Robust Supply Chains Could Help Pave the Way

by Antoinette Lagerwij, Sudeep Suman, Jamie Hintlian, and Kevin Chen

Since the business of making vaccines became a commercial proposition, profitability has often been elusive. The economics are difficult: Costs of development and production, already high, are rising. Profit margins historically have been lower than those of other pharmaceutical products, in part because of the complexities of manufacturing and distributing vaccines as well as their stringent safety, testing, and quality requirements. And scaling-up of immunization programs along with the introduction of new vaccines have put a significant strain on decades-old logistics and delivery systems. All that has been too much for many major manufacturers, especially in the United States. Several have left the market, leaving the vast majority of the world’s production (90%) and two-thirds of research and development (R&D) to companies in Europe (1).

But the economics of this landscape are changing. The once low-margin vaccine market now includes blockbuster and megablockbuster products. Optimism over new candidates — including some for cancers, human immunodeficiency virus (HIV), and adult influenza — has led to expectations of healthy growth. Economists at the World Health Organization (WHO) report that the market has been growing at 10–15% annually, compared with 5–7% growth for other pharmaceutical segments, since 2000. That growth is expected to continue at 8% or better through 2018, reaching almost US$100 billion by 2025 (2, 3). And some signs indicate that vaccine players may be narrowing their focus to a few areas (e.g., biosimilars) to reduce competition. Thus, an examination of the industry value chains reveals significant bottom-line potential.

High costs and associated risks represent a major challenges to the vaccine market. Compare the 38% cost of goods sold (CoGS) with 21% for pharmaceuticals (4). Here, too, the news is promising: Biological products take less time to develop and enjoy longer patent protection than do new chemical entities (NCEs) as defined by the US Food and Drug Administration (FDA), which may help recoup costs in the long term.

Recent developments have made the vaccine industry lucrative. But it is imperative for vaccine companies to develop a disciplined decision- support framework for assessing clinical parameters (e.g., safety, efficacy, probability of success, and operational effectiveness) alongside economic considerations (e.g., scalability, cost, and profit potential). That framework should coordinate efforts of commercial, R&D, operations, and finance in collecting and validating data. It should encompass transparent objectives; open, inclusive, and effective communication; a rigorous scientific approach that complies with regulatory requirements; and a feedback loop with periodic checkpoints for assessing progress. The framework also should include a process for rebalancing and reallocating resources — and for terminating initiatives as needed. Companies also should develop effective and consistent approaches from the perspective of R&D, commercial, manufacturing, and supply chain groups.

Research and Development
The average vaccine takes 10.71 years to develop and has a 6% chance of making it to market (5). Clinical-phase testing is very expensive, with a roughly one in five (21.2%) chance of a given product succeeding. Overall, from phase 1 to market launch, the chance of success for a new drug is close to 17% by comparison (6). According to a UK Office of Health Economics study in December 2012, the fully capitalized out-of- pocket cost for each new drug before approval is US$1.5 billion (with time representing 33% of total cost); biologics development costs are significantly higher (6, 7). The transition from animal testing to clinical trials involving humans remains a major challenge because preclinical results are not easily transferable. R&D costs nearly double during the clinical phase.

To reduce those costs, companies must identify both the R&D and commercial risks at an early stage and carefully balance their allocation of resources, keeping both short-term and long-term goals in mind. It’s imperative to apply the right standards through appropriate modeling and cost– benefit analysis to leverage the full-scale commercial plan; viability and scalability of manufacturing and its impact on CoGS; and finally safety, efficacy, and regulatory concerns.

Segmentation by indication (e.g., acute, chronic, or therapeutic) can be helpful in evaluating candidates. Prophylactic vaccines and those for acute diseases involve shorter time frames (8–10 years) and a higher probability of success; therapeutic vaccines and those for chronic diseases involve longer time frames and lower chances of success (5). Substitutes such as live-attenuated vaccines (LAVs) are more effective than inactivated versions and thus require a lower dosage and less exposure. Although they need to be properly evaluated for safety and efficacy, LAVs may prove useful at reducing operational costs, carrying costs, and waste. Use of synthetic peptides/proteins in a subunit approach involves no infectious material at all and may not present as many safety and efficacy challenges, but the approach is subject to longer lead times in research.

The key to cutting vaccine R&D costs is reducing the time and expense of clinical trials. Some costs can be reduced through outsourcing or leveraging testing capabilities in emerging markets, where R&D costs are lower. Another highly promising idea is that of partnering with competitors in complex areas of vaccine research, which has occurred recently with research into Alzheimer’s disease and some forms of cancer.

 

BPI Theater: Vaccine ManufacturingThe BioProcess Theater at the 2013 BIO International Convention (22–25 April 2013) in Chicago, IL, was a 50-seat amphitheater located on the exhibition floor at the heart of the BioProcess Zone. It provided attendees with daily, complimentary opportunities to listen to, learn from, and interact with leading experts as they presented, discussed, and debated the latest business and scientific trends in development and manufacture of biotherapeutics. Four presenters focused on the topic of vaccine manufacturing, and you can access their talks in podcast form online.

