Vaccine Development and Production Challenges Manufacturers

Vaccines are front-page news these days. Researchers are advancing new vaccines for Ebola and other devastating diseases, while manufacturers work with FDA to bring to market new products to combat dangerous infections and strategies to improve supplies of seasonal influenza shots. Vaccine development was discussed as important for global security at the World Economic Forum in Davos, Switzerland in January 2015. The first draft of the US House of Representatives “21st Century Cures” initiative includes actions to speed up vaccine approval and coverage. Proposals seek to tighten timelines for the Centers for Disease Control and Prevention (CDC) to recommend new vaccines, for FDA to expedite vaccine exports, and for the National Institutes of Health (NIH) to advance vaccine development. Researchers are looking for formulations that reduce cold-chain requirements, methods to boost process yield, and new approaches to document product quality.

Some global health advocates, however, continue to rail against too-high vaccine prices, as seen in a confrontation over discounts offered to the Global Alliance for Vaccine Immunization (GAVI) by manufacturers of vaccines against pneumonia, diarrhea, and cervical cancer. Doctors Without Borders complained that price cuts proposed by Pfizer and GlaxoSmithKline (GSK) were inadequate; manufacturers countered that they were providing their products below cost (1). The dispute reflects ongoing tensions over how to fund research and production of vaccines for third-world diseases.

More troubling is the highly emotional anti-vaccine movement, which has been linked to a serious outbreak of measles that began at California’s Disneyland in December 2014 and had sickened more than 150 Americans through February 2015. CDC and medical leaders urged all parents to get their children vaccinated to prevent further spread of the disease. Even though measles was declared eliminated in the United States in 2000, CDC reported nearly 650 cases of measles in 27 states in 2014. The disease now has spread to multiple communities, as vaccine opponents continue to cite discredited beliefs that vaccines can lead to autism and other health problems. Most at risk are infants too young to be vaccinated, children with illnesses that compromise their immune systems, and a broader population that looses immunity over time.

Combating Ebola

Meanwhile, the potential for vaccines to prevent and limit deadly disease has spurred a global race to develop vaccines against Ebola. NIH is collaborating with industry and leading scientists in Liberia to launch a large Phase II/III trial of two leading vaccine candidates from GSK and Merck with NewLink Genetics, explained Anthony Fauci, director of NIH’s National Institute of Allergy and Infectious Diseases (NIAID), at a January 2015 press briefing.  The planned three-arm randomized, double-blinded trial began in early February 2015, and aims to enroll 27,000 healthy volunteers to support this effort to collect clear evidence of safety, efficacy, and immune response for the vaccines. In addition, CDC was designing a phased-introduction study in Sierra Leone to compare the effect of early vs. later vaccination.  The recent decline in new Ebola cases in Liberia, though, may necessitate changes in the study protocols.

To ensure supplies for clinical trials and anticipated commercialization, the Biomedical Advanced Research and Development Authority (BARDA) in HHS is working with vaccine makers to validate and optimize assays. These would facilitate comparability studies for eventual licensure of the vaccines from GSK and Merck, as well as one being developed by Johnson & Johnson/Bavarian Nordic. A related effort at BARDA aims to devise vaccine formulations that don’t require freezing.

Further advances

Researchers also report progress in developing new vaccines to combat Dengue fever, a mosquito-borne illness that is widespread throughout Latin America, Asia, and parts of Australia. Although less lethal than Ebola, Dengue infects more than 50 million people a year and has no ready treatment or preventive. Scientists recently reported positive clinical trial results, particularly from a large Phase III study in Latin America of a tetravalent Dengue vaccine developed by Sanofi Pasteur.

And a malaria vaccine may be on the horizon. In 2014, GSK filed for approval of its RTS,S vaccine by the European Medicines Agency (EMA) under an EMA assessment process that could support a recommendation by the World Health Organization for marketing authorization in African nations.

Back in the US, two vaccines to protect against meningitis B have been approved by FDA, using expedited processes to ensure a licensed supply in case of another serious meningococcal disease outbreak, as occurred at two US universities in 2013. At that time, FDA had to authorize emergency use of Novartis’ Bexsero vaccine, which was licensed in Europe, but not the US. FDA facilitated licensing by granting “breakthrough” status and accelerated approval for the vaccine candidates, and the Center for Biologics Evaluation and Research (CBER) approved Pfizer’s Trumenba in October 2014, and then Bexsero in January 2015.

Pfizer reported at the January 2015 CASSS-sponsored WCBP symposium in Washington, D.C. that its development program for its meningococcal serogroup B vaccine benefited from the application of  “an extensive analytical toolkit.” That facilitated in-depth characterization of both process and product, and delivery of a “robust comparability package” supported Phase III clinical trials and ultimately accelerated approval.

Last year, CBER also approved expanded indications for Merck’s Gardasil 9 vaccine based on studies showing effectiveness against a wider set of human papilloma virus. A Merck scientist similarly explained at WCBP how a matrix approach to demonstrating process and product comparability was leveraged to evaluate manufacturing changes. That was key to demonstrating that product made in new facilities for launch was comparable to that used in pivotal Phase III studies.

Flu vaccine challenges

Manufacturers faced serious difficulties in developing and producing seasonal influenza vaccines this past flu season, as production snafus forcedd key producers to delay vaccine shipments last fall. Sanofi Pasteur had problems growing one of the four target flu strains, and GSK experienced contamination problems at its manufacturing facility in Quebec. The resulting vaccine, moreover, turned out to have low effectiveness due to a serious mutation in a key influenza virus strain.

FDA advisors will meet in early March 2015 to identify what they hope will be more relevant flu strains for the coming season, a task always complicated by the need to select targets early enough for manufacturers to have six months to grow viral strains, most of that still done in chicken eggs.

Protein Sciences’ new Flublok vaccine uses a faster process, and the company hopes to expand production over the coming year. Novartis’ vaccine plant in Holly Springs, NC was recently licensed to produce Flucelvax using mammalian cell culture. But the plant’s future is murky following Novartis’ divestiture of most of its vaccine business to GSK and its flu vaccine program to Australia’s CSL.

A House Energy & Commerce subcommittee held a hearing in early February 2015 to examine the recent flu vaccine problems and strategies for FDA to improve its virus selection process. A Committee report (2) recommended that FDA issue guidance for manufacturers on developing new vaccine assays and adjuvants and supported efforts to devise a “universal” flu vaccine. Committee members raised concerns about 2015’s low flu immunization rate and damage done to public confidence in vaccines, developments that they feared would only fan anti-vaccine fears and undermine support for advancing vaccine development.

References

1.  Médecins Sans Frontières, "MSF responds to Pfizer announcement of pneumococcal vaccine price reduction," MSF.org (27 January 2015), www.msf.org/article/msf-responds-pfizer-announcement-pneumococcal-vaccine-price-reduction, accessed Feb. 17, 2015.

2.  Energy and Commerce Committee, "Examining the U.S. Public Health Response to Seasonal Influenza," Feb. 3, 2015, http://energycommerce.house.gov/hearing/examining-us-public-health-response-seasonal-influenza