Scripps Research Spin-Off Ushers a "New Era" in Vaccinology With Platform Technology

Scripps Research spin-off company Ufovax employs the single-component self-assembling protein nanoparticle (1c-SApNP®) platform technology, that was created in the laboratory of Professor Jiang Zhu, to address some of the key challenges in modern vaccine development.

The COVID-19 global pandemic has further emphasized the need for efficient vaccine design, testing and large-scale manufacturing. Ufovax's "plug-and-play" vaccine platform offers to "streamline" the development process and has already delivered vaccine candidates for global health challenges such as HIV, Ebola and MERS-CoV. Now the company is pursuing a preventive vaccine for SARS-CoV-2, the coronavirus responsible for COVID-19. An initial evaluation of more than 50 designs has led to five candidates that have been validated in preclinical models.

Technology Networks spoke with Dr Colette F Saccomanno, senior vice president of corporate affairs at Ufovax to learn how the platform works and enables low-cost vaccine manufacturing that is readily scalable.

Molly Campbell (MC): For our readers that are unfamiliar the with the company, please can you tell us about Ufovax?

Colette F Saccomanno (CFS): Ufovax is vaccine company and spin-off from Scripps Research (La Jolla). With advanced approaches to bio-manufacturing, nanotechnology and the rational design of vaccines that optimize antigens via small but critical stabilizing mutations, Ufovax is ushering in a new era in vaccinology and will offer safe and effective solutions that the myriad of vaccines currently available – or under development – do not.

The company holds exclusive Intellectual property rights to certain vaccine work of a team led by Associate Professor Jiang Zhu, PhD, who holds appointments in the departments of Integrative Structural & Computational Biology and Immunology and Microbiology at Scripps Research.

Ufovax is commercializing a modular, plug-and-play vaccine platform capable of targeting some of the most challenging infectious diseases such as HIV, HCV, RSV, Ebola, MERS, SARS-CoV-1, and now SARS-CoV-2. These are recombinant protein-on-protein-nanoparticle vaccines designed to optimize antigen presentation, simplify manufacturing and maximize a safe and protective immune response for broad use in humans.

MC: How was the 1c-SApNP® vaccine platform technology developed, and how does it work?

CFS: Dubbed the “single-component-self-assembling protein nanoparticle” (1c-SApNP®), the Ufovax platform makes vaccine development as straightforward as a socket wrench and transforms biological complexity to elegant simplicity.

First, we design the “socket”, an optimal antigen structure, which – for viruses utilizing the class-I fusion mechanism – is called the “Uncleaved, pre-Fusion, Optimized Antigen” (“UFOAg”). Second, the UFOAg is genetically fused to the “handle” which is a multilayered nanoparticle unit that encodes a nanoparticle-forming component, a nanoparticle-stabilizing component and, if necessary, one or more immunomodulators. Third, we bio-manufacture to scale via transient or stable expression in GMP cell lines followed by a robust two-step purification process, combining immunoaffinity and size-exclusion chromatography methods (or other size-based separation methods used in the GMP setting).

The 1c-SApNP platform technology is the result of nearly a decade of research and development work conducted by the team led by Zhu. With expertise in rational vaccine design and antibody discovery, the group has been working to perfect structure-based antigen design and nanoparticle engineering. Combining single-cell analysis and library display with next-generation sequencing, they also work to discover and produce functional antibodies as potential therapeutics, or as core components of immunoaffinity methods that enable a highly efficient purification process for vaccine manufacturing. Ufovax now has a strong pipeline of vaccines that show promise against a wide array of viral and non-viral infectious agents.

Trained as a biophysicist, Zhu has applied a unique set of skills and experience in the fields of physics, biochemistry, virology, immunology, and molecular modeling to “see through” the very complicated three-dimensional structures of antigen complexes, both before and after infection. Understanding, at the molecular level how each virus infects humans allows rational design of “virus-like particles” (VLPs) with optimal shape, size, and antigen display. Such VLP-type vaccines can, in principle, induce a rapid and long-lasting immune response to protect against infection.

MC: What production advantages over the traditional virus like particle (VLP) platform does 1c-SApNP have? 

