Intralymphatic immunization enhances DNA vaccination

Abstract

Although DNA vaccines have been shown to elicit potent immune responses in animal models, initial clinical trials in humans have been disappointing, highlighting a need to optimize their immunogenicity. Naked DNA vaccines are usually administered either i.m. or intradermally. The current study shows that immunization with naked DNA by direct injection into a peripheral lymph node enhances immunogenicity by 100-to 1,000-fold, inducing strong and biologically relevant CD8 ؉ cytotoxic T lymphocyte responses. Because injection directly into a lymph node is a rapid and easy procedure in humans, these results have important clinical implications for DNA vaccination.

Multivalent immunity targeting tumor-associated antigens by intra-lymph node DNA-prime, peptide-boost vaccination

“…In addition, repeat plasmid-prime and peptide-boost immunization resulted in the maintenance of immunity to both antigens with a significant increase of T-cell immunity against the dominant epitope and no evidence of immune tolerance against these antigens ( Figure 6). Finally, consistent with the model that while plasmid primes a balanced T-cell response encompassing central memory and peripheral memory/effector cells, and peptide drives the proliferation and differentiation of central memory T cells to peripheral memory/ effector cells, 22 repeat prime-boost immunization actually resulted in the maintenance and even slight elevation of T-cell immunity against the dominant epitope ( Figure 6). Together, these results show that plasmid-priming followed by peptide-boost using intra-lymph node delivery can achieve a robust priming and expansion (on the order of B1/10 CD8 þ T cells) of specific T cells against two distinct TAA epitopes, restricted to the same human leukocyte antigen (HLA) allele.…”

“…To build on previous findings that repeat plasmidprime and peptide-boost immunization cycles can maintain and, in some cases, further enhance T-cell immunity to specific antigens 22,28 rather than inducing immune tolerance, we studied immune responses after a second immunization cycle. The percentage of MART-1/Melan-A 26-35 T cells in blood was significantly increased after a second cycle of intra-nodal immunization, whereas the tyrosinase 369-377-specific T-cell population was maintained.…”

“…In an earlier attempt to improve on DNA vaccination, we used a direct intra-lymph node injection approach to maximize the number of in situ transfected APCs and facilitate their interaction with T cells. Although the preclinical immunogenicity of this approach was superior to immunization using conventional means, 22 the immunological and clinical effects in humans were quite limited. 20,21 More recently, we showed in a preclinical model that an epitope-specific peptide boost after DNA vaccination achieved a significant amplification of the immune response elicited by plasmid.…”

“…18,19 Previously, in an attempt to improve on the in vivo generation and amplification of TAA-specific T cells, we clinically evaluated the intra-lymph node administration of two individual plasmids encompassing either MART-1/Melan-A or tyrosinase antigen fragments in stage-III and IV melanoma patients with measurable disease. [20][21][22] Nevertheless, despite an apparent correlation between immunity and clinical outcome (as measured by time to progression), 20 there were no objective clinical responses (defined by RECIST criteria) in any of these phase-I trials. Evidence from preclinical 23 and clinical studies, especially those involving adoptive T-cell therapy, 9,10 suggested that a robust, continuous presence of TAAspecific T cells with minimal interference by immune inhibitory mechanisms was a prerequisite for an objective tumor response.…”

Direct intralymphatic injection of peptide vaccines enhances immunogenicity

“…The immune response, however, is induced in the draining lymph nodes, where professional APC present the antigenic epitopes of the vaccine to the residing lymphocytes. As lymph nodes accommodate a high number of professional APC, direct administration of the vaccine into the lymph node should be the most efficient route [11]. We compared the efficiency of different routes of immunization with MHC class I-binding peptide vaccines.…”