Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age.

BACKGROUND: Safe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children. METHODS: We conducted a phase 1 dose-finding study and are conducting an ongoing phase 2-3 safety, immunogenicity, and efficacy trial of the BNT162b2 vaccine in healthy children 6 months to 11 years of age. We present results for children 6 months to less than 2 years of age and those 2 to 4 years of age through the data-cutoff dates (April 29, 2022, for safety and immunogenicity and June 17, 2022, for efficacy). In the phase 2-3 trial, participants were randomly assigned (in a 2:1 ratio) to receive two 3-µg doses of BNT162b2 or placebo. On the basis of preliminary immunogenicity results, a third 3-µg dose (≥8 weeks after dose 2) was administered starting in January 2022, which coincided with the emergence of the B.1.1.529 (omicron) variant. Immune responses at 1 month after doses 2 and 3 in children 6 months to less than 2 years of age and those 2 to 4 years of age were immunologically bridged to responses after dose 2 in persons 16 to 25 years of age who received 30 µg of BNT162b2 in the pivotal trial. RESULTS: During the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-µg dose) and 48 children 2 to 4 years of age (3-µg or 10-µg dose). The 3-µg dose level was selected for the phase 2-3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases). CONCLUSIONS: A three-dose primary series of 3-µg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age.

BACKGROUND: Safe, effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in children younger than 12 years of age. METHODS: A phase 1, dose-finding study and an ongoing phase 2-3 randomized trial are being conducted to investigate the safety, immunogenicity, and efficacy of two doses of the BNT162b2 vaccine administered 21 days apart in children 6 months to 11 years of age. We present results for 5-to-11-year-old children. In the phase 2-3 trial, participants were randomly assigned in a 2:1 ratio to receive two doses of either the BNT162b2 vaccine at the dose level identified during the open-label phase 1 study or placebo. Immune responses 1 month after the second dose of BNT162b2 were immunologically bridged to those in 16-to-25-year-olds from the pivotal trial of two 30-µg doses of BNT162b2. Vaccine efficacy against Covid-19 at 7 days or more after the second dose was assessed. RESULTS: During the phase 1 study, a total of 48 children 5 to 11 years of age received 10 µg, 20 µg, or 30 µg of the BNT162b2 vaccine (16 children at each dose level). On the basis of reactogenicity and immunogenicity, a dose level of 10 µg was selected for further study. In the phase 2-3 trial, a total of 2268 children were randomly assigned to receive the BNT162b2 vaccine (1517 children) or placebo (751 children). At data cutoff, the median follow-up was 2.3 months. In the 5-to-11-year-olds, as in other age groups, the BNT162b2 vaccine had a favorable safety profile. No vaccine-related serious adverse events were noted. One month after the second dose, the geometric mean ratio of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing titers in 5-to-11-year-olds to those in 16-to-25-year-olds was 1.04 (95% confidence interval [CI], 0.93 to 1.18), a ratio meeting the prespecified immunogenicity success criterion (lower bound of two-sided 95% CI, >0.67; geometric mean ratio point estimate, ≥0.8). Covid-19 with onset 7 days or more after the second dose was reported in three recipients of the BNT162b2 vaccine and in 16 placebo recipients (vaccine efficacy, 90.7%; 95% CI, 67.7 to 98.3). CONCLUSIONS: A Covid-19 vaccination regimen consisting of two 10-µg doses of BNT162b2 administered 21 days apart was found to be safe, immunogenic, and efficacious in children 5 to 11 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.).

Safety and Immunogenicity of an Andes Virus DNA Vaccine by Needle-Free Injection: A Randomized, Controlled Phase 1 Study.

