Effectiveness and safety of the simulation-based first-dose design of voriconazole.

BACKGROUND: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert. METHODS: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms. RESULTS: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 µg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group. CONCLUSIONS: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy.

Evaluation of the First-Dose Anti-VEGF Anatomical Response in Polypoidal Choroidal Vasculopathy Patients: Correlation with the Third-Dose Response and Risk Factor Analysis.

INTRODUCTION: The aims of the study were to investigate whether first-dose efficacy can predict third-dose anatomical response and analyze the risk factors for first-dose response of polypoidal choroidal vasculopathy (PCV) patients. METHODS: We retrospectively reviewed patients' medical records from 27 centers of China PCV Research Alliance. PCV patients treated with intravitreal injections of conbercept (IVC) based on the 3+ pro re nata regimen (three initial monthly injections, followed by injections as needed) with complete 3-month injection data were included. Response correlations, risk factor associations, changes in central macular thickness (CMT) or best-corrected visual acuity (BCVA), and number of injections in the first year of follow-up were evaluated separately in the pachy-PCV and non-pachy-PCV phenotypes. RESULTS: Overall, 165 eligible patients were included. There was a significant correlation between first-dose and third-dose anatomical response in pachy-PCV or non-pachy-PCV patients (rs = 0.611, p < 0.001; rs = 0.638, p < 0.001). Multivariate analysis revealed associations of good first-dose anatomical response in pachy-PCV patients with baseline CMT with a predicted area under the curve (AUC) of 0.847, while a good response in non-pachy-PCV patients was associated with baseline BCVA, baseline CMT, pigment epithelial detachment (PED) height, higher proportion of intraretinal fluid, and lower PED minimum diameter with a predicted AUC of 0.940. CMT in the good first-dose response group was significantly decreased from baseline at all first-year follow-up visits in both groups (p < 0.001), and mean BCVA was improved in the good versus poor first-dose anatomical response group (5.4 vs. 1.6 ETDRS letters in pachy-PCV, 10.6 vs. 7.4 letters in non-pachy-PCV) after the third injection. No significant difference was observed in the number of injections in the first year of follow-up between different response groups. CONCLUSION: In PCV patients receiving IVC, the first- and third-dose responses are significantly correlated, and different factors influence the first-dose response in different subtypes of PCV.

Optimization of Vancomycin Initial Dose in Term and Preterm Neonates by Machine Learning.

INTRODUCTION: Vancomycin is one of the antibiotics most used in neonates. Continuous infusion has many advantages over intermittent infusions, but no consensus has been achieved regarding the optimal initial dose. The objectives of this study were: to develop a Machine learning (ML) algorithm based on pharmacokinetic profiles obtained by Monte Carlo simulations using a population pharmacokinetic model (POPPK) from the literature, in order to derive the best vancomycin initial dose in preterm and term neonates, and to compare ML performances with those of an literature equation (LE) derived from a POPPK previously published. MATERIALS AND METHODS: The parameters of a previously published POPPK model of vancomycin in children and neonates were used in the mrgsolve R package to simulate 1900 PK profiles. ML algorithms were developed from these simulations using Xgboost, GLMNET and MARS in parallel, benchmarked and used to calculate the ML first dose. Performances were evaluated in a second simulation set and in an external set of 82 real patients and compared to those of a LE. RESULTS: The Xgboost algorithm yielded numerically best performances and target attainment rates: 46.9% in the second simulation set of 400-600 AUC/MIC ratio vs. 41.4% for the LE model (p = 0.0018); and 35.3% vs. 28% in real patients (p = 0.401), respectively). The Xgboost model resulted in less AUC/MIC > 600, thus decreasing the risk of nephrotoxicity. CONCLUSION: The Xgboost algorithm developed to estimate the initial dose of vancomycin in term or preterm infants has better performances than a previous validated LE and should be evaluated prospectively.

Active Surveillance of Adverse Events in Healthcare Workers Recipients After Vaccination with COVID-19 BNT162b2 Vaccine (Pfizer-BioNTech, Comirnaty): A Cross-Sectional Study.

