SolaVAX: Novel Production of Vaccines Comprising Inactivated Viral Particles
Figure 1. Depiction of the general concept of an endogenous photosensitizer such as Riboflavin and UV light to carry out specific changes in nucleic acid
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US Utility Patent Pending (Not Yet Published)
Raymond P. Goodrich
Richard A. Bowen
At A Glance
Researchers at Colorado State University have developed a vaccine for COVID-19 produced through a novel method (SolaVAX™) for inactivation of a whole virion particle. The vaccine has been tested in a sensitive hamster animal model for its ability to prevent infection upon challenge with SARS-CoV-2 virus and has been demonstrated to be effective in providing protection against COVID-19 disease.
The use of this methodology may afford a means to rapidly produce vaccine candidates in response to both emergent and existing disease threats. Due to the specificity of the chemistry, the ability to achieve inactivation using this photochemical method may have several significant advantages over the approaches used today which utilize chemical agents such as formalin, Beta propiolactone and ethyleneimine derivatives. This may make possible the production of vaccine candidates with much better immunogen profiles than existing and includes the potential to extend such an approach to agents that may recalcitrant with regard to current technology.
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This method employs the use of a photochemical (riboflavin or vitamin B2) in combination with UV light in the UVA and UVB wavelength regions to carry out specific nucleic acid alterations through electron transfer chemistry-based processes. The method was originally developed for the treatment of blood products to prevent transfusion transmitted diseases and has been in routine clinical use for prevention of transfusion transmitted viral, bacterial, and parasitic diseases since 2008. The process utilizes a well-established and demonstrated capability of riboflavin and UV light to modify nucleic acid structure primarily through modification of guanine bases in a non-oxygen dependent process utilizing the natural electron donor-acceptor chemistry associated with guanine and riboflavin, respectively.
Figure 2. Apparatus used to produce photoinactivated vaccine candidates
The process allows for retention of plasma and cell-bound protein structure post treatment to an extent that such products may still be efficacious in functional utilization for transfusion support of patients. Furthermore, this approach has a well-established safety toxicology profile, is non-mutagenic and non-carcinogenic and poses little to no toxicity or disposal risk to facility personnel or the environment. This safety profile has been documented extensively in pre-clinical and clinical programs in human subjects.
The approach was based on the hypothesis that the ability to inactivate virus replication without inducing damage to protein epitopes, could result in the generation of a potent vaccine candidate with intact protein antigen targets comparable to native, live-type virus. Furthermore, such a candidate would be able to induce a potent immune response with relatively low doses of immunogen and thus provide protective immunity against live virus challenge.
Studies have demonstrated the ability of the products made via this method to induce a potent immune response to vaccination (Fig. 3). This response triggered both Th1 and Th2 type immune pathways, leading to generation of neutralizing antibodies and cellular responses capable of protecting vaccinated animals against intranasal challenge with 105 pfu SARS-CoV-2. The use of adjuvants was found to boost the levels of neutralizing antibody titers. The non-adjuvanted formulation still provided sufficient protection to prevent viral production and shedding in challenged animals.
Adjuvanted formulations, particularly CpG 1018 demonstrated the lowest levels of viral shedding, preservation of normal lung morphology and airway passage integrity and reduced number of infiltrates in the trachea and lung tissue. Both adjuvants used in these studies are known to promote Th1 immune pathway responses. Prior work with vaccine candidates suggested that ADE leading to lung immunopathology might be avoided by using Th1 promoting adjuvants. The results observed here are consistent with those observations.
Animal Model Data
Hamsters were challenged with plaque forming units (pfu) of live SARS-CoV-2 intranasally. Then oral-pharyngeal swabs were taken 1-3 days post-infection (dpi) to monitor viral replication. None of the hamsters showed any clinical adverse reactions to the vaccination. Data indicated 3 days post-infection of SARS-CoV-2 that the vaccinated hamsters reduced the amount of viral replication in the oropharynx. Moreover, there was a significant decrease in viral titers (in tissues of the respiratory tract) in the group having had IM injection of the SolaVax + CpG 1018 adjuvant (Fig. 4).
Among the vaccinated hamsters, those in the SolaVax + CpG 1018 adjuvant group (vaccinated via IM) were the best protected from viral-induced pathology. Hamsters immunized with this formulation had improved air space capacity, a lack of consolidating inflammation, and bronchi or trachea with mild inflammatory changes or essentially normal morphology (Fig. 5).
Furthermore, in the blood, the SolaVAX-vaccinated IM groups with adjuvants had significantly lower numbers of CD8+ CXCR4+ CD4- 279 CXCR3- IL-6- Tbet- IFN-γ- IL-4- IL-10- GATA- TNF-α- cells compared to the Control group.
Fig. 3. The detection of neutralizing antibodies in hamsters by PRNT90 after vaccination (A and B), and serum reactivity to spike protein’s RBD, S1 and S2 region (C-E). A plaque reduction neutralization test with a cutoff of 90% was used to determine neutralizing antibody production after 21- and 42-days post vaccination (DPV) for both SC (A) and IM (B) routes of vaccine administration. The prime vaccination was given at 0 DPV and a booster vaccination given at 21 DPV. Data points represent group mean +/- SD. Results of ELISAs measuring serum reactivity to RBD (C) and S1 (D) and S2 (E) protein. Graphs on the left panel shows optical density (OD) at 450 nm (y-axis) vs serum dilutions (x-axis). Values represent mean +/- SD, n=4. Right panel shows area under the curve (AUC) calculated for each dilution for individual hamsters.
