defer muscle biopsy in the facial muscles. The facial swelling almost resolved with medium-dose glucocorticoid therapy but relapsed in days at glucocorticoid doses lower than 15 mg/day. Combination therapy with either azathioprine, mycophenolate, or methotrexate was not successful in maintaining clinical remission, and the swelling became more severe after relapses. A US-guided core-needle biopsy was subsequently performed in the right masseter muscle. On pathologic examination, there was a patchy CD4 + T cell-dominant lymphoplasmacytic infiltration in the stroma, necrosis of the myofibrils and prominent perifascicular atrophy. Based on those findings, a diagnosis of clinically amyopathic dermatomyositis was made. Therapy with gamma-globulin was not effective in maintaining remission. In the sixth week after starting rituximab, she presented to emergency room with altered mental state from acute respiratory failure. Despite treatment with antibiotics, glucocorticoid pulse, cyclosporin, and polymyxin B-immobilized fiber column direct hemoperfusion, she died three weeks later from persistent hypoxemic respiratory failure. CONCLUSIONS: This case showed the full spectrum and severity of internal organ involvement of dermatomyositis, although the patient presented exclusively with subcutaneous edema limited to the head. The prognosis may be more closely associated with a specific auto-antibody profile than the benign-looking initial clinical manifestation. Close follow-up of lung involvement with prophylactic treatment for Pneumocystis pneumonia and prompt implementation of emerging therapeutic regimens may improve the outcome.

Intrathyroid metastasis of breast cancer: Sonographic findings.

Metastasis of ductal carcinoma of the breast to the thyroid gland is uncommon and usually detected at autopsy. The incidences of metastases to the thyroid have been reported at 3%, and the most common primary malignancy is renal cell carcinoma. We report a rare case of intrathyroid metastatsis of breast ductal carcinoma in a patient who was treated for breast cancer 15 years earlier.

Safety and immunogenicity of Vi-DT conjugate vaccine among 6-23-month-old children: Phase II, randomized, dose-scheduling, observer-blind Study.

BACKGROUND: Typhoid causes significant mortality among young children in resource-limited settings. Conjugate typhoid vaccines could significantly reduce typhoid-related child deaths, but only one WHO-prequalified typhoid conjugate vaccine exists for young children. To address this gap, we investigated the safety, immunogenicity and dose-scheduling of Vi-DT typhoid conjugate vaccine among children aged 6-23 months. METHODS: In this single center, observer blind, phase II trial, participants were randomly assigned (2:2:1) to receive one or two doses of Vi-DT or comparator vaccine. Anti-Vi IgG titer and geometric mean titers (GMT) were determined at 0, 4, 24 and 28 weeks. Data were analyzed using per-protocol and immunogenicity (a subset of intention-to-treat analysis) sets. The trial is registered with ClinicalTrials.gov (NCT03527355). FINDINGS: Between April and July 2018, 285 children were randomized; 114 received one or two doses of Vi-DT while 57 received comparator. 277 completed the study follow-up per protocol; 112 and 110 from single- and two-dose Vi-DT schedules, respectively and 55 from the placebo group were included in the per protocol analysis. Safety profile is satisfactory. Thirteen serious adverse events were reported during the 28-week follow-up, none of which were related to Vi-DT. The seroconversion rate four weeks after the first dose was 100% (95% CI 98·3-100) in Vi-DT recipients and 7·0% (95% CI 2·8-16·7) in comparator recipients (p<0·0001). Similarly, the seroconversion rate 4 weeks after the second dose was 98·2% (95% CI 93· 6-99·5) and 21·8% (95% CI 13·0-34·4) among Vi-DT and comparator groups, respectively (p<0·0001). Anti-Vi IgG GMT was significantly higher in Vi-DT than in control group at all post-vaccination visits (p<0·0001). INTERPRETATION: Both single and two doses of Vi-DT vaccine are safe, well tolerated, and immunogenic for infants and toddlers in a moderately endemic setting.

Immunogenicity and safety of a 12-valent pneumococcal conjugate vaccine in infants aged 6-10 weeks: a randomized double-blind active-controlled trial.

