부산대학교 도서관

Background: We developed a series of 30+ VSV-based constructs containing HIV-1 Env chimeras with or without SIV gag in absence of VSV-G and with or without the Ebola glycoprotein. After pre-clinical analyses of production/expression and small animal testing, a subset of 4 were used to immunize macaques that were later challenge with low dose SHIV. Methods: VSVdelG-based vectors were produced to express codon optimized HIV-1 ecto Env of NL4-3 or subtype A, strain 74 Env with N425K Env with different transmembrane and intracellular tails (TMIC) of the VSV G, Ebola GP, mutated HIV-1 and SIVmac239 Env. VSVdelG replication was driven either by the functional Env chimera or by cis addition of Ebola or Marburg GP. Expression and Env function for entry was tested and VSV vectors were produced for mouse immunizations to measure humoral (binding and neutralizing Abs) and CTL responses. The best candidates were then tested in rabbits and macaque challenge studies. Results: Details of the three year preclinical screening and subsequent correlates of protection for the best vaccine candidates will be provided in the presentation. The best candidate, VSVdelG_A74-gp140/SIV-TMIC_Ebola-GP was used as the prime followed by a boost with VSVdelG_SIV-Gag + A74-gp140/SIV-TMIC_Ebola-GP and then a boost with VSVdelG_A74-gp140/SIV-TMIC_Ebola_GP (Grp1). Eight of ten of the control macaques (Grp2) and 10 of 10 in an alternative vaccine regimen (Grp2) were infected with SHIV_SF162-p3 by the final low dose 7 challenges. Four of ten animals of the best performing vaccinated group were infected by challenge 7th. Conclusions: Building on the VSV-Ebola vaccine technology, we engineered/tested an improved VSV-based HIV vaccine and observed one of the best protections against low dose heterologous challenges in macaques to date. Findings also suggest that use of VSV-HIV_Env construct with Gag may be important for protection, especially in boosting CTL response, but its inclusion in the final boost (groups 2 and 4) may promote an activated CD4+ T cell population capable of increasing SHIV infection. These findings suggest an important balance of cell-based versus humoral immunity in prime/boost vaccine strategies for optimal protection. The current study is one of the first reports of meaningful cross-clade heterologous protection.
OA12.04LB E. Arts (1); A. Berger (2); J. Pedersen (2); M.-A. Lafrance (2); J. Knapp (1); H. Azizi (2); Y. Li (1); F. Scholte (2); J. Mann (1); A. Kamen [...]