IMT504: A New and Potent Adjuvant for Rabies Vaccines Permitting Significant Dose Sparing

Abstract

Background: Rabies virus infection causes encephalitis, which is almost always fatal. Vaccination can be extremely effective at preventing disease but is prohibitively costly. Vaccine formulations allowing dose-sparing and fewer inoculations with faster antibody response would be extremely desirable. IMT504, an immunostimulatory non-CpG oligodeoxynucleotide, is a highly potent vaccine adjuvant. Methods: Human and rat antibody measurements, and rat challenge studies were performed. Results: In rats, highly effective immune responses with IMT504 were observed even after diluting vaccine up to 1/625. In highly lethal, live intracerebral rabies challenge studies, protection occurred even with extremely dilute vaccine plus IMT504. In humans, antibody titers developed faster and were significantly higher with IMT504-adjuvanted diluted vaccine vs non-adjuvanted vaccine (full strength or diluted). All five administered IMT504-adjuvanted diluted vaccine reached protective antibodies (≥0.5 IU/ml) after the second injection. After the third injection, individuals receiving IMT504-adjuvanted diluted vaccine reached levels approximately 10 times higher than controls (M ± SEM: 31.0 ± 10.9 vs 3.40 ± 0.99 IU/ml). Conclusions: These data suggest that IMT504 may allow fewer inoculations, highly significant dose-sparing of vaccine, rapid antibody production and protection from rabies. Extensive clinical studies are necessary to confirm if the use of IMT504 will permit significantly greater access to highly effective life-saving rabies vaccines.

Rabies – epidemiology, pathogenesis, public health concerns and advances in diagnosis and control: a comprehensive review

“…Various novel approaches like application of vectors, lipopeptide vaccines, plasmid DNA and plant virus-based rabies vaccines are also being explored (Ohara et al 2013). Also, the paucity of vaccine adjuvants, essentially limited to aluminum salts, is corrected at last by producing new emulsions (oil-in-water), toll-like receptor agonists, liposomes, cytokines, cpG oligonucleotides and other materials (Yusibov et al 2002;Fischer et al 2003;Consales and Bolzan 2007;Dhama et al 2008;Montaner et al 2012;Dhama et al 2013).…”

Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy

“…Most of these effects indicate that IMT504 incubation empowers B cells for competent presentation of antigens to CD4+ T cells. In line with this, addition of IMT504 to different vaccines greatly increases their activity[371-373]. However, the strong secretion of IL-6 and IL-10 induced by IMT504 suggests that IMT504-activated B cells may also participate in regulation of the immune response.…”

“…Primary targets of IMT504 are B lymphocytes (B), PDCs, NK and NKT cells. IMT504 acting on B and PDCs induces a phenotype of antigen presenting cells, which in the presence of an appropriate antigenic stimulus initiates a strong adaptive immune response[371-373]. On the other hand, IMT504 acting on NK and NKT cells, in collaboration with IL-2, induces the strong secretion of IFN-γ and TNF-α that can induce MSC immunosuppressive properties and of GM-CSF that can activate MDSCs.…”

Antiviral Therapy for Human Rabies

“…Intravenous administration of rabies immune globulin in association with a method of opening the BBB for entry into the CNS may be effective. Immunostimulatory substances (for example, oligodeoxynucleotides) have been shown to be effective adjuvants for rabies vaccines [83] and also may potentially be useful for therapy of rabies.…”