Diagnostic accuracy of SARS-CoV-2 antigen test in the pediatric population: A systematic review and meta-analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused the global coronavirus disease 2019 (COVID-19) pandemic. Rapid identification and isolation of patients infected with SARS-CoV-2 are critical methods for blocking COVID-19 transmission. The advantages of antigen tests, such as their relatively low cost and short turnaround time, can contribute to the prompt identification of infectious individuals. However, the diagnostic accuracy of antigen tests for COVID-19 in children remains inconclusive. This meta-analysis aimed to evaluate the diagnostic performance of antigen tests for SARS-CoV-2 in the pediatric population. METHODS: We conducted a literature search for relevant studies in the PubMed, Embase, Google Scholar, and Biomed Central databases. Studies evaluating the diagnostic accuracy of antigen tests for SARS-CoV-2 in pediatric patients were included. In addition, we included studies that provided sufficient data to construct a 2 × 2 table on a per-patient basis. The final literature search was performed on October 10, 2021. Days after symptom onset, asymptomatic and symptomatic individuals may have been potential sources of heterogeneity. The overall sensitivity and specificity of the antigen tests were generated using a bivariate random-effects model. RESULTS: Five studies with 4400 participants were included. The meta-analysis of antigen tests generated a pooled sensitivity of 65.9% (95% CI: 52.8%-77.0%) and pooled specificity of 99.9% (95% CI: 98.9%-100.0%). A subgroup analysis of studies reporting antigen test data for symptomatic patients showed a pooled sensitivity of 64.5% and a pooled specificity of 99.7%. The subgroup analysis of studies that included 881 asymptomatic participants generated a pooled sensitivity of 48.4% and a pooled specificity of 99.5%. CONCLUSION: Antigen tests exhibit moderate sensitivity and high specificity for detecting SARS-CoV-2 in children. Antigen tests might have moderate sensitivity for detecting SARS-CoV-2 in symptomatic children, and serial testing might effectively prevent further SARS-CoV-2 transmission.

Outcomes and Effects of Vaccination on SARS-CoV-2 Omicron Infection in Kidney Transplant Recipients

Background Kidney transplant recipients (KTRs) are at high risk from COVID-19, vaccination is significant efficacy to prevent and reduce the severity of infection. Omicron infections are less severe than previous strains, but breakthrough disease is more common, thus we conducted this study to observe the vaccine efficacy in our KTRs. Methods The surge Omicron variant since May 2022, we retrieved 365 KTRs at least their 1st dose of various COVID vaccines until June 30, 2022. KTRs (n=168) at least post 2nd vaccination to assess their outcomes until September 30, 2022, which was the time before open the border for tourism. Results The antibody response in KTRs after the 1st and 2nd dose SARS-CoV-2 vaccines demonstrated significant increase from the 1st dose (median: 0.4;IQR: 0.4-8.4 U/mL, P < 0.001) to the 2nd dose (median: 57.5;IQR: 0.4-799.2 U/mL), and the response rate rise from 32% to 65% (P < 0.001). SARS-CoV-2 infection was identified in 14/365 (3.8%) at least post 1st dose, and 7/187 (3.7%) at least 7 days beyond post 2nd dose. The majority of KTRs had a mild course but 3 (17%) were hospitalized due to pneumonia. Conclusions our data demonstrate lower response rate and anti-S titers after 2nd dose vaccination in KTRs than general population, but lower incidence of SARS-CoV-2 infection after vaccination during Omicron pandemic. The breakthrough infections found in ordinary vaccinated KTRs, however, we need to emphasize the importance of vaccination and boosters to prevent severe illness, hospitalizations, and death amongst those developing infection.

A learnable Gabor Convolution kernel for vessel segmentation.

Vessel segmentation is significant for characterizing vascular diseases, receiving wide attention of researchers. The common vessel segmentation methods are mainly based on convolutional neural networks (CNNs), which have excellent feature learning capabilities. Owing to inability to predict learning direction, CNNs generate large channels or sufficient depth to obtain sufficient features. It may engender redundant parameters. Drawing on performance ability of Gabor filters in vessel enhancement, we built Gabor convolution kernel and designed its optimization. Unlike traditional filter using and common modulation, its parameters are automatically updated using gradients in the back propagation. Since the structural shape of Gabor convolution kernels is the same as that of regular convolution kernels, it can be integrated into any CNNs architecture. We built Gabor ConvNet using Gabor convolution kernels and tested it using three vessel datasets. It scored 85.06%, 70.52% and 67.11%, respectively, ranking first on three datasets. Results shows that our method outperforms advanced models in vessel segmentation. Ablations also proved that Gabor kernel has better vessel extraction ability than the regular convolution kernel.