In Silico and In Vitro tools for Accelerated Vaccine Design: This podcast features Yvette Stallwood (head of applied protein services at Lonza Custom Manufacturing). Her company is a leader in outsourced viral vaccine and viral vector product development, offering services in a range of product types such as adenoviral vectors, AAV vectors, and lentiviral vectors.www.bioprocessintl.com/bpi-theater/bpi-theater- vaccine-manufacturing/in-silico-and-in-vitro-tools-for- accelerated-vaccine-design

Five Traits of Successful Vaccine Development and Production: This podcast features James Richardson (Advanced Bioscience Laboratories). His company is involved in contract development and production of preclinical and clinical virus-based biologics. From 30 years of groundbreaking work with human immunodeficiency virus (HIV) to supporting the latest gene therapy technologies, ABL offers a portfolio of services for design, development, production, and testing of vaccine and gene therapy candidates.www.bioprocessintl.com/bpi-theater/bpi-theater- vaccine-manufacturing/five-traits-of-successful- vaccine-development-and-production

Development of Protein Capsular Matrix Vaccine (PCMV) Platform Technology: This podcast features Kevin Killeen (chief scientific officer for Matrivax Research and Development Corporation). His company spun out from Harvard Medical School to commercialize protein capsular matrix vaccine (PCMV) manufacturing technology.www.bioprocessintl.com/bpi-theater/bpi-theater- vaccine-manufacturing/development-of-protein- capsular-matrix-vaccine-pcmv-platform-technology

Simpler and More Efficient Vaccine Manufacturing: This podcast features Fabien Moncaubeig (senior application specialist at ATMI LifeSciences). A leader in single-use bioprocess sytems and consumables, his company was acquired by Pall Corporation later in 2013.www.bioprocessintl.com/bpi-theater/bpi-theater- vaccine-manufacturing/simpler-and-more-efficient- vaccine-manufacturing

 

Biotechnology Makes a Difference: The biggest savings of all might result from a scientific discipline that is changing immunology: genetic engineering. Genetically engineered vaccines hold the promise of increasing safety, reducing reactogenicity, and improving immunogenicity. Numerous diseases previously beyond the reach of vaccination might be prevented or controlled through these means, with HIV, cancer, and malaria topping that list.

The new wave of vaccines, along with the techniques developed for creating and delivering them, is radically affecting the vaccine supply chain. DNA vaccines stimulate a strong cellular response and are safer than LAVs. They are relatively easy and inexpensive to design, produce, and transport because they do not require temperature-controlled environments. They are also easier to administer, allowing vaccination teams to use less sophisticated (and less expensive) equipment, which ultimately reduces costs associated with supply, training, and waste.

Advancements in antigen design, improved formulations, inclusion of molecular adjuvants, and new physical methods of delivery have greatly enhanced the immunogenicity of second- generation DNA vaccines. Research continues into the use of DNA in combined vaccine platforms with enhanced delivery methods and new molecular adjuvants. Along with new investments and the results of ongoing clinical trials, this continued focus will be pivotal to driving value in the vaccine industry for years to come.

Vaccine companies should assess the impact of genetically engineered vaccines now — before they come to market. The possibility of a disruptive impact on the supply chain and entire operations is significant; the end result could be underused capacity. It’s important for management to quantify the potential impact of long-term shifts in technology. A collaborative decision-making process involving commercial, production, and technology groups can help prioritize investments and allocate resources, thus significantly improving the potential return on investment.

Sales and Commercial Resources
It is extremely important that R&D and commercial teams work closely together in a collaborative partnership and that long-term corporate goals and strategies are aligned. Decisions on prioritization and resource allocation for short-term projects — as well as long-term innovations — should be made by consensus based on a robust analytical framework. Organizations should develop capabilities and processes for determining the feasibility, risk, and chance of success for new candidates — then rebalance resources accordingly, terminating some projects if necessary. Process champions and decision makers should have the authority to ensure that team and corporate goals are aligned.

Companies typically carry out full-scale commercial viability and profitability analyses that focus on market, growth, competitive, and demographic considerations. But when incentives are misaligned, over aggressive projections and estimates can result. The data and analyses necessary for decision support are not always available as a commercial launch decision nears. Ideally, organizations should develop accurate projections and detailed commercial analyses at project inception, but adequate data are often severely lacking at that point.

Overall, the vaccine industry is spending less on marketing and sales (17% compared with 31% of sales for the pharmaceutical sector as a whole) as its target customer base has become more concentrated. With sales focusing on the public sector and professional prescribers, vaccine companies should take the state of the market (especially the maturity of a given regulatory environment and government commitment to public health care) into account when developing a commercial plan for new products.

Organizations can improve their market intelligence on a given candidate by partnering with health monitoring and disease-control organizations such as WHO, the US Centers for Disease Control, the United Nations Children’s Fund (UNICEF), and the Global Alliance for Vaccine and Immunization (GAVI). In particular, linking demand assumptions with vaccine projections from UNICEF, the UK National Health Service, the US National Institutes of Health (NIH), and the US National Institute of Allergy and Infectious Diseases (NIAID) can help a company prepare for seasonal demand and large tenders, as well as mitigate market risk. Preparation for government tenders and competitive bids involving huge demand can help prevent problems involving capacity, capability, and agility in the supply chain, such as those surrounding the recent high-profile shortage of influenza vaccines. Commercial analyses should go beyond sales, market share, and growth to account for gross margin — or ideally, net margin. For example, genetically engineered antigens can reduce the need for stringent temperature control requirements and thus complex cold-chain operations.

When it comes to initiatives or projects that rely on new technologies or unapproved methods or ingredients, organizations should consider several factors in deciding how to allocate resources. For example, most adjuvants that are not based on salts or alum are considered toxic to humans, but adjuvant use in animal vaccines allows for more flexibility. An assessment of future strategies that includes potential applications in other species can help vaccine companies allocate resources appropriately and recoup some investments sooner rather than later.

Vaccine sales are normally more projectable than those of other pharmaceuticals, a prime example being pediatric vaccine forecasts based on annual birth counts. A real challenge comes from costly regulatory hurdles with uncertain outcomes. According to some analysts, the vaccine market’s “winner-take-all” dynamic results in a limited number of suppliers for each product class (3) and makes the cost of losing a tender bid even more significant. On the other hand, the feasibility of vaccines targeted at limiting unpredictable outbreaks (e.g., H1N1 and other influenza viruses) is hard to predict. Poor forecasting can lead to delays or shortfalls in delivery, additional costs, and reputational risk.

