An important aspect of
ocular herpes simplex virus type 1 (HSV-1)
vaccine development is identification of an appropriate adjuvant capable of significantly reducing both virus replication in the eye and explant reactivation in trigeminal ganglia. We showed recently that a recombinant HSV-1
vaccine expressing
interleukin-4 (IL-4) is more efficacious against ocular HSV-1 challenge than recombinant viruses expressing
IL-2 or
gamma interferon (IFN-gamma) (Y. Osorio and H. Ghiasi, J. Virol. 77:5774-5783, 2003). We have now constructed and compared recombinant HSV-1 viruses expressing
IL-12p35 or
IL-12p40 molecule with IL-4-expressing HSV-1 recombinant virus. BALB/c mice were immunized intraperitoneally with IL-12p35-, IL-12p40-, IL-12p35+IL-12p40-, or IL-4-expressing recombinant HSV-1 viruses. Controls included mice immunized with parental virus and mice immunized with the avirulent strain KOS. The efficacy of each
vaccine in protecting against ocular challenge with HSV-1 was assessed in terms of survival,
eye disease, virus replication in the eye, and explant reactivation.
Neutralizing antibody titers, T-cell responses, and expression of 32
cytokines and
chemokines were also evaluated. Mice immunized with recombinant HSV-1 expressing
IL-12p35 exhibited the lowest virus replication in the eye, the most rapid virus clearance, and the lowest level of explant reactivation. The higher efficacy against ocular virus replication and explant reactivation correlated with higher
neutralizing antibody titers, cytotoxic-T-lymphocyte activities, and IFN-gamma expression in recombinant HSV-1 expressing
IL-12p35 compared to other
vaccines. Mice immunized with both
IL-12p35 and
IL-12p40 had lower
neutralizing antibody responses than mice immunized with
IL-12p35 alone. Our results confirm that recombinant virus
vaccines expressing
cytokine genes can enhance the overall protection against
infection, with the
IL-12p35 vaccine being the most efficacious of those tested. Collectively, the results support the potential use of
IL-12p35 as a
vaccine adjuvant, without the toxicity-associated concerns of
IL-12.