Longitudinal Neutralizing Antibody Responses after SARS-CoV-2 Infection: A Convalescent Cohort Study in Taiwan

Background Understanding the neutralizing antibody (NAb) titer against COVID-19 over time is important to provide information for vaccine implementation. The longitudinal NAb titer over one year after SARS-CoV-2 infection is still unclear. The purposes of this study are to evaluate the duration of the neutralizing NAb titers in COVID-19 convalescents and factors associated with the titer positive duration. Methods A cohort study followed COVID-19 individuals diagnosed between 2020 and 2021 May 15th from the COVID-19 database from the Taiwan Centers for Disease Control. We analyzed NAb titers from convalescent SARS-CoV-2 individuals. We used generalized estimating equations (GEE) and a Cox regression model to summarize the factors associated with NAb titers against COVID-19 decaying in the vaccine-free population. Results A total of 203 convalescent subjects with 297 analytic samples were followed for a period of up to 588 days. Our study suggests that convalescent COVID-19 in individuals after more than a year and four months pertains to only 25% of positive titers. The GEE model indicates that longer follow-up duration was associated with a significantly lower NAb titer. The Cox regression model indicated the disease severity with advanced condition was associated with maintaining NAb titers (adjusted hazard ratio: 2.08, 95% CI: 1.12–3.61) and that non-smoking also was associated with maintaining NAb titers (adjusted hazard ratio: 1.69, 95% CI: 1.08–2.64). Conclusions Neutralizing antibody titers diminished after more than a year. The antibody titer response against SARS-CoV-2 in naturally convalescent individuals provides a reference for vaccinations.

Adherence to Diabetes Medications and Health Care Use During the COVID-19 Pandemic Among High-Risk Patients.

INTRODUCTION: The COVID-19 pandemic caused potentially disruptive shocks to chronic condition care. We examined how diabetes medication adherence, related hospitalizations, and primary care use changed in high-risk veterans prepandemic and postpandemic. METHODS: We conducted longitudinal analyses on a cohort of high-risk diabetes patients in the Veterans Affairs (VA) health care system. Primary care visits by modality, medication adherence, and VA acute hospitalizations and emergency department (ED) visits were measured. We also estimated differences for subgroups of patients by race/ethnicity, age, and rural/urban location. RESULTS: Patients were 95% male with mean age 68 years. Prepandemic patients received a mean per quarter of 1.5 in-person primary care visits and 1.3 virtual visits, 0.10 hospitalizations, and 0.22 ED visits, with mean adherence of 0.82. The early pandemic was associated with fewer in-person primary care visits, more virtual visits, fewer hospitalizations and ED visits per patient, and no change in adherence; there were no midpandemic versus prepandemic differences in hospitalizations or adherence. Black and nonelderly patients had lower adherence during the pandemic. CONCLUSION: Adherence to diabetes medications and primary care use remained high for most patients even though virtual care replaced in-person care. Black and nonelderly patients may require additional intervention to address lower adherence.

Longitudinal neutralizing antibody responses after SARS-CoV-2 infection: A convalescent cohort study in Taiwan.

