Abstract
Studies were conducted in mice, hamsters, sheep, and two species of nonhuman primates which demonstrate the adjuvant activity of a new metabolizable lipid emulsion with marginally immunogenic doses of Formalin-inactivated viral vaccines. The lipid base consists of highly refined peanut oil emulsified in aqueous vaccines with glycerol and lecithin. Hamsters and mice inoculated with lipid emulsion plus western or Venezuelan equine encephalitis vaccine were significantly more resistant than vaccinated controls to lethal homologous virus challenge. Sheep given one dose of lipid emulsion plus Rift Valley fever vaccine developed significantly higher antibody titers than control sheep receiving only vaccine. Cynomolgous monkeys inoculated with lipid emulsion plus Rift Valley fever vaccine developed 16-fold greater peak primary and 20-fold greater secondary antibody titers than those of vaccine controls. Similar lipid emulsion-Rift Valley fever studies in rhesus monkeys resulted in 37- and 300-fold increases in primary and secondary titers, respectively, compared with monkeys given vaccine alone. Neither the sequence of combining antigen with lipid nor the exact ratio of aqueous phase to lipid phase affected the survival of Venezuelan equine encephalitis-vaccinated mice challenged with homologous lethal virus. This lipid formulation has several advantages over other water-in-oil adjuvants for potential use in humans. The components are metabolizable or normal host constituents, it is easily emulsified with aqueous vaccines by gentle agitation, and it is relatively nonreactogenic in recipients.
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Selected References
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- ASHWORTH C. T., STEMBRIDGE V. A., SANDERS E. Lipid absorption, transport and hepatic assimilation with electron microscopy. Am J Physiol. 1960 Jun;198:1326–1328. doi: 10.1152/ajplegacy.1960.198.6.1326. [DOI] [PubMed] [Google Scholar]
- Bartelloni P. J., McKinney R. W., Calia F. M., Ramsburg H. H., Cole F. E., Jr Inactivated western equine encephalomyelitis vaccine propagated in chick embryo cell culture. Clinical and serological evaluation in man. Am J Trop Med Hyg. 1971 Jan;20(1):146–149. doi: 10.4269/ajtmh.1971.20.146. [DOI] [PubMed] [Google Scholar]
- Chedid L., Lederer E. Past, present and future of the synthetic immunoadjuvant MDP and its analogs. Biochem Pharmacol. 1978;27(18):2183–2186. doi: 10.1016/0006-2952(78)90074-6. [DOI] [PubMed] [Google Scholar]
- Cole F. E., Jr, May S. W., Eddy G. A. Inactivated Venezuelan equine encephalomyelitis vaccine prepared from attenuated (TC-83 strain) virus. Appl Microbiol. 1974 Jan;27(1):150–153. doi: 10.1128/am.27.1.150-153.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cole F. E., Jr, McKinney R. W. Use of hamsters of potency assay of Eastern and Western equine encephalitis vaccines. Appl Microbiol. 1969 Jun;17(6):927–928. doi: 10.1128/am.17.6.927-928.1969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cole F. E., Jr, Pedersen C. E., Jr, Robinson D. M. Early protection in hamsters immunized with attenuated Venezuelan equine encephalomyelitis vaccine. Appl Microbiol. 1972 Oct;24(4):604–608. doi: 10.1128/am.24.4.604-608.1972. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dancey G. F., Yasuda T., Kinsky S. C. Effect of liposomal model membrane composition on immunogenicity. J Immunol. 1978 Apr;120(4):1109–1113. [PubMed] [Google Scholar]
- Earley E., Peralta P. H., Johnson K. M. A plaque neutralization method for arboviruses. Proc Soc Exp Biol Med. 1967 Jul;125(3):741–747. doi: 10.3181/00379727-125-32194. [DOI] [PubMed] [Google Scholar]
- FREEMAN J. A., ROBERTS K. E. A fine structural study of renal glycosuria. Exp Mol Pathol. 1963 Feb;2:83–92. doi: 10.1016/0014-4800(63)90010-8. [DOI] [PubMed] [Google Scholar]
- FREUND J. The mode of action of immunologic adjuvants. Bibl Tuberc. 1956;(10):130–148. [PubMed] [Google Scholar]
- Fendler J. H., Romero A. Liposomes as drug carriers. Life Sci. 1977 Apr 1;20(7):1109–1120. doi: 10.1016/0024-3205(77)90481-7. [DOI] [PubMed] [Google Scholar]
