Virus-like particle displaying SARS-CoV-2 receptor binding domain elicits neutralizing antibodies and is protective in a challenge model

While the effort to vaccinate people against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has largely been successful, particularly in the developed world, the rise of new variants as well as waning immunity illustrate the need for a new generation of vaccines that provide broader and/or more durable protection against infection and severe disease. Here we describe the generation and characterization of IVX-411, a computationally designed, two-component virus-like particle (VLP) displaying the ancestral SARS-CoV-2 receptor binding domain (RBD) on its surface. Immunization of mice with IVX-411 generates neutralizing antibodies against the ancestral strain as well as three variants of concern. Neutralizing antibody titers elicited by IVX-411 are durable and significantly higher than those elicited by immunization with soluble RBD and spike antigens. Furthermore, immunization with IVX-411 is shown to be protective in a Syrian Golden hamster challenge model using two different strains of SARS-CoV-2. Overall, these studies demonstrate that IVX-411 is highly immunogenic and capable of eliciting broad, protective immunity.

Stabilization of the SARS-CoV-2 Spike receptor-binding domain using deep mutational scanning and structure-based design

The unprecedented global demand for SARS-CoV-2 vaccines has demonstrated the need for highly effective vaccine candidates that are thermostable and amenable to large-scale manufacturing. Nanoparticle immunogens presenting the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein (S) in repetitive arrays are being advanced as second-generation vaccine candidates, as they feature robust manufacturing characteristics and have shown promising immunogenicity in preclinical models. Here, we used previously reported deep mutational scanning (DMS) data to guide the design of stabilized variants of the RBD. The selected mutations fill a cavity in the RBD that has been identified as a linoleic acid binding pocket. Screening of several designs led to the selection of two lead candidates that expressed at higher yields than the wild-type RBD. These stabilized RBDs possess enhanced thermal stability and resistance to aggregation, particularly when incorporated into an icosahedral nanoparticle immunogen that maintained its integrity and antigenicity for 28 days at 35-40{degrees}C, while corresponding immunogens displaying the wild-type RBD experienced aggregation and loss of antigenicity. The stabilized immunogens preserved the potent immunogenicity of the original nanoparticle immunogen, which is currently being evaluated in a Phase I/II clinical trial. Our findings may improve the scalability and stability of RBD-based coronavirus vaccines in any format and more generally highlight the utility of comprehensive DMS data in guiding vaccine design.

Analysis of patient-specific quality assurance for Elekta Unity adaptive plans using statistical process control methodology.

The Elekta Unity MR-linac utilizes daily magnetic resonance imaging (MRI) for online plan adaptation. In the Unity workflow, adapt to position (ATP) and adapt to shape (ATS) treatment planning options are available which represent a virtual shift or full re-plan with contour adjustments respectively. Both techniques generate a new intensity modulated radiation therapy (IMRT) treatment plan while the patient lies on the treatment table and thus adapted plans cannot be measured prior to treatment delivery. A statistical process control methodology was used to analyze 512 patient-specific IMRT QA measurements performed on the MR-compatible SunNuclear ArcCheck with a gamma criterion of 3%/2 mm using global normalization and a 10% low dose threshold. The lower control limit (LCL) was determined from 68 IMRT reference plan measurements, and a one-sided process capability ratio ( C p , l ) was used to assess the pass rates from 432 measured ATP and 80 measured ATS plans. Further analysis was performed to assess differences between SBRT or conventional fractionation pass rates and to determine whether there was any correlation between the pass rates and plan complexity. The LCL of the reference plans was determined to be a gamma pass rate of 0.958, and the C p , l of the measured ATP plans and measured ATS plans were determined to be 1.403 and 0.940 for ATP and ATS plans, respectively, while a C p , l of 0.902 and 1.383 was found for SBRT and conventional fractionations respectively. For plan complexity, no correlation was found between modulation degree and gamma pass rate, but a statistically significant correlation was observed between the beam-averaged aperture area and gamma pass rate. All adaptive plans passed the TG-218 guidelines, but the ATS and SBRT plans tended to have a smaller beam-averaged aperture area with slightly lower gamma pass rates.