Interim safety and immunogenicity of COVID-19 omicron BA.1 variant-containing vaccine in children in the USA: an open-label non-randomised phase 3 trial.

BACKGROUND: Variant-containing mRNA vaccines for COVID-19 to broaden protection against SARS-CoV-2 variants are recommended based on findings in adults. We report interim safety and immunogenicity of an omicron BA.1 variant-containing (mRNA-1273.214) primary vaccination series and booster dose in paediatric populations. METHODS: This open-label, two-part, non-randomised phase 3 trial enrolled participants aged 6 months to 5 years at 24 US study sites. Eligible participants were generally healthy or had stable chronic conditions, without known SARS-CoV-2 infection in the previous 90 days. Individuals who were acutely ill or febrile 1 day before or at the screening visit or those who previously received other COVID-19 vaccines (except mRNA-1273 for part 2) were excluded. In part 1, SARS-CoV-2-vaccine-naive participants received two-dose mRNA-1273.214 (25 µg; omicron BA.1 and ancestral Wuhan-Hu-1 mRNA) primary series. In part 2, participants who previously completed the two-dose mRNA-1273 (25 µg) primary series in KidCOVE (NCT04796896) received a mRNA-1273.214 (10 µg) booster dose. Primary study outcomes were safety and reactogenicity of the mRNA-1273.214 primary series (part 1) or booster dose (part 2) as well as the inferred effectiveness of mRNA-1273.214 based on immune responses against ancestral SARS-CoV-2 (D614G) and omicron BA.1 variant at 28 days post-primary series (part 1) or post-booster dose (part 2). The safety set included participants who received at least one dose of the study vaccine; the immunogenicity set included those who provided immunogenicity samples. Interim safety and immunogenicity are summarised in this analysis as of the data cutoff date (Dec 5, 2022). This trial is registered with ClinicalTrials.gov, NCT05436834. FINDINGS: Between June 21, 2022, and Dec 5, 2022, 179 participants received one or more doses of mRNA-1273.214 primary series (part 1) and 539 received a mRNA-1273.214 booster dose (part 2). The safety profile within 28 days after either dose of the mRNA-1273.214 primary series and the booster dose was consistent with that of the mRNA-1273 primary series in this age group, with no new safety concerns or vaccine-related serious adverse events observed. At 28 days after primary series dose 2 and the booster dose, both mRNA-1273.214 primary series (day 57, including all participants with or without evidence of prior SARS-CoV-2 infection at baseline) and booster (day 29, including participants without evidence of prior SARS-CoV-2 infection at baseline) elicited responses that were superior against omicron-BA.1 (geometric mean ratio part 1: 25·4 [95% CI 20·1-32·1] and part 2: 12·5 [11·0-14·3]) and non-inferior against D614G (part 1: 0·8 [0·7-1·0] and part 2: 3·1 [2·8-3·5]), compared with neutralising antibody responses induced by the mRNA-1273 primary series (in a historical comparator group). INTERPRETATION: mRNA-1273.214 was immunogenic against BA.1 and D614G in children aged 6 months to 5 years, with a comparable safety profile to mRNA-1273, when given as a two-dose primary series or a booster dose. These results are aligned with the US Centers for Disease Control and Prevention recommendations for the use of variant-containing vaccines for continued protection against the emerging variants of SARS-CoV-2. FUNDING: Moderna.

Evaluation of mRNA-1273 Covid-19 Vaccine in Children 6 to 11 Years of Age.

BACKGROUND: Vaccination of children to prevent coronavirus disease 2019 (Covid-19) is an urgent public health need. The safety, immunogenicity, and efficacy of the mRNA-1273 vaccine in children 6 to 11 years of age are unknown. METHODS: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled expansion evaluation of the selected dose. In part 2, we randomly assigned children (6 to 11 years of age) in a 3:1 ratio to receive two injections of mRNA-1273 (50 µg each) or placebo, administered 28 days apart. The primary objectives were evaluation of the safety of the vaccine in children and the noninferiority of the immune response in these children to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives included determination of the incidences of confirmed Covid-19 and severe acute respiratory syndrome coronavirus 2 infection, regardless of symptoms. Interim analysis results are reported. RESULTS: In part 1 of the trial, 751 children received 50-µg or 100-µg injections of the mRNA-1273 vaccine, and on the basis of safety and immunogenicity results, the 50-µg dose level was selected for part 2. In part 2 of the trial, 4016 children were randomly assigned to receive two injections of mRNA-1273 (50 µg each) or placebo and were followed for a median of 82 days (interquartile range, 14 to 94) after the first injection. This dose level was associated with mainly low-grade, transient adverse events, most commonly injection-site pain, headache, and fatigue. No vaccine-related serious adverse events, multisystem inflammatory syndrome in children, myocarditis, or pericarditis were reported as of the data-cutoff date. One month after the second injection (day 57), the neutralizing antibody titer in children who received mRNA-1273 at a 50-µg level was 1610 (95% confidence interval [CI], 1457 to 1780), as compared with 1300 (95% CI, 1171 to 1443) at the 100-µg level in young adults, with serologic responses in at least 99.0% of the participants in both age groups, findings that met the prespecified noninferiority success criterion. Estimated vaccine efficacy was 88.0% (95% CI, 70.0 to 95.8) against Covid-19 occurring 14 days or more after the first injection, at a time when B.1.617.2 (delta) was the dominant circulating variant. CONCLUSIONS: Two 50-µg doses of the mRNA-1273 vaccine were found to be safe and effective in inducing immune responses and preventing Covid-19 in children 6 to 11 years of age; these responses were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Lubiprostone for Pediatric Functional Constipation: Randomized, Controlled, Double-Blind Study With Long-term Extension.

