Hybrid immunity strategies: heterologous vaccination combined with natural SARS-CoV-2 infection

The continuous evolution of SARS-CoV-2 poses a significant challenge to existing immune barriers, highlighting the limitations of single-modality immunization. Hybrid immunity, shaped by the combination of natural infection and vaccination, induces more potent, broad-spectrum, and durable protective immunity. This review proposes that heterologous vaccination - the sequential use of vaccines based on different technological platforms - can serve as an active public health strategy to simulate and optimize hybrid immunity. We systematically elaborate on the synergistic advantages of hybrid immunity at both the humoral and cellular levels, citing evidence from multiple clinical trials that for both convalescent individuals and infection-naïve populations, heterologous vaccination regimens outperform homologous regimens in enhancing the breadth of neutralizing antibodies, strengthening cross-protection, and establishing robust immune memory. By mimicking the antigenic distance effect, heterologous vaccination safely replicates the immunological benefits of natural infection without the associated risks, positioning it as a key strategic tool to counter persistent viral evolution and build a resilient population-wide immune barrier.