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 oligo-deoxynucleotide, is a highly potent vaccine adjuvant. Methods: Human and rat antibody measurements, and rat chal-lenge 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.
KeywordsIMT504AdjuvantRabiesVaccineHumanAnimal
N. Johnson, A. F. Cunningham and A. R. Fooks, “The Immune Response to Rabies Virus Infection and Vaccination,” Vaccine, Vol. 28, No. 23, 2010, pp. 3896-3901. doi:10.1016/j.vaccine.2010.03.039
M. J. Warrell and D. A. Warrel, “Rabies and Other Lyssavirus Diseases,” Lancet, Vol. 363, No. 9413, 2004, pp. 959-969. doi:10.1016/S0140-6736(04)15792-9
WHO, “WHO Position Paper on Rabies Vaccines,” Weekly Epidemiol Record, Vol. 82, No. 49-50, 2007, pp. 425-436.
G. S. Turner, “Immunoglobulin (IgG) and (IgM) Antibody Responses to Rabies Vaccine,” Journal of General Virology, Vol. 40, 1978, pp. 595-604. doi:10.1099/0022-1317-40-3-595
Centers for Disease Control and Prevention, “Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies,” Morbidity and Mortality Weekly Report, Vol. 59, No. 2, 2010, pp. 1-9.
H. L. Davis, R. Weeratna, T. J. Waldschmidt, L. Tygrett, J. Schorr, A. M. Krieg and R. Weeranta, “CpG DNA is a Potent Enhancer of Specific Immunity in Mice Immunized with Recombinant Hepatitis B Surface Antigen,” The Journal of Immunology, Vol. 160, No. 2, 1998, pp. 870-876.
S. A. Halperin, G. Van Nest, B. Smith, S. Abtahi, H. Whiley and J. J. Eiden, “A Phase I Study of the Safety and Immunogenicity of Recombinant Hepatitis B Surface Antigen Co-Administered with an Immunostimulatory Phosphorothioate Oligonucleotide Adjuvant,” Vaccine, Vol. 21, No. 19-20, 2003, pp. 2461-2467. doi:10.1016/S0264-410X(03)00045-8
A. M. Krieg, “CpG Motifs in Bacterial DNA and Their Immune Effects,” Annual Review of Immunology, Vol. 20, No. 1, 2002, pp. 709-760. doi:10.1146/annurev.immunol.20.100301.064842
F. Elias, J. Flo, R. A. Lopez, J. Zorzopulos, A. Montaner and J. M. Rodriguez, “Strong Cytosineguanosine-Independent Immunostimulation in Humans and Other Primates by Synthetic Oligodeoxynucleotides with PyNTT- TTGT Motifs,” The Journal of Immunology, Vol. 171, No. 7, 2003, pp. 3697-3704.
A. Hernando-Insua, A. D. Montaner, J. M. Rodriguez, F. Elias, J. Flo, R. A. Lopez, J. Zorzopulos, E. L. Hofer and N. A. Chasseing, “IMT504, the Prototype of the Immunostimulatory Oligonucleotides of the PyNTTTTGT Class, Increases the Number of Progenitors of Mesenchymal Stem Cells both in Vitro and in Vivo: Potential use in Tissue Repair Therapy,” Stem Cells, Vol. 25, No. 4, 2007, pp. 1047-1054. doi:10.1634/stemcells.2006-0479
Council for International Organizations of Medical Sciences International, “Ethical Guidelines for Biomedical Research Involving Human Subjects,” Bulletin of Medical Ethics Bull Med Ethics, Vol. 182, 2002, pp. 17-23.