BACKGROUND & AIMS: Pediatric functional constipation (PFC) is a common problem in children that causes distress and presents treatment challenges to health care professionals. We conducted a randomized, placebo-controlled trial (study 1) in patients with PFC (6-17 years of age) to evaluate the efficacy and safety of lubiprostone, followed by an open-label extension for those who completed the placebo-controlled phase (study 2). METHODS: Study 1 (NCT02042183) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 12-week study evaluating the efficacy and safety of lubiprostone 12 µg twice daily (BID) and 24 µg BID. Study 2 (NCT02138136) was a phase 3, long-term, open-label extension of study 1. In both studies, lubiprostone doses were based on patients' weight. Efficacy was assessed solely based on study 1, with a primary endpoint of overall spontaneous bowel movement (SBM) response (increase of ≥1 SBM/wk vs baseline and ≥3 SBMs/wk for ≥9 weeks, including 3 of the final 4 weeks). RESULTS: 606 patients were randomized to treatment (placebo: n = 202; lubiprostone: n = 404) in study 1. No statistically significant difference in overall SBM response rate was observed between the lubiprostone and placebo groups (18.5% vs 14.4%; P = .2245). Both the 12-µg BID and 24-µg BID doses of lubiprostone were well tolerated in the double-blind and extension phases, with a safety profile consistent with that seen in adult studies. CONCLUSIONS: Lubiprostone did not demonstrate statistically significant effectiveness over placebo in children and adolescents with PFC but did demonstrate a safety profile similar to that in adults. (ClinicalTrials.gov: Number: NCT02042183; Number: NCT02138136).

A Phase II Trial of Safety, Tolerability and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, Compared With 13-Valent Pneumococcal Conjugate Vaccine in Healthy Infants.

BACKGROUND: Pneumococcal disease remains a public health priority worldwide. This phase 2 study (V114-008; NCT02987972; EudraCT 2016-001117-25) compared safety and immunogenicity of 2 clinical lots of V114 (investigational 15-valent pneumococcal vaccine: 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 22F*, 23F, 33F*) to 13-valent pneumococcal conjugate vaccine (PCV13) in healthy infants (*serotypes unique to V114). METHODS: Healthy infants 6-12 weeks old were randomized to receive a 4-dose regimen of V114 Lot 1, V114 Lot 2 or PCV13 at 2, 4, 6 and 12-15 months old. Adverse events were evaluated after each dose. Primary immunogenicity endpoint was to demonstrate noninferiority of V114 Lot 1 and V114 Lot 2 relative to PCV13 based on proportion of infants achieving serotype-specific IgG concentration ≥0.35 µg/mL for 13 serotypes shared with PCV13 at 1 month postdose 3 (PD3). Serotype-specific IgG geometric mean concentrations (GMCs) for all 15 V114 serotypes were measured at PD3, predose 4 and 1 month postdose 4 (PD4). RESULTS: Overall, 1044 of 1051 randomized infants received ≥1 dose of vaccine (V114 Lot 1 [n = 350], V114 Lot 2 [n = 347] or PCV13 [n = 347]). Adverse events were generally comparable across groups. At PD3, both V114 lots met noninferiority criteria for all 13 serotypes shared with PCV13. IgG GMCs were comparable among V114 and PCV13 recipients at PD3 and PD4. Serotype 3 responses were higher following receipt of V114 than PCV13. Both V114 lots induced higher GMCs than PCV13 to the 2 unique V114 serotypes. CONCLUSIONS: Immunogenicity of both V114 lots was noninferior to PCV13 for all 13 shared serotypes between the 2 vaccines and displayed comparable safety and tolerability profiles to PCV13.

Trends in Utilization of Outpatient Respiratory Syncytial Virus Prophylaxis with Palivizumab among Medicaid- and Commercially Insured Infants.

INTRODUCTION: Palivizumab is indicated for the prevention of respiratory syncytial virus (RSV) infection in high-risk children. Previous palivizumab utilization studies examined prior authorization claims but did not examine utilization within insured populations as a whole. This study describes outpatient palivizumab utilization trends and characterizes high-risk infants receiving palivizumab within Medicaid- and commercially insured populations. METHODS: Infants born July 1, 2003 through June 30, 2013 were identified in the MarketScan® Multistate Medicaid and Commercial claims databases. Infants with ≥ 18 months of continuous medical insurance enrollment with pharmacy benefits after birth and evidence of chronic lung disease of prematurity (CLDP), congenital heart disease (CHD), or preterm birth without CLDP or CHD were studied. Palivizumab use and demographic and clinical characteristics were measured in infant subgroups. Outpatient palivizumab utilization rates were calculated for each seasonal year (July-June) and for each infant subgroup. RESULTS: In total, 29,350 (2.1%) Medicaid-insured and 9589 (2.5%) commercially insured infants received palivizumab and had CLDP, CHD, or were born at < 37 weeks gestational age (wGA). Infants with CLDP (82%) and those < 29 wGA (78%) had the highest utilization. Decreases in utilization rates between the 2003-2004 and 2012-2013 seasons were seen among Medicaid-insured infants born at 29-36 wGA (all P < .0001), and commercially insured infants born at 31-32 wGA (P < .0001), 33-34 wGA (P = .055), 35-36 wGA (P < .0001), and with CHD (P = .003). Utilization by month was consistent across subgroups among Medicaid- and commercially insured infants, with most doses administered from November to March. CONCLUSION: Palivizumab use is targeted to a small percentage of infants who are at highest risk of hospitalization for RSV disease. Utilization declined in recent years in both Medicaid- and commercially insured infant groups. Most palivizumab doses were administered from November to March, with most infants receiving ≤ 5 doses. FUNDING: AstraZeneca.