BACKGROUND: Understanding the neutralizing antibody (NAb) titer against COVID-19 over time is important to provide information for vaccine implementation. The longitudinal NAb titer over one year after SARS-CoV-2 infection is still unclear. The purposes of this study are to evaluate the duration of the neutralizing NAb titers in COVID-19 convalescents and factors associated with the titer positive duration. METHODS: A cohort study followed COVID-19 individuals diagnosed between 2020 and 2021 May 15th from the COVID-19 database from the Taiwan Centers for Disease Control. We analyzed NAb titers from convalescent SARS-CoV-2 individuals. We used generalized estimating equations (GEE) and a Cox regression model to summarize the factors associated with NAb titers against COVID-19 decaying in the vaccine-free population. RESULTS: A total of 203 convalescent subjects with 297 analytic samples were followed for a period of up to 588 days. Our study suggests that convalescent COVID-19 in individuals after more than a year and four months pertains to only 25% of positive titers. The GEE model indicates that longer follow-up duration was associated with a significantly lower NAb titer. The Cox regression model indicated the disease severity with advanced condition was associated with maintaining NAb titers (adjusted hazard ratio: 2.01, 95% CI: 1.11-3.63) and that smoking was also associated with higher risk of negative NAb titers (adjusted hazard ratio: 0.55, 95% CI: 0.33-0.92). CONCLUSIONS: Neutralizing antibody titers diminished after more than a year. The antibody titer response against SARS-CoV-2 in naturally convalescent individuals provides a reference for vaccinations.

Remote scoring models of rigidity and postural stability of Parkinson's disease based on indirect motions and a low-cost RGB algorithm.

Background and objectives: The Movement Disorder Society's Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) is mostly common used for assessing the motor symptoms of Parkinson's disease (PD). In remote circumstances, vision-based techniques have many strengths over wearable sensors. However, rigidity (item 3.3) and postural stability (item 3.12) in the MDS-UPDRS III cannot be assessed remotely since participants need to be touched by a trained examiner during testing. We developed the four scoring models of rigidity of the neck, rigidity of the lower extremities, rigidity of the upper extremities, and postural stability based on features extracted from other available and touchless motions. Methods: The red, green, and blue (RGB) computer vision algorithm and machine learning were combined with other available motions from the MDS-UPDRS III evaluation. A total of 104 patients with PD were split into a train set (89 individuals) and a test set (15 individuals). The light gradient boosting machine (LightGBM) multiclassification model was trained. Weighted kappa (k), absolute accuracy (ACC ± 0), and Spearman's correlation coefficient (rho) were used to evaluate the performance of model. Results: For model of rigidity of the upper extremities, k = 0.58 (moderate), ACC ± 0 = 0.73, and rho = 0.64 (moderate). For model of rigidity of the lower extremities, k = 0.66 (substantial), ACC ± 0 = 0.70, and rho = 0.76 (strong). For model of rigidity of the neck, k = 0.60 (moderate), ACC ± 0 = 0.73, and rho = 0.60 (moderate). For model of postural stability, k = 0.66 (substantial), ACC ± 0 = 0.73, and rho = 0.68 (moderate). Conclusion: Our study can be meaningful for remote assessments, especially when people have to maintain social distance, e.g., in situations such as the coronavirus disease-2019 (COVID-19) pandemic.

Influencing Factors of Mental Health Status of Dentists Under COVID-19 Epidemic.

Objective: To investigate dentists' psychological status and influencing factors in Shaanxi Province during the COVID-19 epidemic and assess their perceived wellness. Methods: The study was conducted among dentists from Shaanxi Province in China. The basic information was collected through the network questionnaire star platform. Depression, Anxiety, and Stress Scales (DASS-42) and Perceived Wellness Survey (PWS) were used to assess subjects' psychological status and perceived wellness. Univariate linear regression analysis and multivariate analysis were performed on the influencing factors of depression, anxiety, and stress, and t-test and analysis of variance were used to analyze the perceived wellness results. Results: The results demonstrated that 33.2% of the surveyed dentists were in a state of depression, 37.1% were anxious, and 34.4% reported stress among 256 subjects. Linear Regression analysis results showed that: "years of working," "the impact of COVID-19 on their life, work, and sleep," "worrying about occupational exposure/virus infection," "lacking the awareness of prevention and control measures," "overtime work during the epidemic," "worrying about participating in the supporting work," and "continuous exhaustion from work" were significant contributors to depression, anxiety, and stress status. In addition, the results of PWS found that each dimension of PWS was correlated with depression, anxiety, and stress state, which indicates the individual's physical and mental health state was associated with multiple factors. Conclusion: COVID-19 has significantly impacted dentists' mental health in Shaanxi Province. With these findings, we aim to educate and promote targeted interventions that can be utilized to improve dentists' mental health by analyzing the influencing factors.

