Cardiovascular Safety of COVID-19 Vaccination in Patients With Cancer: A Self-Controlled Case Series Study in Korea.

BACKGROUND: Cancer patients have an increased risk of cardiovascular outcomes and are susceptible to coronavirus disease 2019 (COVID-19) infection. We aimed to assess the cardiovascular safety of COVID-19 vaccination for cancer patients in South Korea. METHODS: We conducted a self-controlled case series study using the K-COV-N cohort (2018-2021). Patients with cancer aged 12 years or older who experienced cardiovascular outcomes were identified. Cardiovascular outcomes were defined as myocardial infarction, stroke, venous thromboembolism (VTE), myocarditis, or pericarditis, and the risk period was 0-28 days after receiving each dose of COVID-19 vaccines. A conditional Poisson regression model was used to calculate the incidence rate ratio (IRR) with 95% confidence interval (CI). RESULTS: Among 318,105 patients with cancer, 4,754 patients with cardiovascular outcomes were included. The overall cardiovascular risk was not increased (adjusted IRR, 0.99 [95% CI, 0.90-1.08]) during the whole risk period. The adjusted IRRs of total cardiovascular outcomes during the whole risk period according to the vaccine type were 1.07 (95% CI, 0.95-1.21) in the mRNA vaccine subgroup, 0.99 (95% CI, 0.83-1.19) in the ChAdOx1 nCoV-19 vaccine subgroup, and 0.86 (95% CI, 0.68-1.10) in the mix-matched vaccination subgroup. However, in the analysis of individual outcome, the adjusted IRR of myocarditis was increased to 11.71 (95% CI, 5.88-23.35) during the whole risk period. In contrast, no increased risk was observed for other outcomes, such as myocardial infarction, stroke, VTE, and pericarditis. CONCLUSION: For cancer patients, COVID-19 vaccination demonstrated an overall safe profile in terms of cardiovascular outcomes. However, caution is required as an increased risk of myocarditis following COVID-19 vaccination was observed in this 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.

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.

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.

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.

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 Correlating Outcome in Young Infants With Congenital Muscular Torticollis.

PURPOSE: No previous study using follow-up ultrasonography for evaluating the factors associated with the successful regression of congenital muscular torticollis in young infants has been published. This study aimed to assess clinical factors and sonographic features potentially influencing regression in patients with congenital muscular torticollis. METHODS: From January 2010 to December 2012, 80 infants underwent neck ultrasonography because of clinical suspicion of congenital muscular torticollis. We statistically analysed the correlation between complete resolution and clinicosonographic findings when complete resolution was defined as no visible lesion on follow-up ultrasonography. RESULTS: Of the 80 infants, 61 had congenital muscular torticollis and all were followed up by ultrasonography: 1) 34 underwent physiotherapy, and 27 of them (79.4%) revealed complete resolution in follow-up; 2) 27 did not undergo physiotherapy, and 15 of them (55.6%) showed complete resolution. A statistically significant correlation was found between physiotherapy and complete resolution, but not between complete resolution and patient sex; size, volume, and echogenicity of the lesion; and thickness ratio. CONCLUSIONS: Physiotherapy was the only factor influencing complete resolution in young infants with congenital muscular torticollis.

Low-dose CT for patients with clinically suspected acute appendicitis: optimal strength of sinogram affirmed iterative reconstruction for image quality and diagnostic performance.

