Enhancing Anti-SARS-CoV-2 Neutralizing Immunity by Genetic Delivery of Enveloped Virus-like Particles Displaying SARS-CoV-2 Spikes
Author:
Yang Yongping1ORCID, Kong Wing-Pui1, Liu Cuiping1, Ruckwardt Tracy J.1, Tsybovsky Yaroslav2, Wang Lingshu1, Wang Shuishu1ORCID, Biner Daniel W.1, Chen Man1, Liu Tracy1, Merriam Jonah1ORCID, Olia Adam S.1, Ou Li1ORCID, Qiu Qi1, Shi Wei1, Stephens Tyler2, Yang Eun Sung1, Zhang Baoshan1, Zhang Yi1, Zhou Qiong1, Rawi Reda1, Koup Richard A.1, Mascola John R.1, Kwong Peter D.1ORCID
Affiliation:
1. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA 2. Vaccine Research Center Electron Microscopy Unit, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 20701, USA
Abstract
New vaccine delivery technologies, such as mRNA, have played a critical role in the rapid and efficient control of SARS-CoV-2, helping to end the COVID-19 pandemic. Enveloped virus-like particles (eVLPs) are often more immunogenic than protein subunit immunogens and could be an effective vaccine platform. Here, we investigated whether the genetic delivery of eVLPs could achieve strong immune responses in mice as previously reported with the immunization of in vitro purified eVLPs. We utilized Newcastle disease virus-like particles (NDVLPs) to display SARS-CoV-2 prefusion-stabilized spikes from the WA-1 or Beta variant (S-2P or S-2Pᵦ, respectively) and evaluated neutralizing murine immune responses achieved by a single-gene-transcript DNA construct for the WA-1 or Beta variant (which we named S-2P-NDVLP-1T and S-2Pᵦ-NDVLP-1T, respectively), by multiple-gene-transcript DNA constructs for the Beta variant (S-2Pᵦ-NDVLP-3T), and by a protein subunit–DNA construct for the WA-1 or Beta variant (S-2P-TM or S-2Pᵦ-TM, respectively). The genetic delivery of S-2P-NDVLP-1T or S-2Pᵦ-NDVLP-1T yielded modest neutralizing responses after a single immunization and high neutralizing responses after a second immunization, comparable to previously reported results in mice immunized with in vitro purified S-2P-NDVLPs. Notably, genetic delivery of S-2Pᵦ-NDVLP-3T yielded significantly higher neutralizing responses in mice after a second immunization than S-2Pᵦ-NDVLP-1T or S-2Pᵦ-TM. Genetic delivery also elicited high spike-specific T-cell responses. Collectively, these results indicate that genetic delivery can provide an effective means to immunize eVLPs and that a multiple-gene transcript eVLP platform may be especially efficacious and inform the design of improved vaccines.
Funder
Vaccine Research Center
Subject
Pharmacology (medical),Infectious Diseases,Drug Discovery,Pharmacology,Immunology
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