Results from the HIPRA-HH-3 clinical study demonstrate that PHH-1V (a recombinant fusion protein vaccine based on a beta-alpha heterodimer) is safe and immunogenic as a heterologous booster dose in adolescents previously vaccinated with BNT162b2. The induced immune response was significantly higher than that observed in young adults (≥18 to ≤25 years) from the HIPRA-HH-2 study, with elevated levels of neutralizing antibodies against variants such as Omicron BA.1, Wuhan Hu1 (WH1), Beta, and Delta. Additionally, a greater amount of total antibodies and an increase in cellular response (T cells) against BA.1 and Beta were observed. Adverse events were mostly mild or moderate (injection site pain and headache), and no serious events were reported. These results support the use of PHH-1V as a booster in adolescents within SARS-CoV-2 vaccination strategies