Cross-Linked Protein Crystals for Vaccine Delivery

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 17; pp. 9469 - 9474
• Main Authors: St. Clair, Nancy, Shenoy, Bhami, Jacob, Lawrence D., Margolin, Alexey L.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 17.08.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Animals; Antibodies; Antibody Formation; Antigens; Biological Sciences; Computer Simulation; Cross-Linking Reagents; Crystallization; Crystals; Drug Delivery Systems; Female; Freund's Adjuvant; Health savings accounts; Humans; Immune response; Immunity (Disease); Leukocytes; Particulate matter; Protein Conformation; Protein Structure, Secondary; Proteins; Proteins - administration & dosage; Quaternary ammonium compounds; Rabbits; Rats; Rats, Sprague-Dawley; Serum Albumin - immunology; Spectroscopy, Fourier Transform Infrared; Subunit vaccines; Sulfates; Vaccination; Vaccines
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.17.9469

The progress toward subunit vaccines has been limited by their poor immunogenicity and limited stability. To enhance the immune response, subunit vaccines universally require improved adjuvants and delivery vehicles. In the present paper, we propose the use of cross-linked protein crystals (CLPCs) as antigens. We compare the immunogenicity of CLPCs of human serum albumin with that of soluble protein and conclude that there are marked differences in the immune response to the different forms of human serum albumin. Relative to the soluble protein, crystalline forms induce and sustain over almost a 6-month study a 6- to 10-fold increase in antibody titer for highly cross-linked crystals and an approximately 30-fold increase for lightly cross-linked crystals. We hypothesize that the depot effect, the particulate structure of CLPCs, and highly repetitive nature of protein crystals may play roles in the enhanced production of circulating antibodies. Several features of CLPCs, such as their remarkable stability, purity, biodegradability, and ease of manufacturing, make them highly attractive for vaccine formulations. This work paves the way for a systematic study of protein crystallinity and cross-linking on enhancement of humoral and T cell responses.