Toward a pan-SARS-CoV-2 vaccine targeting conserved epitopes on spike and non-spike proteins for potent, broad and durable immune responses.

BACKGROUND: The SARS-CoV-2 non-Spike (S) structural protein targets on nucleocapsid (N), membrane (M) and envelope (E), critical in the host cell interferon response and memory T-cell immunity, are grossly overlooked in COVID vaccine development. The current Spike-only vaccines bear an intrinsic shortfall for promotion of a fuller T cell immunity. Vaccines designed to target conserved epitopes could elicit strong cellular immune responses that would synergize with B cell responses and lead to long-term vaccine success. We pursue a universal (pan-SARS-CoV-2) vaccine against Delta, Omicrons and ever-emergent new mutants. METHODS AND FINDINGS: We explored booster immunogenicity of UB-612, a multitope-vaccine that contains S1-RBD-sFc protein and sequence-conserved promiscuous Th and CTL epitope peptides on the Sarbecovirus N, M and S2 proteins. To a subpopulation (N = 1,478) of infection-free participants (aged 18-85 years) involved in a two-dose Phase-2 trial, a UB-612 booster (third dose) was administered 6-8 months after the second dose. The immunogenicity was evaluated at 14 days post-booster with overall safety monitored until the end of study. The booster induced high viral-neutralizing antibodies against live Wuhan WT (VNT50, 1,711) and Delta (VNT50, 1,282); and against pseudovirus WT (pVNT50, 11,167) vs. Omicron BA.1/BA.2/BA.5 variants (pVNT50, 2,314/1,890/854), respectively. The lower primary neutralizing antibodies in the elderly were uplifted upon boosting to approximately the same high level in young adults. UB-612 also induced potent, durable Th1-oriented (IFN-γ+-) responses (peak/pre-boost/post-boost SFU/106 PBMCs, 374/261/444) along with robust presence of cytotoxic CD8+ T cells (peak/pre-boost/post-boost CD107a+-Granzyme B+, 3.6%/1.8%/1.8%). This UB-612 booster vaccination is safe and well tolerated without SAEs. CONCLUSIONS: By targeting conserved epitopes on viral S2, M and N proteins, UB-612 could provide potent, broad and long-lasting B-cell and T-cell memory immunity and offers the potential as a universal vaccine to fend off Omicrons and new VoCs without resorting to Omicron-specific immunogens. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04773067; ClinicalTrials.gov ID: NCT05293665; ClinicalTrials.gov ID: NCT05541861.

Enterovirus infection is associated with an increased risk of childhood type 1 diabetes in Taiwan: a nationwide population-based cohort study.

AIMS/HYPOTHESIS: This study compared the incidence rate of type 1 diabetes in children diagnosed with enterovirus (EV) infections with that in age- and sex-matched children without EV infection in a population-based cohort. In addition, we examined whether the direction or magnitude of the association between EV infection and type 1 diabetes differs according to atopic disease status in children. METHODS: We used insurance claims data from Taiwan's National Health Insurance Research Database to derive type 1 diabetes incidence in children aged up to 18 years with or without a diagnosis of EV infection during 2000-2008. Incidence rate ratios and HRs of type 1 diabetes for EV infection were estimated by Poisson regression and Cox's proportional hazard regression model. RESULTS: Overall incidence of type 1 diabetes was higher in the EV than in the non-EV infection cohort (5.73 vs 3.89 per 100,000 person-years; incidence rate ratio 1.48 [95% CI 1.19, 1.83]), with an adjusted HR of 1.48 (95% CI 1.19, 1.83). Among children without EV, incidence increased with age at diagnosis of EV infection, except in those aged 5-10 years. The HRs of type 1 diabetes in children with allergic rhinitis, bronchial asthma or either one of these atopic diseases showed more variation than in those children without these diseases. CONCLUSIONS/INTERPRETATION: This nationwide retrospective cohort study found a positive correlation between type 1 diabetes and EV infection. The results suggest that a preventive strategy, such as an effective vaccine against EV infection, may lessen the incidence of type 1 diabetes in Taiwan.

