Use of CD40L immunoconjugates to overcome the defective immune response to vaccines for infections and cancer in the aged.

Multiple investigators have reported the presence of defects in the immune response of the elderly [Castle In: Clin Infect Dis 31:578, 2000; Ortqvist et al. In: Eur Respir J 30:414-422, 2007; Saurwein-Teissl et al. In: J Immunol 168:5893, 2002; Haynes et al. In: Proc Natl Acad Sci USA 100:15053-15058, 2003]. These defects reduce the magnitude of the immune response to infection and to vaccination. In individuals greater than 55 years of age, the probability of developing a fully protective neutralizing antibody response to the yearly multivalent particle inactivated influenza vaccine is less than 20% [Jefferson et al. In: Lancet 264:1165-1174, 2005; Goodwin et al. In: Vaccine 24:1159-1169, 2006; Jackson et al. In: Lancet 372:398-405, 2008; Simonsen and Taylor In: Lancet 7:658-666, 2007]. The defects in the aged immune system that are responsible for this limited response to vaccination in the older age groups include functional defects of the antigen presenting cells, functional defects in CD4 helper CD4 T cells and monocytes, and an altered microenvironment [Eaton et al. In: J Exp Med 200:1613-1622, 2004; Dong et al. In: J Gen Virol 84:1623-1628, 2003; Deng et al. In: Immunology 172:3437-3446, 2004; Cella et al. In: J Exp Med 184:747-752, 1996]. Starting at puberty, the involution of the thymus and the consequent reduction of the export of naïve T cells specific to neo-antigens leads to the reduction of the ratio of antigen naïve to memory cells as chronological age advances [Prelog In: Autoimmun Rev 5:136-139, 2006; McElhaney et al. In: J Immunology 176:6333-6339, 2006]. Changes in glycosylation of T cells and target antigens acquired during the aging process and the antibodies to these new glycopeptides and glycoproteins may also contribute to a reduction in the functioning of the adaptive immune response [Ishii et al. In: J Clin Neurosci 14:110-115, 2007; Shirai et al. In: Clin Exp Immunol 12:455-464, 1972; Adkins and Riley In: Mech Ageing Dev 103:147-164, 1998; Ben-Yehuda and Weksler In: Cancer Investigation 10:525-531, 1992]. One of the more interesting examples of the functional defects in the cells of the adaptive immune response is a reduced level of expression in the surface cytoadhesion and activation receptor molecules on CD4 helper T cells undergoing activation during vaccination. Upon infection or vaccination, CD40L is typically increased on the surface of CD4 helper T cells during activation, and this increased expression is absolutely essential to the CD40L promotion of expansion of antigen-specific B cells and CD 8 effector T cells in response to infection or vaccination [Singh et al. In: Protein Sci 7:1124-1135, 1998; Grewal and Flavell In: Immunol Res 16: 59-70, 1997; Kornbluth In: J Hematother Stem Cell Res 11:787-801, 2002; Garcia de Vinuesa et al. In: Eur J Immunol 29:3216-3224, 1999]. In aged human beings and mice, the reduced levels of expression of CD40 ligand (CD40L) in activated CD4 helper T cells is dramatically reduced [Eaton et al. In: J Exp Med 200:1613-1622, 2004; Dong et al. In: J Gen Virol 84:1623-1628, 2003]. To circumvent the reduction in CD40L expression and the subsequent reduction in immune response in the elderly, we have developed a chimeric vaccine comprised of the CD40L linked to the target antigen, in a replication incompetent adenoviral vector and in booster protein. This review will discuss the implementation the potential use of this approach for the vaccination of the older populations for cancer and infection.