CFS: First, the Ufovax nanoparticles are pure protein nanoparticles with a well-defined structure. Since the geometry is mathematically defined, there is no ambiguity in its structure and antigen display can be accurately designed and modeled on a computer. Since there is no lipid involved, the manufacturing process is easy and robust. Second, while both traditional and 1c-SApNP VLPs are self-assembling, traditional VLP assembly is a delicate and sometimes multiple-step process that is susceptible to many factors, whereas 1c-SApNP VLP assembly is a fast, single-step reaction. As a result, the materials produced are cleaner and the polishing process is easier. Third, since 1c-SApNPs often have exposed N- and C-termini on the surface, it is possible to genetically fuse a large antigen (e.g., HIV-1 and coronavirus spike proteins) to a 1c-SApNP subunit and the fusion construct will still express and self-assemble. This would be very difficult, if not impossible, for VLPs derived from virus shells. Finally, SApNPs of bacterial origin are robust proteins tolerant of mutations and insertions, allowing further protein design and engineering to optimize their function as antigen carriers (on the 1c-SApNP surface) or as cargo for immune modulators (inside the 1c-SApNP shell).

Perhaps the single, stand-out differentiator of the Ufovax 1c-SApNP production process is the “one-for-all” bioprocess that works the same way for all vaccine products. For any given vaccine candidate, a single plasmid that encodes ALL structural/functional components of the vaccine is transfected into the same widely-used GMP CHO cell expression system and forms the desired nanoparticle vaccine product through self-assembly. These nanoparticle vaccines resemble the target both morphologically and antigenically but lack any infectious capacity.

MC: How is 1c-SApNP optimized for low-cost, large-scale industrial manufacturing? Why might this be advantageous in the context of the COVID-19 global pandemic?

CFS: The Ufovax 1c-SApNP is the best-in-class platform technology for protein nanoparticle vaccines. The optimal construct design coupled with the robust expression/purification system enables both high yield and high purity. As a platform, this makes Ufovax vaccine manufacturing low-cost and readily scalable. Moreover, the fully assembled 1c-SApNP vaccine is thermostable, which facilitates distribution and minimizes supply chain concerns. In contrast, most viral vector vaccines would require “cold-chain” storage and distribution. This is especially important in the context of any global pandemic, not just COVID-19.

MC: Please can you discuss the company's creation of a vaccine against SARS-CoV-2? How does the vaccine work and at what stage of preclinical testing is the vaccine currently? 

CFS: Zhu has been conducting vaccine research for more than ten years, including his time at the National Institutes of Health (NIH) Vaccine Research Center. Prior to the emergence of the COVID-19 pandemic, he had been a co-Investigator on two NIH-sponsored vaccine programs for coronaviruses, specifically SARS (now SARS-CoV-1) and MERS and the rapid development of our COVID-19 candidate(s) was enabled by this foundational understanding of coronaviruses.

Against this backdrop, the 1c-SApNP approach was proven to be a bona-fide plug-and-play platform technology. Our first COVID-19 candidate was purified on February 28, 2020. Further evaluation of 150 constructs led us to five final candidates and our pre-clinical mouse immunogenicity study was initiated in late May.

The serological analysis of over 80 samples was recently completed and represents one of the first examples of a “systematic” rational design and preclinical study for COVID-19 vaccine development. Our mouse data demonstrate high titers of neutralizing antibodies and is consistent with the expectation of a single- or two-dose regimen. A publication is in preparation.

The Ufovax COVID-19 1c-SApNP vaccine is a spike-based vaccine but with a twist – one that locks the spike in its pre-fusion state and presents 20 such spikes per nanoparticle. A very potent immune response is thereby elicited. In fact, the Ufovax design “predicted” and accounted for the pre- to post-fusion conformational changes that were recently reported in Science (Y. Cai et al., Science 10.1126/science.abd4251 (2020). Our patent application covering vaccine design strategies for all three coronaviruses was filed on June 29^th.

MC: Can you discuss the portfolio of 1c-SApNP vaccines candidates that have been developed thus far?

CFS: As a spin-off of Scripps Research, the Ufovax pipeline has a strong and distinguished pedigree. Built on the history of all the work and attempts to create an effective vaccine against one of the most challenging global health crisis in recent history, Ufovax began with the intention of advancing its HIV-1 vaccine. With the Company’s strategic plan based on the most impactful infectious diseases, we then moved on to HCV, RSV, SARS/MERS, Malaria and Ebola, until the world was interrupted by COVID-19 and nearly all attention shifted.

