Newcastle Disease Virus-Like Particles Displaying Prefusion-Stabilized SARS-CoV-2 Spikes Elicit Potent Neutralizing Responses

Abstract

The COVID-19 pandemic highlights an urgent need for vaccines that confer protection from SARS-CoV-2 infection. One approach to an effective COVID-19 vaccine may be through the display of SARS-CoV-2 spikes on the surface of virus-like particles, in a manner structurally mimicking spikes on a native virus. Here we report the development of Newcastle disease virus-like particles (NDVLPs) displaying the prefusion-stabilized SARS-CoV-2 spike ectodomain (S2P). Immunoassays with SARS-CoV-2-neutralizing antibodies revealed the antigenicity of S2P-NDVLP to be generally similar to that of soluble S2P, and negative-stain electron microscopy showed S2P on the NDVLP surface to be displayed with a morphology corresponding to its prefusion conformation. Mice immunized with S2P-NDVLP showed substantial neutralization titers (geometric mean ID50 = 386) two weeks after prime immunization, significantly higher than those elicited by a molar equivalent amount of soluble S2P (geometric mean ID50 = 17). Neutralizing titers at Week 5, two weeks after a boost immunization with S2P-NDVLP doses ranging from 2.0 to 250 μg, extended from 2125 to 4552, and these generally showed a higher ratio of neutralization versus ELISA than observed with soluble S2P. Overall, S2P-NDVLP appears to be a promising COVID-19 vaccine candidate capable of eliciting substantial neutralizing activity.

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization

“…A soluble trimeric RBD, as applied in BNT162b1 mRNA clinical trials, showed very promising immunogenicity including stimulation of antibodies and T cell responses [81,82]. In addition to trimerization, membrane anchoring seems to further improve immunogenicity, as transmembrane anchored prefusion-stabilized full-length S protein was reported to elicit higher VNA levels than corresponding secreted constructs [1,83]. Both in terms of immunogenicity and potential association of circulating SARS-Cov-2 S1 subunit with enhanced blood clotting [84], use of a small membrane-anchored antigen is rational.…”

Process development for cross‐flow diafiltration‐based VLP disassembly: A novel high‐throughput screening approach

“…This has been evaluated in several preclinical and clinical trials, and recently, a vaccine against the circumsporozoite protein of the malaria pathogen has been locally approved (European Medicines Agency, 2015). Recent efforts to develop VLP‐based severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccines underline the flexibility and simplicity of chimeric VLPs (Ghorbani et al, 2020; Yang et al, 2021). However, the versatile platform of chimeric VLPs not only comes with promises, but also with fundamental challenges, such as the ability to form stable capsids (Borisova et al, 1999; Böttcher et al, 2006; Nassal et al, 2005; Pumpens & Grens, 2001).…”

Current and future nanoparticle vaccines for COVID-19

“…A candidate poised for rapid advancement is avian pathogen Newcastle disease virus-like particles (NDVLPs) used to display pre-fusion stabilized SARS-CoV-2 S ectodomain (S2P) [39]. The S2P transmembrane and cytoplasmic domains were replaced with those from NDV to create a fusion protein that when co-expressed with NDV matrix and nucleocapsid proteins form S2P-NDVLPs.…”