M. Feyssaguet, L. Dacheux, L. Audry, A. Compoint, J. L. Morize, I. Blanchard and H. Bourhy, “Multicenter Comparative Study of a New ELISA, PLATELIA RABIES II, for the Detection and Titration of Anti-Rabies Glycoprotein Antibodies and Comparison with the rapid Fluorescent Focus Inhibition Test (RFFIT) on Human Samples from Vaccinated and Non-Vaccinated People,” Vaccine, Vol. 25, No. 12, 2007, pp. 2244-2251. doi:10.1016/j.vaccine.2006.12.012
R. J. Welch, B. L. Anderson, C. M. Litwin, “An Evaluation of Two Commercially Available ELISAs and One In-House Reference Laboratory ELISA for the Determination of Human Anti-Rabies Virus Antibodies,” Journal of Medical Microbiology, Vol. 58, No. 6, 2009, pp. 806-810. doi:10.1099/jmm.0.006064-0
S. M. Moore and C. A. Hanlon, “Rabies-Specific Antibodies: Measuring Surrogates of Protection against a Fatal Disease,” PLoS Neglected Tropical Diseases, Vol. 4, 2010, pp. 1-6. doi:10.1371/journal.pntd.0000595
S. A. Plotkin, “Vaccines: Correlates of Vaccine-Induced Immunity,” Clinical Infectious Diseases, Vol. 47, No. 3, 2008, pp. 401-409. doi:10.1086/589862
C. Strady, R. Jaussaud, I. Béguinot, M. Lienard and A. Strady, “Predictive Factors for the Neutralizing Antibody Response Following Pre-Exposure Rabies Immunization: Validation of a New Booster Dose Strategy,” Vaccine, Vol. 18, No. 24, 2000, pp. 2661-2667. doi:10.1016/S0264-410X(00)00054-2
M. J. Warrell, A. Riddell, L.-M. Yu, J. Phipps, L. Diggle, H. Bourhy, J. J. Deeks, A. R. Fooks, L. Audry, S. M. Brookes, F.-X. Meslin, R. Moxon, A. J. Pollard and D. A. Warrell, “A Simplified 4-Site Economic Intradermal Post-Exposure Rabies Vaccine Regimen: A Randomised Controlled Comparison with Standard Methods,” PLoS Neglected Tropical Diseases, Vol. 2, No. 4, 2008, pp. 1-9. doi:10.1371/journal.pntd.0000224
M. J. Warrell, P. Suntharasamai, K. G. Nicholson, D. A. Warrell, P. Chanthavanich, C. Viravan, A. Sinhaseni, R. Phanfung, C. Xueref and J. C. Vincent-Falquet, “Multi-Site Intradermal and Multi-Site Subcutaneous Rabies Vaccination: Improved Economical Regimes,” Lancet, Vol. 1, No. 8382, 1984, pp. 874-876. doi:10.1016/S0140-6736(84)91340-0
J. Lang, D. Q. Hoa, N. V. Gioi, N. C. Vien, C. V. Nguyen, N. Rouyrre and R. Forrat, “Immunogenicity and Safety of Low-Dose Intradermal Rabies Vaccination Given during an Expanded Programme on Immunization Session in Viet Nam: Results of a Comparative Randomized Trial,” Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol. 93, No. 2, 1999, pp. 208-213. doi:10.1016/S0035-9203(99)90309-7
X. Wang, M. Bao, M. Wan, H. Wei, L. Wang, H. Yu, X. Zhang, Y. Yu and L. Wang, “A CpG Oligonucleotide Acts as a Potent Adjuvant for Inactivated Rabies Virus Vaccine,” Vaccine, Vol. 26, No. 15, 2008, pp. 1893-1901. doi:10.1016/j.vaccine.2008.01.043
F. Elias, J. Flo, J. M. Rodriguez, A. D. Nichilo, R. A. Lopez, J. Zorzopulos, C. Nagle, M. Lahoz and A. Montaner, “PyNTTTTGT Prototype Oligonucleotide IMT504 is a Potent Adjuvant for the Recombinant Hepatitis B Vaccine that Enhances the Th1 Response,” Vaccine, Vol. 23, No. 27, 2005, pp. 3597-3603.
A. D. Montaner, A. Denichilo, J. M. Rodríguez, J. Fló, R. A. López, A. Pontoriero, V. Savy, E. Baumeister, R. Frank, J. Zorzopulos and F. Elías, “Addition of the Immunostimulatory Oligonucleotide IMT504 to a Seasonal Flu Vaccine Increases Hemagglutinin Antibody Titers in Young Adult and Elder Rats, and Expands the Anti-Hemagglutinin Antibody Repertoire,” Nucleic Acid Therapeutics, Vol. 21, No. 4, 2011, pp. 265-274. doi:10.1016/j.vaccine.2004.12.030