 

Looking for a Vaccine Meetingplace?7–9 April 2015, Washington DC World Vaccine Congress 2015 www.terrapinn.com/conference/world-vaccine- congress-washington/index.stm         Now in its 15th year, this event is made of up seven highly focused, co-located conferences.

13–15 April 2015, Bethesda, MD 2015 Annual Conference on Vaccine Research www.nfid.org/acvr#sthash.eWqb0ZC1.dpuf                                                                    The Annual Conference on Vaccine Research (ACVR) provides current reports of scientific progress and best practices for research and development of vaccines and associated technologies for disease control through immunization. It draws on an international audience of scientists and researchers, healthcare professionals and trainees, veterinarians, vaccine manufacturers, and public health officials.

TBD May 2015, Amsterdam, The Netherlands VAX 1-2-1 2015 www.phacilitate.co.uk/vax-1-2-1                                                                                            This event builds on the Phacilitate Vaccine Forum and Partnering for Emerging Markets event series. It brings together corporate, manufacturing, and R&D executives with key external stakeholders including nongovernmental organizations and investors.

8–10 June 2015, Chicago, IL International Conference on Flu http://flu.conferenceseries.com                                                                                       With a theme of “Understanding the Flu: Pathology, Prevention, Containment, and Risk Analysis,” this event will bring together virologists, immunologists, microbiologists, epidemiologists, doctors, public health planners, pharmacologists, computational biologists, and those in applied fields conducting influenza-related research.

8–10 July 2015, Boston, MA 13th Vaccines Research and Development: All Things Considered Conference www.nfid.org/acvr                                                                 This conference brings together leaders in vaccinology from industry, academia, and the government to examine vaccine development from basic research to marketing.

18–20 October 2015, Seoul, South Korea 9th Vaccine and ISV Congress www.vaccinecongress.com                                                                                             The aim of this conference is to provide a forum for researchers, professionals, and policy makers to present, share, and exchange the latest cutting-edge discoveries in vaccines and vaccinations. The organizers hope to facilitate new collaborations between experts in the field and inspire new and innovative ideas in vaccine development.

 

Manufacturing and Operations
Developing a safe and reliable process for mass production and delivery of vaccines to meet unpredictable demand cost-efficiently is no easy task. An accurate understanding of available capacity, efficiency of a supply chain operating model, and the need for investment or expansion can lead to timely and successful market launches. In the process, managers should understand their companies’ capacity at different platforms and identify possible bottlenecks, such as inadequate configurators or freeze-drying capacity. Organizations also should accurately assess demand and where it might come from. If specific geographies are expected to drive growth, then manufacturing can be outsourced to emerging countries, and timely registration and approval could be very effective in rollout.

An efficient, centralized supply chain can ensure that the right product arrives at the right place and at the right time — thereby reducing waste, meeting market demand, and reducing operating costs. But that goal can be difficult to achieve. Manufacturing vaccines involves a complex interaction of laboratories, other facilities and/or contract manufacturing organizations (CMOs), and suppliers. New technologies and processes can have significant impact. Poor assessments can lead to costly disruptions.

Organizations should consider value-stream mapping as a way to reduce costs, forming accurate assessments of margin impacts on competitive generic vaccines, and enhancing companies’ ability to react quickly to changing market needs and events such as bid tenders. To make value-stream mapping work, an organization must have an accurate picture of capacity standards across its manufacturing and distribution network so that managers can understand the pros and cons of a dispersed or coordinated supply chain response.

Executives developing strategies and future-state visions must consider challenges such as antigen loss and yield loss during transportation, as well as other challenges such as sourcing risks, CMO network issues, underused capacity, and many more factors. Organizations also should assess the agility of their supply chains and ability to react to unplanned demands, implement technological changes, absorb capacity, and streamline distribution. Understanding the risks associated with third parties and suppliers is vital, as well.

Companies that design a site–platform linkage based on available transfer to inventory costing information can better analyze the effects of resource loading and unloading due to volume increases, substitutions, and phase-outs. Manufacturing groups should work closely with the commercial side to leverage sales and operation planning and establish a process for frequent demand-projection updating for sites/platforms nearing capacity. This helps empower management to evaluate and prioritize technological changes, product transfers, and stocking strategies to prevent supply chain disruptions.

Those who develop a process to review excess capacity proactively with the commercial team can identify areas where incremental growth could be realized — which in turn would accelerate absorption of fixed overhead through product campaigns, substitutions, transfers, and so on.

Another leading practice is to develop and implement planning standards that drive efficiency through batch-size maximization and optimized level-loading of production over time. Based on Mercer Management Consulting’s analysis of vaccine production costs (15% variable, 60% fixed, and 25% semivariable or different for each batch), one effective way to improve margins is to maximize batch size. Doubling batch size effectively brings overall costs down by 12.5% (8). An organization should determine where batch sizes are limited by equipment or regulation and address related issues. Remember also that batching involves several other possible limiting factors that often go overlooked or underanalyzed.

Unlike a typical industrial product’s manufacturing process, vaccines involve significant amounts of nonstandard and unknown variables due to the biological nature of viruses and microbes. But a focused effort on analytics and statistical modeling can capture factors and variance over several runs through historical tests in the laboratory. That will help improve quality and predictability to drive supply reliability and product lead times, as Institut Pasteur discovered in attempts to improve rabies vaccine production (9). Improved quality and production yield not only reduces end-to-end lead times but also lowers working capital and frees up quality and testing resources. Organizations normally recognize inconsistencies in quality management, but they rarely implement prioritized, comprehensive programs to identify and address those inconsistencies.