Nosocomial neonatal legionellosis associated with water in infant formula, Taiwan.

We report 2 cases of neonatal Legionella infection associated with aspiration of contaminated water used in hospitals to make infant formula. The molecular profiles of Legionella strains isolated from samples from the infants and from water dispensers were indistinguishable. Our report highlights the need to consider nosocomial legionellosis among neonates who have respiratory symptoms.

Bacterial coinfections in hospitalized children with COVID-19 during the SARS-CoV-2 Omicron BA.2 variant pandemic in Taiwan.

Background: Bacterial coinfections have been widely recognized in adults with coronavirus disease 2019 (COVID-19). However, bacterial coinfections in hospitalized children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been sufficiently researched. This study aimed to determine the clinical presentations and risk factors for bacterial coinfections of pediatric inpatients during the SARS-CoV-2 Omicron BA.2 variant pandemic. Methods: This retrospective, observational study included patients younger than 18 years of age who were hospitalized for COVID-19 confirmed by polymerase chain reaction (PCR) or antigen rapid tests during the SARS-CoV-2 Omicron BA.2 variant pandemic. Data and outcomes of these patients with or without bacterial coinfections were compared. Results: During this study period, 161 children with confirmed COVID-19 were hospitalized. Twenty-four had bacterial coinfections. The most frequently reported concurrent diagnosis was bacterial enteritis, followed by lower respiratory tract infections. Children with bacterial coinfections had higher white blood cell (WBC) counts and PCR cycle threshold values. The bacterial coinfection group comprised a relatively greater proportion of patients who required high-flow nasal cannula oxygen and remdesivir. The length of stay in the hospital and that in the intensive care unit were longer for children with COVID-19 with bacterial coinfections. Mortality was not observed in either group. Abdominal pain, diarrhea, and comorbidity with neurologic illnesses were risk factors for bacterial coinfections with COVID-19. Conclusion: This study provides clinicians with reference points for the detection of COVID-19 in children and its possible association with bacterial infections. Children with COVID-19 and neurologic diseases who present with abdominal pain or diarrhea are at risk of bacterial coinfections. Prolonged fever duration and higher PCR test cycle threshold values, WBC levels, and high-sensitivity C-reactive protein (hsCRP) levels may indicate bacterial coinfections in children with COVID-19.

Expert review of global real-world data on COVID-19 vaccine booster effectiveness and safety during the omicron-dominant phase of the pandemic.

INTRODUCTION: COVID-19 vaccines have been highly effective in reducing morbidity and mortality during the pandemic. However, the emergence of the Omicron variant and subvariants as the globally dominant strains have raised doubts about the effectiveness of currently available vaccines and prompted debate about potential future vaccination strategies. AREAS COVERED: Using the publicly available IVAC VIEW-hub platform, we reviewed 52 studies on vaccine effectiveness (VE) after booster vaccinations. VE were reported for SARS-CoV-2 symptomatic infection, severe disease and death and stratified by vaccine schedule and age. In addition, a non-systematic literature review of safety was performed to identify single or multi-country studies investigating adverse event rates for at least two of the currently available COVID-19 vaccines. EXPERT OPINION: Booster shots of the current COVID-19 vaccines provide consistently high protection against Omicron-related severe disease and death. Additionally, this protection appears to be conserved for at least 3 months, with a small but significant waning after that. The positive risk-benefit ratio of these vaccines is well established, giving us confidence to administer additional doses as required. Future vaccination strategies will likely include a combination of schedules based on risk profile, as overly frequent boosting may be neither beneficial nor sustainable for the general population.

Detection of respiratory pathogens by application of multiplex PCR panel during early period of COVID-19 pandemic in a tertiary hospital in Central Taiwan.

