The World Health Organization (WHO) estimates that 5 to 15% of the world population gets seasonal influenza annually, resulting in ~1 billion cases per year, 3-5 million cases of severe illness, and 300,000-500,000 deaths annually worldwide. Further, flu is the cause of 10% to 12% of all absenteeism worldwide. Recommendations for universal immunization of the US population with seasonal influenza vaccine are being implemented, with full inclusion planned for 2013. Additionally, the rising uptake of seasonal vaccines through national immunization programs means demand will increase. Demand for seasonal vaccine will continue to grow in developed countries, and in addition significant demand will increase in developing countries, both for those with programs already in place, as well as those setting up new programs. Overall, projections indicate that seasonal vaccine demand will double or triple by 2016 from the 340 million trivalent doses produced in 2007.
The global market for vaccines totaled $23 billion in 2008, up from $8.5 billion in 2003, and is projected to grow to $36 billion by 2013. Pediatric vaccines have traditionally led the human vaccine segment, but adult and therapeutic vaccines will likely take over this position in the coming years. Paradigm shifts in the economics of vaccine production make quality, speed and cost important differentiating factors.
The 2004 failure in the production of influenza vaccine for the US market pointed out both the opportunity for a new production solution and the enormous market for such vaccines. Influenza vaccine production is beginning the shift away from the 19th century method of culturing vaccines in fertilized eggs and into a 21st century recombinant expression system. The emerging A/H1N1 pandemic further illustrates the need for rapid, cost effective vaccine production. Of all the cell based and recombinant systems known, the NeuBIOS™ system offers the fastest and least expensive way to produce these vaccines.
The human vaccine market outlook has improved significantly over the past decade, with the rejuvenation of the industry by new Federal liability exemptions, recommendations for expanded recipient populations, and a new wave of approved recombinant vaccines. Recombinant vaccine antigens provide significant improvement in terms of product characterization and safety compared to traditional attenuated or inactivated vaccine approaches. Newer production approaches also provide significantly reduced cost of goods compared to traditional expression systems. Fungal production systems such as yeast provide advantages similar to bacterial production systems, but in addition allow larger proteins to be produced, including native, correctly folded eukaryotic protein antigens important for the efficacy of many vaccines. Recombinant yeast-produced vaccine products now on the market include Engerix ®-B (GSK), Recombivax HB ® and Gardasil™ (Merck). A logical next step is to use the NeuBIOS™ platform for these biopharmaceuticals to exploit the dramatically increased productivity of filamentous fungi in comparison to the single-celled yeast.
Soluble subunit antigens can be purified by standard chromatography techniques, dependent upon the biochemical characteristics of the antigen. For most human biologics, a histidine tag is not recommended for regulatory reasons. For veterinary applications, however, a tagged approach may be appropriate. In general, the complexity of the clarified broth feedstock is significantly lower in secretory systems such as NeuBIOS™ vs. platforms that require cell lysis, like most bacterial or plant systems. This simplifies the purification and reduces overall costs. Products are also more soluble and refolding is rarely necessary, improving yields.
Neugenesis is currently contracted by PATH, a non-profit dedicated to improving healthcare in the developing world, to create VLP-based influenza vaccine candidates for in vivo testing. After this first-year proof of concept project, a second stage contract in 2010 will provide support to Neugenesis for the preclinical development and early-stage manufacturing to take these candidate vaccines to Phase I clinical trials in 2011. Additional opportunities to develop other vaccines with PATH are possible when the influenza program demonstrates proof of concept in Q2 2010.
The development and regulatory timelines for seasonal influenza vaccines are unlike those for other vaccines or pharmaceuticals. Development timelines, including regulatory approval, are very short (approximately six months) once a process is initially validated. Product volumes are high and margins low, creating an advantage for the low cost producer. The traditional egg based production platform is dependant on a sufficient supply of SPF eggs and results in low product yield. Newer production platforms do not rely on eggs and improve product yield. As technology progresses the cost advantages of these systems, of which NeuBIOS™ is one, will come to dominate the field.
| Technology | Seasonal Cost Summary (Indexed to Egg Inactivated = 1) |
||
| Bulk | Finished | ||
| High Cost | Egg Inactivated | 1.00 | 1.00 |
| Cell Inactivated | 1.75 | 1.72 | |
| Medium Cost | Egg Inactivated w/ Adjuvant | 0.13 | 0.17 |
| Cell Inactivated w/ Adjuvant | 0.21 | 0.25 | |
| Recombinant | 0.20 | 0.22 | |
| Low Cost | Egg Live | 0.03 | 0.08 |
| Cell Live | 0.03 | 0.08 | |
| Recombinant w/ Adjuvant | 0.01 | 0.05 | |
The NeuBIOS™ expression system’s advantages over traditional vaccine production methods fall into three categories: yield, development time, and cost per dose. Of the three, increased yield is the most significant, as can be seen below.
| Numbers based on production of monovalent bulk and 15 ug HA dose.
*MMC information from the Novartis website. **NeuBIOS™ calculations use a conservative yield estimate for the system | |||
| Production Method | HA mg/L Final Yield |
Vaccine Doses/L |
L to generate 10 MM doses |
|---|---|---|---|
| Eggs | 7 | 470 | 21,277 |
| Mammalian Cell Culture * | 2.7 | 180 | 55,000 |
| NeuBIOS™ ** | 100 | 6,667 | 1,500 |
The veterinary vaccine market is even more cost sensitive than the market for human influenza vaccines. The potential market, however, is both large and varied with many unmet needs. Neugenesis is exploring veterinary opportunities, building off of our human recombinant vaccine development program.
Vastly improved yield, when combined with reduced development timelines and other factors such as low cost media, results in an exceptionally low cost per dose for vaccines produced with Neugenesis’ technology. The figure below plots the data developed by BioPharm Services in an analysis of the NeuBIOS™ platform's cost structure. Even at low concentrations, the system delivers very low cost product.
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| Cost table calculated by BioPharm Services based upon a 50 ug dose |
In summary, the NeuBIOS™ platform has the capacity for rapid, high yield protein production, resulting in shorter production timeframes while producing more vaccine doses. The system is scalable and projections indicate vaccine costs significantly lower than other flu vaccines. Additionally, the platform is flexible – capable of making a variety of protein biologics. Altogether, the NeuBIOS™ platform has the potential for positive impacts on public health.
