Chikungunya, Influenza, Nipah, and Semliki Forest Chimeric Viruses with Vesicular Stomatitis Virus: Actions in the Brain

Abstract

Recombinant vesicular stomatitis virus (VSV)-based chimeric viruses that include genes from other viruses show promise as vaccines and oncolytic viruses. However, the critical safety concern is the neurotropic nature conveyed by the VSV glycoprotein. VSVs that include the VSV glycoprotein (G) gene, even in most recombinant attenuated strains, can still show substantial adverse or lethal actions in the brain. Here, we test 4 chimeric viruses in the brain, including those in which glycoprotein genes from Nipah, chikungunya (CHIKV), and influenza H5N1 viruses were substituted for the VSV glycoprotein gene. We also test a virus-like vesicle (VLV) in which the VSV glycoprotein gene is expressed from a replicon encoding the nonstructural proteins of Semliki Forest virus. VSVΔG-CHIKV, VSVΔG-H5N1, and VLV were all safe in the adult mouse brain, as were VSVΔG viruses expressing either the Nipah F or G glycoprotein. In contrast, a complementing pair of VSVΔG viruses expressing Nipah G and F glycoproteins were lethal within the brain within a surprisingly short time frame of 2 days. Intranasal inoculation in postnatal day 14 mice with VSVΔG-CHIKV or VLV evoked no adverse response, whereas VSVΔG-H5N1 by this route was lethal in most mice. A key immune mechanism underlying the safety of VSVΔG-CHIKV, VSVΔG-H5N1, and VLV in the adult brain was the type I interferon response; all three viruses were lethal in the brains of adult mice lacking the interferon receptor, suggesting that the viruses can infect and replicate and spread in brain cells if not blocked by interferon-stimulated genes within the brain. IMPORTANCE Vesicular stomatitis virus (VSV) shows considerable promise both as a vaccine vector and as an oncolytic virus. The greatest limitation of VSV is that it is highly neurotropic and can be lethal within the brain. The neurotropism can be mostly attributed to the VSV G glycoprotein. Here, we test 4 chimeric viruses of VSV with glycoprotein genes from Nipah, chikungunya, and influenza viruses and nonstructural genes from Semliki Forest virus. Two of the four, VSVΔG-CHIKV and VLV, show substantially attenuated neurotropism and were safe in the healthy adult mouse brain. VSVΔG-H5N1 was safe in the adult brain but lethal in the younger brain. VSVΔG Nipah FϩG was even more neurotropic than wild-type VSV, evoking a rapid lethal response in the adult brain. These results suggest that while chimeric VSVs show promise, each must be tested with both intranasal and intracranial administration to ensure the absence of lethal neurotropism.

Replication-Competent Vesicular Stomatitis Virus Vaccine Vector Protects against SARS-CoV-2-Mediated Pathogenesis in Mice

“…Replacing the glycoprotein of VSV with a foreign glycoprotein often results in virus attenuation in vivo . Indeed, the vast majority of cases where VSV recombinants express a heterologous viral glycoprotein (e.g., chikungunya virus, H5N1 influenza virus, Lassa virus, lymphocytic choriomeningitis virus, or Ebola virus) and were injected via intracranial route into mice or NHPs, no disease was observed ( Mire et al., 2012 ; Muik et al., 2014 ; van den Pol et al., 2017 ; Wollmann et al., 2015 ). One exception is when VSV expressing the glycoproteins of the highly neurotropic Nipah virus was injected via an intracranial route into adult mice ( van den Pol et al., 2017 ).…”

Replication-competent vesicular stomatitis virus vaccine vector protects against SARS-CoV-2-mediated pathogenesis

“…Replacing the glycoprotein of VSV with a foreign glycoprotein often results in virus attenuation in vivo. Indeed, the vast majority of cases where VSV recombinants express a heterologous viral glycoprotein (e.g., chikungunya virus, H5N1 influenza virus, Lassa virus, lymphocytic choriomeningitis virus, or Ebola virus) and were injected via intracranial route into mice or NHPs, no disease was observed (Mire et al, 2012;Muik et al, 2014;van den Pol et al, 2017;Wollmann et al, 2015). One exception is when VSV expressing the glycoproteins of the highly neurotropic Nipah virus was injected via an intracranial route into adult mice (van den Pol et al, 2017).…”

Recombinant vesicular stomatitis virus vector vaccines for WHO blueprint priority pathogens

“…109 Of note, the combined administration of rVSVΔG-G/F(NiV) was found to be lethal when given intranasally in 5/8 postnatal mice in a later study, while the individual administration of either vaccine candidate did not cause any symptoms, even when directly injected into the brain. 110 Vaccination with rVSVΔG-G-or -F(NiV) was demonstrated to be fully protective against NiV challenge in a Syrian hamster model, where none of the animals developed disease. 111 Similarly, the vector VSV-EBOV, complemented with NiV F or G protein downstream of EBOV-GP, was assessed in the hamster model and conferred the same level of protection from disease.…”