Preclinical Safety and Biodistribution of Sindbis Virus Measles DNA Vaccines Administered as a Single Dose or Followed by Live Attenuated Measles Vaccine in a Heterologous Prime–Boost Regimen

Abstract

Measles still causes considerable morbidity and mortality among infants and young children in developing countries. To develop a new public health tool to reduce this burden, we designed two Sindbis virus replicon vaccines encoding measles virus (MV) hemagglutinin (H) and fusion (F) proteins (pMSIN-H and pMSINHFdU). Our goal is to administer the vaccines to young infants at 6 and 10 weeks of age to prime the immune system to safely and effectively respond to subsequent immunization at age approximately 14 weeks with the licensed attenuated measles vaccine. In preparation for a phase 1 clinical trial, studies of plasmid distribution, integration, and toxicology were performed in rabbits. Biodistribution was assessed after a single DNA immunization delivered intradermally by needle-free injection. Toxicity was assessed using a heterologous prime-boost regimen consisting of a repeat-dose DNA prime followed by a live-attenuated measles vaccine boost. The only vaccine-related adverse effects observed were minimal transient erythema, edema, and inflammation confined to the injection site. Plasmids were detected in the subcutis and muscle at the site of inoculation. A small proportion of animals exhibited plasmids in the regional lymph nodes. There was no evidence of plasmid integration into the host genome. Both Sindbis-based vaccine plasmids were immunogenic in rabbits; pMSIN-H elicited higher virus-neutralizing antibody levels. Both vaccines were shown to be well tolerated and suitable for clinical trials and they are currently being tested in phase 1 studies in young adults.

Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression

“…By using the l-PEI polyplex delivery vehicle we avoid the attendant problems of viral vectors in gene delivery, including immune reactions30 and oncogenesis. Using pDNA vectors the integration rate of the extrachromosomal gene into the host genome in vivo was negligible31-34. We also estimated the potential of in vivo-jetPEI™ as a pPEG-HSV1tk delivery vehicle for detecting metastases in bone and brain, organs considered to be relatively difficult to access through systemic administration.…”

Biodistribution, persistence and lack of integration of a multigene HIV vaccine delivered by needle-free intradermal injection and electroporation

“…During the efforts to prove the safety of plasmid DNA, the biodistribution of plasmids has been studied in several animal species, and the results from published experiments all indicate that the plasmid is rapidly cleared from the body (Table 1 [1][2][3][4][5][6][7][8][9][10][11]). Directly after injection into skin or muscle, low levels of plasmids are transported via the blood stream and can therefore often be detected in various organs at early time points 0264-410X/$ -see front matter © 2010 Elsevier Ltd. All rights reserved.…”

Delivery strategies for novel vaccine formulations

“…(2) recombination of the vaccine strain with wild type, pathogenic virus [10] ; (3) ability of viral genomes to persist in tissues or the proviral genomes to integrate into the host genome [11] ; and (4) the dysregulation of the immune system by viral proteins [12] . As alternatives to live vectors, a variety of other antigen delivery systems are available for vaccine research.…”