Reactogenicity, immunogenicity and breakthrough infections following heterologous or fractional second dose COVID-19 vaccination in adolescents (Com-COV3): A randomised controlled trial.

BACKGROUND: This was the first study to investigate the reactogenicity and immunogenicity of heterologous or fractional second dose COVID-19 vaccine regimens in adolescents. METHODS: A phase II, single-blind, multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022. Healthy 12-to-16 years olds were randomised (1:1:1) to either 30 µg BNT162b2 (BNT-30), 10 µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), 8 weeks after a first 30 µg dose of BNT162b2. The primary outcome was solicited systemic reactions in the week following vaccination. Secondary outcomes included immunogenicity and safety. 'Breakthrough infection' analyses were exploratory. FINDINGS: 148 participants were recruited (median age 14 years old, 62% female, 26% anti-nucleocapsid IgG seropositive pre-second dose); 132 participants received a second dose. Reactions were mostly mild-to-moderate, with lower rates in BNT-10 recipients. No vaccine-related serious adverse events occurred. Compared to BNT-30, at 28 days post-second dose anti-spike antibody responses were similar for NVX (adjusted geometric mean ratio [aGMR]) 1.09 95% confidence interval (CI): 0.84, 1.42] and lower for BNT-10 (aGMR 0.78 [95% CI: 0.61, 0.99]). For Omicron BA.1 and BA.2, the neutralising antibody titres for BNT-30 at day 28 were similar for BNT-10 (aGMR 1.0 [95% CI: 0.65, 1.54] and 1.02 [95% CI: 0.71, 1.48], respectively), but higher for NVX (aGMR 1.7 [95% CI: 1.07, 2.69] and 1.43 [95% CI: 0.96, 2.12], respectively). Compared to BNT-30, cellular immune responses were greatest for NVX (aGMR 1.73 [95% CI: 0.94, 3.18]), and lowest for BNT-10 (aGMR 0.65 [95% CI: 0.37, 1.15]) at 14 days post-second dose. Cellular responses were similar across the study arms by day 236 post-second dose. Amongst SARS-CoV-2 infection naïve participants, NVX participants had an 89% reduction in risk of self-reported 'breakthrough infection' compared to BNT-30 (adjusted hazard ratio [aHR] 0.11 [95% CI: 0.01, 0.86]) up until day 132 after second dose. BNT-10 recipients were more likely to have a 'breakthrough infection' compared to BNT-30 (aHR 2.14 [95% CI: 1.02, 4.51]) up to day 132 and day 236 post-second dose. Antibody responses at 132 and 236 days after second dose were similar for all vaccine schedules. INTERPRETATION: Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic. The enhanced performance of the heterologous schedule using NVX-CoV2373 against the Omicron SARS-CoV-2 variant suggests this mRNA prime and protein-subunit boost schedule may provide a greater breadth of protection than the licensed homologous schedule. FUNDING: National Institute for Health Research and Vaccine Task Force. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number registry: 12348322.

Long-term seroprotection after an adolescent booster meningococcal serogroup C vaccination.

OBJECTIVES: To determine long-term seroprotection after serogroup C meningococcal (MenC) vaccination at the age of 9-12 years, with or without booster vaccination at the age of 13-15 years. DESIGN: Observational cohort study; follow-on from randomised study. SETTING: Participants were recruited from English secondary schools (in Oxfordshire and Buckinghamshire). PARTICIPANTS AND INTERVENTIONS: Participants were primed with MenC CRM-glycoconjugate vaccine at the age of 9-12 years in the UK routine immunisation campaign. In previous studies they were randomised at 13 to 15 years of age to receive a booster dose of MenC-CRM glycoconjugate vaccine (CRM-group) or bivalent meningococcal serogroup A/C polysaccharide vaccine (PS-group), or they received no additional doses of MenC vaccine (control group). In this follow-on study, a blood sample was obtained 11 years after primary immunisation. Of 531 individuals eligible to participate, 134 were enrolled, and 124 were included in the analysis. MAIN OUTCOME MEASURES: MenC serum bactericidal antibody (SBA) geometric mean titre; proportion of participants with SBA titre ≥8 (putative protective threshold). RESULTS: Median ages at priming, boosting and blood sampling were 10.61, 14.42 and 22.11 years, respectively. Geometric mean titres for MenC SBA were: CRM group 1373 (95% CI 954 to 1977); PS group 1024 (687 to 1526); and controls 284 (167 to 483). SBA titres ≥8 were present in 50/54 (92.6%) controls and 70/70 (100%) boosted individuals. CONCLUSIONS: The planned introduction in the UK of an adolescent booster of MenC conjugate vaccine in 2013 is likely to provide sustained protection against MenC disease. TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT01459432).

Pandemic influenza A (H1N1) 2009 vaccination in children: a UK perspective.

Pandemic H1N1 influenza infection was common in the UK in 2009 and children were particularly vulnerable. Most cases were mild or subclinical, but there was significant mortality, predominantly in those with pre-existing disease. Despite the rapid development of monovalent pandemic vaccines, and the fast-tracked approval process, these products were not available for large-scale use until the end of the second wave of infection. Vaccine uptake was relatively low, both among children and health-care workers. The monovalent pandemic vaccines and the 2010/2011 trivalent seasonal influenza vaccines were immunogenic and effective, and they probably reduced the impact of the third wave of infection. Vaccines containing novel adjuvants enabled antigen sparing, but safety concerns could limit the future use of these adjuvanted influenza vaccines in children. Public perceptions that the threat of the pandemic was exaggerated by the authorities, and concerns about vaccine safety, might prompt an inadequate response to the next influenza pandemic, potentially compromising public health.

Persistence of serum bactericidal antibody one year after a booster dose of either a glycoconjugate or a plain polysaccharide vaccine against serogroup C Neisseria meningitidis given to adolescents previously immunized with a glycoconjugate vaccine.

BACKGROUND: Bactericidal antibody induced by immunization of infants with serogroup C Neisseria meningitidis (MenC) vaccines wanes rapidly during childhood. Adolescents are at particular risk from meningococcal disease, therefore they might benefit from a booster dose of vaccine. The duration of serologic response to such a booster in adolescents is unknown. METHODS: In a previous study, English schoolchildren, aged 9 to 12 years, who had received a monovalent MenC glycoconjugate vaccine in 1999-2000, were given either a plain polysaccharide vaccine (MenC-PS group, n = 150) or a glycoconjugate vaccine (MenC-CRM group, n = 95) at 13 to 15 years of age. In this follow-up study, serum bactericidal antibody titers and specific immunoglobulin G concentrations were assessed 1 year later. Results were compared with unboosted controls of similar age (control group, n = 298). RESULTS: Compliance with study protocol was achieved for 146 of the MenC-PS group, 92 of the MenC-CRM group, and 293 of the control group. Compared with the control group, both the MenC-PS and MenC-CRM groups had a significantly higher (P < 0.0001) geometric mean serum bactericidal antibody titers 1 year after the booster dose (geometric mean titers for MenC-PS group 3388 [95% confidence interval {CI}: 2460-4665]; MenC-CRM group 4417 [95% CI: 2951-6609]; control group 316 [95% CI: 252-396]). Specific immunoglobulin G concentration also rose and remained elevated 1 year after the booster. CONCLUSIONS: A booster dose of MenC vaccine given to adolescents produced a marked rise in bactericidal antibody, which remained elevated 1 year later. Introduction of an adolescent booster of MenC vaccine might provide enhanced long-term population control of the disease.