Supply Chain and Distribution
The final consideration is distribution: the logistics of and delivery to end users. Unlike classical drugs, vaccines are biologic agents that can be compromised during processing. Whether killed-virus, whole-cell, bacterial, or live-attenuated, vaccines can be disrupted at several points from the laboratory to the vial and beyond. Quality control, sterilization, and monitoring are nonnegotiable. Even with strict standards, however, the possibility of contamination remains, although it is far less likely today than it was several decades ago. In addition, vaccine production must be closely supervised to ensure that the products will induce immunity without causing serious infection.

A major obstacle to delivering vaccines to populations in the developing world is the temperature sensitivity of such products. It forces manufacturers to leverage an expensive cold chain for distribution. Shelf-life management is key, especially at distribution centers. Ensuring product stability is critical, and many markets have limited capacity in this area.

The industry is working to develop temperature-resistant or -insensitive vaccines. One study demonstrated that making a pentavalent vaccine thermostable increased its availability from 87% to 97% (10). Success in this endeavor will have a significant impact on the market and end users while radically simplif9ying the supply chain and reducing overall costs. Some newer vaccines are offered in single- or two-dose packages. Although those help to reduce waste, they also require more cold-chain space per dose compared with traditional EPI (expanded program on immunization) vaccines, which are distributed in 10- and 20-dose vials (7). The new packaging requires at least five times the amount of physical space in cold storage. So technical improvements must be evaluated based on their overall impact from development to delivery, including the supply chain.

Another issue is how long goods sit in customs. Given the dynamics in many emerging markets and potential delays in working with necessary ports, vaccine distributors must make sure that they have good relationships with relevant intermediaries for dealing with freight forwarding and import/export. Implications differ by distribution model. Inactivated vaccines can bypass some concerns, but organizations must consider the need for large doses, the application of adjuvants, and delayed impact responses, among other factors.

Distribution models such as direct-to- consumer (DTC) marketing are increasingly popular for driving margins, but such models work best when demand is stable and repetitive. Vaccines would be administered in a conventional clinical setting: typically packaged in cold-chain containers, sent to a wholesaler or distributor, repackaged in smaller quantities, and then sent for delivery. Frequent changes of custody can present challenges in ensuring against temperature deviations and verifying that time spent out of refrigeration does not exceed established limits.

Increasing need for transparent and trackable distribution is driving introduction of new technologies for improving end-to-end efficiency. Such technologies could prove especially useful to companies launching new products, seeking to capture market share, or looking to penetrate new markets. Accurate real-time information required to help them reduce buffer stocks to a minimum and provide just-in-time delivery rests on the use of sophisticated information systems and technologies that can track an organization’s universe of fragmented, nonstreamlined market- site interactions.

Seize the Moment
The promise of consistent profitability in the vaccine industry has never been closer to reality. But to transform that possibility into reality, manufacturers must engage all the right players, set the right priorities, and develop coherent strategies based on realistic assessments of the clinical, commercial, and operational environment. Only then will vaccine companies be prepared to respond to market needs quickly and decisively — and thus create greater value for stakeholders and shareholders alike.

References
1 Galambos L. What Are the Prospects for a New Golden Era in Vaccines? UK Vaccines Industry Group, London, UK, 2008; www.abpi.org.uk/our-work/library/medical-disease/ Documents/golden-era-vaccines.pdf.

2 Kaddar M. Global Vaccine Market Features and Trends. World Health Organization: Geneva, Switzerland, 2013; http://who.int/influenza_vaccines_plan/resources/session_10_ kaddar.pdf.

3 Palmer E, Bryant A. Top 5 Vaccine Companies By Revenue 2012. Fierce Vaccines 14 March 2013; www.fiercevaccines.com/special-reports/top-5-vaccine-companies- revenue-2012.

4 Angelmar R, Morgon PA. Vaccine Marketing (Faculty and Research Working Paper). Institut Privé d’Enseignement Supérieur: Fontainebleau, France, November 2012; www.insead. edu/facultyresearch/research/details_papers.cfm?id=29932.

5 Pronker ES, et al. Risk in Vaccine Research and Development Quantified. PLoS ONE 8(3) 2013.

6 Mestre-Ferrandiz J, et al. The R&D Cost of a New Medicine. Office of Health Economics: London, UK, 2012; www.ohe.org/publications/rd-cost-new-medicine.

7 DiMasi JA, Hansen RW, Grabowski HG. The Price of Innovation: New Estimates of Drug Development Costs. J. Health Econ. 22(2) 2003: 151–185.

8 Salinsky E, Werble C. The Vaccine Industry: Does It Need a Shot in the Arm? George Washington University: Washington, DC, 25 January 2006, ; www.nhpf.org/library/ background-papers/BP_VaccineIndustry_01-25-06.pdf.

9 Trabelsi K, et al. Optimization of Virus Yield As a Strategy to Improve Rabies Vaccine Production By Vero Cells in a Bioreactor. J. Biotechnol. 121(2) 2006: 261–271.

10 Lee BY, et al. The Impact of Making Vaccines Thermostable in Niger’s Vaccine Supply Chain. Vaccine 30(38) 2012: 5637–5643.

Antoinette Lagerwij is a supply chain operations executive (370 17th Street #3300, Denver, CO 80202; 1-720- 931-4000), Sudeep Suman is manager of transaction advisory services (55 Ivan Allen Jr. Boulevard #1000, Atlanta, GA 30308; 1-404-874-8300), Jamie Hintlian is a principal partner in life sciences supply chain (200 Clarendon Street, Boston, MA 02116; 1-617-266-2000), and Kevin Chen is a manager of transaction advisory services (5 Times Square, New York, NY 10035, 1-212-773-8188), all at Ernst & Young; www.ey.com.