BACKGROUND: As there is increased concern over the radiation exposure particularly in adolescents and young adults, computed tomography (CT) dose reduction is needed in the diagnosis of acute appendicitis. PURPOSE: To evaluate the optimal strength of sinogram affirmed iterative reconstruction (SAFIRE) to obtain the best image quality on a 30-mAs applied low-dose CT (LDCT 30mAs) and to compare the diagnostic performances of the LDCT 30mAs with different SAFIRE strengths with that of the 100-mAs applied LDCT (LDCT 100mAs) for the diagnosis of acute appendicitis. MATERIAL AND METHODS: A total of 102 consecutive patients (47 men, 55 women; mean age, 41.2 years; range, 15-82 years) with right lower quadrant pain underwent abdominal-pelvic CT, consisting of arterial phase LDCT 100mAs and portal venous phase LDCT30mAs under a fixed 120 kV. LDCT 30mAs images were reconstructed separately with five strength levels (S1-S5). Two blinded radiologists recorded scores for the subjective image quality of the LDCT 30mAs dataset (S0-S5) and confidence scores for the diagnosis of acute appendicitis on each dataset and LDCT 100mAs. CT image noise was measured for each set. RESULTS: The study population consisted of 58 patients with confirmed appendicitis and 44 without appendicitis. There was no significant difference in diagnostic performance between LDCT 100mAs and LDCT 30mAs with any strength for both readers (AUC for reader 1, LDCT 30mAs with S0-S5 = 0.97, LDCT 100mAs = 0.93, P = 0.0936; for reader 2, LDCT 30mAs with S0-S5 = 0.96, LDCT 100mAs = 0.97, P = 0.128). The measured noise decreased as the strength increased from S0 to S5 (mean, 20.8 > 17.7 > 15.6 > 13.5 > 11.5 > 9.5, P < 0.0001). However, overall subjective image quality on S3 was better than the other strengths for both readers (S0 < S1 < S2 < S3 > S4 > S5, P < 0.0001). CONCLUSION: Although measured noise declined as SAFIRE strength increased, S3 seems optimal for the best subjective image quality on LDCT 30mAs. The diagnostic performance of LDCT 30mAs with any strength is comparable to that of LDCT 100mAs for the diagnosis of acute appendicitis.

Postoperative low-dose follow-up computed tomography for patients with stomach cancer: optimal blending ratio of adaptive statistical iterative reconstruction for image quality and diagnostic performance.

OBJECTIVE: To compare the diagnostic performance of adaptive statistical iterative reconstruction applied low-dose computed tomography (CT) (LDCT) with that of the standard-dose CT (SDCT) for local recurrence in patients with stomach cancer. METHODS: Seventy-nine consecutive patients who had undergone surgical resection for stomach cancer were enrolled. To monitor recurrence, SDCT (120 kilovolt peak [kVp], 200mAs) had been performed. The LDCT (120 kVp, 100 mA s) was taken, and images were reconstructed with 4 levels of adaptive statistical iterative reconstruction (ASIR) blending (0%, 30%, 50%, and 70%). Two blinded radiologists recorded the diagnostic confidence scores for local recurrence in each data set using a 5-point scale. Endoscopic biopsy results served as the reference standard. Receiver operating characteristic (ROC) curve analysis was used to calculate the diagnostic performance. RESULTS: The diagnostic performance of LDCT with variable ASIR blending ratios was comparable to that of SDCT (area under ROC curve, 0.727-0.734, 0.687, respectively, P > 0.05). CONCLUSIONS: The diagnostic performance of ASIR applied LDCT is comparable to that of SDCT.

Sonographic appearances of juvenile fibroadenoma of the breast.

OBJECTIVES: The purpose of this study was to evaluate characteristic features of juvenile fibroadenoma of the breast on sonography. METHODS: Our study included 34 juvenile fibroadenomas confirmed by surgical biopsy or sonographically guided 8-gauge vacuum-assisted biopsy in 23 patients (age range, 15-47 years; mean age, 25 years). Sonographic findings of the lesions were analyzed retrospectively by 2 radiologists in consensus according to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) lexicon. The BI-RADS final assessment category was also established. RESULTS: On sonography, all fibroadenomas presented as masses. The mean size was 30 mm. Regarding shape, there were 29 oval, 2 round, and 3 irregular masses. The margins were circumscribed in 24, indistinct in 5, microlobulated in 4, and angular in 1. Regarding echogenicity, 16 masses were hypoechoic, 16 isoechoic, and 2 complex echoic. Posterior acoustic characteristics included posterior acoustic enhancement in 22 masses (65%), posterior shadowing in 1, and no posterior acoustic features in 9; this information was not available in 2. The lesion boundary presented as an abrupt interface in 32 and an echogenic halo in 2. The orientation was parallel in 32 and nonparallel in 2. Calcifications were present in 3 cases and absent in 31. On color Doppler sonography, the masses were usually hypervascular with vessel counts of 5 or more (87%). The BI-RADS final assessment categories were 3 in 24 and 4a in 10. CONCLUSIONS: The dominant sonographic presentation of juvenile fibroadenoma is a circumscribed oval hypoechoic or isoechoic mass, which resembles that of simple fibroadenoma. Juvenile fibroadenomas frequently show posterior acoustic enhancement and hypervascularity on color Doppler sonography.

