In March, the Pharmaceutical Research and Manufacturers of America released a new report “Medicines in Development – Biologics, 2013 Report.” The report lists 907 biologics currently in development by “America’s biopharmaceutical research companies.” The list includes biologics targeting more than 100 diseases that are currently in human clinical trials or are under review by the Food and Drug Administration (FDA). Of the 907 biologics, there were 250 vaccines included. After reviewing the list of vaccines in development, I decided to explore a handful of interesting viral vaccines that are in late stage development.
GlaxoSmithKline’s H5N1 Avian Flu Vaccine Candidate
The vaccine called Q-Pan H5N1 is designed for use in an avian flu pandemic. In November 2012, the FDA’s Vaccines and Related Biological Products Advisory Committee voted unanimously 14-0 to support approval of the product for immunization of persons 18 years or older who are at increased risk of exposure to the H5N1 influenza virus. Then in March, FDA issued a Complete Response Letter on Q-Pan, which delayed approval. The recent Reuters article, FDA Delays Approval of GSK Bird Flu Vaccine, discusses the delay in more detail and GSK issued a statement stating, “the U.S. Food and Drug Administration (FDA) decided it needed more time to assess the product due to an administrative matter that has recently been rectified.”
While there has been no confirmation, there has been speculation that the delay might be related to the growing concern about a possible link between the adjuvant AS03 (in Q-Pan) and narcolepsy. Another Reuters article, Narcolepsy link to Glaxo vaccine poses challenge for FDA, describes how recent studies conducted in England, Sweden, Finland and Ireland have found a heightened risk of developing narcolepsy for those who received GSK’s Pandemrix vaccine during the H1N1 swine flu pandemic. The Pandemrix vaccine contains the same AS03 adjuvant and there is concern that it is the adjuvant causing the increased risk.
However it is important to note that H5N1 (avian flu) has an entirely different risk profile than H1N1 (swine flu). While the mortality rate from H1N1 was estimated at less than 1 percent, the mortality rate with H5N1 is estimated at nearly 60 percent. The high mortality rate presents quite a dilemma for FDA. In the Reuters Narcolepsy article, it states that GSK administered 30 million doses of the Pandermix vaccine and 800 developed narcolepsy, mostly children. So the FDA must weigh the known high mortality rate of H5N1 against the adjuvant’s possible link to narcolepsy and decide if the benefit of the vaccine outweighs the risk.
Sanofi Pasteur’s Dengue Fever Vaccine Candidate
There has been much anticipation of Sanofi’s Dengue Fever Vaccine. While there are several other Dengue Fever vaccines candidates in various phases of development, Sanofi’s is the furthest along. Since there is currently no treatment for Dengue Fever and WHO estimates 50-100 million infections each year, finding a vaccine is critical. It is of particular importance in tropical and subtropical regions, which are most affected by the virus.
As a result of the great need, there was much excitement about the Sanofi candidate, then in 2012 results from one of the vaccine’s clinical trials in Thailand failed to produce expected results. A September 2012 New York Times article, In a Setback, Sanofi’s Dengue Fever Vaccine Falls Short of Its Goal, describes the disappointing results in more detail. The primary setback was that the study’s goal was to achieve 70 percent efficacy, but the Thailand trial demonstrated only 30 percent efficacy. The lower efficacy is believed to be the result of the vaccine preventing only 3 of the 4 serotypes. Serotype 2 was not covered by the vaccine and happened to be the most prevalent type in Thailand at the time of the trial.
Sanofi is currently conducting several large Phase III clinical trials in ten different countries and when those results are in, a clearer picture of the vaccine’s efficacy will be able to be determined.
Merck’s V503 Human Papillomavirus (HPV) Vaccine Candidate
Merck was the first to receive approval for an HPV vaccine with approval of Gardasil™ for females aged 9-26 in 2006 and for males aged 9-26 in 2009. Gardasil is a quadrivalent vaccine for HPV types 6, 11, 16, and 18. These types account for up to 75 percent of cervical cancers. Now Merck is developing the V503 vaccine, which will include five additional HPV types for a total of nine types. As a result, the new vaccine should demonstrate increased protection.
While Gardasil is very effective, there have been problems with adherence since vaccination is not mandatory. In a previous blog titled “New Vaccines Coming Soon to a Doctor’s Office Near You,” we discussed a study conducted by Cincinnati Children’s Hospital. In the study they found that Gardasil cut HPV infection rates in vaccinated women by 69 percent and in women without the vaccine infections were cut by 49 percent due to herd immunity.
Baxter’s Preflucel Seasonal Influenza Vaccine Candidate
Baxter’s vero cell culture derived Preflucel was approved in 2011 in 13 European Countries, but is still awaiting approval by the FDA. On November 20, 2012, FDA announced that it approved the use of Flucelvax manufactured by Novartis to prevent seasonal flu in people over age 18. This approval was the first for a cell culture-based seasonal influenza vaccine in the United States. Instead of using the traditional chicken egg production method, Novartis propagates the virus in Madin Darby Canine Kidney (MDCK) cells. There are many advantages to using a cell culture-based manufacturing system for vaccines – it is quicker to manufacture, efficiently scalable and offers more control over the manufacturing environment.
Will Baxter’s Preflucel become the second cell culture-based influenza vaccine approved in time for the 2013-2014 flu season?
Sanofi Pasteur’s Rabies VRVg Vaccine Candidate
Sanofi is working on a next generation, serum-free purified vero rabies vaccine. In a 2007 study published in Vaccine, Immunogenicity and safety of a new Vero cell rabies vaccine produced using serum-free media, Sanofi described the product in the abstract as “The immunogenicity and safety of a new human rabies vaccine, produced in Vero cells by a process that does not require supplementation with human or animal derived components in production, were assessed. Thus, the objective is to produce a safer vaccine at a lower cost.” Sanofi demonstrated in that study that the new vaccine was both safe and immunogenic.
Now in a recent study published in Vaccine in April 2013, A serum-free, purified vero cell rabies vaccine is safe and as immunogenic as the reference vaccine Verorab™ for pre-exposure use in healthy adults: Results from a randomized controlled phase-II trial, Sanofi demonstrated that the vaccine candidate now called PVRV-NG was shown to be at least as immunogenic as Verorab (current rabies vaccine) with a similar safety profile.
While we frequently talk about the importance of moving biologics to serum-free manufacturing, it is encouraging to see Sanofi making the effort to create a next generation product that is manufactured in a serum-free environment.
There are several other innovative vaccines in clinical development and for the sake of space; I wasn’t able to include them all. Please add any others that you find interesting to our comments section below.