BACKGROUND: Pneumococcal diseases among children aged <5 years worldwide are associated with high annual mortality rates. PURPOSE: This study aimed to evaluate the immunogenicity and safety of GBP411, a 12-valent pneumococcal conjugant vaccine, with a dosing schedule of 2 primary doses plus 1 booster dose (2p+1) in healthy infants. METHODS: This randomized active-controlled (Prevnar 13) double-blind phase 2 trial enrolled healthy subjects aged 6-10 weeks. Three serum concentrations of pneumococcal serotype-specific immunoglobulin G (IgG) were evaluated using the pneumococcal serotype-specific pneumonia polysaccharide enzyme-linked immunosorbent assay at 1 month after the primary doses and before and 1 month after the booster dose. The pneumococcal serotype-specific IgG titer was evaluated using a multiplex opsonophagocytic assay in a subset of 15 subjects per group. RESULTS: After administration of the primary doses, the proportion of subjects who achieved pneumococcal serotype-specific IgG concentrations of >0.35 µg/mL was lower for some serotypes in the GBP411 group than in the comparator group (6B: 20.83% vs. 39.22%, P=0.047 and 19A: 58.33% vs. 90.20%, P<0.001). However, after administration of the booster dose, >97% of the subjects in each group achieved IgG concentrations of ≥0.35 µg/mL for all 12 serotypes. Increased immunogenicity was observed for some serotypes that showed significant intergroup differences after administration of the primary doses but not after the booster dose. We also found no significant intergroup difference in the overall incidence of solicited local adverse events. Furthermore, the overall incidence of solicited systemic adverse events was significantly lower in the GBP411 group than in the comparator vaccine group (79.59% vs. 98.04%; P=0.003). CONCLUSION: The GBP411 vaccine with a dosing schedule of 2p+1 may be immunogenic and safe for healthy infants.

Immunogenicity, safety and reactogenicity of a Phase II trial of Vi-DT typhoid conjugate vaccine in healthy Filipino infants and toddlers: A preliminary report.

BACKGROUND: Typhoid fever remains an important public health problem in developing countries and is endemic in many parts of Asia and Africa where the incidence of disease typically peaks in school-aged children. Age restrictions and other limitations of existing oral live-attenuated typhoid and parenteral Vi polysaccharide vaccines have triggered the development of Vi conjugate vaccines with improved immunological properties, use in younger age range, and longer durability of protection. We present the safety, reactogenicity, and immunogenicity data from a Phase II study after a single dose of Vi polysaccharide conjugated to diphtheria toxoid (Vi-DT) conducted in 6-23-month old Filipino children. METHODS: This is a randomized, observer-blinded Phase II study to assess the immunogenicity, safety and reactogenicity of Vi-DT compared to placebo, conducted in Muntinlupa City, The Philippines. Participants aged 6-23 months were enrolled and randomized to Vi-DT (25 µg) or placebo (0.9% sodium chloride) and evaluated for immunogenicity and overall safety 28 days post vaccination. RESULTS: A total of 285 participants were enrolled and age-stratified: 6 to < 9 months, 9-12 months, and 13-23 months. Seventy-six (76) participants received Vi-DT and 19 received placebo per each strata. All participants seroconverted after a single dose of Vi-DT versus 7% of placebo recipients. Anti-Vi IgG GMT was 444.38 [95% CI (400.28; 493.34)] after a single dose of Vi-DT; there was no change in GMT after placebo administration, 0.41 [95% CI (0.33; 0.51), p < 0.0001]. A similar pattern of immunogenicity was reported across all age strata. The vaccine reported to be safe and well tolerated. CONCLUSIONS: Vi-DT vaccine was immunogenic, safe, and well tolerated in children aged 6-23 months. ClinicalTrials.gov registration number: NCT03527355.

Revisiting Rupture of Benign Thyroid Nodules after Radiofrequency Ablation: Various Types and Imaging Features.

BACKGROUND: To evaluate the imaging features, clinical manifestations, and prognosis of patients with thyroid nodule rupture after radiofrequency ablation (RFA). METHODS: The records of 12 patients who experienced thyroid nodule rupture after RFA at four Korean thyroid centers between March 2010 and July 2017 were retrospectively reviewed. Clinical data evaluated included baseline patient characteristics, treatment methods, initial presenting symptoms, imaging features, treatment, and prognosis. RESULTS: The most common symptoms of post-RFA nodule rupture were sudden neck bulging and pain. Based on imaging features, the localization of nodule rupture was classified into three types: anterior, posterolateral, and medial types. The anterior type is the most often, followed by posterolateral and medial type. Eight patients recovered completely after conservative treatment. Four patients who did not improve with conservative management required invasive procedures, including incision and drainage or aspiration. CONCLUSION: Thyroid nodule rupture after RFA can be classified into three types based on its localization: anterior, posterolateral, and medial types. Because majority of thyroid nodule ruptures after RFA can be managed conservatively, familiarity with these imaging features is essential in avoiding unnecessary imaging workup or invasive procedures.

Comparison of Real-Time and Static Ultrasonography Diagnoses for Detecting Incidental Diffuse Thyroid Disease: A Multicenter Study.