In this cross-sectional study, adverse events after the first and second dose of BNT162b2 mRNA (Pfizer-BioNTech, Comirnaty) vaccine against coronavirus disease 2019 were investigated among employees of clinics in central Italy. A 42-items questionnaire was administrated to vaccine recipients. Adverse events were classified based on severity and occurrence as reported in the literature. A descriptive/univariate analysis using Chi-square or Fisher's Exact tests was performed. Odds ratio (OR) and 95% confidence intervals were calculated to assess risk factors. 340 individuals (61.5% females; median age 49 years) participated. Adverse events were reported by 279 (82%) and 281 (82.6%) individuals as induced by the first and second dose, respectively. Mild reactions were mainly reported (80.9% and 80.3%), followed by moderate (11.8% and 37.1%) and severe (3.8% and 4.7%). Adverse events were identical to those already described as very common (81.8% and 80.6%), although vaccine-coincidental events not cited in the literature were reported by 6% and 15.6% following each dose. Age ≤ 55 years was a risk factor for any adverse event after each injection (ORs: 2.942 and 2.818), as well as female sex for those mild (ORs: 1.856 and 2.818) and common (ORs: 3.452 and 2.145). Findings were consistent with national reports as most of the adverse events were mild and associated with female sex and young age, while investigations are needed for reactions not described elsewhere. Data are useful to support the vaccine safety profile, also because largely targeted healthcare personnel more skilled than general population in self-diagnosis of health-related issues.

Analysis of cardiac monitoring and safety data in patients initiating fingolimod treatment in the home or in clinic.

BACKGROUND: Fingolimod (Gilenya®) is approved for relapsing forms of multiple sclerosis in the USA. Owing to transient heart-rate effects when initiating fingolimod, eligible patients undergo precautionary baseline assessment and first-dose observation (FDO) for ≥6 h. Prior to 2014, FDO was undertaken only in clinics. As the FDO period is short, and fingolimod has accumulated evidence of a positive benefit:risk ratio, an in-home treatment-initiation program, Gilenya@Home, was developed to offer a convenient alternative. METHODS: Cardiac parameters and adverse events (AEs) were recorded by healthcare professionals performing fingolimod FDOs in the US Gilenya@Home program or in US Gilenya Assessment Network clinics. Anonymized data were collated retrospectively from the first 34 months in the home setting and from 78 months in clinics; data are reported descriptively. Satisfaction with Gilenya@Home was rated by patients using a 7-item questionnaire that considered aspects such as ease of scheduling, courtesy, and competency. RESULTS: Data were captured as part of standard care from 5573 patients initiating fingolimod in-home (October 2014 to July 2017) and from 15,025 patients initiating in-clinic (July 2010 to December 2016). In the Gilenya@Home questionnaire, 91.7% of 1848 respondents rated their overall satisfaction as "very good," and 7.6% rated their satisfaction as "good." AEs were reported for 30.7 and 32.6% of in-home and in-clinic patients, respectively. In total, 557 in-home (10.0%) and 398 in-clinic (2.6%) patients were monitored for > 6 h; 15 (0.3%) in-home and 129 (0.9%) in-clinic patients were transferred to an emergency room for overnight monitoring. The mean (standard deviation) heart rate (HR; bpm) pre-FDO was 74.8 (12.2) in-home and 74.2 (11.3) in-clinic; reduction in HR at 6 h postdose was 10.6 (12.0) and 6.3 (9.6), respectively. New-onset first-degree atrioventricular block was experienced by 132 (2.4%) in-home and 74 (0.5%) in-clinic patients, and Wenckebach (Mobitz type I) second-degree atrioventricular block by four (0.07%) and nine (0.1%) patients, with no cases of third-degree atrioventricular block. CONCLUSIONS: A substantial number of patients have initiated fingolimod at home, reporting very high levels of satisfaction. Gilenya@Home was as rigorous as the clinic setting in detecting cardiovascular events. Overall, FDO safety outcomes were similar with Gilenya@Home and in-clinic.

Implications of culture collection after the first antimicrobial dose in septic emergency department patients.