Fig. 4. Viral loads from oropharyngeal swab and respiratory tract tissues after challenge with live virus. Oropharyngeal swabs were taken from all hamsters on 1, 2, and 3 days post infection (DPI). Viral titers of swabs collected from hamsters vaccinated via SC (A) and via IM (B) were determined by plaque assay. The presence of infectious virus was also determined in turbinates (C), trachea (D), right cranial lung lobe (E), and right caudal lung (F) of each hamster three days after live virus challenge. Data points represent group mean +/- SD. SC, subcutaneous vaccination. IM, intramuscular vaccination. Asterisks above bars indicate statistically significant difference in viral titers between Control and vaccine group (**** =p<0.0001, *** =p<0.001, **=p<0.01, * =p<0.05). Limit of detection denoted as horizontal dotted line.
Fig. 5. Representative histology of differences between unimmunized SARS-CoV-2 infected controls (A, C and E) and infected hamsters vaccinated with SolaVAX prepared SARS-CoV-2 virus and CpG 1018 adjuvant (B, D and F). (A) Trachea with dense submucosal lymphocytic and neutrophilic inflammation infiltrating mucosal epithelium (arrow) and accumulation of neutrophils within the tracheal lumen (arrowhead). (B) Trachea with mild submucosal lymphocytic inflammation. (C) Large bronchus with dense lymphocytic and suppurative inflammation in the interstitium (arrow) and accumulation of neutrophils in the lumen with loss of mucosal epithelium (arrowhead). (D) Large bronchus minimally affected by inflammation (arrow). (E) Effacement of lung alveolar tissue by consolidating interstitial pneumonia (arrow) and overall decrease in alveolar air space (arrowhead). (F) Interstitial pneumonia increasing alveolar wall thickness (arrowhead) without compromising alveolar air space (arrowhead).
- Ability to produce vaccines with high immunogenicity at low immunogen doses. This is exemplified by COVID-19 Vaccine induced potent immune response with relatively low doses of immunogen
- Vaccine candidates produced using this method are fully attenuated with regard to replication capabilities while maintaining viral protein structural integrity as close to the native virus as possible
- Well-established safety toxicology profile for chemicals and components used in the vaccine manufacturing process, i.e., non-mutagenic and non-carcinogenic materials that pose little to no toxicity or disposal risk to facility personnel or the environment in contrast to conventional methods for producing inactivated vaccine candidates.
- Safety profile of materials and methods has been documented extensively in pre-clinical and clinical programs in human subjects through clinical use of products in blood safety applications dating from 2007 to present.
- Rapid and affordable production of the inactivated vaccine is both practical and cost-effective. Raw material costs and production time is minimal for even bulk production of vaccine candidates.
- Utilizes existing equipment, reagents and disposables that are in routine use for treatment of blood products. Equipment is commercially available and in widespread, global distribution and use.
- COVID-19 Vaccination
- Vaccinations for both human and veterinary uses
- Development of other vaccinations against viruses, or other bacterial and parasitic agents including, but not limited to: Dengue, Zika, Chikungunya, Influenza, SARS-CoV, MERS-CoV, Lassa Fever, Nipah, Leishmania, Typhoid Fever, African Swine Fever, or Japanese Encephalitis Virus (VEE, WEE, EEE, etc.)
Ragan, Izabela K, et al. “A Whole Virion Vaccine for COVID-19 Produced via a Novel Inactivation Method: Results from Animal Challenge Model Studies.” BioRxiv, Cold Spring Harbor Laboratory, 13 Nov. 2020, www.biorxiv.org/content/10.1101/2020.11.13.381335v1.full.
Last updated: November 2020
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#CSUInvents – #TechTuesday! Researchers at Colorado State University are developing an inactivated #virus #vaccine (SolaVAX™) for #covid19, repurposing an existing technology platform that inactivates #pathogens in blood products. The platform has been shown to efficiently inactivate MERS-CoV & has been evaluated for production of vaccine products using adeno-associated & Lentivirus constructs.
#CSU Researchers will utilize this platform with stock virus cultures grown in CSU’s BioMARC BSL-3 facility, a cGMP compliant manufacturing facility operated on a non-profit basis. BioMARC is a Regional Center of Excellence & currently operates as part of the Regional Biocontainment/National Biocontainment laboratory network under National Institute of Allergy and Infectious Diseases (NIAID).
Inventors include: Raymond Goodrich, professor CSU Microbiology, Immunology & Pathology, & Dick Bowen, professor Biomedical Sciences, CSU College of Veterinary Medicine and Biomedical Sciences
#vaccines #AUTM #covid19research #FLC #publichealth #health #MIP #sciencematters Centers for Disease Control and Prevention The National Institutes of Health Terumo BCT Alan Rudolph CSU Vice President for Research