Design and validation of VLP/mRNA-based vaccine strategies against SARS-CoV2

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Following the success of our HIV vaccine platform based on co-formulated Env+Gag mRNA in order to produce non-infectious VLPs (Zhang et al., Nat. Med. 27:2234, 2021), in collaboration with Moderna, Inc., we have designed a similar vaccine platform for SARS-CoV-2. The major results obtained include the following: 1. We synthesized different tail-modified SARS-CoV2 envelope spikes (S) in order to facilitate protein-protein interaction and VLP formation with lentivirus core proteins. In order to facilitate the assembly of VLPs containing lentivirus (HIV-1 or SIV) core proteins, we have designed S proteins modified in their cytoplasmic tails (CT) by replacement of the natural tail with either the HIV-1 or SIV gp41 CT. A truncated form of the lentivirus tails has been used, based on our original design for the HIV-1 vaccine, to promote a more efficient surface membrane expression. Moderna Inc. has produced the specific mRNAs according to our design. 2. In vitro, we tested the efficiency of production of VLPs with the modified spike proteins. The spike protein mRNAs were co-transfected into mammalian cells in all possible combinations with mRNAs encoding HIV-1 or SIV Gag or Gag-Pol. The extracellular VLPs were harvested and concentrated by ultracentrifugation on sucrose cushions. The produced VLPs have been extensively characterized both quantitatively and qualitatively using a wide array of physical and immunological assays, including virion capture by mAbs followed by ELISA for lentivirus core antigen quantification, Western blot and others. 3. We have started to test the immunogenicity of our hybrid SARS-CoV-2-SIV VLP-forming vaccine in mice. Preliminary results demonstrate that our VLP-forming vaccine is superior to the SARS-CoV-2 spike protein alone in eliciting neutralizing antibodies. Thus, our results indicate that VLPs comprising the CoV2 Spike protein and a lentiretrovirus core can be efficiently produced and display the native-like form of the S-protein on their surface. A VLP-forming SARS-CoV-2 vaccine may be more effective than our current vaccines for induction of protective immunity.