BACKGROUND: Previous research has illustrated the importance of collection of microbiologic cultures prior to first antimicrobial dose (FAD) in septic patients to avoid sterilization of pathogens and thus allowing confirmation of infection, identification of pathogen(s), and de-escalation of antimicrobial therapy. There is currently a lack of literature characterizing the implications and clinical courses of patients who have cultures collected after FAD. METHODS: In this single-center, retrospective chart review of 163 sepsis cases in the emergency department, the primary outcome was positive-cultures from appropriate sources. Secondary outcomes included time to FAD (TFAD); ICU and hospital lengths of stay (LOS); rate of antibiotic restart; secondary infection rate; readmission; and mortality. Cases were divided based on culture timing relative to FAD: culture-first (CF) or antimicrobial-first (AF) cohorts. RESULTS: Cultures were more frequently positive in the CF cohort vs. AF cohort overall (80.4% vs. 46.7%, p < 0.005). TFAD was greater in the CF cohort (202 min vs. 153 min, p = 0.036) and these cases trended toward shorter ICU and hospital LOS (6.8 days vs. 8.4 days, p = 0.122; 11.5 days vs. 13.5 days, p = 0.218). Antibiotic restart was less frequent in the CF cohort (10.7% vs. 17.8%, p < 0.005). C. difficile infection and mortality trended toward lower incidence in the CF cohort, and readmission rates were similar. CONCLUSIONS: Sepsis patients who have cultures obtained after FAD (represented in the AF cohort) had less positive-cultures, shorter TFAD, a trend toward longer ICU and hospital LOS, and perhaps higher risk of C. difficile infection, and mortality.

Cardiodynamic Interactions between Two S1P1 Receptor Modulators in an Experimental Clinical Setting: Different Pharmacokinetic Properties as an Opportunity to Mitigate First-Dose Heart Rate Effects.

A decrease in heart rate (HR) is a well-established first-dose effect of sphingosine-1-phosphate subtype 1 receptor (S1P1R) modulators. For compounds with a short half-life (t1/2), this can be mitigated by gradual up-titration to therapeutic doses, whereas this is not required for compounds with a long t1/2 due to the less pronounced first-dose-related negative chronotropic effects. Based on this conceptual framework, this mechanistic study investigated whether first-dose HR effects of ponesimod (t1/2 ~32 h) can be mitigated by prior administration of cenerimod (t1/2 ~415 h). Healthy subjects (n = 12) were randomly assigned to active or placebo (2:1 ratio). Active treatment consisted of a single dose of 10 mg ponesimod on Day 1, 18, and 37 and multiple-dose administration of 2 mg once daily cenerimod (Day 9-36). Placebos of cenerimod and ponesimod were used as reference treatment. Cardiodynamic parameters were derived from 24 h Holter electrocardiogram (ECG) assessments on Day 1, 9, 10, 18, 36, and 37. Ponesimod (10 mg) alone triggered a transient mean decrease from baseline in hourly mean HR of 17 bpm. In contrast, decreases of 5.0 and 4.8 bpm were observed when ponesimod was given at near half steady-state (Day 18) or steady-state (Day 37) cenerimod, respectively. Hourly mean HR decreased after first administration of cenerimod and placebo was 7.4 and 4.0 bpm, respectively. Treatment with ponesimod and cenerimod alone or in combination was safe and tolerated. First-dose-related negative chronotropic effects of ponesimod were less pronounced when administered after initiation of cenerimod suggesting mitigation of this class-related liability.

Prolonged First-Dose Hypotension Induced by Sacubitril/Valsartan.

Entresto was recommanded by major guidelines as the frontline therapy for heart failure with reduced ejection fraction since its clinical benefit was proved by the PARADIGM-HF trial. Angiotensin converting enzyme inhibitors are the cornerstone of the treatment of HF. Varying incidences of first-dose hypotension have been reported and recognized as a potential limiting factor for prescribing. According to previous reports, the onset of hypotension mostly occur 3-5 hours after the first dose. However, the pattern of entresto-related hypotension has not been reported. We present a case of HF, who had delay onset (about 8 to 18 hours) and prolonged (3 to 6 days) first-dose hypotension. Further investigation is required to illustrate this phenomenon.

Electrocardiographic assessments and cardiac events after fingolimod first dose - a comprehensive monitoring study.

