Vaccine Innovation Yields New Products and Processes

There is great enthusiasm for developing new vaccines to combat debilitating diseases, which is spurring improvements in analytical methods and production strategies that are more efficient and provide greater assurance of product quality. Vaccine production has become more attractive to pharmaceutical manufacturers seeking new products to help offset the decline in revenues and profits from patent expirations on blockbuster therapies. Although vaccines may not be big moneymakers for biopharmaceutical companies, vaccines can produce solid revenues by providing highly cost-effective treatments for stable markets.

Jill Wechsler

There also are strong moral and public health reasons for industry investment in treatments that can prevent the spread of infectious diseases and new pathogens. The World Health Assembly approved a 10-year Global Vaccine Action Plan in May 2012 to develop and distribute more new preventive drugs around the world, with Dengue fever and malaria at the top of the list of targeted illnesses. Research on vaccines to treat global diseases also may lead to more lucrative preventives against widespread conditions such as cancer and other diseases caused by viruses, bacteria, or parasites. Two approved vaccines that prevent cervical cancer are on the market, Merck's Gardasil and Cervarix from GlaxoSmithKline, along with the first cancer treatment vaccine, Dendreon's Provenge, for metastatic prostate cancer.

The challenges in devising safe and effective vaccines, however, are all too apparent. Years of research have failed to produce a vaccine to prevent HIV/AIDS. Therapeutic vaccines are proving elusive, as seen in difficulties using vaccine technology to treat nicotine addiction, diabetes, and Alzheimer's disease. A notable disappointment is the recent failure of a promising tuberculosis vaccine following a study on almost 3000 South African infants. Scientists at Oxford University, vaccine maker Aeras, the Wellcome Trust, and the Bill and Melinda Gates Foundation tried to sound positive in announcing the results, stating that important evidence was obtained from this model, placebo-controlled trial, and that the vaccine still might be effective in adults.

MORE NEW VACCINES

At the same time, there is much good news in the vaccine world. This year started with FDA approval of wider use of Pfizer's Prevnar 13 vaccine to prevent pneumococcal bacterial infections. That followed approval in 2012 of Glaxo's MenHibrix, a combination vaccine to protect against meningococcal and Haemophilus influenzae type b (Hib).

Notable advances in formulations and manufacturing processes for influenza vaccines have attracted considerable attention in this year's more severe flu season. The flu vaccine crop of 2012 included two quadrivalent products (i.e., vaccines that protect against four virus strains instead of three) from Glaxo and AstraZeneca.

Manufacturers, moreover, are shifting away from producing flu vaccine in chicken eggs, as seen in FDA approval in November 2012 of Novartis' Flucelvax, produced in cultures of dog kidney cells. It will be scaled up at Novartis' new vaccine plant in Holly Springs, NC, built with some $500 million in support from the US government. Similarly, Protein Sciences Corp. (Meriden, CT) gained FDA approval in January 2013 for FluBlok, which utilizes recombinant DNA technology to produce large quantities of flu virus protein using an insect virus (baculovirus) expression system. Protein Sciences also has benefited from more than $100 million in federal funding and plans production at a former Pfizer manufacturing site in Pearl River, NY.

Many of these advances reflect increased US government investment in vaccine production methods since 2006 when the Department of Health and Human Services (HHS) provided more than $1 billion to six manufacturers to develop cell-based flu vaccine technology and production capacity in the US that can ramp up production quickly in case of pandemic or other health crises. The looming H1N1 swine flu fear in 2009 added funding to expand domestic vaccine production, and in 2012, HHS provided $400 million to three research consortia to further enhance production of vaccines and medical countermeasures. HHS assistant secretary Nicole Lurie noted, in an HHS press release, that the three public-private partnerships—which include Glaxo, Novartis, and Maryland-based Emergent BioSolutions; academic research centers; and small biotech companies—will use the funds to retrofit existing facilities or build new ones with "flexible, innovative manufacturing platforms that can be used to manufacture more than one product."

A cadre of other new vaccines is in the works. Novartis recently obtained approval in Europe for a new vaccine against meningitis B, while Glaxo has linked up with an Indian manufacturer to develop a six-in-one combination pediatric vaccine. Baxter has another cell-based vaccine for avian flu on the market in Europe, and genetically engineered flu vaccines are being tested by Novavax (Rockville, MD) and Vaxinnate Corp. (Cranbury, NJ). A long-term goal is to develop a universal flu vaccine that fights multiple virus strains and can be administered every 5 to 10 years. There also is promising research on new vaccine delivery technologies and products that don't require cold-chain distribution.

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ANALYTICAL ADVANCES

Continued progress involves addressing difficult vaccine quality and safety issues, as discussed at the January 2013 WCBP symposium in Washington, DC, sponsored by CASSS and FDA. Scientists noted the need to "solve the riddle" of how to make these complex products at moderate cost using modern biotechnology. This progress involves defining the range of acceptable variability in characterizing these inherently heterogeneous products, including release and stability data that reflect both process/analytical capability and biological suitability of the final product. Participants in a WCBP vaccine workshop further explored issues in achieving manufacturing control and in defining critical attributes for newer vaccines. There was discussion about strategies for designing appropriate potency assays, for setting release and stability specifics, and for justifying a range of variability with available clinical data. Concerns that some newer, highly purified vaccines may appear less efficacious than older, heterogeneous products illustrate a need for clear potency assays.

The importance of harmonization in national vaccine regulatory policies was emphasized at the December 2012 PDA/FDA vaccine conference in Bethesda, MD, which also examined issues related to expanding global access to effective vaccines. Leading vaccine makers expressed frustration with frequently changing standards, data requirements, approval processes, and policy interpretations by regulatory authorities around the world. Manufacturers would like to see a functional "mutual recognition" process for vaccine market approvals, or perhaps a global body that reviews standardized data for all markets. The vaccine industry is working closely with the world health community to greatly expand access to crucial vaccines for millions of children around the world, a goal that would benefit from regulatory processes able to identify products that do and don't meet quality standards, as well as an international process for identifying and monitoring vaccine safety problems.

Further research also is needed to address still prevalent "anti-vaccine" fears held by many parents and patients. A report issued by the Institute of Medicine (IOM) in January 2013 confirmed the safety and benefits of the US childhood immunization schedule and advised against moves by parents to stretch out or delay childhood vaccination (1). Even so, immunization rates in most states fall below the desired 95% level and are even worse in Britain and many other countries. Manufacturers need to join with the health community to support research on still-prevalent fears about vaccination and to bolster evidence on the critical benefits of immunization.

Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, jwechsler@advanstar.com.

REFERENCE

1. IOM, "The Childhood Immunization Schedule and Safety: Stakeholder Concerns, Scientific Evidence and Future Studies," (Jan. 16, 2013), www.nap.edu, accessed Feb. 12, 2013.