Use of Interleukin 12 to Enhance the Cellular Immune Response of Swine to an Inactivated Herpesvirus Vaccine

Vaccination is the single most successful medical measure against infectious disease. However, the major barrier for achieving the full protective effect or immunization is how to render attenuated, killed, or subunit vaccines as immunogenic as the fully infectious versions of these microbes (Hughes and Babiuk, 1995; Rabinovich et al., 1994). In the case of PrV, infection with wild-type virus induces an immune response superior to vaccination with a live modified vaccine. After primary intranasal infection with wild-type PrV, the replication of a homologous secondary virus challenge is completely inhibited, and the much sought "sterile immunity" is generated (Kimman et al., 1994). In contrast, the immune response of pigs similarly exposed to PrV mutants, which have been attenuated by removal of the thymidine kinase (TK) and the envelope glycoprotein gE gene (McGregor et al., 1985; Zuckermann et al., 1988), is insufficient for preventing the replication of a homologous wild-type virus challenge (Kimman et al., 1994). Furthermore, inactivated PrV vaccines are even less effective at inducing protective immunity than are live modified PrV vaccines (de Leeuw and Van Orischot, 1985; Stellman et al., 1989; Vannier, 1985). The importance of inactivated and subunit vaccines resides in their stability and safety, since no infectious microbe is being introduced into the animal. However, because of the recognized lower effectiveness of inactivated vaccine types, they usually fall in disfavor when a modified live vaccine alternative is available. There is a critical need to develop strategies to enhance the immunogenicity of live, inactivated, and sub-unit vaccines for human and veterinary use (Hughes and Babiuk, 1995; Rabinovich et al., 1994). Although the inoculation of an animal with a virulent microbe is obviously not the desired method to produce sterile immunity, the immune response generated to infection with wild-type PrV clearly demonstrates that this type of immunity is possible. Research directed at devising strategies to increase the immunogenicity of different types of vaccines is necessary. Because of the wealth of information available on PrV immunity (reviewed by Chinsakchai and Molitor, 1994; Nauwynck, 1997), on PrV vaccines (Kimman et al., 1992, 1994; Mettenleiter, 1991; Scherba and Zuckermann, 1996) and increasingly on the porcine immune system (Lunney, 1993; Lunney et al., 1996; Saalmüller, 1995), the swine herpesvirus model is ideal for investigating the development of vaccine formulations with enhanced immunogenicity. Among the strategies currently being examined for the enhancement of the immunogenicity of inactivated and subunit vaccines is the use of recombinant cytokines administered together with antigen (Hughes and Babiuk, 1995; Rabinovich et al., 1994). The ability to regulate the development of an immune response by cytokines such as IL-12 provides the theoretical basis to use these cytokines as adjuvants to immunopotentiate the response to an inactivated vaccine. More importantly, it provides a model to investigate the mechanisms behind the induction of protective immunity and the components of a vaccine necessary for stimulating such a response. By providing cytokines such as IL-12 or IFN-gamma in combination with the vaccine inoculum, it is reasonable to expect that they will be able to direct the differentiation of T cells during the primary immune response. Modulation, in a predictable and desired manner of the quality and quantity of the induced protective immunity, should be achievable. The ability to manipulate a vaccine-induced immune response in the direction of a predominantly cellular response (Th1-like) instead of a predominantly humoral one (Th2-like) is perhaps best illustrated by the need to develop an effective vaccine against the porcine reproductive and respiratory syndrome (PRRS) virus, whose infectivity can be significantly enhanced in vitro and in vivo by antibody induced by vaccination