PubMed · 8100390
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W R Benjamin, B Jaffee. 1993. Immunoregulation workshop.. https://pubmed.ncbi.nlm.nih.gov/8100390/
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PLGA microspheres containing bovine serum albumin (BSA) as a model antigen, were prepared by a double emulsion/solvent extraction method and their in vitro characterization was performed. The same microspheres were used in a series of in vivo studies to evaluate the immune response induced after subcutaneous or oral inoculation following different immunization protocols. The in vivo data confirm that the immunogenicity of the albumin is not affected by the encapsulation procedure. The subcutaneous administration of microspheres showed an immune response (serum IgG levels by ELISA) statistically above BSA solution, even when the dose administered was 10 times lower. The adjuvanticity of the microspheres was found to be comparable to that of Freund's complete adjuvant (FCA), but in contrast to FCA they are biocompatible and did not induce any adverse reaction at the site of injection. A single oral administration of the microspheres was not a successful strategy for the induction of a reproducible response. Therefore, microspheres of 1 and 5 micrometer were orally administered on 3 consecutive days and the response obtained showed that the use of a boosting dose was not necessary for the 1 micrometer particles. These results suggest the possibility of simplifying the immunization schedule to a primary immunization if 1 micrometer particles are administered.
The classical adjuvants alum and Freund's Incomplete Adjuvant (IFA) are frequently used as references for the design of new adjuvants and antigen delivery systems, e.g., microspheres (MS). Poly(dl-lactic-co-glycolic acid) (PLGA) MS have been proposed for delivering antigen booster doses in vivo after a single injection. However, as antigen release kinetics from conventional adjuvants are generally unknown, it appears presumptuous to propose a desired antigen release pattern from PLGA MS. Therefore, we have studied the tetanus toxoid (Ttxd) in vitro release from alum, IFA formulations and MS in four different test systems. The results showed a stronger Ttxd association to alum than to IFA, and the release from both formulations lasted between 3-9 days. The total of ELISA-responsive antigen released was 60-85% of the actual dose. Both the total amount and the prolongation of release depended on the Ttxd dose. Furthermore, the incomplete in vitro release of Ttxd from the adjuvants and also from PLGA 50:50 MS was shown to be partly due to experimental conditions. Typically, Ttxd adsorbed on the glass vials used for the release test and also on the surface of the PLGA 50:50 MS, wherefrom it was released. In conclusion, the test system depending rate and quantity of release observed evidence the limitations of in vitro release data. Finally, for mimicking conventional vaccination schedules, i.e. injections typically at time points 0, 1, 3, and 12-24 months, PLGA MS should release antigen doses at the corresponding time points, and the release pulse should only last for a few days.
Mucosal immunity is difficult to induce with subunit vaccines unless such vaccines are administered with a mucosal adjuvant such as cholera toxin (CT); however, CT is toxic in humans. Synthetic oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG) are potent adjuvants for the induction of Th1-like systemic immune responses against parenterally delivered proteins. Here, we show in mice that intranasal delivery of hepatitis B surface Ag, which alone has no effect, elicits good immune responses when given with CpG oligodeoxynucleotides and/or CT. Overall, CpG is superior to CT for the induction of humoral and cell-mediated systemic immunity as well as mucosal immune responses (IgA) at local (lung) and distant (feces) sites. Furthermore, CpG and CT act synergistically, giving stronger responses than those observed with 10 times more of either adjuvant alone. Ab isotypes were predominantly IgG1 (Th2-like) with CT, mixed IgG1/IgG2a (Th0) with CpG, and predominantly IgG2a (Th1-like) with CpG and CT together.