Effective Induction of Simian Immunodeficiency Virus-Specific Systemic and Mucosal Immune Responses in Primates by Vaccination with Proviral DNA Producing Intact but Noninfectious Virions

Abstract

We report a pilot evaluation of a DNA vaccine producing genetically inactivated simian immunodeficiency virus (SIV) particles in primates, with a focus on eliciting mucosal immunity. Our results demonstrate that DNA vaccines can be used to stimulate strong virus-specific mucosal immune responses in primates. The levels of immunoglobulin A (IgA) detected in rectal secretions of macaques that received the DNA vaccine intradermally and at the rectal mucosa were the most striking of all measured immune responses and were higher than usually achieved through natural infection. However, cytotoxic T lymphocyte responses were generally low and sporadically present in different animals. Upon rectal challenge with cloned SIVmac239, resistance to infection was observed, but some animals with high SIV-specific IgA levels in rectal secretions became infected. Our results suggest that high levels of IgA alone are not sufficient to prevent the establishment of chronic infection, although mucosal IgA responses may have a role in reducing the infectivity of the initial viral inoculum.

Control of Simian/Human Immunodeficiency Virus Viremia and Disease Progression after IL-2-Augmented DNA-Modified Vaccinia Virus Ankara Nasal Vaccination in Nonhuman Primates

“…They may be capable of engendering immunity qualitatively similar to that obtained with attenuated viral vaccines, without establishing the persistent infection associated with attenuated viruses (23,25). These noninfectious viral particles incorporate Env proteins and bind the viral receptor on target cells as well as the wild-type virus.…”

“…These studies represent important steps in the study of SIV DNA vaccines, but were not designed to evaluate mucosal immunity, and the challenge did not involve mucosal exposure. Only recently has SIV or simian/human immunodeficiency virus (SHIV) 3 DNA been investigated as a mucosal immunogen (21,23,36).…”

“…The DNA plasmid pVacc4 used in the vaccination is a derivative of pVacc1 (23). pVacc1 includes a full SIVmac239 genome with multiple mutations in the NC basic domain and the functional domains of RT and INT, under the control of the CMV promoter.…”

“…The collection method and procedure for secretion extraction have been described (43). Total IgA was measured as described (23), with the exception that unlabeled and biotinylated purified polyclonal goat antimonkey IgA Abs (both Rockland, Gilbertsville, PA) were used as the coating and secondary reagents, respectively.…”

“…ELISAs for antiviral Abs were performed as described (23). Briefly, plates were coated with 250 ng of SIVmac251 viral lysate (Advanced Biotechnologies, Columbia, MD), 100 ng of HIV-1 rgp120 MN , or 100 ng of HIV-1 rgp41 MN (both ImmunoDiagnostics, Woburn, MA).…”