Formulation development and comparability studies with an aluminum-salt adjuvanted SARS-CoV-2 Spike ferritin nanoparticle vaccine antigen produced from two different cell lines (preprint)

The development of safe and effective second-generation COVID-19 vaccines to improve affordability and storage stability requirements remains a high priority to expand global coverage. In this report, we describe formulation development and comparability studies with a self-assembled SARS-CoV-2 spike ferritin nanoparticle vaccine antigen (called DCFHP), when produced in two different cell lines and formulated with an aluminum-salt adjuvant (Alhydrogel, AH). Varying levels of phosphate buffer altered the extent and strength of antigen-adjuvant interactions, and these formulations were evaluated for their (1) in vivo performance in mice and (2) in vitro stability profiles. Unadjuvanted DCFHP produced minimal immune responses while AH-adjuvanted formulations elicited greatly enhanced pseudovirus neutralization titers independent of ~100%, ~40% or ~10% of the DCFHP antigen adsorbed to AH. These formulations differed, however, in their in vitro stability properties as determined by biophysical studies and a competitive ELISA for measuring ACE2 receptor binding of AH-bound antigen. Interestingly, after one month of 4C storage, small increases in antigenicity with concomitant decreases in the ability to desorb the antigen from the AH were observed. Finally, we performed a comparability assessment of DCFHP antigen produced in Expi293 and CHO cells, which displayed expected differences in their N-linked oligosaccharide profiles. Despite consisting of different DCFHP glycoforms, these two preparations were highly similar in their key quality attributes including molecular size, structural integrity, conformational stability, binding to ACE2 receptor and mouse immunogenicity profiles. Taken together, these studies support future preclinical and clinical development of an AH-adjuvanted DCFHP vaccine candidate produced in CHO cells.

Employing functionalized graphene quantum dots to combat coronavirus and enterovirus.

The ongoing COVID-19 (i.e., coronavirus) pandemic continues to adversely affect the human life, economy, and the world's ecosystem. Although significant progress has been made in developing antiviral materials for the coronavirus, much more work is still needed. In this work, N-functionalized graphene quantum dots (GQDs) were designed and synthesized as the antiviral nanomaterial for Feline Coronavirus NTU156 (FCoV NTU156) and Enterovirus 71 (EV71)) with ultra-high inhibition (>99.9%). To prepare the GQD samples, a unique solid-phase microwave-assisted technique was developed and the cell toxicity was established on the H171 and H184 cell lines after 72 h incubation, indicating superior biocompatibility. The surface functionality of GQDs (i.e., the phenolic and amino groups) plays a vital role in interacting with the receptor-binding-domain of the spike protein. It was also found that the addition of polyethylene glycol is advantageous for the dispersion and the adsorption of functionalized GQDs onto the virus surface, leading to an enhanced virus inhibition. The functionality of as-prepared GQD nanomaterials was further confirmed where a functionalized GQD-coated glass was shown to be extremely effective in hindering the virus spread for a relatively long period (>20 h).

Efficacy of online training at the International Mental Health Training Center Taiwan (IMHTCT): Pre and during the COVID-19 pandemic.

STUDY OBJECTIVES: The coronavirus disease 2019 (COVID-19) pandemic has resulted in major disruption to regular learning and training for medical staff. The aim of this study was to compare the learning efficacy between on-site training before the COVID-19 pandemic and online training during the pandemic for nurses, psychologists, social workers, and occupational therapists from Southeast Asia. METHOD: The current study derived data from the International Mental Health Training Center Taiwan (IMHTCT) from 2018 to 2020. IMHTCT Trainees Learning Effect Questionnaire (ITLEQ) scores of the medical staff and demographic variables were collected. Reliability and validity of the ITLEQ were estimated. The independent t-test was used to compare differences in ITLEQ scores between the pre-training and post-training stages among the trainees. In addition, generalized estimating equations were used to estimate the predictive effect of online training on changes in ITLEQ scores over time. FINDINGS: A total of 190 trainees were enrolled, including 92 social workers, 16 occupation therapists, 24 psychologists, and 58 nurses. The reliability and validity were satisfactory. The efficacy of the training programs at IMHTCT was significant for all of the healthcare workers. Furthermore, better training efficacy was found in the social workers and occupational therapists who received online training compared to those who received on-site training. The potential efficacy of online training was found in the nurses. CONCLUSION: Our results demonstrate the importance of online training for mental healthcare workers during the COVID-19 pandemic. Online training may be implemented into regular training courses in the future.