BACKGROUND: First dose observation for cardiac effects is required for fingolimod, but recommendations on the extent vary. This study aims to assess cardiac safety of fingolimod first dose. Individual bradyarrhythmic episodes were evaluated to assess the relevance of continuous electrocardiogram (ECG) monitoring. METHODS: START is an ongoing open-label, multi-center study. At the time of analysis 3951 patients were enrolled. The primary endpoints are the incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree AV blocks during treatment initiation. The relevance of Holter was assessed by matching ECG findings with the occurrence of clinical symptoms as well as by rigorous analysis of AV blocks with regard to the duration of pauses and the minimal heart rate recorded during AV block. RESULTS: Thirty-one patients (0.8%) developed bradycardia (<45 bpm), 62 patients (1.6%) had second-degree Mobitz I and/or 2:1 AV blocks with a lowest reading (i.e. mean of ten consecutive beats) of 35 bpm and the longest pause lasting for 2.6 s. No Mobitz II or third-degree AV blocks were observed. Only one patient complained about mild chest discomfort and fatigue. After 1 week, there was no second-/third-degree AV block. CONCLUSIONS: Continuous Holter ECG monitoring in this large real-life cohort revealed that bradycardia and AV conduction abnormalities were rare, transient and benign. No further unexpected abnormalities were detected. The data presented here give an indication that continuous Holter ECG monitoring does not add clinically relevant value to patients' safety. TRIAL REGISTRATION: NCT01585298 ; registered April 23, 2012.

Early safety and efficacy of fingolimod treatment in Denmark.

BACKGROUND: Initiation of fingolimod treatment is associated with a transient decrease of heart rate, and atrioventricular (AV) conduction block may occur. OBJECTIVE: To evaluate the therapeutic effect and safety of fingolimod treatment in MS patients in Denmark with focus on cardiac and pulmonary side effects at treatment onset. MATERIALS & METHODS: We analysed data from the first 496 fingolimod-treated Danish patients, observed for at least 3 months. In a subset of 204 patients, we monitored cardiac and pulmonary adverse effects following treatment initiation. RESULTS: The overall annualized relapse rate (ARR) was 0.37 (95% CI 0.31-0.44); 0.22 (95% CI 0.03-0.81) in de novo-treated patients, 0.29 (95% CI; 0.23-0.37) in patients switching from IFN-beta or GA and 0.46 (9 5% CI 0.34-0.60) after natalizumab. In the subset of 204 patients, 8 (3.9%) required prolonged cardiac monitoring due to bradycardia and/or second-degree AV block type I. All patients recovered spontaneously. Two patients discontinued fingolimod. Eleven (5.4%) patients reported respiratory complaints and two of these patients discontinued treatment. CONCLUSIONS: Fingolimod appears to be safe and effective in MS patients in a clinical setting. Mild cardiac adverse effects occurred at a similar rate as in clinical trials.

Comparing infusion-related reactions of the first full dose (600 mg) biosimilar ocrelizumab administration with the standard divided protocol in multiple sclerosis patients: a randomized controlled trial study.

BACKGROUND: Ocrelizumab is a humanized antiCD20, thought to be a highly effective disease-modifying therapy (DMT). Its most frequent adverse effects are infusion-related reactions (IRRs). To reduce these reactions, the first dose of ocrelizumab is administered as two 300 mg infusions separated by two weeks. However, in the phase II trial of ocrelizumab, severe IRRs were not significantly different between two doses of 600 mg dose (two separate 300 mg doses) and 2000 mg dose (two separate 1000 mg doses). We compared the IRRs in undivided full (one 600 mg) and divided (two 300 mg) doses of ocrelizumab which is the standard protocol. METHODS: MS patients (relapsing or primary progressive MS) who are selected to receive ocrelizumab by neurologist or MS fellowship were enrolled in an open-label randomized controlled trial. Iranian biosimilar of the drug (Xacrel® by Cinnagen, approved by the Iranian Food and Drug Administration in 2021) was used. The participants received the first dose of ocrelizumab as either one 600 mg dose in one session or two 300 mg doses in two weeks apart. IRRs during or in the first 24 h after infusion were recorded. RESULTS: Of 332 participants, 150 received two 300 mg doses, and 182 received one 600 mg dose (by random selection). Life-threatening adverse effects were not observed in both groups. Overnight admission or permanent drug discontinuation was not needed. Temporary drug discontinuation was significantly higher in the one 600 mg dose group (p-value < 0.001). During the infusions, malaise (p-value: 0.003), skin reactions (p-value: 0.04), throat swelling (p-value: 0.03), and dyspnea (p-value: 0.01) were significantly increased in the intervention group. However, in the first 24 h, there was no significant difference between two different treatment protocols (one 600 mg dose or two 300 mg doses) in the onset of IRRS (p-value: 0.12). CONCLUSION: These findings suggest one 600 mg dose of ocrelizumab administration for the first dose is relatively safe. With some protocol modifications, it could lead to fewer patient referrals, saving time and cost and improvement the access for patients.