BACKGROUND: Andes virus (ANDV), a rodent-borne hantavirus, causes hantavirus pulmonary syndrome (HPS). The safety and immunogenicity of a novel ANDV DNA vaccine was evaluated. METHODS: Phase 1, double-blind, dose-escalation trial randomly assigned 48 healthy adults to placebo or ANDV DNA vaccine delivered via needle-free jet injection. Cohorts 1 and 2 received 2 mg of DNA or placebo in a 3-dose (days 1, 29, 169) or 4-dose (days 1, 29, 57, 169) schedule, respectively. Cohorts 3 and 4 received 4 mg of DNA or placebo in the 3-dose and 4-dose schedule, respectively. Subjects were monitored for safety and neutralizing antibodies by pseudovirion neutralization assay (PsVNA50) and plaque reduction neutralization test (PRNT50). RESULTS: While 98% and 65% of subjects had at least 1 local or systemic solicited adverse event (AE), respectively, most AEs were mild or moderate; no related serious AEs were detected. Cohorts 2, 3, and 4 had higher seroconversion rates than cohort 1 and seropositivity of at least 80% by day 197, sustained through day 337. PsVNA50 geometric mean titers were highest for cohort 4 on and after day 197. CONCLUSIONS: This first-in-human candidate HPS vaccine trial demonstrated that an ANDV DNA vaccine was safe and induced a robust, durable immune response. Clinical Trials Registration. NCT03682107.

Acute severe respiratory syndrome coronavirus-2 treatment overview for pediatrics.

PURPOSE OF REVIEW: The novel severe respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has caused a world-wide pandemic with devastating effects. Fortunately, most children display only mild-to-moderate symptoms, but there are a subset that will have severe symptoms warranting treatment. This review evaluates the current evidence for antiviral and anti-inflammatory treatment of acute SARS-COV-2 infections, including coronavirus disease 2019 in pediatrics. RECENT FINDINGS: Treatment recommendations continue to evolve with emerging results from clinical trials. Initial therapies were tailored to repurposed medications, and have now transitioned toward more specific antiviral therapy. In addition to specific antiviral therapy, there is also support to modulate the immune system and reduce inflammatory damage seen in coronavirus disease 2019. Much of the data result from adult studies with subsequent extrapolation to pediatrics. SUMMARY: Recommended therapy will continue to adapt as results return from clinical trials. A continued commitment from the National Institutes of Health and research community to assist in determining optimal therapies for pediatric patients is essential. Until then, most recommendations will likely be informed from the results seen in adult populations.

A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.

Hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients are at increased risk for Clostridioides difficile infection (CDI). We conducted a multicenter retrospective study to describe the incidence of CDI in children transplanted between January 2010 and June 2013. Nested case-control substudies, matched 1:1 by transplant type, institution, patient age, and time of year (quartile) of transplant, identified CDI risk factors. Cohorts included 1496 HCT and 1090 SOT recipients. Among HCT recipients, 355 CDI episodes were diagnosed in 265 recipients (18.2%). Nested case-control study identified prior history of CDI (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5-4.7), proton pump inhibitors (PPIs; OR 2.1, 95% CI 1.3-3.4), and exposure to third- (OR 2.4, 95% CI 1.4-4.2) or fourth-generation (OR 2.1, 95% CI 1.2-3.7) cephalosporins as risk factors. Notably, fluoroquinolone exposure appeared protective (OR 0.6, 95% CI 0.3-0.9). Ninety-two episodes of CDI were diagnosed among 79 SOT recipients (7.3%), and exposure to PPIs (OR 2.4, 95% CI 1.1-5.4) and third-generation cephalosporin therapy (OR 3.9, 95% CI 1.4-10.5) were identified as risk factors. Strategies to decrease PPI use and changes in the class of prophylactic antibiotics may impact CDI incidence and warrant further study.

Fall 2023 ACIP Update on Meningococcal, RSV, COVID-19, and Other Pediatric Vaccines.

