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New formulations and expanded vaccine production are encouraged.
Vaccine development is on a roll, boosted by biomedical research uncovering new molecular targets for preventives and treatments, as well as innovative techniques for enhancing vaccine potency and production. There is high demand for new vaccines to prevent deadly tropical diseases, illustrated by the recent Ebola virus outbreak, and for capacity to respond quickly to global pandemics and bioterrorist attacks at home and abroad. More manufacturers seek to devise new versions of vaccines for pneumococcal disease, meningitis, and more potent influenza preventives, encouraged by positive coverage and reimbursement decisions.
At the same time, early optimism about developing vaccines to prevent and treat HIV/AIDS has diminished, along with hopes for prompt discovery of a vaccine against drug-resistant tuberculosis. There has been progress in research on therapeutic vaccines for cancer, but so far these are highly targeted and expensive. The ability of manufacturers to produce high-quality, safe and effective vaccines to meet public health needs remains crucial to building public confidence in vaccination schedules that have expanded with the approval of more effective products.
Meanwhile, frequent vaccine shortages point to the need for more extensive and reliable manufacturing operations. David Swerdlow, associate director for science of the National Center for Immunization and Respiratory Disease at the Centers for Disease Control and Surveillance (CDC), emphasized the need to increase United States vaccine manufacturing capability at Terrapin’s World Vaccine Congress in Washington, D.C. in March. Swerdlow noted growing concerns about the MERS outbreak in Saudi Arabia and the Near East, and the potential for this and other deadly diseases to travel to Europe and elsewhere.
Jesse Goodman, former chief scientist at FDA and now forming the Center on Medical Product Access, Safety and Stewardship (COMPASS) at the Georgetown University Medical Center, commented on the importance of vaccine supply chain security in assuring global access to treatment. He acknowledged considerable progress in establishing a more reliable influenza vaccine supply, noting advances in dual-use capacity and in developing cell-based products. Goodman also cited numerous challenges. Current flu vaccines have limited effectiveness, and health authorities have difficulty each year predicting which seasonal flu strains pose the most risk. Vaccine production capacity is limited, he added, and supply shortfalls occur all too frequently.
The Biomedical Advanced Research and Development Authority (BARDA) in the Department of Health and Human Services (HHS) is responding with funds to support flexible manufacturing capacity that uses disposable technology to enhance US capability for fast scale-up of vaccines and treatments during a pandemic or health emergency. Such facilities also can provide support for biotech firms developing new vaccines and medical countermeasures. BARDA has awarded more than $400 million to establish three Centers for Innovation in Advanced Development and Manufacturing (CIADMs): Emergent Manufacturing is forming a biologics development and manufacturing suite in Baltimore; Novartis Vaccines and Diagnostics is expanding its cell-based vaccine production facility in North Carolina with a pilot plant to produce clinical lots of medical countermeasures; and Texas A&M University is establishing several development and manufacturing facilities. Each organization also is partnering with other biopharma companies and research entities to develop new pandemic influenza vaccine candidates.
BARDA also is forming a Fill Finish Manufacturing Network with $40 million awarded to Cook Pharmica (Bloomington, Ind.), DMS Pharmaceuticals (Greenville, NC), JHP Pharmaceuticals (Parsippany, NJ), and Nanotherapeutics (Alachua, FL). The network will be capable of packaging 117 million doses of flu vaccine in 12 weeks and will support the CIADMs in building capacity for four-month production of 150 million doses of pandemic flu vaccine. The CIADMs will produce test countermeasures for clinical trials and provide commercial capacity to help remedy shortages in vaccines and biologics. A recent report on the program by the Government Accountability Office (1) notes that the value of this investment will begin to emerge as BARDA issues task orders this year to test the quality of CIADM core services and their success in spurring development of new therapies and vaccines.
Another prominent strategy for expanding the nation’s vaccine supply is to develop adjuvanted products that require less antigen for comparable or expanded immune response. FDA is working with manufacturers to facilitate licensure of such products, noted Marion Gruber, director of the Office of Vaccine Research and Review in FDA’s Center for Biologics Evaluation and Research (CBER), at the Vaccine Congress. Such formulations may boost immune response in elderly and other special populations; achieve immunity with fewer doses; and reduce booster shots needed to extend immune response. While a number of adjuvanted vaccines have been approved in Europe, Gruber reported that FDA “finally” has done the same with the licensing of two adjuvanted products in the US.
Gruber explained that FDA has no special pathway for approving adjuvanted vaccines, as adjuvants are not active ingredients, but considered “constituent materials” to a vaccine formulation. The adjuvanted vaccine must be pure and of high quality, and it must demonstrate that the added ingredient does not reduce vaccine safety and potency. Manufacturers have to establish consistent production processes and provide a rationale for using an adjuvant, usually based on studies that compare a vaccine with and without the adjuvant to see what advantage is created. While FDA does not require an adjuvanted vaccine to demonstrate added benefit, such data may be requested if safety concerns emerge or if the manufacturer plans to make comparative claims for the reformulated product.
FDA is willing to infer effectiveness of an adjuvanted vaccine from the immune response induced in populations in clinical trials and then confirm clinical benefit in post-marketing studies, as is usual for seasonal influenza vaccines. The agency wants to see 12 months follow-up to be sure to detect further adverse effects, but emphasizes that there’s no one-size-fits-all approach to developing and testing these products.
Supply chain improvements
Manufacturing innovation also can address many of the challenges in distributing vaccines to patients in third- world regions. While efforts continue to develop thermostable vaccines and medical products, Raja Rao, senior program officer at the Bill & Melinda Gates Foundation, noted at the Vaccine Congress that interest is growing in additional strategies. He discussed the need to mitigate the dangers of vaccine freezing under current distribution systems, which can greatly reduce potency, as well as identification of products that don’t need refrigeration if delivered to clinics in 30 or 60 days. Gates is looking more at improving supply-chain equipment and at devising more efficient vaccine delivery networks as less costly approaches than a “moon shot” investment in thermostability, Rao observed.
Many of these initiatives are outlined in the March 2014 HHS National Vaccine Plan, which cites efforts by BARDA and other government agencies to ensure stable supply and public access in the US to recommended vaccines (2). One innovation is the SMART vaccines program that uses software and other tools to help set priorities for developing and testing new vaccine targets. The report also describes federal programs for developing new vaccine production technologies, including use of a silk-based stabilizer to enhance vaccine stability in hot climates, and new vaccine delivery methods that conserve antigen and may be important during emergencies.