Several studies, including our own, suggest that hybrid immunity confers more effective cross-variant neutralization than a natural infection alone (Fig. 1a,c). Vaccination after infection with the SARS-CoV-2 ancestral Wuhan-Hu-1 strain or with Alpha, Delta and Beta variants increases the number of SARS-CoV-2 memory T cells and B cells by more than an order of magnitude by recruiting new B cell clones into the memory pool and expanding persistent clones1,2 (Fig. 1c). Formation of memory B cells by vaccination and robust enhancement of serologic responses by SARS-CoV-2 infection results in durable2, high levels of cross-variant neutralizing antibodies1 and reduces the risk of reinfection3.

a | Emerging Omicron sub-variants escape immunity conferred by infection with non-Omicron SARS-CoV-2 variants4,5. b | A second dose of mRNA vaccine gives moderate protection for non-Omicron and limited protection against Omicron variants 6–8 months post-vaccination4,5. c | Hybrid immunity elicited by BA.1 breakthrough infection in vaccinated individuals (2 doses) provides cross-variant protection but causes neutralization escape for newly emerging Omicron variants2,8. d | Hybrid immunity generated by Delta infection in vaccinated individuals elicits broader protection against non-micron and Omicron (BA.1) variants6. e | Compared with B.1.617.2, immune imprinting generated by infection with Wuhan/B.1.1.7, vaccination (3 doses) and Omicron reinfection decreases Omicron neutralizing antibodies and T cell recognition, which may increase chances of Omicron reinfection. Consistent with Reynolds et al.9.

These actions hold for Omicron, at least to a certain degree. A BA.1 breakthrough infection elicits a broad cross-variant neutralizing activity against, for example, the ancestral WA1 and Delta variants, whereas BA.1 infection in the absence of prior vaccination only induces neutralization of BA.1 (ref.4). But titres are lower overall: anti-BA.1 neutralizing titres elicited by a BA.1 breakthrough infection average sixfold lower than the anti-Delta neutralizing titres elicited by a Delta breakthrough infection4,5 (Fig. 1d). Consequently, newly emerging Omicron variants, including BA.2.12.1, BA.4 and BA.5, show neutralization escape when tested with sera from BA.1-infected individuals6 (Fig. 1c). The immunity recall after breakthrough infections varies with respect to pathogenicity of variants. For Delta breakthrough infections, the neutralizing antibody titres against Delta and other variants are high and correlate with disease severity5, but Omicron breakthrough infections generate weak immunity against Omicron and emerging sub-lineages. The reasons include the altered antigenic properties of the Omicron subvariants, based on a substantial number of additional spike mutations6, and the lowered pathogenicity of the Omicron subvariants, with replication mostly confined to the upper respiratory tract, mortality reduced in animal models, and ex vivo viral replication weakened.