Abstract
Phacilitates 1st Partnering event for Vaccine Emerging Markets brought together approximately 100 attendees from developed and developing world vaccine manufacturers, leading non-profit organizations and industry suppliers. The goal was to discuss the vaccine needs in the developing world and how these needs can be met by leveraging collaboration and partnership models, by improving access to existing, new and next generation vaccines, by using novel technologies to drive competitive advantage and economics of vaccine manufacturing and by investing in localized capacity, including capacity for pandemic vaccines. The present article summarizes insights out of 30 oral contributions on how quality and capacity requirements can be balanced with cost by using novel manufacturing technologies and operating models.
Ensuring Supply of Qualitative Vaccines at a Minimal Cost Per Dose
With the Global Vaccine Action Plan (GVAP), the World Health Organization (WHO), represented at this meeting by Joachim Hombach, set out to reach 5 ambitious goals:
Achieve a world free of Poliomyelitis,
Meet vaccination coverage targets in every region, country and community,
Exceed the Millennium Development goal 4 target for reducing child mortality,
Meet global and regional elimination targets (like Measles) and
Develop and introduce new and improved vaccine technologies.
An important partner in this mission is the GAVI Alliance (Global Alliance for Vaccines and Immunization), who focuses on ensuring the supply of appropriate and qualitative vaccines at a minimal cost and cost-implication per dose by working closely with vaccine manufacturers. Melissa Malhame from GAVI demonstrated this with a case study on Pentavalent (DTwP/Hib/HepB) vaccines, where over a period of 10 y the number of suppliers was increased from a single initially to five at present, substantially increasing the number of doses of this vaccine made annually, and reducing the price per dose. She further referred to this year’s introduction by the GAVI alliance of HPV in the vaccination program, at a commitment from the manufacturers to make the vaccine available for less than $5 per dose, a price that is only 1/3rd of the current lowest public sector price.
Hannah Kettler, from the Bill and Melinda Gates Foundation, introduced the Foundations Global Health program, which relies on partnerships to reach its goals. Vaccine manufacturers are essential partners to the Gates Foundation because they have the know-how, capabilities and resources, and they are driving the required innovation in R&D, on production technology as well as on vaccine delivery.
A good example of such a partnership is the Meningitis Vaccine Project (MVP), presented by Jean-Marie Préaud from MVP. This partnership between PATH (Program for Appropriate Technology in Health) and WHO, funded by the Gates Foundation, led to the development and launch of the meningococcal conjugated polysaccharide vaccine MenAfriVac® for Africa. This project set out with a challenging goal to sustainably supply this vaccine to Africa at a target price of less than $0.5 per dose. To achieve this, collaborations were set up including Synco Biopartners (NL) for the development of the group A polysaccharide, the Center for biologics Evaluation and Research of the US. Food and Drug Administration (CBER/FDA) (US) for the conjugation method development and transfer, Aerial (France) for the lyophilization and stabilization technology transfer and Serum Institute of India (India) for the tetanus toxoid production and the final manufacture of the vaccine.
Increasing Vaccine Manufacturing Capacity
Increasing the manufacturing capacity of vaccines is a key challenge that needs to be addressed to ensure a worldwide supply. Through the north-to-south transfer of technology and capacity, and market pushing/pulling approaches as described above, local manufacturers have expanded manufacturing capacity and are playing an increasing role next to established vaccine manufacturers in the United States or Europe, which was the focus of presentations by Suresh Jadhav from the Serum Institute of India and Allan Jarvis (JBBDA, llc).
It was pointed out that vaccine manufacturers in emerging market economies are currently supplying more than 80% of worlds vaccine doses, at a share of less than 80% of the money spent. The biggest challenge for the local vaccine manufacturers is hence to maintain quality, production capacities, facilities and compliance to ever increasing regulatory expectations on quality, safety and efficacy of vaccines while facing high cost pressures (Suresh Jadhav, Serum Institute of India).
Access to novel manufacturing technologies is important to meet capacity and cost-of-goods challenges. According to Allan Jarvis (JBBDA, llc), a major delay exists in the adoption of such new manufacturing technologies (including recombinant or conjugate vaccines) by manufacturers in emerging markets, mainly due to lack of finance and education capabilities. To bridge this gap, special technology transfer initiatives are required. Eventually, with the growing biotech-trained populations in emerging markets, their dependency on developed countries should decline. While the current model for vaccine access in emerging markets is a ‘trickle down’ of manufacturing technology, capability and products from developed markets, this model can only sustain as long as the developed markets stay on top in innovation. However, with the emerging markets manufacturers catching up, the dynamics of vaccine product development and supply might change in the future.
Emerging market based manufacturers looking to access novel vaccine manufacturing technologies, and developed world manufacturers targeting emerging markets, have to weigh benefits and tradeoffs from a build, buy or partner strategy to produce new vaccines. In the view of Suresh Jadhav (Serum Institute of India) partnering offers the quickest route to market, with lowest cost and risk, but also with the least control and profit. “Building” on the other hand gives the highest profit opportunities, but also highest cost and risk, and a longer time to commercialization. The latter is the strategy taken by the Serum Institute of India, following some initial partnerships. Harish Iyer of Shantha Biotech, now part of Sanofi, gave the advantages from the buy strategy side, where the combination of global Sanofi standards and the cost-of-goods advantages of emerging market manufacturing created a key supplier of high quality, affordable vaccines for global health. Partnerships are currently the only model for supply to the Brazilian market and for the introduction of new vaccines in that country as was presented by Jorge Kalil from Instituto Butantan.
