Recombinant Vaccine-Induced Protection against the Highly Pathogenic Simian Immunodeficiency Virus SIV_mac251: Dependence on Route of Challenge Exposure

Abstract

Vaccine protection from infection and/or disease induced by highly pathogenic simian immunodeficiency virus (SIV) strain SIVmac251 in the rhesus macaque model is a challenging task. Thus far, the only approach that has been reported to protect a fraction of macaques from infection following intravenous challenge with SIVmac251 was the use of a live attenuated SIV vaccine. In the present study, the gag, pol, and env genes of SIVK6W were expressed in the NYVAC vector, a genetically engineered derivative of the vaccinia virus Copenhagen strain that displays a highly attenuated phenotype in humans. In addition, the genes for the α and β chains of interleukin-12 (IL-12), as well as the IL-2 gene, were expressed in separate NYVAC vectors and inoculated intramuscularly, in conjunction with or separate from the NYVAC-SIV vaccine, in 40 macaques. The overall cytotoxic T-lymphocyte (CTL) response was greater, at the expense of proliferative and humoral responses, in animals immunized with NYVAC-SIV and NYVAC–IL-12 than in animals immunized with the NYVAC-SIV vaccine alone. At the end of the immunization regimen, half of the animals were challenged with SIVmac251 by the intravenous route and the other half were exposed to SIVmac251 intrarectally. Significantly, five of the eleven vaccinees exposed mucosally to SIVmac251 showed a transient peak of viremia 1 week after viral challenge and subsequently appeared to clear viral infection. In contrast, all 12 animals inoculated intravenously became infected, but 5 to 6 months after viral challenge, 4 animals were able to control viral expression and appeared to progress to disease more slowly than control animals. Protection did not appear to be associated with any of the measured immunological parameters. Further modulation of immune responses by coadministration of NYVAC-cytokine recombinants did not appear to influence the outcome of viral challenge. The fact that the NYVAC-SIV recombinant vaccine appears to be effective per se in the animal model that best mirrors human AIDS supports the idea that the development of a highly attenuated poxvirus-based vaccine candidate can be a valuable approach to significantly decrease the spread of human immunodeficiency virus (HIV) infection by the mucosal route.

Comparison of early plasma RNA loads in different macaque species and the impact of different routes of exposure on SIV/SHIV infection

“…Separate reports have previously noted similar plasma RNA and cell associated virus loads in rhesus macaques following i.v. or rectal challenge [2,11]. We cannot rule out that daily or weekly measurements might reveal some subtle differences in the viral load kinetics such as the slope of the decline of peak loads, but the magnitudes reported in this study are unlikely to be different.…”

The Evolution of Poxvirus Vaccines

“…For this reason, NYVAC-based recombinants are underintensepreclinical and clinical investigation as recombinant vaccines against multiple infectious diseases [305,306,483] (see Table 8). JEV prM, E, NS1 clinical [456,457] HIV/AIDS SIVK6W Env-Gag-Pol, SHIV89.6P Env, SIVmac239 Gag-Pol-Nef preclinical [487,[495][496][497] Env (clade B) preclinical [411] clade C trimeric soluble gp140(ZM96), clade C Gag(ZM96)-Pol-Nef(CN54) as VLPs preclinical [498] Env, Gag-Pol-Nef (clade C) clinical [499][500][501][502][503] Env, Gag-Pol-Nef (clade B) clinical [504,505] AIV HA preclinical [408] HTLV-1 Env, Env + Gag preclinical [458,506,507] Parasitic diseases NYVAC Malaria LSA-1, CS preclinical [508] CS, SSP2, LSA1, MSP1, SERA, AMA1, Pfs25 clinical [509] Abbreviations Most of the studies involved in the deletion of immune-modulating VACV genes have been performed in the VACV WR strain and the general results showed that deletion of many VACV genes attenuated the virus [289], but the impact on immunogenicity was variable. Thus, deletion of some immunomodulatory VACV genes from different strains (mainly WR and MVA) increased the immunogenicity against VACV antigens, as it is described for VACV genes E3L [510], B15R/B16R [511][512][513], A41L [514], B13R and B22R [515], C12L [516], A35R [517] or C6L [518].…”

Factors Associated with Slow Disease Progression in Macaques Immunized with an Adenovirus-Simian Immunodeficiency Virus (SIV) Envelope Priming-gp120 Boosting Regimen and Challenged Vaginally with SIVmac251

“…Vaccine approaches, including targeted iliac lymph node immunization (37), infection with live, attenuated SIVmac251 with a deletion in the nef gene (17), exposure to naturally attenuated HIV type 2 (HIV-2) (53) or SHIV (55), and immunization with NYVAC-SIV recombinant vaccines, in the presence or absence of cytokine adjuvants (6), have shown various degrees of protection against subsequent SIV intrarectal challenges. Psoralen-and formalin-inactivated SIV preparations, in some cases encapsulated as microspheres, have shown a degree of protection against both intrarectal and intravaginal challenges (15,43,44,64).…”