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Vaccine Development and Production
Disease and Pandemic Research, Discovery, and Innovation

a conference report by Cheryl Scott
On 8–9 December 2014 at the Hilton Boston Back Bay hotel in Boston, MA, IBC Life Sciences (Westborough, MA) presented its Vaccine Development and Production Summit. Topics covered by the intensive two-day agenda included vaccine “cold-case” programs, adjuvants and conjugate products, emerging and infectious diseases, technological innovations, and next-generation products. Presentations highlighted the challenges and triumphs of product developers advancing innovations to combat infectious and other diseases by harnessing the power of the human immune system.

Keynote speakers represented the Biomedical Advanced Research and Development Authority (BARDA) at the US Department of Health and Human Services, Indian Immunologicals Ltd., Merck & Co., and the US Food and Drug Administration’s Center for Biologic Evaluation and Research. Together they provided an overview of the current state of the vaccine industry with a focus on its increasing globalization and broadening patient base.

Chief general manager at Indian Immunologicals Limited in Hyderabad, India, GS Reddy discussed emerging vaccine markets and their potential from the perspective of a leading maker of human and animal vaccines. Such markets are playing an increasingly important role for the vaccine industry. Emerging economies such as Brazil, Russia, India, and China (the “BRIC” countries) as well as South Korea, Mexico, Indonesia, Turkey, Iran, and Saudi Arabia boast huge populations and high growth rates in their gross domestic products (GDPs). Opportunities in such markets are opening up as they grow their middle classes, people who can spend more on health care. In addition, Reddy pointed out, great advances have been made over the past decade toward government immunization program expansion and introduction of new vaccines. He pointed to developing countries as the “next big vaccine markets.”

Hari Pujar (global product leader and executive director at Merck & Co.) offered a US perspective on vaccine globalization, focusing on challenges and opportunities for bioprocess development and biomanufacturing. Echoing Reddy’s points, he said that “the past decade has witnessed significant advances in vaccine globalization, ranging from technology transfers to indigenous vaccine development and manufacturing.” That progress has been enabled by an “ecosystem” of accomplished local talent around the world and nongovernment organizational funding, with technological and logistical support. Despite the successes so far, Pujar said, “many challenges still remain for more widespread adoption of vaccines.”

Some companies may find help in working with government organizations such as the BARDA in the United States. Arlene Joyner (BARDA’s senior project officer and program manager) discussed some key core service programs. Two examples are the Fill and Finish Manufacturing Network (FFMN) and the Centers for Innovation in Advanced Development and Manufacturing (CIADM). Both assist pharmaceutical companies in developing novel vaccines and biopharmaceutical therapeutics that can help the United States protect its populace against chemical, biological, radiological, and nuclear (CBRN) threats as well as emerging infectious diseases such as Ebola and pandemic influenza.

Some challenges are regulatory in nature, especially when it comes to next-generation products. Tina Roecklein (a consumer safety officer with FDA/CBER’s office of vaccine research and review in the division of bacterial, parasitic and allergenic products) provided a US regulatory perspective on characterization of conjugate vaccines. Glycoconjugates can be very effective at preventing diseases caused by encapsulated bacteria. Their regulatory life should begin in early development and clinical testing stages and extend through postlicensure for as long as such products are on the market. As Roecklein pointed out, characterization is essential throughout that life span.

Vaccines and Virotherapies
The program’s overall content fell into two basic categories, the first being more industry and disease focused and the second being more product focused. Early talks provided overviews and descriptions of general approaches to specific markets and conditions, whereas later presentations delved more into the details of vaccine development and production.

Cold-Case Files: One early session focused on infectious diseases with no prophylactic vaccines on the market. Chlamydia and herpes, for example, have thus far eluded researchers and product developers alike. On Monday morning, 8 December 2014, panelists discussed those and other “cold- case” diseases for which vaccines are currently in development. In examining recent efforts to develop novel vaccines, they reviewed lessons learned along with the difference that new technologies are making on conquering such diseases.

Mark Parrington (a senior director at Sanofi Pasteur) described his company’s experience with respiratory syncytial virus (RSV) (1). When healthy people are infected with this virus, they usually experience mild, cold-like symptoms and recover in a week or two. But RSV can be serious for infants and older adults. In fact, it is the most common cause of bronchiolitis (inflammation of the small airways in the lung) and pneumonia in US children under a year old. And it’s becoming a significant cause of respiratory illness in elderly patients.

Since 1989, Sanofi has considered a number of approaches to developing a vaccine for infants: from nucleic acids or vectors expressing RSV antigens to recombinant subunit vaccines to live attenuated viruses. For seniors, the company has focused on a subunit approach, both with and without adjuvants. One of those projects advanced to phase 2b but was terminated in 2004. Three different virus subunits were copurified from the surface of RSV-infected Vero cells using a gentle process designed to retain the native conformation of these surface glycoproteins. It was highly immunogenic in both young adults and the elderly and required no adjuvant. Parrington called the formulation “the most immunogenic candidate ever tested in clinical trials.”

However, only two of 656 people in the placebo group were hospitalized over two-year trial. In fact, rates of influenza diagnosis were double that of RSV in a flu-vaccinated population. Because of those low rates, the company determined that clinical development of this product would be very expensive and take several years. In addition, it was unclear whether payers would recommend a vaccine for reimbursement with such low hospitalization rates. Nor was it clear whether that vaccine would sufficiently lessen RSV disease occurrence in elderly populations.

In a 2008 article, Sanofi further detailed its decision to discontinue the program (2): “The expanding elderly population in developed countries and the large burden of RSV disease make further development of an RSV vaccine for high-risk adults worthwhile. However, the relatively low incidence of disease presents a formidable challenge for the design and implementation of a vaccine efficacy trial.” Several companies are currently taking different approaches to RSV, primarily for pediatric indications, with MedImmune and Novavax farthest advanced (3, 4).

