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Principal Investigator: Bernard Moss
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2021
Award: $1,846,692
Funding agency: National Institute of Allergy and Infectious Diseases
There are many diseases for which there are no vaccines and others for which the vaccines are not optimal or have significant side effects. The objectives of this project are to develop new vectors, characterize viral antigens, determine targets of humoral and cell mediated immunity, and use this information to develop candidate vaccines. Live recombinant viral vaccines, DNA vaccines and recombinant protein vaccines are being developed. Presently we are working on vaccinia virus-vectored vaccines for HIV and SARS CoV-2.
The attenuated vaccine vector known as modified vaccinia virus Ankara (MVA) was derived by extensively passaging the parental strain of vaccinia virus Ankara in chick embryo fibroblasts and is unable to replicate in most mammalian cells. The MVA host range restriction is exceptional in that synthesis of the abundant viral proteins appears unaffected, but morphogenesis of virus particles is abortive. Despite the importance of the host range restriction for vaccine safety, the basis for this antiviral effect has remained an enigma.
We demonstrated that the zinc finger antiviral protein (ZAP), previously shown to be an inhibitor of RNA viruses, is a specific host restriction factor for replication of MVA in human cells. Moreover, the intact vaccinia virus C16 protein, which was disrupted during the attenuation of MVA, sequesters ZAP in cytoplasmic punctae, and effectively counteracts the inhibitory effects of ZAP.
We constructed a panel of recombinant MVAs that express unmodified or modified SARS-CoV-2 spike (S) protein. Intramuscular injection of mice with the rMVAs induced antibodies, which neutralized a pseudovirus in vitro and upon passive transfer protected hACE2 transgenic mice from lethal infection with SARS-CoV-2, as well as S-specific CD3+CD8+IFNg+ T cells. Antibody boosting occurred following a second rMVA or adjuvanted purified RBD protein. Immunity conferred by a single vaccination of transgenic hACE2 mice prevented morbidity and weight loss upon intranasal infection with SARS-CoV-2 three or seven weeks later. One or two rMVA vaccinations also prevented detection of infectious SARS-CoV-2 and subgenomic viral mRNAs in the lungs and greatly reduced induction of cytokine and chemokine mRNAs. A low amount of virus was found in the nasal turbinates of only one of eight rMVA-vaccinated mice on day 2 and none later. Detection of low levels of subgenomic mRNAs in turbinates indicated that replication was aborted in immunized animals.
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