Centuries of global pandemics have taught society that if a virus, or any biological threat, is highly infectious, it can spread quickly and propagate in vast numbers of people.

Despite social distancing guidelines and more restricted international borders, once they spread, viruses can significantly affect the ability of health care systems to respond effectively. Now more than ever pharma needs to respond rapidly with an effective and affordable vaccine.

When confronted with a global health crisis, the speed at which therapeutic or preventative solutions can be developed is critical as is the ability to manufacture enough doses at an affordable cost to affect outcomes. This article explains how a next-generation protein expression may offer science and society a better way to stop viral pandemics like COVID-19.

Taking vaccines from millions to billions
A pandemic’s capacity to spread so quickly means the key challenge for any vaccine is addressing the magnitude and scale of reaching billions of patients. In this scenario, the economics of protein expression becomes even more critical to the equation.

Better suited for small populations and the rhythms of seasonal flu, the long timelines of pharma’s current methods of vaccine development may no longer be able to respond adequately to the next global health crisis.

For developers and manufacturers wanting to stop COVID-19 or disrupt future viral threats from spreading infection, finding an effective vaccine is just the first step. Manufacturing a safe and effective vaccine, distributing it in sufficient quantity at a price that payers and society can afford, can bring a range of new challenges to the fore.

Vaccine production costs are unsustainable
Established in 2016, the Coalition for Epidemic Preparedness (CEP) was set up to develop vaccines that contribute to preparedness for outbreaks of epidemic infectious diseases.

Because evidence on vaccine development costs for such diseases was limited, the organization embarked on a study with the goal to estimate the minimum cost for achieving a vaccine response to a portfolio of 11 epidemic infectious diseases.

CEP researchers collected data on a pipeline of 224 vaccine candidates from preclinical through to phase II for 11 priority epidemic infectious diseases including MERS, SARS, Zika and Rift Valley fever.
Drawing from published estimates of vaccine R&D probabilities of success, coalition researchers simulated costs for advancing these 224 vaccine candidates through to the end of phase IIa. Via a stochastic optimization model, researchers combined those findings to determine minimum costs for progressing at least one vaccine through to the end of phase IIa per epidemic infectious disease.

According to a study published by The Lancet,¹ the cost of successfully advancing one epidemic infectious disease vaccine with a high probability of success through to the end of phase 2a can now potentially cost as much as $1.1 billion.

Assuming these candidates and funding were made available, CEP finds progressing at least one vaccine through to the end of phase IIa for each of the 11 epidemic infectious diseases they studied, had the potential cost of $8.4 billion, just to develop the vaccine. In the discussion section they note that these costs do not include mass production and distribution costs.

Drivers of vaccine development costs
The study suggests that R&D timelines, indirect costs, sectoral affiliation (i.e., commercial versus non-commercial public or private sectors) all influenced cost structures and probability of success. They also found that current platform technology complexity and pharma’s current vaccine manufacturing business models were all major contributing factors to vaccine research and development costs.

The alternatives
With demand for a COVID-19 vaccine likely to hit billions of doses—the numbers will likely become starkly apparent revealing that under current best commercial practice, the economics of current Good Manufacturing Practice (cGMP) manufacturing in highly centralized large capacity facilities may not prove sustainable in the long run.

Currently, the world mainly relies on Chinese Hamster Ovary (CHO) cells or insect cells for expression as the gold standard, but its expense and processing complexity is driving developers to consider emerging cell line alternatives—hosts in which to express these proteins and vaccines).

Authors of the CEP report suggest that development costs are higher than they might be due to the industry being wedded to their current technological platforms. Study authors also noted that the industry’s resistance to instituting advanced vaccine development technologies is largely due to flawed ROI assumptions, limited data and biased cost/benefit analyses.

Although the study did not conclude one gene expression system was better than another, the reference to the costs associated with development platforms and protein expression was clear, as was the industry’s false impression that the financial barriers to adopting new more advanced platforms were too high to risk change.

Expression platforms based on yeast are an example of a well-understood reliable technology known to biologic science that so far has not been used to develop a vaccine for human use. Even though industrial processors have seen commercial success with the platform, pharma still seems to regard it as an outlier technology.

Next-generation expression platform C1
Starting with the company’s proven industrial bioscience, Dyadic’s research team developed a higher-performing strain of fungus that has the potential to disrupt the cost curves and accelerate the timelines associated with human biologic drug development and commercialization. Known as C1, Dyadic’s platform is based on Thermothelomyces heterothallica, a fungus originally isolated from Russian soil.

