Serum amyloid P component facilitates DNA clearance and inhibits plasmid transfection: implications for human DNA vaccine

Abstract

The demonstration that naked plasmid DNA can induce strong immune responses in mice has attracted considerable attention in the vaccine community. However, similar immunizations have been less/not effective in clinical trials during the past decade, and the underlying mechanisms remain unknown. In this study, we hypothesized that some DNA-binding proteins in human serum may serve as host barriers, responsible for the low efficiency of plasmids' transfection in vivo. Using proteomics, we showed that human serum amyloid P component (hSAP) is specifically present in human DNA-protein complexes. Further analysis indicated that hSAP effectively binds plasmid DNA, inhibits DNA transfection into somatic cells and facilitates the endocytosis of DNA by macrophages, whereas mouse SAP (mSAP) has similar, but much weaker, activities. In the presence of hSAP, the plasmid DNA expression in vivo and plasmid DNA-induced immune responses also significantly decreased. Therefore, our results suggest that hSAP contributes to extracellular DNA clearance and the inhibition of plasmid DNA transfection in vivo. This mechanism may be partly responsible for the insufficient immune responses to DNA vaccination in human beings; therefore, it may serve as a novel target for the improvement of DNA vaccines and DNA-based gene therapy.

The future of human DNA vaccines

“…One recent proteomics study screened proteins for interaction with plasmid DNA and found that human serum amyloid P (SAP) inhibited plasmid transfection and enhanced plasmid clearance. SAP may contribute to the low efficacy of DNA vaccines in humans, as in other species suppressive effects of SAP are much weaker (Wang et al, 2011d). Hence SAP could, for example, serve as a new siRNA target for enhancing DNA vaccine efficacy, although the feasibility, effectiveness and safety of such an approach would first need to be tested in suitable animal models.…”

The influence of delivery vectors on HIV vaccine efficacy

“…Apart from effective delivery strategies and routes of immunization, there is evidence showing that expression of DNA vaccines and subsequent immunogenicity in humans and other primates can be limited by serum amyloid P component (SAP), a protein found in blood and known to bind strongly to DNA (Wang et al, 2011, 2012). In small animals this protein either binds weakly or does not exist at all.…”

“…Thus, depletion of SAP protein prior to administration of DNA vaccines is another new strategy being tested to improve DNA vaccine immunogenicity. This concept has been proven in mice, where depletion of SAP using the bis-d-proline compound CPHPC (Bodin et al, 2010; Gillmore et al, 2010) was shown to augment antibody and cellular immune responses to a DNA vaccine expressing Hepatitis B surface antigens (Wang et al, 2012). The concept is currently being tested in a Phase 1 clinical trial (HIVCORE003) of healthy adults using the T-cell based HIV candidate vaccine, HIVconsv.…”

The development of a peptide SRM-based tandem mass spectrometry assay for prenatal screening of Down syndrome

“…Of particular relevance to DS pregnancies is that SAP binds to DNA, chromatin and apoptotic cells and aids their clearance [23,24]. Also a recent study has described how human SAP contributes to extracellular DNA clearance and may be responsible for the insufficient immune response to DNA vaccinations in humans [25]. DS affected pregnancies are known to have increased amounts of foetal cells [26] and ffDNA [27] in maternal circulation, which may explain the increased level of SAP.…”