DNA immunization protects nonhuman primates against rabies virus

Abstract

More than 40,000 people die annually from rabies worldwide. Most of these fatalities occur in developing countries, where rabies is endemic, public health resources are inadequate and there is limited access to preventive treatment. Because of the high cost of vaccines derived from cell culture, many countries still use vaccines produced in sheep, goat or suckling mouse brain. The stability and low cost for mass production of DNA vaccines would make them ideal for use in developing countries. To investigate the potential of DNA vaccines for rabies immunization in humans, we vaccinated Macaca fascicularis (Cynomolgus) monkeys with DNA encoding the glycoprotein of the challenge virus standard rabies virus, or with a human diploid cell vaccine (HDCV). The monkeys then were challenged with a non-passaged rabies virus. DNA or HDCV vaccination elicited comparable primary and anamnestic neutralizing antibody responses. All ten vaccinated monkeys (DNA or HDCV) survived a rabies virus challenge, whereas monkeys vaccinated with only the DNA vector developed rabies. Furthermore, serum samples from DNA- or HDCV-vaccinated monkeys neutralized a global spectrum of rabies virus variants in vitro. This study shows that DNA immunization elicits protective immunity in nonhuman primates against lethal challenge with a human viral pathogen of the central nervous system. Our findings indicate that DNA vaccines may have a promising future in human rabies immunization.

Preclinical and clinical progress of particle-mediated DNA vaccines for infectious diseases

“…Langerhans cells) of the viable epidermis [19,20]. Since the earliest DNA vaccine studies, direct comparisons of PMED to needle-based approaches for DNA vaccine delivery in mice [21][22][23][24][25][26][27] and monkeys [28][29][30][31] have shown that PMED can induce higher antibody and/or CD8 + T cell responses with substantially lower doses (100-1000-fold) of DNA. The eVectiveness of this system is likely related to the use of a delivery technology that deposits DNA directly into cells [18,20] as well as the immune competence of the epidermis as a delivery site [32,33].…”

“…However, optimization of the delivery device [37], vaccine vectors [38], and immunization regimens [26,38] substantially improved this technology so that later studies employing a clinical research device achieved robust and protective levels of immunity in nonhuman primates after only 1-3 doses [29,30,39,40]. Recent studies have shown that the delivery device employed can inXuence the immunogenicity of PMED in nonhuman primates.…”

“…In swine, 3 doses of 0.5-1.5 g of a hepatitis B DNA vaccine administered by PMED induced protective levels of antibody that were comparable to levels induced with 3 doses of a licensed recombinant protein vaccine [64]. Similarly, 2 doses of a rabies DNA vaccine administered by PMED induced comparable antibody and protection against lethal infection with rabies virus as a human diploid cell vaccine (HDCV) [29]. A single dose of this rabies DNA vaccine also aVorded post-exposure protection [65] and induced memory B cell responses that aVorded protection 1 year post-immunization [39].…”

“…Where tested, PMED induced comparable CD8 + T cell responses [31] and superior antibody [29][30][31] with 100-1000-fold less DNA when compared to injection of naked DNA into the skin or muscle with a needle. Similarly, in swine, administration of a porcine RSV DNA vaccine by PMED induced signiWcantly higher antibody responses than a combined approach employing both intramuscular and intradermal inoculation of naked DNA with a needle [68].…”

“…Similarly, in swine, administration of a porcine RSV DNA vaccine by PMED induced signiWcantly higher antibody responses than a combined approach employing both intramuscular and intradermal inoculation of naked DNA with a needle [68]. PMED has also been shown to aVord superior protection against viral infections when compared to intramuscular or intradermal DNA delivery [29,31].…”