BACKGROUND: Respiratory tract infections (RTIs) represent a major cause of clinical visits worldwide. Viral epidemiology of RTIs in adults has been less studied compared to children. FilmArray respiratory panel (FA-RP), a multiplex, real time polymerase chain reaction method can simultaneously detect the nucleic acids of multiple pathogens. The purpose of this study is to analyze the epidemiology and clinical presentations of an RTI cohort. METHODS: This retrospective cohort study was conducted at China Medical University Hospital (CMUH) and China Medical University Children's Hospital (CMUCH), from January 2020 to June 2020. The FA-RP results were collected and analyzed according to upper versus lower RTIs. RESULTS: Among 253 respiratory samples tested, 135 (53.4%) were from adults and 118 (46.6%) from children. A total positive rate of 33.9% (86/253) was found, with 21.48% (29/135) in adults and 48.31% (57/118) in children. Human rhinovirus/Enterovirus (HRV/EV) was detected in most of the age groups and was more common in URIs. HRV/EV was found as a frequent co-detection virus. Among children, HRV/EV was the most detected pathogen of URIs, while the most predominant pathogen in LRIs was Mycoplasma pneumoniae. CONCLUSIONS: FA-RP has the potential to improve the detection rate of respiratory pathogens. The positive rate of FA-RP was higher in children compared to adults, which likely corresponds to the higher incidence of viral RTIs in children. Different pathogens may lead to different types of respiratory infections.

Bacillus Calmette-Guérin (BCG) osteomyelitis among children: Experience in a single tertiary center in central Taiwan.

BACKGROUND: The insidious nature of BCG-osteomyelitis makes it challenging for clinicians to detect it early on. METHODS: This 12-year retrospective analysis was conducted at a single tertiary hospital in central Taiwan. Electronic medical records of pediatric patients treated for BCG-osteomyelitis were reviewed. Demographics, clinical features, and laboratory findings were compared with patients diagnosed with culture-proven pyogenic osteomyelitis. RESULTS: In total, eight patients fulfilled our inclusion criteria. Their median age was 16 months, and no obvious gender prevalence was found. Six of the eight patients had lesions involving the lower extremities. When compared with the pyogenic osteomyelitis group, age of disease onset was found to be significantly younger in the BCG osteomyelitis group (p=0.038). Absence of fever and pain in the BCG osteomyelitis group was found to be statistically significant when compared with the pyogenic group (p=0.002 and p=0.026 respectively). CRP and ESR were found to be significantly higher in the pyogenic osteomyelitis group (p=0.000 and p=0.004 respectively). CONCLUSION: BCG-related osteomyelitis must be considered when evaluating an afebrile child presenting with an unexplainable swelling or limp, and especially when the lesion is located on a lower limb. Laboratory studies may reveal normal WBC and CRP, with a normal to modest elevation of ESR. Imaging studies, including plain radiographs, magnetic resonance imaging (MRI), or computed tomography (CT) should be employed to rule out BCG-related osteomyelitis. Early diagnosis help minimize inappropriate antibiotics use, and may lead to a better outcome.

Expert review on global real-world vaccine effectiveness against SARS-CoV-2.

INTRODUCTION: COVID-19 vaccines have been highly effective in reducing morbidity and mortality during the pandemic. While primary series vaccination rates are generally high in Southeast Asian (SEA) countries, various factors have limited the rollout and impact of booster doses. AREAS COVERED: We reviewed 79 studies in the International Vaccine Access Center (IVAC) VIEW-hub platform on vaccine effectiveness (VE) after primary immunizations with two-dose schedules. VE data were reported for SARS-CoV-2 infection, COVID-19-related hospitalizations and deaths, and stratified across variants of concern, age, study design and prior SARS-CoV-2 infection for mRNA vaccines (BNT162b2, mRNA-1273, and combinations of both), vector vaccines (AstraZeneca, AZD1222 [ChAdOx1 nCoV-19] 'Vaxzevria'), and inactivated virus vaccines (CoronaVac). EXPERT OPINION: The most-studied COVID-19 vaccines provide consistently high (>90%) protection against serious clinical outcomes like hospitalizations and deaths, regardless of variant. Additionally, this protection appears equivalent for mRNA vaccines and vector vaccines like AZD1222, as supported by our analysis of Asian and relevant international data, and by insights from SEA experts. Given the continued impact of COVID-19 hospitalizations and deaths on health-care systems worldwide, encouraging vaccination strategies that reduce this burden is more relevant than attempting to prevent broader but milder infections with specific variants, including Omicron.