Dengue fever is another condition for which vaccine development has been a challenge. Also known as “breakbone fever” because of the debilitating muscle and joint pain it causes, this virus infects >300 million people every year. Some patients experience circulatory failure, shock, coma, and even death. With four serotypes, the virus is transmitted to humans by tropical and subtropical mosquitoes and has no available vaccine. With the human population concentrated in such areas (and travelers from other areas facing potential exposure), the global need could be billions of doses per year — suggesting that there is plenty of room for several different products in the market.

Sean Du is chief operating officer of Altravax, Inc., one of several companies with programs in progress for this challenging indication (5). He spoke in depth about the difficultues. Infection with one Dengue serotype confers life-long protection against that one but only short-term protection against the other three serotypes. And sequential infections increase a patient’s risk of developing severe and potentially lethal disease. So a safe and effective vaccine would have to be tetravalent and provide strong and long-lived protection against all four serotypes. Multivalent products face manufacturing complexities, technical difficulties, and increased cost of goods.

Du said that crossreactive neutralizing antibodies have been isolated from some patients. That has encouraged his company to consider creating a single-component vaccine that could induce tetravalent immunity. He also said that virus-like particles (VLPs) are a promising vaccine format, but that known Dengue sequences cannot yet form VLPs with scalable efficiency. So his company seeks to improve their expression and processing to make a manufacturable product.

As Du reported, Altravax has completed in vivo characterization in mice for its lead candidate, with B- and T-cell analysis systems established and a sterile process established for small-scale VLP production. Scale-up feasibility has been systematically evaluated, and collaborators have been identified for neutralization assays, product characterization, and animal models for proof-of- concept testing. Patents have been awarded in several countries, and the company seeks government support for animal testing.

Vaccines and Cancer: Patrick Ott (clinical director of the melanoma disease center and Center for Immuno-Oncology at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School) talked about a cancer vaccine for melanoma. He said that the concept is not new and that vaccines have been shown to induce an immune response in melanoma patients, “although clinical benefit has not been clearly documented.” Recent achievements with immune- checkpoint blockades are showing promise, however. Ott explained that with increased understanding of tumor immunity, “the limitations of previous cancer vaccination approaches have become evident. Rapid progress in technologies that enable better vaccine design raise the expectation that these limitations can be overcome, thus leading to a clinically effective melanoma vaccine in the near future.”

Cell therapies such as Dendreon’s Provenge dendritic cell treatment for prostate cancer present another type of cancer vaccine. Justin Skoble (senior director of technical operations at Aduro BioTech, Inc.) described his company’s approach to pancreatic cancer immunotherapy (6). Combining two cellular immunotherapies — a prime and boost regimen of “GVAX Pancreas” and “CRS-207” products — uses lethally irradiated allogeneic tumor cells that secrete granulocyte macrophage colony-stimulating factor (GM-CSF) to induce T-cell immunity to cancer antigens, including mesothelin. That first product is administered along with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells.

The second product is a live-attenuated, double- deleted Listeria monocytogenes bacterial strain expressing mesothelin that induces innate and adaptive immunity to the tumor. “Prime–boost vaccination with GVAX and CRS-207 demonstrates synergy in mice,” Skoble said. “We have recently completed a 90-patient randomized phase 2 clinical trial in which metastatic pancreatic adenocarcinoma patients who received or refused more than one prior chemotherapy were treated with Cy/GVAX followed by either four doses of CRS-207 or six doses of Cy/GVAX every three weeks.” No vaccine- related serious adverse events or unexpected toxicities were observed. And the four-dose group had a statistically significant survival benefit over the six-dose group. Skoble suggested that combining these two novel cellular immunotherapies could create a potent immunotherapy regimen. Additional clinical studies are under way.

Mark Federspiel (director of the viral vector production laboratory at the Mayo Clinic’s Comprehensive Cancer Center) presented a unique approach to multiple-myeloma cancer treatment using a recombinant measles virus (7). Technically, this is more of a virotherapy than a vaccine. “A complete clinical response was recently achieved in one patient with multiple myeloma after systemic treatment with a single, high dose of measles virus,” he explained. Large-scale production and purification of such a large and fragile enveloped virus was a challenge, requiring aseptic techniques throughout virus production and purification. For this program, the Mayo Clinic worked with Magnis Therapeutics and Omnis Pharma.

Recombinant oncolytic viruses can be made tumor specific for efficient killing of malignant cells, stimulating a unique antitumor activity. For large-scale good manufacturing practice (GMP) production of measles virus, the partners used infected Vero cells. Because the virus is cytotoxic, they could not develop specific characterized producer cell lines. Genomic DNA contamination also makes adventitious virus testing difficult. And the process was complicated by inefficient virus release from infected cells. All that led to regulatory concerns: The manufacturers needed to guarantee that no intact cells could pass through their process. And they had to keep genomic DNA contamination to <10 ng/dose (or digest all DNA strands down to <500-bp size) to make the final product “as clean as possible,” balancing purity with potency. Advanced cancer patients, however, are often willing to take more risk than those suffering from less serious conditions.

Federspiel was followed by a speaker who offered a rare perspective for conferences of this type: that of the patient he had mentioned (8). Stacy Erholtz (Pequot Lakes, MN) had battled myeloma, a blood cancer that affects bone marrow, when she participated in a two-patient clinical trial at the Mayo Clinic. She also had amyloidosis, the rare disease highlighted in this month’s “Spotlight” section (see page 8 of the main issue). After suffering from a swollen tongue and mouth sores, fatigue and nausea, weight loss, sudden-onset carpal tunnel syndrome, cracked vertebrae, and bruising around her eyes, she was treated in 2004 with thalidomide, dexamethasone, and a stem-cell transplant, which led to 2.5 years of remission. In 2007, however, she had to undergo chemotherapy and radiation treatments, followed by two years of weekly bortezomib and dexamethasone, followed by another stem-cell transplant. After such an ordeal, she found herself relapsing in 2013 — when she volunteered for the measles-virus infusion that appears to have cured her.