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts that provides advice to the Centers for Disease Control and Prevention, normally meets 3 times per year to develop US vaccine recommendations. The ACIP met October 25 to 26, 2023, to discuss meningococcal vaccines, mpox vaccines, respiratory syncytial virus (RSV) vaccines, influenza vaccines, coronavirus disease 2019 (COVID-19) vaccines, and the combined pediatric and adult immunization schedules for 2024. The ACIP also held special meetings on September 12 and September 22 to discuss COVID-19 2023-2024 vaccine recommendations and RSV immunization in pregnant women. This update summarizes the proceedings of these meetings that are most relevant to the pediatric population. Major updates for pediatric clinicians include recommendations for XBB monovalent COVID-19 immunization for the 2023-2024 respiratory season, the recently licensed pentavalent meningococcal conjugate vaccine and mpox vaccination in high-risk young adults, and discussion regarding the parallel strategies of protection against RSV disease in infants via maternal immunization during pregnancy or direct prophylaxis of infants with nirsevimab.

June 2024 ACIP Meeting Update: Influenza, COVID-19, RSV, and Other Vaccines.

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts that provides advice to the Centers for Disease Control and Prevention, normally meets 3 times per year to develop US vaccine recommendations. The ACIP met June 26 through 28, 2024. This update summarizes the proceedings of this meeting, with an emphasis on topics that are most relevant to the pediatric population. Major updates for pediatric clinicians include COVID-19 and influenza vaccine recommendations for the 2024 to 2025 season, meningococcal vaccination considerations, information regarding preferred Haemophilus influenzae type B containing vaccines for American Indian and Alaskan Native infants, and updates regarding implementation and effectiveness of RSV immunization in pregnant people and infants.

February 2024 ACIP Meeting Update: Meningococcal, RSV, COVID-19, and Other Vaccines.

The Advisory Committee on Immunization Practices, a group of medical and public health experts that provides advice to the Centers for Disease Control and Prevention, normally meets 3 times per year to develop US vaccine recommendations. The Advisory Committee on Immunization Practices met February 28 to 29, 2024, to discuss coronavirus disease 2019 vaccines, chikungunya vaccines, diphtheria-tetanus vaccine, influenza vaccines, polio vaccines, respiratory syncytial virus vaccines, meningococcal vaccines, pneumococcal vaccines, and Vaxelis (Diphtheria, Tetanus, Pertussis, Inactivated Poliovirus, Haemophilus influenzae b Conjugate, and Hepatitis B Vaccine). This update summarizes the proceedings of these meetings, with an emphasis on topics that are most relevant to the pediatric population. Major updates for pediatric clinicians include information about changes on influenza vaccine composition, meningococcal vaccination considerations, updated guidance for children with a contraindication to pertussis-containing vaccines, and recommendations of the world's first chikungunya vaccine for certain populations.

Bivalent Omicron BA.4/BA.5 BNT162b2 Vaccine in 6-Month- to <12-Year-Olds.

BACKGROUND: With the future epidemiology and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uncertain, the use of safe and effective coronavirus disease 2019 (COVID-19) vaccines in pediatric populations remains important. METHODS: We report data from two open-label substudies of an ongoing phase 1/2/3 master study (NCT05543616) investigating the safety and immunogenicity of a variant-adapted bivalent COVID-19 vaccine encoding ancestral and Omicron BA.4/BA.5 spike proteins (bivalent BNT162b2). The open-label groups presented here evaluate dose 4 with bivalent BNT162b2 in 6-month- to <12-year-olds who previously received three original (monovalent) BNT162b2 doses. In 6-month- to <5-year-olds, primary immunogenicity objectives were to demonstrate superiority (neutralizing titer) and noninferiority (seroresponse rate) to Omicron BA.4/BA.5 and noninferiority (neutralizing titer and seroresponse rate) to SARS-CoV-2 ancestral strains in participants who received bivalent BNT162b2 dose 4 compared with a matched group who received three doses of original BNT162b2 in the pivotal pediatric study (NCT04816643). In 5- to <12-year-olds, primary immunogenicity comparisons were descriptive. Reactogenicity and safety following vaccination were evaluated. RESULTS: In 6-month- to <5-year-olds, dose 4 with bivalent BNT162b2 met predefined immunogenicity superiority and noninferiority criteria against Omicron BA.4/BA.5 and ancestral strains when compared with dose 3 of original BNT162b2. In 5- to <12-year-olds, bivalent BNT162b2 induced robust Omicron BA.4/BA.5 and ancestral strain neutralizing titers comparable with dose 3 of original BNT162b2. The safety profile for dose 4 of bivalent BNT162b2 given as dose 4 was consistent with that of original BNT162b2 in 6-month- to <12-year-olds. Reactogenicity events were generally mild to moderate. No adverse events led to discontinuation. CONCLUSIONS: These safety and immunogenicity data support a favorable benefit-risk profile for a variant-adapted BNT162b2 in children <12 years old.