New-onset inflammatory arthritis after COVID-19 vaccination: A systematic review.

AIM: To analyze the clinical patterns of new-onset inflammatory arthritis after COVID-19 vaccination among patients without pre-existing rheumatic or autoimmune diseases. METHOD: Case reports and series of new-onset inflammatory arthritis after COVID-19 vaccination were collected before April 2022. Clinical characteristics including diagnosis, age, gender, vaccine types, time interval between events, joint involvement (poly- or oligo-/monoarthritis), and laboratory data reflecting inflammatory status were sorted and P values between these parameters are calculated with independent sample Student's t test or 2 × 2 Fisher's exact test. RESULTS: Among 39 cases with new-onset post-vaccination arthritis including 25 females and 13 males (1 unknown), the most common diagnosis is adult-onset Still's disease (AoSD, 10 cases), and the most common vaccine types are BNT162b2 (16 cases) and AZD-1222 (or ChAdOx1-nCoV19, 15 cases). Sub-analysis reveals that post-vaccination polyarthritis is more common among females (P = .016, by 2 × 2 Fisher's exact test, compared with male patients) and older patients (P = .006, by Student's t test). The C-reactive protein level is significantly higher in cases with post-vaccination inflammatory polyarthritis than oligoarthritis (P = .029), as well as in cases with AoSD than other causes of post-vaccination arthritis (P = .004). However, serum level of erythrocyte sedimentation rate in patients with post-vaccination AoSD are independent of other clinical variables in the analysis. CONCLUSION: New-onset post-vaccination polyarthritis are more common in females and older patients. Although COVID-19 vaccines may lead to inflammatory arthritis, the benefits of vaccination substantially outweigh the potential risks of such serious adverse effects due to their rarity.

Federated Active Learning for Multicenter Collaborative Disease Diagnosis.

Current computer-aided diagnosis system with deep learning method plays an important role in the field of medical imaging. The collaborative diagnosis of diseases by multiple medical institutions has become a popular trend. However, large scale annotations put heavy burdens on medical experts. Furthermore, the centralized learning system has defects in privacy protection and model generalization. To meet these challenges, we propose two federated active learning methods for multicenter collaborative diagnosis of diseases: the Labeling Efficient Federated Active Learning (LEFAL) and the Training Efficient Federated Active Learning (TEFAL). The proposed LEFAL applies a task-agnostic hybrid sampling strategy considering data uncertainty and diversity simultaneously to improve data efficiency. The proposed TEFAL evaluates the client informativeness with a discriminator to improve client efficiency. On the Hyper-Kvasir dataset for gastrointestinal disease diagnosis, with only 65% of labeled data, the LEFAL achieves 95% performance on the segmentation task with whole labeled data. Moreover, on the CC-CCII dataset for COVID-19 diagnosis, with only 50 iterations, the accuracy and F1-score of TEFAL are 0.90 and 0.95, respectively on the classification task. Extensive experimental results demonstrate that the proposed federated active learning methods outperform state-of-the-art methods on segmentation and classification tasks for multicenter collaborative disease diagnosis.

Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital.

Considerable attention has been focused on the clinical features of coronavirus disease 2019 (COVID-19), but it is also important for clinicians to differentiate it from influenza virus infections. In the present study, the rate of coexisting disease was lower in the severe COVID-19 group than in the influenza A group (p = 0.003). Radiologically, severe COVID-19 patients had fewer instances of pleural effusion (p < 0.001). Clinically, severe COVID-19 patients had relatively better disease severity scores, less secondary bacterial infections, shorter times to beginning absorption on computed tomography, but longer durations of viral shedding from the time of admission (p < 0.05). Although the more severe influenza A patients required noninvasive respiratory support, these two groups ultimately yielded comparable mortalities. Based on the multiple logistic regression analysis, severe COVID-19 infection was associated with a lower risk of severe acute respiratory distress syndrome [odds ratio (OR) 1.016, 95% [confidence interval (CI)] 1.001-1.032, p = 0.041] and a better pneumonia severity index (OR 0.945, 95% [CI] 0.905-0.986, p = 0.009); however, these patients exhibited longer durations of viral shedding (OR 1.192, 95% [CI] 1.047-1.357, p = 0.008) than patients with severe influenza A infection. In conclusion, the conditions of severe influenza A patients appeared to be more critical than that of severe COVID-19 patients. However, relatively lower mortalities of these two severe cases are expected in the context of sufficient medical supplies.