Beating the clock: Reduced time to first antibiotic dose administration following an audit and feedback intervention.

OBJECTIVE: Quality improvement interventions and policy revisions have been shown to improve clinical practice and patient outcomes. This study evaluated an intervention to shorten the time from the first antibiotic dose ordering to its administration in patients hospitalised with bacterial infections. METHODS: An intervention consisting of a weekly email report to nurse and physician leaders in hospital departments was introduced. The report included the percentage of patients who received their first antibiotic dose within 3 hours and details of those who did not. Interrupted time series analysis was used to compare the delay between the order and administration of antibiotics in various wards (surgical and medical) and daily nursing shifts. RESULTS: The total number of orders pre-intervention and post-intervention was 58 320 and 52 127, respectively. The most protracted delays were observed during the morning shift in the surgical and medical wards (161 and 100 minutes, respectively). Comparing the pre- to post-intervention time to the first antibiotic dose (TTFAD), a reduction in the morning shift was noted both in the surgical wards (87 minutes, 55%) and medical wards (37 minutes, 37%) and with a preserved trend (P < 0.001). The slope's angle before and after the intervention was not affected. CONCLUSION: Using an audit and feedback automatic weekly report significantly reduced TTFAD in hospitalised patients. This intervention proved to be simple and sustainable over time. Raising staff awareness of current medical care practices is an effective way of improving performance.

First-Dose Antimicrobial Infusion Reactions in Patients Enrolled in Outpatient Parenteral Antimicrobial Therapy Services.

After receiving a monitored first-dose antimicrobial infusion at an infusion center, 6 of 93 (6%) patients enrolled in outpatient parenteral antimicrobial therapy services experienced an immediate reaction, none of which were consistent with immunoglobulin E-mediated reactions. These findings suggest it would be reasonable to forgo monitoring for most patients receiving first-dose intravenous antimicrobials outpatient.

Adverse events reported after first dose of SARS-CoV-2 vaccine in the Northern Region of Ghana.

AIM: The study examined the associated adverse events following SARS-CoV-2 vaccination among healthcare workers during the first dose of the vaccine in the Northern Region of Ghana. DESIGN: The study was a cross-sectional survey involving 463 healthcare workers. METHOD: The data were collected using a structured questionnaire. The data were analysed descriptively, and binary logistics was performed using SPSS version 25. RESULTS: The mean age was 33.4 ± 9.7 years, the majority (43.6%) being ≤30 years and males (57.2%). The self-reported prevalence of SARS-CoV-2 vaccine adverse events was 75.5%. Common systemic adverse events comprised headache (47.5%), dizziness (18.4%) and local adverse events included generalized body pains (44.0%) and abscess around the injection sites (11.2%). The study found a high prevalence of self-reported SARS-CoV-2 vaccine adverse events involving both systemic and local adverse events. Our study gives useful information that can be used for public health-targeted interventions to boost public confidence in SARS-CoV-2 vaccines.

Rituximab induced cytokine release with high serum IP-10 (CXCL10) concentrations is associated with infusion reactions.

