tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2023 Jul 18;120(29):e2305896120.
doi: 10.1073/pnas.2305896120. Epub 2023 Jul 10. Increased neutralization potency and breadth elicited by a SARS-CoV-2 mRNA vaccine forming virus-like particles
Peng Zhang[SUP] 1 [/SUP], Samantha Falcone[SUP] 2 [/SUP], Yaroslav Tsybovsky[SUP] 3 [/SUP], Mamta Singh[SUP] 1 [/SUP], Vinay Gopan[SUP] 1 [/SUP], Huiyi Miao[SUP] 1 [/SUP], Yuna Seo[SUP] 1 [/SUP], Denise Rogers[SUP] 1 [/SUP], Isabella Renzi[SUP] 2 [/SUP], Yen-Ting Lai[SUP] 2 [/SUP], Elisabeth Narayanan[SUP] 2 [/SUP], Guillaume Stewart-Jones[SUP] 2 [/SUP], Sunny Himansu[SUP] 2 [/SUP], Andrea Carfi[SUP] 2 [/SUP], Anthony S Fauci[SUP] 1 [/SUP], Paolo Lusso[SUP] 1 [/SUP]
Affiliations
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[SUB]CT.745[/SUB] (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.
Keywords: COVID-19; mRNA; neutralizing antibodies; vaccine.
. 2023 Jul 18;120(29):e2305896120.
doi: 10.1073/pnas.2305896120. Epub 2023 Jul 10. Increased neutralization potency and breadth elicited by a SARS-CoV-2 mRNA vaccine forming virus-like particles
Peng Zhang[SUP] 1 [/SUP], Samantha Falcone[SUP] 2 [/SUP], Yaroslav Tsybovsky[SUP] 3 [/SUP], Mamta Singh[SUP] 1 [/SUP], Vinay Gopan[SUP] 1 [/SUP], Huiyi Miao[SUP] 1 [/SUP], Yuna Seo[SUP] 1 [/SUP], Denise Rogers[SUP] 1 [/SUP], Isabella Renzi[SUP] 2 [/SUP], Yen-Ting Lai[SUP] 2 [/SUP], Elisabeth Narayanan[SUP] 2 [/SUP], Guillaume Stewart-Jones[SUP] 2 [/SUP], Sunny Himansu[SUP] 2 [/SUP], Andrea Carfi[SUP] 2 [/SUP], Anthony S Fauci[SUP] 1 [/SUP], Paolo Lusso[SUP] 1 [/SUP]
Affiliations
- PMID: 37428933
- DOI: 10.1073/pnas.2305896120
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[SUB]CT.745[/SUB] (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.
Keywords: COVID-19; mRNA; neutralizing antibodies; vaccine.