Durable immune response and protection induced by mosaic RBD‐np/SAS immunization from SARS‐CoV‐2 WT, and VOCs challenge. Five months (9 months for BA.5) after the final immunization, mice were infected with SARS‐CoV‐2 WT and VOCs (Alpha, Beta, Delta, BA.1.1, and BA.5), and serum were collected before the infection to detect the neutralization titre by FRNT. A) Neutralization titres of SARS‐CoV‐2 after 5 months of boost immunization were detected by FRNT. n = 3 mice in PBS group; n = 4‐6 mice in mosaic RBD‐NP/SAS group. B) Five months after boost immunization, mice were transduced with 2.5 × 108 PFU of Ad5‐hACE2. Five days later, mice were intranasally infected with B) 1 × 105 FFU of SARS‐CoV‐2 WT, 5 × 104 FFU of SARS‐CoV‐2 Delta; Mice were directly infected with 5 × 104 FFU of SARS‐CoV‐2 Alpha, Beta, BA.1.1, and BA.5. Weight was monitored daily until day 10 post‐infection. C) Viral load in lung is expressed as FFU/g tissue. n = 3‐4 mice per group. D) Sections of paraffin embedded lungs from infected mice were stained with hematoxylin/eosin at day 4 post‐infection. Scale bar = 50 um. All results are expressed as mean ± SEM. Statistical analyses were performed using two‐way ANOVA.