A multitope SARS-CoV-2 vaccine provides long-lasting B cell and T cell immunity against Delta and Omicron variants.

BackgroundThe Delta and Omicron variants of SARS-CoV-2 are currently responsible for breakthrough infections due to waning immunity. We report phase I/II trial results of UB-612, a multitope subunit vaccine containing S1-RBD-sFc protein and rationally designed promiscuous peptides representing sarbecovirus conserved helper T cell and cytotoxic T lymphocyte epitopes on the nucleocapsid (N), membrane (M), and spike (S2) proteins.MethodWe conducted a phase I primary 2-dose (28 days apart) trial of 10, 30, or 100 µg UB-612 in 60 healthy young adults 20 to 55 years old, and 50 of them were boosted with 100 µg of UB-612 approximately 7 to 9 months after the second dose. A separate placebo-controlled and randomized phase II study was conducted with 2 doses of 100 µg of UB-612 (n = 3,875, 18-85 years old). We evaluated interim safety and immunogenicity of phase I until 14 days after the third (booster) dose and of phase II until 28 days after the second dose.ResultsNo vaccine-related serious adverse events were recorded. The most common solicited adverse events were injection site pain and fatigue, mostly mild and transient. In both trials, UB-612 elicited respective neutralizing antibody titers similar to a panel of human convalescent sera. The most striking findings were long-lasting virus-neutralizing antibodies and broad T cell immunity against SARS-CoV-2 variants of concern (VoCs), including Delta and Omicron, and a strong booster-recalled memory immunity with high cross-reactive neutralizing titers against the Delta and Omicron VoCs.ConclusionUB-612 has presented a favorable safety profile, potent booster effect against VoCs, and long-lasting B and broad T cell immunity that warrants further development for both primary immunization and heterologous boosting of other COVID-19 vaccines.Trial RegistrationClinicalTrials.gov: NCT04545749, NCT04773067, and NCT04967742.FundingUBI Asia, Vaxxinity Inc., and Taiwan Centers for Disease Control, Ministry of Health and Welfare.

Factors associated with nasal colonization of methicillin-resistant Staphylococcus aureus among healthy children in Taiwan.

Methicillin-resistant Staphylococcus aureus (MRSA) has been identified as a major cause of community-associated (CA) S. aureus infections in the past decade. The main reservoir in the community for MRSA and the factors contributing to its worldwide spread remain poorly defined. Between July 2005 and June 2008, a total of 6,057 healthy children 2 to 60 months of age were screened for carriage of S. aureus and Streptococcus pneumoniae in Taiwan. The prevalence and epidemiological factors influencing MRSA carriage were determined. MRSA strains were tested for antimicrobial susceptibility and underwent molecular characterization. The overall prevalences of MRSA and S. aureus carriage were 7.8% and 23.2%, respectively. A majority (88%) of MRSA isolates belonged to a common Asian-Pacific CA-MRSA lineage, multilocus sequence type 59, and were resistant to multiple non-beta-lactam antibiotics. The carriage rate of MRSA was higher among subjects 2 to 6 months old (P < 0.0001), residing in northern Taiwan (P = 0.0003), and enrolled later in the study (P < 0.0001). MRSA colonization was associated with the number of children in the family (adjusted odds ratio [aOR], 1.114; 95% confidence interval [CI], 1.002 to 1.240; P = 0.0463) and day care attendance (aOR, 1.530; 95% CI, 1.201 to 1.949; P = 0.0006). Breast feeding (P < 0.0001) and colonization with S. pneumoniae (P = 0.0170) were protective against MRSA colonization. We concluded that epidemic CA-MRSA strains increasingly colonized Taiwanese children between 2005 and 2008. The carriage rate varied significantly across different demographical features. Crowding was an independent environmental risk factor that might accelerate CA-MRSA transmission in the community.

