Vaccine development isn't generally considered an area ripe for innovation. Yet, research and development in this area has been flourishing over the last 10 years. And despite the controversy surrounding Tamiflu (oseltamivir), which has led many to question the logic of stockpiling antivirals in case of an influenza pandemic, seasonal influenza vaccines continue to be beneficial come flu time.
According to information presented by Rick Bright, Acting Director of the Influenza Division at the Department of Health and Human Services (DHHS), there were a staggering 94 flu vaccines in development as of May 2014. In fact, according to Bright’s presentation, there has been whirlwind of progress in flu shot development since 1994, when all seasonal vaccines were egg-based and manufactured using technology from the 1950s.
In 2004, a production failure at just one manufacturing facility led to a widespread shortage of seasonal vaccine and put the most vulnerable members of the population—the very old and the very young—at risk. This crisis highlighted just how precarious and outdated flu vaccine manufacturing was at the time. For instance, production was limited to a six-month window from January to June, and manufacturing capacity was limited.
Novartis introduces the first egg-free influenza vaccine
But since 2004, manufacturing capacity has grown dramatically, with companies such as Sanofi Pasteur and Novartis emerging as innovators and leaders. For example, Sanofi has been able to expand capacity by retrofitting its vaccine development infrastructure.
More recently, Novartis gained the distinction of becoming the first company to develop an egg-free influenza vaccine—Flucelvax (influenza virus vaccine), the first FDA-approved seasonal vaccine not manufactured with chicken eggs. In June, the FDA licensed Novartis’s manufacturing facility in Holly Springs, NC for the production of Flucelvax, making this facility the first U.S. pandemic-ready site licensed by the FDA to produce cell-culture influenza vaccines.
From a manufacturing perspective, using cell cultures instead of chicken eggs to produce inoculations is easier to control and more flexible, allowing for scalability and an increased level of responsiveness to an emergency situation.
The Tamiflu controversy
In spite of all of the progress in the area of influenza vaccination R&D, the controversy surrounding Genentech’s Tamiflu (oseltamivir), a neuraminidase inhibitor, has led to widespread distrust of flu vaccinations in general. When Tamiflu was approved by the FDA in 1999 and the European Medicines Agency (EMA) in 2002, it was hailed as the holy grail of flu shots—a way to prevent and treat influenza virus.
In the mid-2000s, concerns over the specter of an H5N1 avian-flu virus—which has a mortality rate of 60%—pandemic led the U.S. government to stockpile supplies of Tamiflu. However, over time the underlying evidence base for Tamiflu was called into question.
That skepticism was vindicated in April when the Cochrane Collaboration published shocking new findings about Tamiflu based on analysis of numerous randomized, controlled trials. The upshot of the group's analysis was that the benefits of Tamiflu did not outweigh the adverse events and that, in general, Tamiflu was of little clinical use.
Dr. Barry Mennen, a Washington, DC-based physician, told BioPharma Dive, “When it comes to Tamiflu, there seems to be little benefit worth the side effects or expense. In adults, a shortening of the symptomatic course by half a day was seen. This does not seem clinically significant to me. In children, the Cochrane review found a slightly better effect as the duration of the symptoms was shortened by a day, and this may be enough to move some pediatricians and family practitioners to prescribe.”
In fact, Dr. Mennen notes that the overall take-away from the Cochrane review was that “they have not found any evidence of a true antiviral effect” for Tamiflu.
Flu season 2014
The fall-out from the Tamiflu controversy has not been good for the reputation of influenza vaccines; however, Dr. Mennen says, “the data are more favorable for the seasonal vaccines—though not as good as we might hope for.”
Nonetheless, vaccination is still widely recommended by the Centers for Disease Control and Prevention (CDC). All year long, the 100 national influenza centers receive and test thousands of viral samples from patients who are suspected of having the flu. That information is sent to World Health Organization collaboration centers and used to make recommendations for the composition of seasonal influenza vaccines in the northern hemisphere.
The recommendations for the 2014-15 season are as follows:
- A/California/7/2009 (H1N1)-like virus
- A/Texas/50/2012 (H3N2)-like virus
- B/Massachusetts/2/2012-like (Yamagata lineage) virus.
The CDC continues to recommend universal vaccination for everyone aged six months and older, as long as there are no contraindications. And although influenza vaccinations are not always 100% effective, changes in production have significantly improved their efficacy.
In part 2 of this series, BioPharma Dive speaks with Emmanuel Dejean, CEO of France-based Calixar, a company that has developed an innovative manufacturing process for high-performance influenza vaccines.