February 2023 Updates of the Advisory Committee on Immunization Practices.

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts who provides expert advice to the Centers for Disease Control and Prevention, normally meets three times per year to develop U.S. vaccine recommendations. The ACIP met on February 22-24, 2023, to discuss mpox vaccine, influenza vaccines, pneumococcus vaccines, meningococci vaccines, polio vaccines, respiratory syncytial virus (RSV) vaccine, chikungunya vaccines, dengue vaccines, and COVID-19 vaccines.

Summer 2023 ACIP Update: RSV Prevention and Updated Recommendations on Other Vaccines.

The Advisory Committee on Immunization Practices (ACIP), a group of medical and public health experts that provides advice to the Centers for Disease Control and Prevention, normally meets 3 times per year to develop US vaccine recommendations. The ACIP met June 21-23, 2023, to discuss respiratory syncytial virus (RSV) vaccines, influenza vaccines, pneumococcal vaccines, meningococcal vaccines, and COVID-19 vaccines. The ACIP also held a special meeting on August 3, 2023, to discuss RSV prophylaxis in infants. This update summarizes the proceedings of these meetings that are most relevant to the pediatric population. Major updates for pediatric clinicians include a new recommendation for the monoclonal antibody nirsevimab for prevention of RSV disease in all infants, recommendations regarding use of 20-valent pneumococcal conjugate vaccine, and discussion of potential forthcoming changes to meningococcal and COVID-19 vaccination recommendations.

Tocilizumab for Treatment of Children and Young Adults With Severe Acute COVID-19: Experience at a Quaternary-care Children's Hospital.

We describe the clinical characteristics and outcomes of 16 children and young adults with severe acute COVID-19 who were treated with tocilizumab. Patients who were discharged by day 28 were more likely to be treated with tocilizumab earlier in their COVID-19 illness and had lower ferritin and interleukin-6 levels compared with those who were not discharged by day 28.

Single Site Experience of the use of Monoclonal Antibodies for the Treatment of COVID-19 in High-risk Pediatric and Young Adult Patients.

BACKGROUND: Effective therapeutic agents for the treatment of COVID-19 have been investigated since the onset of the pandemic. Monoclonal antibodies targeting the spike protein of SARS-CoV-2 have been developed for the treatment of mild or moderate COVID disease in high-risk populations. Despite widespread use in the adult population, data are limited on the safety and efficacy of monoclonal antibody infusions in the adolescent and young adult population. METHODS: Patients who received bamlanivimab, bamlanivimab-etesevimab, casirivimab-imdevimab, or sotrovimab for treatment of mild-to-moderate COVID-19 disease at Cincinnati Children's Hospital Medical Center from 5/1/2020 to 3/1/2022 were identified retrospectively. Patient data including demographics, adverse events, and outcomes were extracted from patients' charts and summarized by standard descriptive summaries. RESULTS: Ninety-four patients received monoclonal antibody therapy, of which 14 (14.9%) received either bamlanivimab or bamlanivimab-etesevimab, 54 (57.4%) received casirivimab-imdevimab, and 26 (27.6%) received sotrovimab. Ten patients (10.6%) experienced one or more infusion-related adverse event. Of the patients who experienced adverse events, all resolved with cessation of infusion. No life-threatening events or deaths occurred. Within 90 days of receiving a monoclonal antibody, 12 patients (12.7%) required additional medical care for ongoing COVID symptoms. Five of these were either hospitalized or received escalation of care while already in the hospital. All subsequently fully recovered. Neither infusion-related adverse events nor progression to hospitalization for ongoing COVID-19 symptoms following monoclonal antibody administration were associated with any particular underlying condition. CONCLUSIONS: Overall, monoclonal antibodies are reasonably well-tolerated COVID-19 therapies in high-risk adolescent and young adult populations.