Ultrasound-guided fine-needle aspiration of thyroid nodules measuring less than 5 mm: effects on specimen adequacy and diagnosis.

OBJECTIVE: We aimed to assess the adequacy and efficacy of ultrasound (US)-guided fine-needle aspiration (US-FNA) for small solid thyroid nodules (SSTNs) with the largest diameter <5 mm and compared these according to nodule size. STUDY DESIGN: Among 656 SSTNs in 569 patients, each SSTN was classified into 1 of 4 groups according to the largest diameter: 1 mm ≤ group A < 2 mm; 2 mm ≤ group B < 3 mm; 3 mm ≤ group C < 4 mm, and 4 mm ≤ group D < 5 mm. We compared the adequacy and efficacy of US-FNA between these groups using histopathologic results as a reference standard. RESULTS: 571 (87.0%) SSTNs were adequately sampled by US-FNA and 200 of these were histopathologically confirmed. The adequacy of US-FNA for SSTNs varied according to the nodule diameter: the smaller the nodule diameter, the lower the diagnostic adequacy. The diagnostic efficacy of US-FNA for SSTNs showed a significant relationship with nodule size: diagnostic efficacy in groups A and B was lower than in groups C and D. CONCLUSIONS: The adequacy of US-FNA for SSTNs tended to decrease with decreased nodule size, and diagnostic efficacy of US-FNA for SSTNs with the largest diameter <3 mm was lower than for those ≥3 mm.

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.

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.

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.

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.

MRI of the cat brain in the study of vascular permeability after intraarterial carotid injection of triolein.

BACKGROUND: Triolein emulsion embolization into the carotid artery depicts reversible increased vascular permeability that can promote the effect of chemotherapy or can reduce the amount of chemotherapeutic drugs for equivalent effectiveness. PURPOSE: To establish the minimum dosage of 0.5% triolein for studying vascular permeability changes in a triolein emulsion model. MATERIAL AND METHODS: Sixty-six cats were divided into six groups based on the amount of emulsified triolein (0.5%) infused into the carotid artery: group 1 (n=12, 6 ml/kg), group 2 (n=12, 4.5 ml/kg), group 3 (n=12, 3 ml/kg), group 4 (n=10, 1.5 ml/kg), group 5 (n=10, 1 ml/kg), and group 6 (n=10, 3 ml/kg of saline (control group)). T1-weighted, T2-weighted, and post-contrast T1-weighted MRI was performed 2 h after the infusion of the triolein emulsion. Contrast enhancement ratios (CERs) were obtained with pre- and post-contrast T1-weighted images in the ipsilateral and contralateral hemispheres. Signal intensity ratios (SIRs) of the ipsilateral and contralateral hemispheres were evaluated on T2-weighted images. After removal of the brain tissues, edema ratios in the ipsilateral and contralateral hemispheres were obtained from wet versus dry brain weights. Data were statistically evaluated by analysis of variance, followed by the Tukey honestly significant difference test to compare the difference in the mean CER of the ipsilateral and contralateral hemispheres, mean SIR on T2-weighted image, and mean edema ratio between each group when overall significance was attained. RESULTS: In the ipsilateral hemispheres, the difference in the CER between the control group and groups 1 (P=0.004), 2 (P=0.043), and 3 (P=0.008) were statistically significant. The difference in the CERs between the triolein emulsion groups was not statistically significant (P>0.05). The T2-weighted SIRs were significantly different between the control group and groups 1 (P=0.027) and 2 (P=0.004). However, the edema ratios of all doses in the triolein emulsion groups showed no significant differences compared with the control group. CONCLUSION: The minimum dosage of 0.5% triolein emulsion to achieve increased vascular permeability in the hemisphere in cat brains appears to be 3 ml/kg. This minimum dosage of triolein emulsion can be useful for acquiring basic data in further studies of vascular permeability changes in a triolein emulsion model.