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. 1997 May;65(5):1716–1721. doi: 10.1128/iai.65.5.1716-1721.1997

Immunogenicity and protection in small-animal models with controlled-release tetanus toxoid microparticles as a single-dose vaccine.

M Singh 1, X M Li 1, H Wang 1, J P McGee 1, T Zamb 1, W Koff 1, C Y Wang 1, D T O'Hagan 1
PMCID: PMC175204  PMID: 9125552

Abstract

Tetanus toxoid (TT) was encapsulated in microparticles prepared from polylactide-co-glycolide polymers by a solvent-evaporation technique. Combinations of small- and large-sized microparticles with controlled-release characteristics were used to immunize Sprague-Dawley rats, and the antibody responses were monitored for 1 year. For comparison, control groups of rats were immunized at 0, 1, and 2 months with TT adsorbed to alum. The antibody responses generated by the TT entrapped in microparticles were comparable to those generated by TT adsorbed to alum in control groups from 32 weeks onwards. Microparticles with a single entrapped antigen (TT) induced better antibody responses than microparticles with two antigens (TT and diphtheria toxoid) entrapped simultaneously. A combination vaccine consisting of TT adsorbed to alum and also entrapped in microparticles gave the best antibody responses. In an inhibition assay designed to determine the relative levels of binding of antisera to the antigens, the sera from the microparticle- and the alum-immunized animals showed comparable levels of binding. In addition, in a passive-challenge study with mice, TT adsorbed to alum and TT entrapped in microparticles provided equal levels of protection against a lethal challenge with tetanus toxin. An intradermal-challenge study was also performed with rabbits, which showed similar levels of protection in sera from alum- and microparticle-immunized animals at 4, 12, and 32 weeks after immunization.