- Friedman H. Macrophages in immunity--concluding remarks and general summary. Fed Proc. 1978 Jan;37(1):102–104. [PubMed] [Google Scholar]
- Frost P., Lance E. M. On the mechanism of action of adjuvants. Immunology. 1978 Jul;35(1):63–68. [PMC free article] [PubMed] [Google Scholar]
- Haywood A. M. 'Phagocytosis' of sendai virus by model membranes. J Gen Virol. 1975 Oct;29(1):63–68. doi: 10.1099/0022-1317-29-1-63. [DOI] [PubMed] [Google Scholar]
- Hilleman M. R. Critical appraisal of emulsified oil adjuvants applied to viral vaccines. Prog Med Virol. 1966;8:131–182. [PubMed] [Google Scholar]
- Hilleman M. R., Woodhour A., Friedman A., Weibel R. E., Stokes J., Jr The clinical application of adjuvant 65. Ann Allergy. 1972 Mar;30(3):152–158. [PubMed] [Google Scholar]
- Kinsky S. C., Nicolotti R. A. Immunological properties of model membranes. Annu Rev Biochem. 1977;46:49–67. doi: 10.1146/annurev.bi.46.070177.000405. [DOI] [PubMed] [Google Scholar]
- Lane F. C., Unanue E. R. Immunologic events during Listeria monocytogenes infection in mice: adjuvanticity and immunogenicity of macrophage-bound antigens. J Immunol. 1973 Mar;110(3):829–834. [PubMed] [Google Scholar]
- MCCANDLESS E. L., SALKY N. K., TRUMBULL M. L., ZILVERSMIT D. B. The preparation and use of anhydrous fat emulsions for intravenous feeding and metabolic experiments. J Lab Clin Med. 1956 Sep;48(3):386–391. [PubMed] [Google Scholar]
- Mooney J. J., Dalrymple J. M., Alving C. R., Russell P. K. Interaction of Sindbis virus with liposomal model membranes. J Virol. 1975 Feb;15(2):225–231. doi: 10.1128/jvi.15.2.225-231.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murray R., Cohen P., Hardegree M. C. Mineral oil adjuvants: biological and chemical studies. Ann Allergy. 1972 Mar;30(3):146–151. [PubMed] [Google Scholar]
- Ozato K., Ziegler H. K., Henney C. S. Liposomes as model membrane systems for immune attack. I. Transfer of antigenic determinants to lymphocyte membranes after interactions with hapten-bearing liposomes. J Immunol. 1978 Oct;121(4):1376–1382. [PubMed] [Google Scholar]
- Randall R., Mills J. W. FATAL ENCEPHALITIS IN MAN DUE TO THE VENEZUELAN VIRUS OF EQUINE ENCEPHALOMYELITIS IN TRINIDAD. Science. 1944 Mar 17;99(2568):225–226. doi: 10.1126/science.99.2568.225. [DOI] [PubMed] [Google Scholar]
- Rosenthal A. S., Barcinski M. A., Rosenwasser L. J. Function of macrophages in genetic control of immune responsiveness. Fed Proc. 1978 Jan;37(1):79–85. [PubMed] [Google Scholar]
- Stuart-Harris C. H. Adjuvant influenza vaccines. Bull World Health Organ. 1969;41(3):617–621. [PMC free article] [PubMed] [Google Scholar]
- Unanue E. R., Cerottini J. C. The immunogenicity of antigen bound to the plasma membrane of macrophages. J Exp Med. 1970 Apr 1;131(4):711–725. doi: 10.1084/jem.131.4.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
- WADDELL W. R., GEYER R. P., SASLAW I. M., STARE F. J. Normal disappearance curve of emulsified fat from the blood stream and some factors which influence it. Am J Physiol. 1953 Jul;174(1):39–42. doi: 10.1152/ajplegacy.1953.174.1.39. [DOI] [PubMed] [Google Scholar]
- WOODHOUR A. F., METZGAR D. P., STIM T. B., TYTELL A. A., HILLEMAN M. R. NEW METABOLIZABLE IMMUNOLOGIC ADJUVANT FOR HUMAN USE. I. DEVELOPMENT AND ANIMAL IMMUNE RESPONSE. Proc Soc Exp Biol Med. 1964 Jun;116:516–523. doi: 10.3181/00379727-116-29295. [DOI] [PubMed] [Google Scholar]
- Wilson T., Papahadjopoulos D., Taber R. Biological properties of poliovirus encapsulated in lipid vesicles: antibody resistance and infectivity in virus-resistant cells. Proc Natl Acad Sci U S A. 1977 Aug;74(8):3471–3475. doi: 10.1073/pnas.74.8.3471. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Woodhour A. F., Metzgar D. P., Lampson G. P., Machlowitz R. A., Tytell A. A., Hilleman M. R. New metabolizable immunologic adjuvant for human use. 4. Development of highly purified influenza virus vaccine in adjuvant 65. Proc Soc Exp Biol Med. 1966 Dec;123(3):778–782. doi: 10.3181/00379727-123-31601. [DOI] [PubMed] [Google Scholar]