Current status and potential application of ISCOMs in veterinary medicine.

The immune stimulating complex (ISCOM) is a 40 nm nanoparticle used as a delivery system for vaccine antigens, targeting the immune system both after parenteral and mucosal administration. The ISCOM is made up of saponin, lipids and antigen usually held together by hydrophobic interaction between these three components. The compulsory elements to form the ISCOM structure are cholesterol and saponin. When the antigen is omitted the ISCOM-MATRIX is formed. There are a number of saponins that can form ISCOMs, and many other substances (including antigens, targeting and immuno-modulating molecules) can be incorporated into the ISCOM provided they are hydrophobic or rendered to be hydrophobic. Thus, it is possible to create ISCOM particles with different properties. After parenteral immunisation of the ISCOM, the T cell response is first detected in the draining lymph node. Subsequently, the T cell response is localised to the spleen, while the B cell response is first found both in the draining lymph nodes and in the spleen. Up to 50 days later, the majority of the antibody producing cells is found in the bone marrow (BM). In contrast, antigens that have been adjuvanted in an oil emulsion, limit the T cell response to the draining lymph nodes while the B cell response is found in the draining lymph nodes and spleen, but not in the BM. The ISCOM efficiently evokes CD8+, MHC class 1 restricted T cell response. The deposit of antigens both to the endosomal vesicles and to the cytosol of antigen presenting cells (APCs) explains why both T helper cells (vesicles) and cytotoxic T lymphocytes (cytosol) are efficiently induced by ISCOMs. The T helper (Th) cell response is balanced in the sense that both Th1 and Th2 cells are induced. Prominent IL-12 production by cells in the innate system is a characteristic reaction induced by ISCOMs, promoting the development of a strong Th1 response. After mucosal administration by the intranasal or the intestinal routes, the ISCOM induces strong specific mucosal IgA responses in local and remote mucosal surfaces. Also T cell responses are evoked by the mucosal administration. A large number of experimental ISCOM vaccines have been tested and protection has been induced against a number of pathogens in various species including chronic and persistent infections exemplified by human immune deficiency virus 1 (HIV-1), and 2 (HIV-2) and simian immune deficiency virus (SIV) in primates, and various herpes virus infections in several species. In contrast to a conventional rabies virus vaccine the ISCOM rabies formulation protected mice after exposure to the virulent virus. Recently, experimental ISCOM vaccines were shown to efficiently induce immune response in newborns of murine and bovine species in the presence of maternal antibodies, while conventional vaccines have failed. ISCOM vaccines are on the market for horses and cattle and several other ISCOM vaccines are under development. Since the ISCOM and the ISCOM-MATRIX can be blended with live attenuated vaccine antigens without hampering the proliferation of the live vaccine antigens, it opens the possibility to use the ISCOM adjuvant system in a mixture of live and killed vaccine antigens.

Immunity in neonates.

Passively derived maternal immunity hampers active immunization of newborns. Further, an immature immune system contributes to a weak and Th2 polarized immunity. This state of immunity in early life sustains endemic infections in man and continuous reinfections in animal herds. The endemic infections of the young occur preferentially when the immune system is still functionally immature and when the low levels of maternal antibodies are no longer protective but yet blocks protective immune responses. Vaccines overcoming these problems would have strong positive effects on the herd health and environmental benefits. The Th2 bias of the newborn is mediated by high levels of progesterone and Th2 cytokines produced in the maternal-fetal interface. The activity of the innate system is enhanced in the mother during the prepartus period, certainly having effects on the offspring. Newborn, 2-days-old, mice can be primed with Sendai virus envelope proteins as model antigens to induce Th1 or Th2 responses, dependent on the supplementation of the virus antigen formulation with Th1 or Th2 adjuvants. This priming has a strong life-long effect when complemented with subsequent boosts. However and importantly this priming effect can be modulated by adjuvants focusing for Th1 and Th2 when applied to the mice at 6 weeks of age, i.e. when they are immunologically adult. It has been shown in various species, besides mice, i.e. dog, sheep, horse and seal, that a strong Th1 driving adjuvant can induce immune response and protection in newborns when conventional vaccines fail. In conclusion, the Th2 bias prevailing around partus can be overcome by appropriate immunological treatments, permitting effective vaccination and protective immunity in the newborn.