Diverse origin of P[19] rotaviruses in children with acute diarrhea in Taiwan: Detection of novel lineages of the G3, G5, and G9 VP7 genes.

We previously reported the detection of genotype P[19] rotavirus strains from children hospitalized with acute dehydrating diarrhea during a 5-year surveillance period in Taiwan. The characterization of five P[19] strains (0.4% of all typed), including three G3P[19], a novel G5P[19], and a unique G9P[19] genotype is described in this study. Phylogenetic analysis of the VP4, VP7, VP6, and NSP4 genes was performed, which demonstrated novel lineages for respective genotypes of the VP4 and the VP7 genes. The sequence similarities of the P[19] VP4 gene among Taiwanese human strains was higher (nt, 91.5-96.2%; aa, 93.7-97.6%) than to other P[19] strains (nt, 83.5-86.6%; aa, 89.4-94.1%) from different regions of the world. The VP7 gene of the three G3P[19] Taiwanese strains shared up to 93.4% nt and 97.5% aa identity to each other but had lower similarity to reference strain sequences available in GenBank (nt, <90.1%; aa, <95.6%). Similarly, the VP7 gene of the novel G5P[19] strain was only moderately related to the VP7 gene of reference G5 strains (nt, 82.2-87.3%; aa, 87.0-93.1%), while the VP7 gene of the single G9P[19] strain was genetically distinct from other known human and animal G9 rotavirus strains (nt, ≤ 92.0%; aa, ≤ 95.7%). Together, these findings suggest that the Taiwanese P[19] strains originated by independent interspecies transmission events. Synchronized surveillance of human and animal rotaviruses in Taiwan should identify possible hosts of these uncommon human rotavirus strains.

Clinical characteristics and prediction analysis of pediatric urinary tract infections caused by gram-positive bacteria.

Gram-positive (GP) pathogens are less accounted for in pediatric urinary tract infection (UTI), and their clinical impact is underrecognized. This study aimed to identify predictors of GP uropathogens in pediatric UTI. In this 14-year retrospective cohort of pediatric patients with UTI, we classified first-time UTIs cases into those caused by GP or Gram-negative (GN) bacteria. We constructed a multivariable logistic regression model to predict GP UTI. We evaluated model performance through calibration and discrimination plots. We developed a nomogram to predict GP UTI that is clinically feasible. Of 3783 children with first-time UTI, 166 (4.4%) were infected by GP and 3617 (95.6%) by GN bacteria. Among children with GP UTI, the most common uropathogens were vancomycin-resistant Enterococcus faecalis (VRE) (27.1%), Staphylococcus saprophyticus (26.5%), and coagulase-negative Staphylococci (12.7%). Eight independent risk factors were associated with GP UTI: Age ≥ 24 months (odds ratio [OR]: 3.21), no prior antibiotic use (OR: 3.13), serum white blood cell (WBC) count < 14.4 × 103/µL (OR: 2.19), high sensitivity C-reactive protein (hsCRP) < 3.4 mg/dL (OR: 2.18), hemoglobin ≥ 11.3 g/dL (OR: 1.90), negative urine leukocyte esterase (OR: 3.19), negative urine nitrite (OR: 4.13), and urine WBC < 420/µL (OR: 2.37). The model exhibited good discrimination (C-statistic 0.879; 95% CI 0.845-0.913) and calibration performance. VR E. faecalis, the leading GP uropathogen causing pediatric UTI, requires early detection for infection control. Our model for predicting GP UTI can help clinicians detect GP uropathogens and administer antibiotic regimen early.

Clinical characteristics and outcomes of culture-negative versus culture-positive osteomyelitis in children treated at a tertiary hospital in central Taiwan.

