A vaccinia-based single vector construct multi-pathogen vaccine protects against both Zika and chikungunya viruses

Abstract

Zika and chikungunya viruses have caused major epidemics and are transmitted by Aedes aegypti and/or Aedes albopictus mosquitoes. The “Sementis Copenhagen Vector” (SCV) system is a recently developed vaccinia-based, multiplication-defective, vaccine vector technology that allows manufacture in modified CHO cells. Herein we describe a single-vector construct SCV vaccine that encodes the structural polyprotein cassettes of both Zika and chikungunya viruses from different loci. A single vaccination of mice induces neutralizing antibodies to both viruses in wild-type and IFNAR−/− mice and protects against (i) chikungunya virus viremia and arthritis in wild-type mice, (ii) Zika virus viremia and fetal/placental infection in female IFNAR−/− mice, and (iii) Zika virus viremia and testes infection and pathology in male IFNAR−/− mice. To our knowledge this represents the first single-vector construct, multi-pathogen vaccine encoding large polyproteins, and offers both simplified manufacturing and formulation, and reduced “shot burden” for these often co-circulating arboviruses.

Zika Virus in the Male Reproductive Tract

“…Mice have proved the most tractable model to investigate ZIKV in the MRT, with a plethora of recent studies ( Table 1 ) [ 31 , 52 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 ]. However, as ZIKV does not naturally replicate and cause disease in wild-type mice, studies of ZIKV pathogenesis have primarily utilized immunodeficient mice ( Table 1 ).…”

“…A study using vasectomized mice showed that sexual transmission of ZIKV still occurred, despite semen containing significantly lower levels of infectious virus [ 84 ]. Overall, studies of pathogenesis in the MRT of mice have detected ZIKV in the testes [ 31 , 52 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 88 , 89 , 90 ] of all animals tested and the epididymis [ 31 , 52 , 76 , 77 , 78 , 80 , 84 , 86 , 87 , 88 , 89 ] of most mice ( Table 1 ). ZIKV was also detected in the seminal fluid inside the lumen of the vas deferens [ 80 ] and the seminal vesicles [ 31 , 84 , 89 ] of some infected mice ( Table 1 ).…”

“…Inhibin B [ 76 ] and testosterone levels [ 76 , 77 , 78 ] were significantly decreased in mice, likely due to Leydig cell infection and apoptosis [ 76 , 78 ]. Furthermore, mouse ZIKV infection typically results in disruption of the BTB [ 77 , 86 ], breakdown of the epithelium and seminiferous tubules [ 76 , 77 , 79 , 86 , 87 , 88 , 90 ], inflammation and tissue injury to the epididymis and testis [ 76 , 77 , 80 , 83 , 84 , 87 , 89 ], and testicular atrophy [ 31 , 76 , 77 , 78 , 81 , 82 , 87 ]. Cytokine production within the testis, as well as infiltration of inflammatory cells, immune cells, and macrophages into this organ, seminiferous and epididymal tubules were observed [ 76 , 77 , 84 , 86 , 87 , 88 ].…”

Fetal Brain Infection Is Not a Unique Characteristic of Brazilian Zika Viruses

“…IFNAR1 −/− mice on a C57BL/6J background were provided by Dr P Hertzog (Monash University, VIC, Australia) [ 26 ] and bred in-house at the Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute. Pregnant female IFNAR1 −/− mice (between 10–20 weeks old) were infected s.c. at the base of the tail with 100 µL of medium at a dose of 10 4 CCID 50 as described [ 24 ]. Mating was verified by the presence of a vaginal plug.…”

“…We previously generated the contemporary Asian lineage isolate ZIKV-Natal from sequence data obtained directly from the brain tissue of an aborted ZIKV-infected human fetus during the 2015 Brazilian outbreak [ 14 , 23 ]. Using a pregnant IFNAR1 −/− mouse model, we previously demonstrated that the Brazilian isolate (ZIKV-Natal) was capable of causing fetal infection and congenital malformations [ 23 , 24 ]. Herein, we sought to determine whether fetal infection is a newly acquired characteristic of Asian lineage strains of ZIKV by comparing ZIKV-Natal to the P6-740 Malaysian 1966 ZIKV isolate (ZIKV-MY).…”