St Clair N, Shenoy B, Jacob L D, Margolin A L
Altus Biologics Inc., 625 Putnam Avenue, Cambridge, MA 02139, USA.
Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9469-74. 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.
亚单位疫苗的发展受到其免疫原性差和稳定性有限的限制。为了增强免疫反应，亚单位疫苗普遍需要改进佐剂和递送载体。在本文中，我们提议使用交联蛋白晶体（CLPCs）作为抗原。我们比较了人血清白蛋白CLPCs与可溶性蛋白的免疫原性，得出对不同形式的人血清白蛋白的免疫反应存在显著差异的结论。相对于可溶性蛋白，在长达近6个月的研究中，结晶形式可使高度交联晶体的抗体滴度提高6至10倍，轻度交联晶体的抗体滴度提高约30倍。我们推测，储存效应、CLPCs的颗粒结构以及蛋白晶体的高度重复性可能在循环抗体的增强产生中发挥作用。CLPCs的几个特性，如它们卓越的稳定性、纯度、生物可降解性和易于制造性，使其对疫苗配方极具吸引力。这项工作为系统研究蛋白质结晶度和交联对体液和T细胞反应增强的影响铺平了道路。
