Protective efficacy of a multicomponent vector vaccine in cynomolgus monkeys after intrarectal simian immunodeficiency virus challenge

Abstract

We investigated the protective efficacy of a systemic triple vector (DNA/rSFV/rMVA)-based vaccine against mucosal challenge with pathogenic simian immunodeficiency virus (SIV) in cynomolgus monkeys. Animals were immunized at week 0 with DNA (intradermally), at weeks 8 and 16 with recombinant Semliki Forest virus (rSFV, subcutaneously) and finally, at week 24, with recombinant modified vaccinia virus Ankara strain (rMVA, intramuscularly). Both DNA and recombinant viral vectors expressed a wide range of SIV proteins (Gag, Pol, Tat, Rev, Env and Nef). This immunization strategy elicited cell-mediated rather than humoral responses that were especially increased following the last boost. Upon intrarectal challenge with pathogenic SIVmac251, three of the four vaccinated monkeys dramatically abrogated virus load to undetectable levels up to 41 weeks after challenge. A major contribution to this vaccine effect appeared to be the T-cell-mediated immune response to vaccine antigens (Gag, Rev, Tat, Nef) seen in the early phase of infection in three of the four vaccinated monkeys. Indeed, the frequency of T-cells producing antigen-induced IFN-c mirrored virus clearance in the vaccinated and protected monkeys. These results, reminiscent of the efficacy of live attenuated virus vaccines, suggest that vaccination with a combination of many viral antigens can induce a robust and stable vaccine-induced immunity able to abrogate virus replication.

Unusually High Frequency MHC Class I Alleles in Mauritian Origin Cynomolgus Macaques

“…Previous work has shown that Cynomolgus macaques generally (65,66), and Mauritian origin Cynomolgus macaques in particular (67)(68)(69), can be infected with pathogenic SIV and develop sAIDS. When compared with Indian Rhesus macaques, Cynomolgus macaques require a higher dose of virus to consistently establish SIV infection (68) and maintain lower viral loads more similar to HIV-infected humans (66). This could complicate the evaluation of vaccines that seek to reduce set point viral load because differences between vaccinees and naive controls may be more difficult to detect.…”

Mhc class I haplotypes associated with survival time in simian immunodeficiency virus (SIV)-infected rhesus macaques

“…RNA copy number in infected monkeys was determined by quantitative real-time PCR as described 57 using TaqMan-based real-time PCR on an ABI-Prism 7500 sequence detection system (Applied Biosystems). Levels of amplified viral RNA were expressed as SIV-RNA copies per ml plasma.…”

Adoptive Transfer of Lymphocytes Isolated from Simian Immunodeficiency Virus SIVmac239Δnef-Vaccinated Macaques Does Not Affect Acute-Phase Viral Loads but May Reduce Chronic-Phase Viral Loads in Major Histocompatibility Complex-Matched Recipients

“…After transfer, recipient animals were challenged with 50,000 TCID 50 of SIVmac239 intrarectally. This dose was chosen at the outset of these experiments due to a previous report suggesting that a 10-foldhigher challenge dose is required to infect cynomolgus macaques than the dose required to infect rhesus macaques (26).…”