Technological Advances
About half of this conference program was devoted to the practical aspects of vaccine development and manufacturing. For example, Penny Post (Protein Sciences Corporation’s regulatory director) presented a case study involving a recombinant influenza vaccine produced by insect cells using the baculovirus expression vector system (BEVS). Regulatory challenges were encountered during the product approval process (9). The BEVS technology has been used to produce some approved products already:

• GlaxoSmithKline’s Cervarix human papillomavirus VLP vaccine was approved for Australia and the European Union in 2007 and for the United States in 2009.
• Dendreon Corporation’s Provenge prostate cancer vaccine uses a patient’s dendritic cells collected, primed to an antigen produced by insect cells, and reinfused.
• Based on recombinant adenoassociated virus produced by insect cells, Uniqure’s Glybera gene therapy for lipoprotein lipase deficiency was approved in Europe late in 2012.

In early 2013, the FDA approved Flublok as the first recombinant flu vaccine for the US market. After investigating the 2009 H1N1 pandemic influenza supply–demand gap, the US presidential science and technology advisory council found that “the fault lay . . . in the inherent shortcomings of current technologies for development and production of influenza vaccines. . . . The greatest potential for substantially shortening the time and increasing the reliability of influenza vaccine production lies in the use of recombinant DNA.”

According to Post, recombinant pandemic flu vaccines would be available much sooner (within 12–16 weeks) than those produced with the long- established egg-based technology (which takes 22–24 weeks). However, her company faced two major hurdles in Flublok development: cell-substrate characterization and seasonal changes in virus strains. Protein Sciences developed a “universal” process for quickly and safely manufacturing the product. She says the same technology could be used to make “a broad range of protein-based vaccines for both human and veterinary use.”

Formulation and Delivery: At the other end of the manufacturing process from vaccine production is formulation, fill, and finish. Several presenters discussed innovative approaches to solving the problems of product stability, enhanced immune response, and delivery. For example, James Norman (a postdoctoral associate in chemical engineering at the Massachusetts Institute of Technology) offered a quantitative economic analysis of patient self-vaccination using microneedle patches. Such devices are in development for painless intradermal vaccination, with a number of products in the pipeline.

A Monday afternoon session focused on adjuvant science and conjugate products. Leonard Friedland (vice president of scientific affairs and public health for vaccines at GlaxoSmithKline) began with an overview of why and when vaccines need adjuvants. These are substances such as aluminum gels or salts added to vaccine formulations to increase patients’ immune responses. Friedland covered general modes of action and safety considerations for vaccines formulated with novel adjuvants, as well as his company’s adjuvant system. He also reported on a malaria vaccine case study and put forth some considerations for use of adjuvanted vaccines in special populations. Because of concerns among the public — no matter their legitimacy — Friedland emphasized the importance of communicating adjuvant science to healthcare providers.

Next, Derek O’Hagan (vice president and global head of vaccine chemistry and formulation research at Novartis Vaccines) looked to the future. Many currently available adjuvants, he explained, were developed with little understanding of how they work. And he pointed out that recombinant antigens (found in the most modern vaccine products) are often poorly immunogenic because they are highly pure and lack natural immune-activating components such as nucleic acids, lipids, and cell membrane components. That makes adjuvants “as delivery systems or immune potentiators” potentially more vital. O’Hagan said that some challenges faced by vaccinologists in creating the next generation of products may be solved through greater understanding of adjuvant science.

Lipids and Encapsulations: Product stability is of particular importance for vaccinating patients in the developing world, where a cold chain cannot always be counted on. And streamlined manufacturing can make vaccines more affordable to people who need them. With these things in mind, Adam Buckley (vice president of operations at VBI Vaccines Inc.) and Kevin Killeen (chief scientific officer at Matrivax R&D Corporation) talked about two different product-encapsulating technologies.

A VBI proprietary technology provides thermostability for biologics such as vaccines (10). Buckley said that the lipid particle vaccine (LPV) platform enables products to withstand months of storage or shipment at constantly fluctuating or elevated temperatures. Three different lipids are layered to encapsulate and protect a protein product in ~450-nm particles in a lyophilized formulation. The company has completed proof-of-concept studies with monoclonal antibodies as well as vaccines for influenza; rabies; and mumps, measles, and rubella (MMR).

Matrivax licensed protein capsular matrix vaccine (PCMV) technology from Harvard Medical School (11). It uses a single chemical reaction to capture and encapsulate different polysaccharides in a protein net (12), whereas older technologies for creating multivalent vaccines typically require a separate chemistry to capture each different polysaccharide. Killeen described the potential of this “virtual conjugation” to enable simplified, low-cost production of complex multivalent polysaccharide products (e.g., pneumococcal and meningococcal vaccines). Pointing out that a very complex, hypothetical 24-valent pneumococcal vaccine could provide >95% protection against all pneumococcal serotypes worldwide, he said that an enabling technology such as his company’s PCMV could make such a vaccine possible. In fact, Matrivax has a typhoid fever product currently in clinical trials and is working on a pneumococcal vaccine at the preclinical level, with a potential salmonella vaccine in consideration. Echoing the globalization keynote discussions, this company is partnering with a contract manufacturer in Haikou, China.