Despite having to address the COVID-19 pandemic, Ufovax is still on-track with other programs, including HIV-1 which was selected by DAIDS/NIH to be included in the NIH’s clinical trial currently scheduled to begin in 2022, and RSV and HCV, with those clinical trials targeted to begin in Q4 2021. We have filed six patent applications covering HIV, HCV, RSV, and the coronaviruses; two of which have been allowed by the USPTO. Our patent on the Ebola vaccine is being prepared for filing in August 2020.

MC: What are your plans for progressing the vaccine against SARS-CoV-2?

CFS: Ufovax is negotiating with several potential partners for SARS-CoV-2 vaccine development. Our plans include completing the ongoing mouse immunogenicity study, conducting GLP-toxicology studies, and filing an IND application in Q4 2020 to enable first-in-human studies by the end of 2020 or in early 2021.

MC: What are the biggest challenges when developing vaccines?

CFS: For scientists pursuing rational vaccine design, the biggest challenge lies in how to present the relevant and correct antigen conformation to the immune system and thereby induce a robust and long-lasting immune response to prevent virus infection. The success of rational design relies, in large part, on the in-depth understanding of the virus fusion mechanism, whereby the virus surface glycoprotein complex undergoes a dramatic conformational change. This change enables the physical contact of the cell and virus membranes and the creation of a fusion pore that allows viral entry into the cell. Many viruses threatening humanity such as HIV-1, Ebola, Flu, RSV, and SARS-CoV-2 use the class-I fusion mechanism, which renders their surface glycoproteins unstable in the pre-fusion conformation. Through evolution, these viruses have also acquired various molecular trickeries to evade immune response by exposing immunodominant epitopes on the unstable glycoproteins or producing numerous “decoys” so that the antibodies generated against these targets are ineffective at blocking the virus entry. Therefore, the biggest challenge in vaccine development for this large family of viruses is to “rationally redesign” their surface glycoproteins to stabilize them in the prefusion state and to present them to the immune system either as a vaccine antigen, or more effectively, on a large virus-mimicking nanoparticle to elicit a strong immune response.

MC: How has the COVID-19 global pandemic impacted vaccine design, testing and manufacturing?

CFS: Long feared and even publicly attacked as doing more harm than good, the value of vaccines is now globally acknowledged. The COVID-19 global pandemic has elevated the urgency for vaccine development to an all-time high. Despite unprecedented funding, there has been little or no impact on the design of vaccines as a result of COVID-19.

The majority of current COVID-19 vaccine designs are largely based on approaches that have not yet produced commercial vaccine products. All “major players” working on COVID-19 are using the wildtype spike S protein as antigen with/without proline capping.  As the aforementioned Science article pointed out, the wildtype spike is unstable and proline capping, as a spike-stabilizing strategy, it is not as effective as previously thought. Such suboptimal antigen designs may lead to a dampened immune response and potentially introduce safety concerns due to the presence of post-fusion or misfolded spikes in these vaccines.

The Ufovax design invokes its UFOAg with patented mutations to eliminate the post-fusion conformation of the spike protein. This confers a higher degree of spike homogeneity, has already demonstrated greater immunogenicity in our mouse study, and suggests fewer safety concerns for future use in humans.

Vaccine manufacturing is often complicated and tedious, posing significant challenges for large-scale production in the time of a pandemic. The field is seeking an easy, fast, scalable, and cost-effective manufacturing process that can be standardized and applied to a wide range of vaccine products. Ufovax’s 1c-SApNP platform technology offers an elegant and workable solution.

Lastly, the testing of vaccines may finally come into the 21^st century as a result of the global reaction to the COVID-19 pandemic. Having a vaccine platform means not having to “re-invent the wheel” every time a new vaccine is needed. With the Ufovax 1c-SApNP approach, much of the safety is “built-in” from the start. Removing regulatory hurdles and getting new vaccines developed more rapidly means that appropriate human trial populations will exist for proper cohort assembly. The Ufovax 1c-SApNP platform is the modular plug-and-play solution.

Colette F Saccomanno CFS was speaking to Molly Campbell, Science Writer for Technology Networks.