Monoclonal antibody induced infusion reactions (IRs) can be serious and even fatal. We used clinical data and blood samples from 37 treatment naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) initiating therapy for progressive disease with a single 50 mg dose of intravenous (IV) rituximab at 25 mg/h. Twenty-four (65 %) patients had IRs at a median of 78 min (range 35-128) and rituximab dose of 32 mg (range 15-50). IR risk did not correlate with patient or CLL characteristics, CLL counts or CD20 levels, or serum rituximab or complement concentrations. Thirty-five (95 %) patients had cytokine release response with a ≥ 4-fold increase in serum concentration of ≥ 1 inflammatory cytokine. IRs were associated with significantly higher post-infusion serum concentrations of gamma interferon induced cytokines IP-10, IL-6 and IL-8. IP-10 concentrations increased ≥ 4-fold in all patients with an IR and were above the upper limit of detection (40,000 pg/ml) in 17 (71 %). In contrast, to only three (23 %) patients without an IR had an ≥ 4-fold increase in serum concentrations of IP-10 (highest 22,013 pg/ml). Our data suggest that cytokine release could be initiated by activation of effector cells responsible for clearance of circulating CLL cells with IRs occurring in those with higher levels of gamma interferon induced cytokines. These novel insights could inform future research to better understand and manage IRs and understand the role of cytokines in the control of cytotoxic immune responses to mAb.

Association between Adverse Reactions to the First and Second Doses of COVID-19 Vaccine.

This study investigated the frequency of adverse reactions to COVID-19 vaccines in Japan and the impact of first-dose adverse reactions on second-dose adverse reactions. Individuals who received an mRNA COVID-19 vaccine at our center in March or April 2021 were included. Data were collected using questionnaires. The main factors were age (<40, 40−59, and >60 years), sex, underlying disease, and first-dose adverse reaction. The primary outcomes were incidence of local and systemic adverse reactions (ARs) attributable to the vaccine. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Among 671 participants, 90% experienced local or systemic ARs. An AR to the first dose was associated with a significantly increased risk of an AR to the second dose (OR: 49.63, 95% CI: 21.96−112.16). ARs were less common among men than among women (OR: 0.36, 95% CI: 0.17−0.76). Local ARs were less common among those aged 60 years or older (OR: 0.35, 95% CI: 0.18−0.66), whereas systemic ARs were more common among those aged under 40 years. Information on ARs to the first dose is important for healthcare providers and recipients when making vaccination decisions.

COVID-19 Vaccines Portray the Bright Side of Human Creativity, But It Means Nothing until They Prove Their Worth: A Study on Seroconversion after the first Dose of Covishield Vaccine in Central Kerala.

Background: COVID-19 vaccines, we believe, have come to rescue us from the clutches of the dreaded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). With rapid ongoing mutations, it is difficult to predict the effectiveness of seroconversion following vaccination. This study aims to find out the proportion of people with seroconversion following first dose of Covishield vaccine. Methods: Randomly selected health-care workers were followed up for SARS-CoV-2 immunoglobulin G (IgG) antibodies between 28 and 42 days after receiving their first vaccine dose. The VITROS SARS-CoV-2 IgG test (Ortho-Clinical Diagnostics, USA) with 100% specificity and > 90% sensitivity was used to assess seroconversion. Results: The first dose of vaccine induced seroconversion in 91.7% of beneficiaries. Nearly one-third (30.2%) of them had high antibody titers, and it showed a significant association with female gender (9.6 ± 5.5 vs. 7.6 ± 5.6) and younger age (P = 0.008). In addition, those with previous COVID infection showed a more robust immune response when compared to others (P = 0.001). Conclusion: Seroconversion rate of more than 90% offers a promising hope toward successful pandemic control. In the current scenario, the inability to attain the targeted coverage due to an upsurge in vaccine hesitancy, compounded with only lower proportion of seroconversion in elderly, faster rollout of the vaccines without any age limit, will help achieve the herd threshold more rapidly.

Critical success factors for high routine immunization performance: A case study of Nepal.