Clinical assessment of SARS-CoV-2 infectivity by rapid antigen test compared with virus isolation.

Although real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR) remains as a golden standard for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, it can not be easily expanded to large-scaled screening during outbreaks, and the positive results do not necessarily correlate with infectious status of the identified subjects. In this study, the performance of Vstrip® RV2 COVID-19 Antigen Rapid Test (RAT) and its correlation with virus infectivity was examined by virus culture using 163 sequential respiratory specimens collected from 26 SARS-CoV-2 infected patients. When the presence of cytopathic effects (CPE) in cell culture was used as a reference method for virus infectivity, the sensitivity, specificity and accuracy of Vstrip® RV2 COVID-19 Antigen Rapid Test was 96.43%, 89.63%, and 90.8%, respectively. The highest Ct value was 27.7 for RdRp gene and 25.79 for E gene within CPE-positive samples, and the highest Ct value was 31.9 for RdRp gene and 29.1 for E gene within RAT positive samples. When the Ct values of specimens were below 25, the CPE and RAT results had high degree of consistency. We concluded that the RAT could be a great alternative method for determining the infectious potential of individuals with high viral load.

Risk Factors for Radiological Progression Within Admissive One Week in the Hospitalized COVID-19 Omicron Variant-Infected Patients.

Purpose: Recently, the SARS-CoV-2 Omicron variant was identified as responsible for a novel wave of COVID-19 worldwide. We perform a retrospective study to identify potential risk factors contributing to radiological progression in the COVID-19 patients due to the Omicron variant infection. These findings would provide guiding information for making clinical decisions that could improve the Omicron infection prognosis and reduce disease-related death. Methods: This is a retrospective cohort study from a single center in China. According to the radiological change within admissive one week, enrolled cases were divided into two groups: the progressive (1w-PD) and the stable or improved disease (1w-non-PD). Separate analyses were performed on patients stratified into subgroups using the Mann-Whitney U-test, the Fisher exact test, or the Chi-squared test and a multivariable logistic regression analysis. Results: Both the 1w-non-PD and 1w-PD cohorts displayed comparable asymptomatic infection, have similar underlying disease, impairment in respiratory function, coagulation dysfunction, tissue injury, SARS-CoV-2 viral load, and disease severity. However, the 1w-PD cohort was more inclined to cluster in populations presented with age between 41 and 65, higher CURB-65 scores, undetectable SARS-CoV-2 IgG, and lung affection. Based on the multiple logistic regression analysis, complicated bilateral and ground-glass opacities (GGOs) like pneumonia at admission were independent risk factors to radiological progression within admissive one week. Conclusion: This study provided preliminary data regarding disease progression in Omicron-infected patients that indicated the development of pneumonia in the context of Omicron infection was worthy of potential risk factors.

A ferritin-based COVID-19 nanoparticle vaccine that elicits robust, durable, broad-spectrum neutralizing antisera in non-human primates (preprint)

While the rapid development of COVID-19 vaccines has been a scientific triumph, the need remains for a globally available vaccine that provides longer-lasting immunity against present and future SARS-CoV-2 variants of concern (VOCs). Here, we describe DCFHP, a ferritin-based, protein-nanoparticle vaccine candidate that, when formulated with aluminum hydroxide as the sole adjuvant (DCFHP-alum), elicits potent and durable neutralizing antisera in non-human primates against known VOCs, including Omicron BQ.1, as well as against SARS-CoV-1. Following a booster ~one year after the initial immunization, DCFHP-alum elicits a robust anamnestic response. To enable global accessibility, we generated a cell line that can enable production of thousands of vaccine doses per liter of cell culture and show that DCFHP-alum maintains potency for at least 14 days at temperatures exceeding standard room temperature. DCFHP-alum has potential as a once-yearly booster vaccine, and as a primary vaccine for pediatric use including in infants.