Nucleic-acid–based vaccines and therapies present specific delivery challenges. Circulating enzymes in a patient’s blood will break down most naked DNA or RNA that gets injected, so these products need a means of making it into their target cells intact. Some developers have exploited the nature of viruses to deliver vaccines and gene therapies of this type; others prefer nonviral methods. Luis Brito (head of formulation science in vaccine chemistry and formulations at Novartis Vaccines) described his company’s lipid nanoparticle (LNP) and a cationic nanoemulsion for delivery of self-amplifying mRNA. Based on a proprietary adjuvant, it has shown success with influenza, respiratory syncytial virus, and human immunodeficiency virus RNA vaccines in animal models including mice and nonhuman primates.

The Next Generation
The conference ended with a glimpse into the future, as several presenters discussed next- generation approaches to vaccine development, manufacturing, analytics, and targets. For example, James Brady (director of technical applications at MaxCyte, Inc.) described a scalable transient transfection production method based on flow electroporation (13). Cary Connelly (senior research scientist at Paragon Bioservices) offered strategies for Ebola vaccine manufacturing, and Sha Ha (a director at Merck & Co.) detailed the analytical characterization of a Chikungunya virus VLP for use as a vaccine, comparing particles derived from mammalian and insect-cell cultures.

Joshua Cohen (a senior research fellow and research assistant professor at the Tufts Center for the Study of Drug Development) brought many of the meeting’s topics together in his report of progress in drug development for neglected diseases (14). Some 35,000 people die every day from neglected diseases, mostly in developing nations. These conditions are generally characterized by high incidence in the developing world and low incidence in the industrialized world. Historically, they haven’t received much R&D investment despite the high profile of some diseases: pediatric HIV, tuberculosis, malaria, typhoid fever, leishmaniasis, Dengue fever, and Ebola. But US$3.2 billion was invested in neglected disease R&D in 2012 — compared with just $70 million in 1999.

“Increased funding through product development partnerships (PDPs) appears to be yielding results,” Cohen said. Approvals and phase 3 products have shown a steady increase since 2000, nearly doubling in 2009–2013 (compared to 2000–2008) in terms of the annual average yield. However, he pointed out, the past 14 years have yielded only three newly approved new molecular entities for neglected diseases. Malaria and pediatric HIV appear to have benefited most from the increased funding. Inclusion of newly approved products on the World Health Organization’s (WHO’s) Essential Drug List has been slow and limited, Cohen said, with only 44% of new approvals added to it. “Uneven progress suggests that funding could be better targeted.” Cohen suggested that PDPs could do more to facilitate access, in particular, by working closely with the WHO.

References
1 Parrington M. Vaccines: Cold Cases — Sanofi Pasteur RSV Vaccine for the Elderly. Vaccine Development and Production Summit, 8 December 2014. IBC Life Sciences: Westborough, MA; www.ibclifesciences.com/Vaccines.

2 Falsey AR, et al. Comparison of the Safety and Immunogenicity of 2 Respiratory Syncytial Virus (RSV) Vaccines — Nonadjuvanted Vaccine or Vaccine Adjuvanted with Alum — Given Concomitantly with Influenza Vaccine to High- Risk Elderly Individuals. J. Infect. Dis. 198(9) 2008: 1317–1326.

3 Hurwitz JL. Respiratory Syncytial Virus Vaccine Development. Exp. Rev. Vaccines. 10(10) 2011: 1415–1433.

4 Respiratory Disease and Infection: A New Insight. Mahboub BH, Ed. InTech Europe: Rijeka, Croatia, 6 February 2013.

5 Du S. Vaccines: Cold Cases — Sanofi Pasteur RSV Vaccine for the Elderly. Vaccine Development and Production Summit, 8 December 2014. IBC Life Sciences: Westborough, MA; www. ibclifesciences.com/Vaccines.

6 Skoble J. Development of Cellular Immunotherapies to Treat Pancreatic Cancer. Vaccine Development and Production Summit, 9 December 2014. IBC Life Sciences: Westborough, MA; www.ibclifesciences.com/Vaccines.

7 Federspiel MJ. Manufacturing A Recombinant Measles Virus for Treating Patients with Multiple Myeloma. Vaccine Development and Production Summit, 8 December 2014. IBC Life Sciences: Westborough, MA; www.ibclifesciences. com/Vaccines.

8 Erholtz S. Let’s Go Viral. Vaccine Development and Production Summit, 8 December 2014. IBC Life Sciences: Westborough, MA; www.ibclifesciences.com/Vaccines.

9 Post P. Challenges Experienced During the Approval Process of a Novel Recombinant Influenza Vaccine. Vaccine Development and Production Summit, 8 December 2014. IBC Life Sciences: Westborough, MA; www.ibclifesciences.com/ Vaccines.

10 Buckley A. LPV Technology: Solid State Formulation Technology for Stabilizing Biologics and Vaccines. Vaccine Development and Production Summit, 8 December 2014. IBC Life Sciences: Westborough, MA; www.ibclifesciences.com/ Vaccines.

11 Killeen KP. Development of Protein Capsular Matrix Vaccine Technology. Vaccine Development and Production Summit, 9 December 2014. IBC Life Sciences: Westborough, MA; www.ibclifesciences.com/Vaccines.

12 Killeen KP, et al. Development of Protein Capsular Matrix Vaccine Platform Technology. BioProcess Int. 11(9) 2013: S26–S31.

13 Steger K, et al. Flow Electroporation for Vaccine Development and Production: From Subunit Vaccines to Ex Vivo Immunotherapy (white paper). MaxCyte, Inc.: Gaithersburg, MD, 2014.

14 Cohen JP. Measuring Progress in Neglected Disease Drug Development. Vaccine Development and Production Summit, 9 December 2014. IBC Life Sciences: Westborough, MA; www.ibclifesciences.com/Vaccines.

Cheryl Scott is cofounder and senior technical editor of BioProcess International, PO Box 70, Dexter, OR 97431; 1-646-957-8879; cscott@bioprocessintl.com. Information and quotes not specifically cited herein come from the conference brochure and published abstracts.