title: Cross-linked protein crystals for vaccine delivery.
abstract: 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.
authors.affiliation: Altus Biologics Inc., 625 Putnam Avenue, Cambridge, MA 02139, USA.
authors.forename: N
authors.initials: N
authors.lastname: St Clair
authors.forename: B
authors.initials: B
authors.lastname: Shenoy
authors.forename: L D
authors.initials: LD
authors.lastname: Jacob
authors.forename: A L
authors.initials: AL
authors.lastname: Margolin
mesh_terms: D000818:Animals; D000917:Antibody Formation; D003198:Computer Simulation; D003432:Cross-Linking Reagents; D003460:Crystallization; D016503:Drug Delivery Systems; D005260:Female; D005620:Freund's Adjuvant; D006801:Humans; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000008:administration & dosage*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000276:immunology; D017550:Spectroscopy, Fourier Transform Infrared; D014612:Vaccines
chemical_list: D003432:Cross-Linking Reagents; D011506:Proteins; D012709:Serum Albumin; D014612:Vaccines; D005620:Freund's Adjuvant