A recombinant measles virus vaccine strongly reduces SHIV viremia and virus reservoir establishment in macaques

Abstract

Replicative vectors derived from live-attenuated measles virus (MV) carrying additional non-measles vaccine antigens have long demonstrated safety and immunogenicity in humans despite pre-existing immunity to measles. Here, we report the vaccination of cynomolgus macaques with MV replicative vectors expressing simian-human immunodeficiency virus Gag, Env, and Nef antigens (MV-SHIV Wt) either wild type or mutated in the immunosuppressive (IS) domains of Nef and Env antigens (MV-SHIV Mt). We found that the inactivation of Nef and Env IS domains by targeted mutations led to the induction of significantly enhanced post-prime cellular immune responses. After repeated challenges with low doses of SHIV-SF162p3, vaccinees were protected against high viremia, resulting in a 2-Log reduction in peak viremia, accelerated viral clearance, and a decrease -even complete protection for nearly half of the monkeys- in reservoir cell infection. This study demonstrates the potential of a replicative viral vector derived from the safe and widely used measles vaccine in the development of a future human vaccine against HIV-1.

Versatility of live-attenuated measles viruses as platform technology for recombinant vaccines

“…The major target antigens for all of these different pathogens are their surface proteins: MeV-derived vaccine candidates against EBV, HBV, HCV, and HPV exclusively rely on the respective surface proteins. Vaccines against HIV-1 and related viruses (SIV or SHIV) also utilize the group-specific antigen (Gag) 50 , 74 – 78 or a fusion protein composed of HIV-1 matrix protein p17, capsid protein p24, reverse transcriptase and Nef (F4) 79 – 81 . Moreover, HIV-1 envelope protein (Env) was modified to be used as an optimized antigen in the MeV context.…”

“…In addition to the binding antibodies detected by ELISA for all experimental vaccines, four of the eight vaccine candidates induced nAbs, namely those encoding the antigens of HCV 71 , HIV-1 76 , 82 , 83 , SHIV 78 , and HPV 72 , 73 . Target-specific nAb titers varied considerably.…”

“…Target-specific nAb titers varied considerably. The range spans from an IC 50 of 30 for SHIV 78 up to ~63,000 for HPV 73 . For the HBV-vaccines 28 , 30 , 69 , only the neutralization capacity of sera against the MeV vector backbone were verified.…”

“…Pathogen-specific T cell responses were characterized predominantly by ELISpot, but also ICS and FluoroSpot analysis, and induced by all five vaccine candidates that were analyzed. MeV-derived vaccines targeting EBV 41 , HIV-1 75 , 76 , 80 – 83 , SHIV 78 , SIV 77 , or Helicobacter pylori 84 induced both vector- and target-specific T cell responses. Only MeV-specific T cell responses were characterized for the vaccines targeting HBV 28 , 69 .…”

“…In contrast, a humanized mouse model (hu-PBL-NOJ), failed to display any immune responses 70 . Despite the demonstration of strong in vivo immunogenicity by all candidates, protective efficacy was recently confirmed only for one vaccine by challenge of cynomolgous macaques with SHIV-SF152p3 after vaccination with a Schwarz strain-derived MeV encoding the HIV-1 Gag, Env, and Nef antigens 78 . The lack of animal models that are not only permissive to MeV, but also reproduce infection of human diseases may explain the scarcity of protective efficacy studies for these diseases.…”