BACKGROUND: The causative pathogen of pediatric osteomyelitis is often unidentified despite culturing attempts. This study evaluated and compared the clinical characteristics, therapeutic approach, and outcomes of osteomyelitis caused by unknown pathogens and identified microorganisms. METHOD: This 17-year retrospective study was conducted at a tertiary hospital in central Taiwan. Medical records of children aged less than 18 years with a diagnosis of osteomyelitis between 2003 and 2019 were reviewed. RESULT: In total, 70 patients (median age = 6.4 years; male = 65.7%) fulfilled the inclusion criteria, of whom 33 (47.1%) were culture negative. Staphylococcus aureus was the main pathogen (67.6% of identified bacteria). The proportion of methicillin-resistant S. aureus (MRSA) was 44% and 54.5% of the MRSA isolates exhibited clindamycin resistance. Compared to children with culture-positive osteomyelitis, those with culture-negative osteomyelitis had a lower rate of concomitant septic arthritis (40.5% vs. 15.2%, p = 0.019) and leukocytosis on presentation (45.9% vs. 21.2%, p = 0.030); they also required fewer surgical interventions (56.8% vs. 24.2%, p = 0.006) and received a shorter course of total antibiotic therapy (49.0 vs. 43.0 days, p = 0.045). In the culture-negative group, the MRSA coverage rate was 18.8% during initial empirical therapy and increased to 59.4% during further adjusted therapy. The overall complication rate was 18.6% and was lower in the culture-negative group (32.4% vs. 3.0%, p = 0.002). CONCLUSION: In areas where community-associated MRSA and clindamycin resistance strains are a concern, empirical glycopeptide-based therapy is suggested in pediatric osteomyelitis, particularly in those with culture-negative infections.

Association between urine pH and common uropathogens in children with urinary tract infections.

BACKGROUND/PURPOSE: Urinary tract infections (UTIs) are one of the most common pediatric infections. Our objective in this study is to investigate the association between urine pH and uropathogens in pediatric patients. METHODS: The source population comprised 26 066 paired urinalysis (UA) and urine culture (UC) samples obtained from pediatric patients. We classified the paired UA-UC samples into UTI positive (N = 6348) and UTI negative (N = 19 718) according to the colony forming units corresponding to the sampling source. We included UTI positive patients with infection caused by a single species of pathogen (N = 5201) and frequency matched them with UTI negative patients (N = 4729) by age, sex, sampling source, and visit type. RESULTS: This study included 5201 pediatric patients with UTIs and found that urine with Proteus mirabilis or Pseudomonas aeruginosa demonstrated the least acidic pH (mean pH = 6.72 and 6.62, respectively), whereas urine with Escherichia coli or Klebsiella pneumoniae exhibited the most acidic pH (pH = 6.21 and 6.18). After stratifying the UTI samples by their pH range (<6, 6-6.9, 7-7.9, and ≥8). The prevalence of P. mirabilis increased significantly across increasing pH categories. CONCLUSION: This research is the first epidemiological study that linked urine pH to specific uropathogens in a pediatric population. Both urine pH and age are associated with certain causative uropathogens. Urine that grew P. mirabilis or P. aeruginosa had the least acidic pH. Additional studies should validate the role of urine pH in predicting uropathogens and UTI.

Immunogenicity and Safety of AS03-adjuvanted H5N1 Influenza Vaccine in Children 6-35 Months of Age: Results From a Phase 2, Randomized, Observer-blind, Multicenter, Dose-ranging Study.

