The SARS-CoV-2 virus, responsible for the COVID-19 pandemic, presents ongoing challenges to global public health, notably through the persistence of immunity and the risk of reinfection. This chapter delves into the mechanisms of immune response to SARS-CoV-2, examining both the innate and adaptive immune responses, with a focus on humoral and cellular immunity. It explores the duration of immunity following natural infection and vaccination, highlighting the roles of neutralizing antibodies, memory B cells and T cells. Factors influencing the risk of reinfection, such as waning immunity, the emergence of variants of concern (VOCs), immune compromise and demographic variables, are thoroughly analyzed. The chapter underscores the importance of booster vaccinations, continuous surveillance and adaptive public health measures in mitigating reinfection risks. Future directions emphasize the need for longitudinal studies, identifying immune correlates of protection and developing personalized immunization strategies. This comprehensive exploration aims to inform and guide public health strategies in managing the long-term impact of COVID-19. This chapter explores the mechanisms of immune response to SARS-CoV-2, the longevity of immune protection, factors influencing reinfection risk and implications for public health strategies.