Robust humoral and cellular recall responses to AZD1222 attenuate breakthrough SARS-CoV-2 infection compared to unvaccinated.

Background: Breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in coronavirus disease 2019 (COVID-19) vaccinees typically produces milder disease than infection in unvaccinated individuals. Methods: To explore disease attenuation, we examined COVID-19 symptom burden and immuno-virologic responses to symptomatic SARS-CoV-2 infection in participants (AZD1222: n=177/17,617; placebo: n=203/8,528) from a 2:1 randomized, placebo-controlled, phase 3 study of two-dose primary series AZD1222 (ChAdOx1 nCoV-19) vaccination (NCT04516746). Results: We observed that AZD1222 vaccinees had an overall lower incidence and shorter duration of COVID-19 symptoms compared with placebo recipients, as well as lower SARS-CoV-2 viral loads and a shorter median duration of viral shedding in saliva. Vaccinees demonstrated a robust antibody recall response versus placebo recipients with low-to-moderate inverse correlations with virologic endpoints. Vaccinees also demonstrated an enriched polyfunctional spike-specific Th-1-biased CD4+ and CD8+ T-cell response that was associated with strong inverse correlations with virologic endpoints. Conclusion: Robust immune responses following AZD1222 vaccination attenuate COVID-19 disease severity and restrict SARS-CoV-2 transmission potential by reducing viral loads and the duration of viral shedding in saliva. Collectively, these analyses underscore the essential role of vaccination in mitigating the COVID-19 pandemic.

Sterility Cultures Following Pancreatectomy with Islet Autotransplantation in the Pediatric Population: Do They Matter?

BACKGROUND: Pancreatectomy with islet autotransplantation (IAT) is a treatment option for children with debilitating chronic pancreatitis. Sterility cultures from preservation solutions are often positive, yet their impact has not been well studied in children. METHODS: A retrospective review of all patients who underwent IAT from 2015 to 2018 at a single institution was performed. Sterility culture data were obtained from both the pancreas transport and islet transplant media. All patients received prophylactic perioperative meropenem and vancomycin for 72 h per our protocol. If cultures resulted positive, antibiotics were extended for a total of 7 days. Primary outcomes were postoperative fever and 30-day infectious complications. RESULTS: Forty-one patients underwent IAT during the study period. Seventeen (41.5 %) patients had negative cultures of both the transport and transplant media, while 24 (58.5 %) patients had a positive culture from either sample. Of these patients, 13 (31.7 %) were positive in both, 10 (24.4 %) were positive in only the transport media, and 1 (2.4 %) was positive in only the transplant media. Patients with positive transplant media were similar with regard to age, gender, etiology, and disease duration compared to those with negative transplant media (all p > 0.05), but the positive group was more likely to have a pancreatic stent in place at the time of surgery (38.5 % vs. 4.2 %, p = 0.01). The overall postoperative infectious complication rate was 31.2 % (n = 13). No difference was detected between the transplant positive and negative culture groups in postoperative fever or 30-day infectious complications (p > 0.05 for each). CONCLUSION: An existing pancreatic stent at the time of pancreatectomy with IAT is a risk factor for positive sterility cultures. However, positive islet transplant media culture was not associated with increased risk of post-IAT infection or morbidity in the setting of an empiric antibiotic protocol. Future work is necessary to study the optimal perioperative antibiotic regimen in pediatric IAT.

Respiratory Viral Infections in Solid Organ and Hematopoietic Stem Cell Transplantation.

Respiratory viruses are common in solid organ and hematopoietic stem cell transplant recipients and a recognized cause of significant morbidity and mortality. Epidemiology, risk factors, and attributable mortality in both populations are reviewed. In addition, virus-specific prevention and treatment options, including emerging investigational therapies, are discussed for respiratory syncytial virus, influenza, adenovirus, parainfluenza, and other respiratory viruses.