Using state-of-the art biosynthetic engineering methods including development of an advanced molecular toolset, Dyadic’s scientists took advantage of a serendipitous mutation that prompted a several 100-fold increase in protein productivity by the C1 filamentous fungus.

Ready for emerging pharmacoeconomics and payer environments
Today, a broad range of biopharmaceuticals, vaccines and biosimilars are being produced from CHO and baculovirus cells.

Because C1 secretes its product into the surrounding cell media (essentially well-defined salts and sugars of the cheapest kind), the down-stream protein harvesting steps are also simpler than those in other next generation systems including E. coli expression systems that require lysing of cells, purifying product from cell fractions and more, all of which add costly complexity.

Great utility and cost-control potential
C1 is a safe, efficient expression system that can potentially speed up the development and production of biologics at flexible commercial scales, and at a lower cost relative to other vaccine development and production models.

The platform and the company’s genetic tool kit provide pharma with new potential to improve biologic drug development. The technology simplifies commercial gene expression processing and removes critical bottlenecks in protein development and manufacturing processes.

Suitable for single-use bioreactors and modular production environments
C1 is a highly agnostic platform, compatible with most single-use bioreactor platforms. That provides rapid scalability and faster commissioning of capacity—all of which has the potential to significantly lower the cost of CapEx and OpEx expenses. With Dyadic’s C1 platform, manufacturers can produce remarkably more doses in a shorter time, and at a fraction of the cost when compared to CHO and baculovirus models.

Dyadic recently demonstrated the capabilities of C1 expression in a 50L XDR-50MO GE single use bioreactor. Leveraging C1’s filamentous fungi, the R&D team produced Certolizumab in yields virtually identical to dedicated stainless-steel reactors.

A proven technology now responding to COVID-19
In order to help combat the Covid-19 outbreak, Dyadic recently developed a C1 cell line that produces a SARS-CoV-2 Receptor Binding Domain (RBD) antigen that expressed the RBD antigen at three grams per liter (3.5 g/l) in only four days. 

Currently, C1 expressed receptor binding domain (RBD) of the SARS-CoV-2 spike protein is being used in animal trials by seven research groups, governmental agencies and biopharma companies. Participants include a collaboration of European Union scientists participating in ZAPI, a coalition of research, industry and academic organizations.

ZAPI is currently testing C1 expressed RBD vaccine candidate(s) in animal trials on a stand-alone basis as well as C1 RBD with nanoparticles and adjuvants. Dyadic currently expects up to 10 animal trials to be completed by the end of 2020. 

Data generated by a number of these expert third parties confirmed that the C1-expressed RBD has the correct structure resulting in high binding and neutralizing capacity. Additionally, a recently concluded IIBR mice study shows that the C1 RBD has the potential to generate excellent immunogenicity responses with very high titers and neutralizing antibodies against the SARS-CoV-2 coronavirus.

Dyadic and its partners are now moving to the next level of development aiming to conduct toxicology testing to produce the C1 expressed SARS-CoV-2 RBD antigen under cGMP condition for Phase 1 and 2 clinical trials.

We can and need to do better
Although pharma’s manufacturers are compelled as much by sunk costs as they are by entrenched industrial practice to trust their current vaccine production processes, the industry should consider a parallel processing strategy, investing in alternative expression technologies like C1 to hedge its bets. 

References

1. https://www.thelancet.com/journals/langlo/article/PIIS2214 109X(18)30346-2/fulltext

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Mark A. Emalfarb is the founder of Dyadic. He has been a member of Dyadic’s board of directors since October 2004 and has served as its chairman as well as president and chief executive officer from October 2004 until April 2007 and from June 2008 until the present. Since founding Dyadic in 1979, Mr. Emalfarb has led and managed the evolution of Dyadic from its origins as a pioneer and leader in providing ingredients used in the stone-washing of blue jeans to the discovery, development, manufacturing and commercialization of specialty enzymes used in various industrial applications and the development of an integrated technology platform based on Dyadic’s patented and proprietary C1 fungal microorganism. Mr. Emalfarb is an inventor of over 25 U.S. and foreign biotechnology patents and patent applications resulting from discoveries related to the company’s patented and proprietary C1 fungus, and has been the architect behind its formation of several strategic research and development, manufacturing and marketing relationships with U.S. and international partners.