Introduction: The essential components of a vaccine delivery system are well-documented, but robust evidence on how and why the related processes and implementation strategies drive catalytic improvements in vaccination coverage are not well established. To address this gap, we identified critical success factors that may have led to substantial improvements in routine childhood immunization coverage in Nepal from 2000 through 2019. Methods: We identified Nepal as an exemplar in the delivery of early childhood immunization through analysis of DTP1 and DTP3 coverage data. Through interviews and focus group discussions at the national, regional, district, health post, and community level, we investigated factors that contributed to high and sustained vaccine coverage. We conducted a thematic analysis through application of implementation science frameworks to determine critical success factors. We triangulated these findings with quantitative analyses using publicly available data. Results: The following success factors emerged: 1) Codification of health as a human right, - along with other vaccine-specific legislation - ensured the stability of vaccination programming; 2) National and multi-national partnerships supported information sharing, division of labor, and mutual capacity building; 3) Pro-vaccine messaging through various mediums, which was tailored to local needs, generated public awareness; 4) Female Community Health Volunteers educated community members as trusted and compassionate neighbors; and 5) Cultural values fostered collective responsibility and community ownership of vaccine coverage. Conclusion: This case study of Nepal suggests that the success of its national immunization program relied on the engagement and understanding of the beneficiaries. The immunization program was supported by consistent and reliable commitment, collaboration, awareness, and collective responsibility between the government, community, and partners. These networks are strengthened through a collective dedication to vaccination programming and a universal belief in health as a human right.

First Dose of the BNT162b2 mRNA COVID-19 Vaccine Reduces Symptom Duration and Viral Clearance in Healthcare Workers.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected more than one hundred million people since the beginning of the worldwide pandemic. In this study, data from a large hospital in central Italy was used to evaluate the impact of the first dose of the BNT162b2 mRNA vaccine on SARS-CoV-2 infections in terms of the prevalence of symptomatic cases, symptom duration, and viral clearance timing. All vaccinated Healthcare Workers (HCWs) with positive RT-PCR by nasopharyngeal (NP) swabs were divided into two cohorts (positive RT-PCR within day 12 and positive RT-PCR between day 13 and day 21 after first dose administration) and compared for the presence and duration of symptoms and the timing of viral clearance. The same variables were evaluated across HCWs with positive RT-PCR within 6 days after first dose administration and non-vaccinated HCWs with positive RT-PCR between 1 October 2020 and 28 February 2021. Eighteen HCWs tested positive on RT-PCR by NP swab from day 1 to day 12 after the 1st dose administration (incidence rate 6.2 × 10-4) and 5 HCWs from day 13 to day 21 (incidence rate 2.3 × 10-4). Symptom duration and viral clearance timing are significantly shorter in the cohort of HCWs with positive RT-PCR 12 days after the first dose of the BNT162b2 mRNA vaccine. The administration of the first dose proved effective in reducing presence, symptom duration, and viral clearance even in HCWs vaccinated for less than 6 days. These results could have implications on public health and post-exposure prophylaxis.

Cyclic Di-Adenosine Monophosphate: A Promising Adjuvant Candidate for the Development of Neonatal Vaccines.

Underdeveloped immunity during the neonatal age makes this period one of the most dangerous during the human lifespan, with infection-related mortality being one of the highest of all age groups. It is also discussed that vaccination during this time window may result in tolerance rather than in productive immunity, thus raising concerns about the overall vaccine-mediated protective efficacy. Cyclic di-nucleotides (CDN) are bacterial second messengers that are rapidly sensed by the immune system as a danger signal, allowing the utilization of these molecules as potent activators of the immune response. We have previously shown that cyclic di-adenosine monophosphate (CDA) is a potent and versatile adjuvant capable of promoting humoral and cellular immunity. We characterize here the cytokine profiles elicited by CDA in neonatal cord blood in comparison with other promising neonatal adjuvants, such as the imidazoquinoline resiquimod (R848), which is a synthetic dual TLR7 and TLR8 agonist. We observed superior activity of CDA in eliciting T helper 1 (Th1) and T follicular helper (TfH) cytokines in cells from human cord blood when compared to R848. Additional in vivo studies in mice showed that neonatal priming in a three-dose vaccination schedule is beneficial when CDA is used as a vaccine adjuvant. Humoral antibody titers were significantly higher in mice that received a neonatal prime as compared to those that did not. This effect was absent when using other adjuvants that were reported as suitable for neonatal vaccination. The biological significance of this immune response was assessed by a challenge with a genetically modified influenza H1N1 PR8 virus. The obtained results confirmed that CDA performed better than any other adjuvant tested. Altogether, our results suggest that CDA is a potent adjuvant in vitro on human cord blood, and in vivo in newborn mice, and thus a suitable candidate for the development of neonatal vaccines.