A chimeric porcine circovirus (PCV) 1–2b vaccine strain and its parental wild-type PCV2b strain from China (PCV2-J) were used separately to vaccinate BALB/c mice and tissue and serum samples were collected from the mice to investigate whether the replication properties of the viruses differed. The spleen lymphocytes from the infected mice were cultured in vitro; the amounts of interferon-γ-secreting cells (IFN-γ-SCs) and levels of interleukin (IL) 2, IL-4 and IL-10 in the culture fluids were monitored. The results showed that PCV1–2b induced higher levels of antibody production in the infected mice than the PCV2b-J isolate. Viremia declined gradually in both infection groups and the DNA copy numbers were nearly equal in both groups of mouse tissues tested. The IFN-γ-SC levels were clearly up-regulated in both the PCV1–2b- and PCV2b-J-infected mice. In both mouse groups, IL-2 was up-regulated, and IL-10 was detected at low levels, while IL-4 was always below the limit of detection. Similar experiments were performed in pigs and the results showed that when infected with either PCV1–2b or PCV2b-J the pigs experienced high-level antibody responses, with no significant differences between the infection groups. In the pig model, the development of IFN-γ-SCs in response to PCV1–2b and PCV2b-J infections was detected. However, the PCV1–2b strain tended to elicit more IFN-γ-SCs in the peripheral blood mononuclear cell population of the infected pigs from 21 to 28 days post infection than the PCV2b-J isolate did. The concentrations of IL-2 were transiently different between the PCV1–2b and PCV2b-J infected pigs, while those of IL-10 and IL-2 were similar in both groups, but were lower than those elicited in mice. These results indicated that BALB/c mouse could be used as an alternate model for evaluating the efficacy of attenuated PCV1–2b vaccines.