The Immunogenicity of Subunit Vaccines for Respiratory Syncytial Virus after Co-formulation with Aluminum Hydroxide Adjuvant and Recombinant Interleukin-12

Abstract

The effects of recombinant interleukin-12 (rIL-12) on immune responses generated by subunit vaccines for respiratory syncytial virus (RSV) were evaluated in BALB/c mice. Parenteral co-administration of rIL-12 with F/AlOH or F/PBS resulted in accelerated clearance of infectious virus from the lungs 4 days after challenge. The immune responses elicited by 0.03 microg of F protein plus 10 ng of rIL-12 adsorbed to AlOH were more efficacious than those induced by 3 microg of F protein co-formulated with 1,000 ng of rIL-12 in PBS alone. Adsorption to AIOH prolonged the presence of rIL-12 in the sera. The resultant systemic humoral immune responses after vaccination with F/AlOH or G/AlOH were dependent on the dose of rIL-12 and characterized by heightened serum immunoglobulin G2a (IgG2a) antibody titers. Co-administration of rIL-12 with F/AlOH was also associated with diminished protein-specific IgE titers, elevated neutralizing antibody titers, and interferon-gamma and (IFN-gamma) in the sera, and enhanced antigen-dependent killer cell activity in the lungs after challenge. For maximum benefit, the data suggested that rIL-12 must be co-administered with F/AlOH. Collectively, the results indicated that rIL-12 directed immune responses toward a type 1 phenotype. However, examination of pulmonary inflammatory cells after challenge suggested that the type 1 phenotype was not absolute. Co-formulation with rIL-12 did not diminish pulmonary eosinophilia upon challenge of naive mice primed with F/AlOH, G/AlOH, or FI-RSV, and CD4+ T cells were expanded relative to the CD8+ T-cell compartment. These results are important for the future design of subunit vaccines against RSV.

General Strategy for Decoration of Enveloped Viruses with Functionally Active Lipid-Modified Cytokines

“…Rabies virus and herpes simplex virus vaccines supplemented with interleukin-2 (IL-2) were found to be successful in animals at about the same time (50,76). Subsequently, other cytokines have been evaluated as adjuvants in a variety of experimental vaccines (22,23,25,26). In a related approach, naked DNA or recombinant vaccine strains have been engineered to express soluble cytokines upon administration to the host (6,7,24,27,35,36).…”

Vaccination of Rhesus Macaques with a Recombinant Measles Virus Expressing Interleukin‐12 Alters Humoral and Cellular Immune Responses

“…IL-12 has also been shown to affect antibody production either directly, by interaction with B cells, or indirectly, by the stimulation of T helper cells [17][18][19], and to promote interferon (IFN)-g production by CD8 + T cells [20]. Consequently, IL-12 has been proposed for use as an adjuvant for a variety of experimental vaccines [21][22][23][24] and is particularly attractive for use with live MV vaccines, because the addition of IL-12 during administration of the live attenuated vaccine may overcome the problems posed by maternal antibody interference and immaturity of the immune system in infants while preventing the immunosuppression associated with high-titer vaccines.…”

Immunopathology of RSV infection: prospects for developing vaccines without this complication

“…MPL also improved the efficacy of a chimeric FG subunit protein in cotton rats; both peribronchiolitis and alveolitis were observed after RSV challenge in cotton rats vaccinated with FG and aluminium hydroxide, but reduced in cotton rats vaccinated with FG formulated with aluminium hydroxide and MPL [185]. A combination of QS-21 and IL-12 proved to be Th1stimulating when formulated with pure F protein [186]. Formulation of FI-RSV with MPL even resulted in reduced polymorphonuclear leukocyte infiltration of lung alveoli [161], and mRNA expression of a number of Th1-and Th2-type cytokines and chemokines normally associated with FI-RSV-primed RSV challenge [187].…”