Increased neutralization potency and breadth elicited by a SARS-CoV-2 mRNA vaccine forming virus-like particles

• DOI: 10.1073/pnas.2305896120
• Publication Date: 2023-07-10T19:06:39Z
• Authors: Peng Zhang; Samantha Falcone; Yaroslav Tsybovsky; Mamta Singh; Vinay Gopan; Huiyi Miao; Yuna Seo; Denise Rogers; Isabella Renzi; Yen-Ting Lai; Elisabeth Narayanan; Guillaume Stewart...; Sunny Himansu; Andrea Carfi; Anthony S. Fauci; Paolo Lusso
• Keywords: Mice; COVID-19 Vaccines; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Humans; Animals; COVID-19; Simian Immunodeficiency Virus; Biological Sciences; Antibodies, Viral; Antibodies, Neutralizing; 3. Good health

Vaccines have played a fundamental role in the control of infectious diseases. We previously developed a messenger RNA (mRNA) vaccine against HIV-1 that forms virus-like particles (VLPs) through coexpression of the viral envelope with Gag. Here, we applied the same principle to the design of a VLP-forming mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To promote cognate interaction with simian immunodeficiency virus (SIV) Gag, we engineered different chimeric proteins encompassing the ectodomain and the transmembrane region of the SARS-CoV-2 Spike protein from the Wuhan-Hu-1 strain fused to the gp41 cytoplasmic tail of either HIV-1 (strain WITO) or SIV (strain mac239) with or without a partial truncation at amino acid 745 to enhance membrane expression. Upon cotransfection with SIV gag mRNA, the Spike-SIV CT.745 (SSt) chimera yielded the highest level of cell-surface expression and extracellular VLP release. Immunization of BALB/c mice with SSt+gag mRNA at 0, 4, and 16 wk induced higher titers of Spike-binding and autologous neutralizing antibodies at all time points compared to SSt mRNA alone. Furthermore, mice immunized with SSt+gag mRNA developed neutralizing antibodies effective against different variants of concern. These data demonstrate that the Gag/VLP mRNA platform can be successfully applied to vaccines against different agents for the prevention of infectious diseases of global relevance.