COVID-19 vaccination has been shown to protect children and adolescents against SARS-CoV-2 infection and disease, with efficacy increasing with additional doses. However, the increased risk of myocarditis associated with mRNA vaccination in adolescents, particularly following a seconddose, suggests a potential role for fractional or heterologous second doses. Data regarding heterologous and fractional dose COVID-19 vaccine schedules in adolescents, however, are lacking. Additionally, the decline in vaccine-induced immunity over time, combined with the emergence of immune-evasive variants of concern underscores the need for booster doses to maintain protection against SARS-CoV-2 infection.This DPhil aimed to investigate the humoral immune response to homologous and heterologous COVID-19 vaccination in adolescents using samples collected as part of the Com-COV3 trial. Com-COV3 was a phase II, single-blind, multi-centre, randomised-controlled trial to determine the reactogenicity and immunogenicity of COVID-19 vaccines in healthy 12-to-16-year-olds. Cohort A participants were randomised to receive either 30 µg BNT162b2 (BNT-30), 10 µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), 8 weeks after a first 30µg dose of BNT162b2. Cohort B participants were randomised to receive either BNT162b2 30μg, BNT162b2 10μg (adult vaccine formulation), BNT162b2 10μg (paediatric formulation), NVXCoV2373, or Meningococcal B vaccine (control) as a third (booster) dose following two-30μg dose BNT162b2 primary regimen received at least 90 days prior to enrolment. The primary outcome was reactogenicity. The secondary outcome was immunogenicity. Exploratory immunological studies to investigate the humoral immune response to both homologous and heterologous second and third dose schedules were also conducted.Reactions were mostly mild-to-moderate across both cohorts. Compared to BNT-30, a comparable antibody response was observed at day 28 following a heterologous second dose (NVX) but significantly lower following a fractional dose (BNT-10). In Cohort B, anti-spike IgG at day 28 post-third dose was similar in the 10μg BNT162b2 (adult) group and significantly lower in the 10μg BNT162b2 (paediatric) and NVXCoV2373 groups compared with 30µg BNT162b2.SARS-CoV-2 spike-specific BMEM responses were substantially increased 28 days after both a 30µg BNT162b2 and NVX-CoV2373 third (booster) dose. Peak BMEM responses were also significantly higher following a booster dose compared to the primary series. Additionally, both homologous and heterologous primary and booster immunisation resulted in significantly increased antibody avidity. Significantly enhanced mucosal spike-specific IgG and IgA responses were also observed following both homologous and heterologous second dose schedules. Following a third (booster) dose, mucosal IgG responses were significantly elevated after mRNA vaccination, while a significant increase in mucosal spike-specific IgA was only observed in participants with prior SARS-CoV-2 infection.This was the first study to investigate the immune response to heterologous COVID-19 vaccine schedules in adolescents. The findings demonstrate that both homologous and heterologous second and third (booster) dose schedules are highly immunogenic and demonstrate favourable reactogenicity.