This study aimed to compare diagnostic accuracy of real-time and static ultrasonography (US) for differentiating diffuse thyroid disease (DTD) from normal thyroid parenchyma (NTP). At 4 participating institutions, 203 patients underwent real-time thyroid US before thyroid surgery. For static US, the same radiologists retrospectively evaluated US findings on a picture archive and communication system after 4 weeks. In real-time and static US diagnoses, US category included no DTD, indeterminate, suspicious for DTD, and DTD. We investigated the diagnostic accuracy of real-time and static US with a receiver operating characteristic curve analysis using histopathologic results as the reference standard. Histopathologic results exhibited NTP (n = 139), Hashimoto thyroiditis (n = 24), non-Hashimoto lymphocytic thyroiditis (n = 33), and diffuse hyperplasia (n = 7). Of 203 patients, there were significant differences in echogenicity, echotexture, glandular margin, and vascularity of the thyroid gland and US category between NTP and DTD groups in both real-time and static US diagnoses (P < 0.001). The diagnostic indices of real-time and static US were highest when the cutoff criterion was chosen as 1 or more abnormal US features. In addition, US category was the only feature with a significant difference between DTD and NTP groups regardless of the practical experience. The receiver operating characteristic curve analysis showed that real-time US was superior to static US in the diagnostic accuracy; however, there was no significant difference (P = 0.09). In conclusion, real-time and static US can be helpful for detecting incidental DTD by using US classification based on abnormal US features.

Diagnostic accuracy of computed tomography for differentiating diffuse thyroid disease from normal thyroid parenchyma: A multicenter study.

This study aimed to assess the diagnostic performance of computed tomography (CT) for differentiating diffuse thyroid disease (DTD) from normal thyroid parenchyma (NTP) using multicenter data. Between January 2016 and June 2016, 229 patients underwent preoperative neck CT and subsequent thyroid surgery at five participating institutions. The neck CT images of each patient were retrospectively reviewed and classified into the following four categories: no DTD, indeterminate, suspicious for DTD, and DTD. The results of the CT image evaluations were compared with the histopathological results to determine the diagnostic accuracy of CT at each institution. According to the histopathological results, there were NTP (n = 151), Hashimoto thyroiditis (n = 24), non-Hashimoto lymphocytic thyroiditis (n = 47), and diffuse hyperplasia (n = 7). The CT categories of the 229 patients were "no DTD" in 89 patients, "indeterminate" in 40 patients, "suspicious for DTD" in 42 patients, and "DTD" in 58 patients. The presence of two or more CT features of DTD, which was classified as "suspicious for DTD" by all radiologists, had the largest area under the receiver-operating characteristic curve (Az = 0.820; 95% confidence interval: 0.764, 0.868), with sensitivity of 85.9% and specificity of 78.2%. However, no statistical significance between readers' experience and their diagnostic accuracy was found. In conclusion, evaluations of CT images are helpful for differentiating DTD from NTP.

Diagnostic Accuracy of Real-Time Sonography in Differentiating Diffuse Thyroid Disease From Normal Thyroid Parenchyma: A Multicenter Study.

OBJECTIVE: The purpose of this multicenter study was to assess the diagnostic accuracy of real-time sonography (US) for differentiating diffuse thyroid disease (DTD) from normal thyroid parenchyma among radiologists blinded to patients' clinical, serologic, and imaging history and to determine the differences in diagnostic accuracy among radiologists from different institutions. MATERIALS AND METHODS: From January to March 2017, 214 patients underwent preoperative thyroid US and subsequent thyroid surgery at four participating institutions. Real-time US was performed at each institution by an attending radiologist, who classified US diagnoses into one of the following four categories based on US findings: no DTD, indeterminate, suspicious for DTD, and DTD. The outcomes of US diagnoses were compared with histopathologic results to determine the diagnostic accuracy of real-time US at each institution. RESULTS: Histopathologic results included normal thyroid parenchyma (n = 143), Hashimoto thyroiditis (n = 29), non-Hashimoto lymphocytic thyroiditis (n = 37), and diffuse hyperplasia (n = 5). Normal thyroid parenchyma and DTD exhibited statistically significant differences in echogenicity, echotexture, size, glandular margin, vascularity of thyroid, and US classification. There was positive correlation between US classification and histopathologic results at all institutions for detecting DTD. The highest diagnostic indexes were obtained when the cutoff criterion was suspicious for DTD. There was favorable diagnostic accuracy, with statistically significant differences, at all institutions for the diagnosis of DTD. CONCLUSION: Real-time US can be helpful for differentiating DTD from normal thyroid parenchyma.

Safety and immunogenicity of a Vi-DT typhoid conjugate vaccine: Phase I trial in Healthy Filipino adults and children.