BACKGROUND: This phase 2 observer-blind, randomized, multicenter, dose-ranging study evaluated immunogenicity and safety of different formulations of an AS03-adjuvanted H5N1 influenza vaccine in children 6-35 months of age. METHODS: One hundred eighty-five children randomized into 5 groups [1.9 µg hemagglutinin (HA)/AS03B, 0.9 µg HA/AS03C, 1.9 µg HA/AS03C, 3.75 µg HA/AS03C or 3.75 µg HA/AS03D] were to receive 2 doses administered 21 days apart (primary vaccination). AS03 was classified by amount of DL-α-tocopherol, with AS03B the highest amount. One year later, all subjects were to receive unadjuvanted 3.75 µg HA as antigen challenge. Immunogenicity was assessed 21 days after primary vaccination (day 42) and 7 days after antigen challenge (day 392). Immunogenicity-fever index, based on hemagglutination inhibition and microneutralization antibody titers at day 42 and fever 7 days after each vaccination, was used to guide the selection of an acceptable formulation. RESULTS: After primary vaccination, formulations elicited strong homologous immune responses with all subjects' hemagglutination inhibition titers ≥1:40 post-vaccination. Immunogenicity-fever index based on hemagglutination inhibition and microneutralization assays showed that 1.9 µg HA/AS03B ranked the highest. Antibody levels persisted >4 times above baseline 12 months after primary vaccination with all formulations (day 385). Antibodies increased >4-fold after antigen challenge (day 392/day 385) with 1.9 µg HA/AS03B, 0.9 µg HA/AS03C and 1.9 µg HA/AS03C formulations. Overall per subject, the incidence of fever ranged from 28.6% (3.75 µg HA/AS03D) to 60.5% (1.9 µg HA/AS03B). CONCLUSIONS: All formulations were highly immunogenic and demonstrated acceptable safety profiles, with the 1.9 µg HA/AS03B providing the most favorable balance of immunogenicity versus reactogenicity for use in children 6-35 months of age.

Safety and immunogenicity of CpG 1018 and aluminium hydroxide-adjuvanted SARS-CoV-2 S-2P protein vaccine MVC-COV1901: interim results of a large-scale, double-blind, randomised, placebo-controlled phase 2 trial in Taiwan.

BACKGROUND: MVC-COV1901, a recombinant protein vaccine containing pre-fusion-stabilised spike protein S-2P adjuvanted with CpG 1018 and aluminium hydroxide, has been shown to be well tolerated with a good safety profile in healthy adults aged 20-49 years in a phase 1 trial, and provided a good cellular and humoral immune responses. We present the interim safety, tolerability, and immunogenicity results of a phase 2 clinical trial of the MVC-COV1901 vaccine in Taiwan. METHODS: This is a large-scale, double-blind, randomised, placebo-controlled phase 2 trial done at ten medical centres and one regional hospital in Taiwan. Individuals aged 20 years or older who were generally healthy or had stable pre-existing medical conditions were eligible for enrolment. Exclusion criteria included (but were not limited to) travel overseas within 14 days of screening, intention to travel overseas within 6 months of the screening visit, and the absence of prespecified medical conditions, including immunosuppressive illness, a history of autoimmune disease, malignancy with risk to recur, a bleeding disorder, uncontrolled HIV infection, uncontrolled hepatitis B and C virus infections, SARS-CoV-1 or SARS-CoV-2 infections, an allergy to any vaccine, or a serious medical condition that could interfere with the study. Study participants were randomly assigned (6:1) to receive two doses of either MVC-COV1901 or placebo, administered via intramuscular injection on day 1 and day 29. MVC-COV1901 contained 15 µg of S-2P protein adjuvanted with 750 µg CpG 1018 and 375 µg aluminium hydroxide in a 0·5 mL aqueous solution, and the placebo contained the same volume of saline. Randomisation was done centrally by use of an interactive web response system, stratified by age (≥20 to <65 years and ≥65 years). Participants and investigators were masked to group assignment. The primary outcomes were to evaluate the safety, tolerability, and immunogenicity of MVC-COV1901 from day 1 (the day of the first dose) to day 57 (28 days after the second dose). Safety was assessed in all participants who received at least one dose. Immunogenicity was assessed by measuring geometric mean titres (GMTs) and seroconversion rates of neutralising antibody and antigen-specific IgG in the per-protocol population. This study is registered with ClinicalTrials.gov, NCT04695652. FINDINGS: Of 4173 individuals screened between Dec 30, 2020, and April 2, 2021, 3854 were enrolled and randomly assigned: 3304 to the MVC-COV1901 group and 550 to the placebo group. A total of 3844 participants (3295 in the MVC-COV1901 group and 549 in the placebo group) were included in the safety analysis set, and 1053 participants (903 and 150) had received both doses and were included in the per-protocol immunogenicity analysis set. From the start of this phase 2 trial to the time of interim analysis, no vaccine-related serious adverse events were recorded. The most common solicited adverse events in all study participants were pain at the injection site (2346 [71·2%] of 3295 in the MVC-COV1901 group and 128 [23·3%] of 549 in the placebo group), and malaise or fatigue (1186 [36·0%] and 163 [29·7%]). Fever was rarely reported (23 [0·7%] and two [0·4%]). At 28 days after the second dose of MVC-COV1901, the wild-type SARS-CoV-2 neutralising antibody GMT was 662·3 (95% CI 628·7-697·8; 408·5 IU/mL), the GMT ratio (geometric mean fold increase in titres at day 57 vs baseline) was 163·2 (155·0-171·9), and the seroconversion rate was 99·8% (95% CI 99·2-100·0). INTERPRETATION: MVC-COV1901 has a good safety profile and elicits promising immunogenicity responses. These data support MVC-COV1901 to enter phase 3 efficacy trials. FUNDING: Medigen Vaccine Biologics and Taiwan Centres for Disease Control, Ministry of Health and Welfare.

