Applying Rapid Countermeasure Preparedness to Development of a Novel COVID-19 Vaccine

The COVID-19 pandemic sweeping across the globe is pushing innovation to the cutting edge throughout the biopharma industry. More rapid development of novel diagnostics, therapeutics, and vaccines is acutely needed to mitigate further spread of the virus and prevent its reoccurrence in the future. iBio is offering its FastPharmingTM  Contract Manufacturing Services to vaccine and therapeutic developers to address the need for speeding time-to-clinic for new antigens, antibodies, and other protein biologics using a plant-based expression system. In addition, iBio is developing its own proprietary solutions, notably IBIO-200, a virus-like particle (VLP) vaccine candidate for  COVID-19 disease.

Potential Vaccine Platforms

The traditional approach to vaccines is to use live or killed viruses to generate immune responses. Development, approval, and commercialization of these types of vaccines can take several years, a model that is clearly unfeasible during this pandemic. New approaches use a reductionist approach by identifying key viral components that can be incorporated into a vaccine that elicits a strong immune response and is also safe and easy to manufacture.1

Such approaches include vaccines that rely on recombinant DNA or messenger RNA (mRNA). San Diego-based Inovio Pharmaceuticals, the first company to advance a vaccine (INO-4700) against MERS-CoV into human testing, is developing a DNA-based vaccine against COVID-19, while both Cambridge, Massachusetts-based Moderna and German biotech CureVac are developing mRNA-based vaccines. There are concerns with many of these approaches, however, particularly DNA and mRNA vaccines. Questions have been raised about their cold-chain requirements compared with traditional vaccine technology platforms. These solutions provide great hope but carry significant risk. 

At present, six COVID-19 or SARS-CoV-2 phase I clinical trials are listed in clinicaltrials.gov, although there are likely more in the works, as registration in the database is not mandatory until phase II.

iBio’s VLP Solutions

Virus-like particles (VLPs) represent a promising alternative to soluble antigens, as their shape, size, repetitive antigen structure, and geometry have been shown to trigger stronger immune response, both humoral and cellular.2 VLPs are artificial constructs comprising multiple proteins organized to resemble a virus, but without including any viral genetic material, thereby rendering them non-infectious. Because they have the components and conformation of the native virus, they can engender stronger and broader immune responses than the antigen itself.

In addition, VLPs can be produced as cost-effectively as other novel platform technologies being used for COVID-19 vaccine development and do not present additional safety concerns compared with those associated with DNA- and mRNA-based solutions.

iBio has extensive capability in this area, having developed plant-based bioprocesses that generate VLPs with the same structures as more traditional methods but via more efficient manufacturing routes. VLP platforms like iBio’s are advantageous because, in addition to obtaining high yields of the individual VLP components, the components automatically self-assemble into a spherical VLP, simplifying both the upstream and downstream purification processes involved in VLP manufacture.

The recent phase III clinical success of a VLP-based influenza vaccine produced in the N. benthamiana system (NCT03739112, NCT03301051), both in terms of efficacy and safety, demonstrates the potential for plant-based VLP vaccine development.3 

IBio-200: A VLP-Based COVID-19 Vaccine Candidate

IBIO-200 is iBio’s lead COVID-19 vaccine candidate.  iBio uses Woodchuck hepatitis virus and human hepatitis B virus core proteins fused to COVID-19 receptor-binding motif (RBM), which self-assemble into empty nanoparticles. The resulting VLPs form 40- to 50-nm diameter nanoparticles. The antigen is displayed in a repetitive structure and geometry, and the particle is decorated with oligomannose molecules to more closely resemble the structure of naturally occurring viruses.  Oligomannose glycosylation is thought to lead to better cellular uptake of the VLPs by antigen-presenting cells via the mannose receptor. As with other VLP-derived vaccines, IBIO-200 is designed to interact with immune cells differently than soluble antigens.

The production of IBIO-200 follows standard and highly optimized protocols. Plants are seeded, germinated, and grown to 5 weeks of age in environmentally controlled grow rooms. At 5 weeks, plants are vacuum infiltrated with Agrobacterium containing transient plant-specific expression vectors encoding COVID-19 antigen constructs. After infiltration, the vector drives vaccine expression for 5–7 days; plant material is shredded, and total soluble protein extracted. Preliminary scalable downstream processes have been designed, including concentration and buffer exchange of clarified extract capture and polishing chromatography.