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Selected References

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  1. Aguado M. T. Future approaches to vaccine development: single-dose vaccines using controlled-release delivery systems. Vaccine. 1993;11(5):596–597. doi: 10.1016/0264-410x(93)90241-o. [DOI] [PubMed] [Google Scholar]
  2. Aguado M. T., Lambert P. H. Controlled-release vaccines--biodegradable polylactide/polyglycolide (PL/PG) microspheres as antigen vehicles. Immunobiology. 1992 Feb;184(2-3):113–125. doi: 10.1016/S0171-2985(11)80470-5. [DOI] [PubMed] [Google Scholar]
  3. Almeida A. J., Alpar H. O., Brown M. R. Immune response to nasal delivery of antigenically intact tetanus toxoid associated with poly(L-lactic acid) microspheres in rats, rabbits and guinea-pigs. J Pharm Pharmacol. 1993 Mar;45(3):198–203. doi: 10.1111/j.2042-7158.1993.tb05532.x. [DOI] [PubMed] [Google Scholar]
  4. Alonso M. J., Gupta R. K., Min C., Siber G. R., Langer R. Biodegradable microspheres as controlled-release tetanus toxoid delivery systems. Vaccine. 1994 Mar;12(4):299–306. doi: 10.1016/0264-410x(94)90092-2. [DOI] [PubMed] [Google Scholar]
  5. Anderson E. L., Mink C. M., Berlin B. S., Shih C. N., Tung F. F., Belshe R. B. Acellular pertussis vaccines in infants: evaluation of single component and two-component products. Vaccine. 1994 Jan;12(1):28–31. doi: 10.1016/0264-410x(94)90007-8. [DOI] [PubMed] [Google Scholar]
  6. Burns R. A., Jr, Vitale K., Sanders L. M. Nafarelin controlled release injectable: theoretical clinical plasma profiles from multiple dosing and from mixtures of microspheres containing 2 per cent, 4 per cent and 7 per cent nafarelin. J Microencapsul. 1990 Jul-Sep;7(3):397–413. doi: 10.3109/02652049009021849. [DOI] [PubMed] [Google Scholar]
  7. Chandrasekaran R., Giri D. K., Chaudhury M. R. Embryotoxicity and teratogenicity studies of poly (DL-lactide-co-glycolide) microspheres incorporated tetanus toxoid in Wistar rats. Hum Exp Toxicol. 1996 Apr;15(4):349–351. doi: 10.1177/096032719601500411. [DOI] [PubMed] [Google Scholar]
  8. Chaudhury M. R., Sharma K., Giri D. K. Poly (D,L-lactide) glycolide polymer microsphere entrapped tetanus toxoid: safety evaluation in Wistar rats. Hum Exp Toxicol. 1996 Mar;15(3):205–207. doi: 10.1177/096032719601500303. [DOI] [PubMed] [Google Scholar]
  9. Clemens J. D., Ferreccio C., Levine M. M., Horwitz I., Rao M. R., Edwards K. M., Fritzell B. Impact of Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine on responses to concurrently administered diphtheria-tetanus-pertussis vaccine. JAMA. 1992 Feb 5;267(5):673–678. [PubMed] [Google Scholar]
  10. Cutright D. E., Perez B., Beasley J. D., 3rd, Larson W. J., Posey W. R. Degradation rates of polymers and copolymers of polylactic and polyglycolic acids. Oral Surg Oral Med Oral Pathol. 1974 Jan;37(1):142–152. doi: 10.1016/0030-4220(74)90171-6. [DOI] [PubMed] [Google Scholar]
  11. Eldridge J. H., Staas J. K., Meulbroek J. A., McGhee J. R., Tice T. R., Gilley R. M. Biodegradable microspheres as a vaccine delivery system. Mol Immunol. 1991 Mar;28(3):287–294. doi: 10.1016/0161-5890(91)90076-v. [DOI] [PubMed] [Google Scholar]
  12. Ferreccio C., Clemens J., Avendano A., Horwitz I., Flores C., Avila L., Cayazzo M., Fritzell B., Cadoz M., Levine M. The clinical and immunologic response of Chilean infants to Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine coadministered in the same syringe with diphtheria-tetanus toxoids-pertussis vaccine at two, four and six months of age. Pediatr Infect Dis J. 1991 Oct;10(10):764–771. doi: 10.1097/00006454-199110000-00009. [DOI] [PubMed] [Google Scholar]
  13. Gupta R. K., Maheshwari S. C., Singh H. The titration of tetanus antitoxin IV. Studies on the sensitivity and reproducibility of the toxin neutralization test. J Biol Stand. 1985 Apr;13(2):143–149. doi: 10.1016/s0092-1157(85)80020-2. [DOI] [PubMed] [Google Scholar]
  14. Jeffery H., Davis S. S., O'Hagan D. T. The preparation and characterization of poly(lactide-co-glycolide) microparticles. II. The entrapment of a model protein using a (water-in-oil)-in-water emulsion solvent evaporation technique. Pharm Res. 1993 Mar;10(3):362–368. doi: 10.1023/a:1018980020506. [DOI] [PubMed] [Google Scholar]
  15. McGee J. P., Singh M., Li X. M., Qiu H., O'Hagan D. T. The encapsulation of a model protein in poly (D, L lactide-co-glycolide) microparticles of various sizes: an evaluation of process reproducibility. J Microencapsul. 1997 Mar-Apr;14(2):197–210. doi: 10.3109/02652049709015333. [DOI] [PubMed] [Google Scholar]
  16. Men Y., Thomasin C., Merkle H. P., Gander B., Corradin G. A single administration of tetanus toxoid in biodegradable microspheres elicits T cell and antibody responses similar or superior to those obtained with aluminum hydroxide. Vaccine. 1995 May;13(7):683–689. doi: 10.1016/0264-410x(94)00046-p. [DOI] [PubMed] [Google Scholar]
  17. O'Hagan D. T., Jeffery H., Roberts M. J., McGee J. P., Davis S. S. Controlled release microparticles for vaccine development. Vaccine. 1991 Oct;9(10):768–771. doi: 10.1016/0264-410x(91)90295-h. [DOI] [PubMed] [Google Scholar]
  18. O'Hagan D. T., Rahman D., McGee J. P., Jeffery H., Davies M. C., Williams P., Davis S. S., Challacombe S. J. Biodegradable microparticles as controlled release antigen delivery systems. Immunology. 1991 Jun;73(2):239–242. [PMC free article] [PubMed] [Google Scholar]
  19. Pitt C. G., Gratzl M. M., Kimmel G. L., Surles J., Schindler A. Aliphatic polyesters II. The degradation of poly (DL-lactide), poly (epsilon-caprolactone), and their copolymers in vivo. Biomaterials. 1981 Oct;2(4):215–220. doi: 10.1016/0142-9612(81)90060-0. [DOI] [PubMed] [Google Scholar]
  20. Rappuoli R., Podda A., Giovannoni F., Nencioni L., Peragallo M., Francolini P. Absence of protective immunity against diphtheria in a large proportion of young adults. Vaccine. 1993;11(5):576–577. doi: 10.1016/0264-410x(93)90235-p. [DOI] [PubMed] [Google Scholar]
  21. Schwendeman S. P., Costantino H. R., Gupta R. K., Siber G. R., Klibanov A. M., Langer R. Stabilization of tetanus and diphtheria toxoids against moisture-induced aggregation. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11234–11238. doi: 10.1073/pnas.92.24.11234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Shepard D. S., Walsh J. A., Kleinau E., Stansfield S., Bhalotra S. Setting priorities for the Children's Vaccine Initiative: a cost-effectiveness approach. Vaccine. 1995;13(8):707–714. doi: 10.1016/0264-410x(94)00063-s. [DOI] [PubMed] [Google Scholar]
  23. Singh M., Singh O., Talwar G. P. Biodegradable delivery system for a birth control vaccine: immunogenicity studies in rats and monkeys. Pharm Res. 1995 Nov;12(11):1796–1800. doi: 10.1023/a:1016294512292. [DOI] [PubMed] [Google Scholar]
  24. Tabata Y., Ikada Y. Effect of the size and surface charge of polymer microspheres on their phagocytosis by macrophage. Biomaterials. 1988 Jul;9(4):356–362. doi: 10.1016/0142-9612(88)90033-6. [DOI] [PubMed] [Google Scholar]

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