Klaus Stöhr from Novartis Vaccines and Diagnostics shared his views and lessons learned on the capacity increase following the H1N1 pandemic in 2009. This pandemic made governments around the world realize that the capacity for influenza vaccine was not sufficient to supply enough vaccines for the world population. Additionally, the available capacity is already mostly reserved for few developed countries. However, in the pandemic aftermath, only few governments, like the US and the Thai government, decided to invest in local influenza manufacturing capacity. Suresh Jadhav from the Serum Institute of India, brought under attention that the WHO global action plan for pandemic influenza (GAP), launched in 2006, did establish new manufacturing capacity at 6 emerging markets manufacturers. However, according to Klaus Stöhr, the main issue is to sustain such manufacturing capacity in periods without a pandemic, particularly when only a low demand for seasonal influenza exists. Here a financial support from the local government would be important. In his opinion, in the next 10 y new technologies need to be developed that allow to build affordable idle capacity, using new manufacturing technologies that can immediately be ramped up to meet global demand.
New Manufacturing Technologies
In order to deal with new disease challenges in a cost-efficient way, novel approaches are implemented for vaccine manufacturing. These approaches include new ‘platform’ cell lines, based on fungal, bacterial, plant, insect and other host cell systems, able to produce a broader range of antigens, or are based on new antigens. Two new dengue fever vaccine candidates, based on recombinant virus antigens, were presented by Dan Stinchcomb (Inviragen now Takeda) and Malcolm Thomas (Arbovax). Although this conference did not focus on the issue of regulatory acceptance of new vaccine manufacturing platforms, it is known to be a major hurdle to reach market, both in developed as emerging market economies.
Following the H1N1 pandemic in 2009, as reviewed by Klaus Stöhr from Novartis Vaccines and Diagnostics, significant efforts were put into developing new influenza manufacturing technologies enabling a faster supply to the market compared with the current egg based vaccines. Novartis focused on developing innovative upstream technologies based on cell culture and synthetic vaccine seeds. Other players like Novavax combined a recombinant antigen approach and a new cell culture system (insect cells at Novavax) with a flexible facility using all disposable technology, as was presented by Russel Wilson from Novavax. Taking a manufacturing approach based on single-use technologies allowed them to build a facility at only a fraction of the cost of egg-based facilities, in a reduced time. It also allows easier transfer and faster set-up of vaccine facilities in emerging areas. As processes based on single-use technologies are consuming much less water for injection (WFI) and energy, and are typically more contained, they allow the set-up of a facility in areas with limited local infrastructure. Moreover, the economics of this approach with a significantly lower fixed cost compared with egg-based manufacturing plants, is giving a lower cost-of-goods, which can be further increased with yield optimizations or lower antigen per dose requirements. Novavax is now partnering up with vaccine manufacturers in the developing countries, such as India, to transfer their technology.
Jean Sébastien Parisse from Aseptic Technologies further elaborated on the benefits of single-use technologies, presenting Aseptic Technologies Crystal® closed vial technology for vaccine filling. These presterilized, ready-to-use vials allow to eliminate most complex steps of aseptic filing, including the WFI washing, the hot-air tunneling, the siliconization and the stoppering. Their economics demonstrate that this technology can be cost efficient when considering the savings made by the absence of cleaning and preparation steps as well as the CAPEX investments related to these steps.
As is recurrent when discussing the increasing implementation of single-use technologies, it was highlighted by the audience that vendor support is crucial, and this includes local supply, liability of the validation, the communication about product changes and their potential impact on performance. At present single-use technologies are still new to the field, especially in emerging markets where the culture still pushes for re-use even when the product is not designed for that. Most issues are typically related to lack of familiarity and will be resolved with more experience.
Another new manufacturing technology allowing to reduce the cost-of-goods per dose of vaccine is the fixed-bed bioreactor iCellis™, introduced by Jose Castillo (ATMI). The growth area available to the cells in a 25 L volume, is equivalent to the surface of 3000 roller bottles. Also for this application, the single-use concept, including the pre-packing with microcarriers, allows for a quick implementation and simplifies the cell culture process. Two cost-of-goods calculation case studies were presented comparing this technology to roller bottles or stirred tank based approaches, both demonstrating again the positive impact single-use technologies can bring to the process economics.
Transferring new manufacturing technologies to emerging market manufacturers can be extra challenging due to the limited local knowledge or experience with these technologies, as was discussed by Allan Jarvis (JBBDA, llc; see above). The message from Abraham Samir (Merck) is to keep it simple and take a step-by-step approach, ideally back-to-front, starting with transferring analytical methods, followed by the formulation and filling, and only in a later stage also the bulk manufacturing. A careful monitoring and a good support of the assurance of quality at the local partner is required, as this can be important to protect your brand.
Also here the outlook from Allan Jarvis (JBBDA, llc) is important to keep in mind. When capabilities, expertise and facilities continue to build-up in the emerging markets, while vaccine innovation slows down in the developed markets and accelerates in the emerging markets and global regulatory homologation occurs, then world-class facilities and innovation will become a reality in both the developed and emerging markets.
| Abbreviations: | ||
| DTwP | = | Diphtheria, Tetanus and whole cell Pertussis |
| Hib | = | Haemophilus influenzae type b |
| HepB | = | hepatitis B virus |
| HPV | = | human papilloma virus |
Financial and Competing Interest Disclosure
Annelies Onraedt is the Global Vaccine Market Manager of Pall Corporation, a bioprocess solutions provider. There are no financial interests or conflicts with the subject matter disclosed in this manuscript. No writing support was provided for the production of this manuscript.