For evaluation purposes, the first screenings measured expression and protein stability. Selected candidates will then be injected into mice for an initial immunization study. IgG response, cytokine profiling, and results of virus neutralization assays will dictate a second candidate screening. Subsequently, selected candidates will enter toxicology studies in appropriate animal models to support an IND filling. A lead candidate and a back-up will then be selected for further in vivo efficacy studies.

In parallel, iBio will develop a process that is scalable to cGMP manufacturing, prepare manufacturing documentation, and develop QC release assays. The FastPharming manufacturing system delivers a tightly controlled particle size, providing considerable quality and scale-up advantages, as uniform antigen display enables better dose definition and higher product yields. 

All of this work will be based on technology proven successful for the clinical development of vaccine candidates in iBio’s U.S.-based, large-scale production facility with all cGMP, QA, QC, scale-up, and regulatory resources; the facility is self-contained and secure with highly reliable logistics.

Extensive Vaccine Experience at iBio

iBio’s FastPharming facility was originally constructed in 2010 with funding from the Defense Advanced Research Projects Agency (DARPA), part of the U.S. Department of Defense (DoD), which was exploring a range of technologies that could enable faster responses to outbreaks. Plant-based expression technology won out, and the facility was one of three commercial sites comprising the “Blue Angel” initiative.

As part of the DARPA Blue Angel H1N1 Program, iBio’s facility was designed and built to manufacture kilogram quantities of recombinant proteins within months versus the historically longer time frames needed for more traditional systems. Its rapid launch to production has been designed specifically for medical countermeasure responses. The iBio facility is among the largest biotherapeutic production facilities in the world for the production of recombinant protein in N. benthamiana, with a current capacity to produce bulk clinical protein at the scale of approximately 500 million doses per year.

iBio technology has been used to produce a number of prophylactic vaccines, including soluble pathogen antigens formulated with adjuvants against anthrax, H5N1 influenza, H1N1 influenza and hookworm, and a virus-like particle (VLP) formulated with an adjuvant against malaria. Phase I clinical studies have been completed for all of these vaccine candidates.

Accelerating Development with iBio’s FastPharming System

Unlike traditional cell-culture bioprocesses that are performed in stainless-steel or single-use bioreactors, iBio’s proprietary FastPharming system uses plants as bioreactors. The plant-specific expression vector containing the gene of interest is transfected into Agrobacterium, which are then vacuum infiltrated into the leaves of iBio’s proprietary Nicotiana benthamiana plants. The target protein is expressed in the leaves as the plants grow. The leaves are then harvested, and the protein is isolated, purified, and formulated into the desired final product.

Plant-based production saves months in initial setup time compared with competing methods. There is, for instance, no need for expensive, labor-intensive cell-line development. The required up-front investment is also less compared with mammalian cell-culture systems. The risks and delays associated with scale-up are also reduced. Scale-up is achieved by simply growing more plants. The material obtained during the research stage is highly comparable to the material obtained at commercial scale. During a pandemic, having the ability to rapidly scale with confidence that vaccine properties will not change, is invaluable.

iBio’s FastPharming technology is well positioned to provide rapid responses and address the need for both therapeutics and vaccines in the event of emerging outbreaks such as COVID-19. The company has  the flexibility to produce small quantities of antigens per vaccine dose or large quantities of antibodies and various other modalities for therapeutic treatments. As importantly, iBio  can rapidly transition from vaccine to drug production in the same facility.

References

  1. Challener, Cynthia. “Can Vaccine Development be Safely Accelerated.” Pharmaceutical Technology. 10 Mar. 2020. Web.
  2. Donaldson, Braden et al. “Virus-like particle vaccines: immunology and formulation for clinical translation.” Expert Review of Vaccines. 17: 833–849 (2018).
  3. Medicago's New Drug Submission accepted for scientific review by Health Canada: An important step for Medicago towards commercialization of its innovative influenza vaccine. 1 Oct. 2019. Web.

Tom Isett

Tom Isett is a strategic advisor and member of iBio’s Board of Directors.  He also serves as Managing Director for i.e. Advising, LLC, a life science strategy and management consulting firm that he founded in January 2015.  Prior to that, Mr. Isett led businesses for GE, Lonza, and BD, ranging in size from start-up to half-a-billion in revenues. Mr. Isett received his B.Sc. in biological sciences from Drexel University.

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