Serum albumin level predicts initial intravenous immunoglobulin treatment failure in Kawasaki disease.

OBJECTIVES: Kawasaki disease (KD) is a systemic vasculitis primarily affecting children who are <5 years old. Intravenous immunoglobulin (IVIG) is the standard therapy for KD. However, many patients with KD still show poor response to initial IVIG treatment. This study was conducted to investigate the risk factors for initial IVIG treatment failure in KD. METHODS: Children who met KD diagnosis criteria and were admitted for IVIG treatment were retrospectively enrolled for analysis. Patients were divided into IVIG-responsive and IVIG-resistant groups. Initial laboratory data before IVIG treatment were collected for analysis. RESULTS: A total of 131 patients were enrolled during the study period. At 48 h after completion of initial IVIG treatment, 20 patients (15.3%) had an elevated body temperature. Univariate analysis showed that patients who had initial findings of high neutrophil count, abnormal liver function, low serum albumin level (≤2.9 g/dL) and pericardial effusion were at risk for IVIG treatment failure. Multivariate analysis with a logistic regression procedure showed that serum albumin level was considered the independent predicting factor of IVIG resistance in patients with KD (p = 0.006, OR = 40, 95% CI: 52.8-562). There was no significant correlation between age, gender, fever duration before IVIG treatment, haemoglobin level, total leucocyte and platelet counts, C-reactive protein level, or sterile pyuria and initial IVIG treatment failure. The specificity and sensitivity for prediction of IVIG treatment failure in this study were 96% and 34%, respectively. CONCLUSION: Pre-IVIG treatment serum albumin levels are a useful predictor of IVIG resistance in patients with KD.

Plasma clusterin levels in predicting the occurrence of coronary artery lesions in patients with Kawasaki disease.

Kawasaki disease (KD) is the leading cause of acquired heart disease during childhood in the developed countries. Coronary artery lesions (CAL) are the major complications of KD. A unique proteomic profiling with increased or decreased fibrinogen, alpha-1-antitrypsin, clusterin, and immunoglobulin free light chains were noted in KD in our previous study. The purpose of this study was to evaluate relations between these biomarkers and CAL in KD and to establish within the markers the appropriate cut-off value with which to predict the occurrence of CAL. A total of 47 KD patients were enrolled, including 14 with CAL and 33 without CAL. Plasma samples from patients with KD before intravenous immunoglobulin administration were indicated for measurement of these biomarkers. A potential relation among CAL, clinical characteristics, and these biomarkers was investigated, and a receiver operating characteristic curve was used to identify a cut-off value of the significant marker that best predicated the occurrence of CAL. Among these biomarkers, only plasma clusterin level was associated with the occurrence of CAL. Using a cut-off value of clusterin <12.0 mg/l, the relative risk for CAL was 4.53-fold (95% confidence interval [CI] 1.060-19.347%, P = 0.014). Results from this study suggest that plasma clusterin level <12.0 mg/l in KD is significantly associated with the occurrence of CAL. Results from this study provide a potential biomarker of KD that may help predict the occurrence of CAL.