BACKGROUND: Typhoid fever remains a major public health problem in low- and middle-income countries where children aged 2-14 years bear the greatest burden. Vi polysaccharide is poorly immunogenic in children <2 years of age, and protection in adults is modest. The limitations of Vi polysaccharide vaccines can be overcome by conjugation of the Vi to a carrier protein. A typhoid conjugate vaccine composed of Vi polysaccharide conjugated to diphtheria toxoid (Vi-DT) has been developed. The Phase I study results are presented here. METHODS: This was a randomized, observer-blinded Phase I study to assess the safety and immunogenicity of Vi-DT compared to Vi polysaccharide vaccine, conducted in Manila, Philippines. Participants enrolled in an age de-escalation manner (18-45, 6-17 and 2-5 years) were randomized between Test (Vi-DT, 25 µg) administered at 0 and 4 weeks and Comparator (Vi polysaccharide, Typhim Vi® and Vaxigrip®, Sanofi Pasteur) vaccines. RESULTS: A total of 144 participants were enrolled (48 by age strata, 24 in Test and Comparator groups each). No serious adverse event was reported in either group. Solicited and unsolicited adverse events were mild or moderate in both groups with the exception of a 4-year old girl in Test group with grade 3 fever which resolved without sequelae. All participants in Test group seroconverted after first and second doses of Vi-DT while the proportions in the Comparator group were 97.1% and 97.2%, after first dose of Typhim Vi® and second dose of Vaxigrip®, respectively. Vi-DT showed 4-fold higher Geometric Mean Titers (GMT) compared to Typhim Vi® (adjusted for age strata, p < 0.001). No further increase of GMT was detected after the second dose of Vi-DT. Anti-DT IgG seroresponse rates were 81.2% and 84.5% post first and second Vi-DT doses, respectively. CONCLUSIONS: Vi-DT vaccine was safe, well-tolerated and immunogenic in participants aged 2-45 years. ClinicalTrials.gov registration number: NCT02645032.

Comparison of ultrasonography and computed tomography for diagnosing diffuse thyroid disease: a multicenter study.

PURPOSE: To compare the diagnostic performance of ultrasonography (US) and computed tomography (CT) for diagnosing incidentally detected diffuse thyroid disease (DTD) in patients who underwent thyroid surgery using multicenter data. METHODS: Between July and December 2016, a total of 177 patients who underwent preoperative thyroid US and neck CT, and subsequent thyroid surgery at 4 participating institutions, were reviewed. US and CT images in each case were retrospectively reviewed by a radiologist at each institution, and classified into one of the following four categories based on US and CT features: no DTD; indeterminate; suspicious for DTD; and DTD. The diagnostic accuracy of US and CT were calculated at each institution by comparison with histopathological results. RESULTS: Respective US and CT classifications in the 177 patients were no DTD in 75 and 71, indeterminate in 46 and 34, suspicious for DTD in 28 and 31, and DTD in 28 and 41. Among the histopathological results, 113 patients had normal thyroid parenchyma, 23 had Hashimoto thyroiditis, 36 had non-Hashimoto lymphocytic thyroiditis, and 5 had diffuse hyperplasia. The presence of ≥ 2 US and CT features of DTD, which was classified as suspicious for DTD or DTD, had the largest area under the receiver operating characteristic curve (0.866 and 0.893, respectively), with sensitivity and specificity of 71.9 and 91.2% in US, and 84.4 and 84.1% in CT, respectively. However, there was no statistically significant difference between readers' experience and their diagnostic performance. CONCLUSION: US and CT imaging may be helpful for detecting incidental DTD.

Factors influencing the outcome from ultrasonography-guided fine-needle aspiration of benign thyroid cysts and partially cystic thyroid nodules: A multicenter study.

PURPOSE: The effect of ultrasonography (US)-guided fine-needle aspiration (US-FNA) for the collapse of benign cystic thyroid nodules is still unclear. This study aimed to assess the positive response rate following US-FNA of the cystic component of thyroid cysts and of partially cystic thyroid nodules (PCTNs), and to evaluate the factors influencing the outcome. METHODS: From June to December 2013, seven radiologists at seven institutions prospectively performed US-FNA on 320 cystic thyroid nodules in 320 patients. Among them, 179 underwent at least one follow-up US examination following US-FNA of the cystic component at each institution by the same radiologist. A variety of factors, including US features of cystic thyroid nodules, the characteristics of the aspirates, and the follow-up US findings, were analyzed. RESULTS: Of 179 cystic thyroid nodules, there were 53 thyroid cysts and 126 PCTNs. Of 179 cystic thyroid nodules, no malignancies were detected. On follow-up US, the mean size reduction rate of the cystic component was 31.9%, and 102 out of 179 thyroid nodules (57.0%) were assigned to the response group. On univariate analysis, the degree of aspiration and time interval between US-FNA and the final follow-up US showed the significant differences between the response and no response groups. On multivariate analysis, the only factor that influenced the outcome was the nodule type. The cystic component's positive response rate after simple aspiration was higher in the thyroid cysts than in the PCTNs. CONCLUSIONS: US-FNA may be effective at collapsing the cystic components of benign thyroid cysts and PCTNs.