Since October 2011, the U.S. Army Medical Materiel Development Activity's Pharmaceutical Systems Project Management Office has been managing the supply of Adenovirus Vaccine Types 4 and 7 for administration to U.S. Service Members during basic training. The vaccine has been highly effective and has helped to greatly reduce respiratory illness in these environments, keeping our trainees healthy during basic training. Dr. Clifford Snyder, Adenovirus Vaccine product manager, has been leading the Adenovirus Vaccine team since March 2011, and it is his job to ensure availability of the vaccine into the future. In light of this, Snyder's team has been involved in efforts to develop a new version of the vaccine, known as Modernized Production Adenovirus Vaccine, for which an Investigational New Drug application for MPAV Prototype A was submitted to the U.S. Food and Drug Administration Jan. 30.
"Our current vaccine has been in use for over five years, and it is a great product," said Snyder. "It's given to more than 200,000 enlisted military trainees each year, throughout all Service branches, and it is very safe and efficacious.
"However, as product manager, my job also entails identifying a possible follow-on product to ensure availability of the vaccine for our troops is not interrupted, in the event of any unforeseen situation with our current supplier, Barr Laboratories, Inc. [a division of Teva Pharmaceuticals]."
To shed light upon the recent pursuit of new methods of production, Snyder offered a brief history of the current vaccine and the impact of febrile respiratory disease on military readiness in World War II. With the draft policy in place to support wartime efforts, "boot camps" across the country witnessed an influx of trainees, with groups arriving and deploying on a frequent basis. Due to the large number of Service Members brought together in close quarters, febrile respiratory illness – specifically, cases caused by Adenovirus Types 4 and 7– emerged among trainees, affecting large populations at the same time. To combat this threat, a vaccine was developed and tested in the 1960's and then routinely administered to prevent febrile respiratory illness among trainees.
Widely used between 1971 and the late 1990's and manufactured by Wyeth Laboratories, Inc., this vaccine was so effective that the threat of illness soon became a memory. In light of this, the funds necessary to maintain the production facility at Wyeth were not made available. As febrile respiratory illness returned to basic training sites soon after Adenovirus Vaccine supplies were exhausted in 1999, senior officials in the Department of Defense requested restoration of vaccine capability and assigned this mission to the U.S. Army Medical Research and Materiel Command, USAMMDA's Higher Headquarters. Restoration of Adenovirus Vaccine production capability, which culminated in FDA approval, took nearly a decade; it has been highly effective since administration began in October 2011.
"When the illness resurfaced after 1999, there was an urgency to remanufacture the vaccine, and the USAMRMC was handed the task of bringing it back as quickly as possible for our Service Members," said Snyder.
However, in working quickly to restore the manufacturing capability once again, Snyder said that the government directed its pharmaceutical contractor to use the same methods and manufacturing practices from the original 1960's version – which was already proven safe and effective – to re-create the same vaccine. The government provided Wyeth's instructions for product manufacturing, which was done in a very controlled, reproducible manner. This was the beginning of a 10-year development effort, including clinical studies in recruit populations, which fortunately had a very successful outcome for our military troops in training camps across the country.
Fast forward to present day, and while the current Adenovirus Vaccine continues to shield our military trainees against febrile respiratory illness, the process of developing new manufacturing methods to address certain risks is ongoing.
As Snyder explains, "There are a number of factors, both business and technical, which have prompted us to seek a new vaccine for Adenovirus, and in doing so we have initiated some interesting partnerships with great potential for advancement of this vaccine, and possibly other pharmaceutical products, as we move forward."
Snyder's dedication to this important effort is very clear, and he detailed the reasons for USAMMDA's present focus on the MPAV program.
"Although we're in the middle of a five-year delivery contract with Barr, the current supplier of the vaccine, it's our job to mitigate possible risk factors, and that's exactly what we're doing," he said.
"In conjunction with the Small Business Innovation Research program, we solicited proposals from numerous companies, and after various levels of review, PaxVax, Inc. was selected as our contractor for development of MPAV and also serves as Regulatory Sponsor," continued Snyder. "Col. Robert Kuschner of Walter Reed Army Institute of Research has been very instrumental in his role as SBIR topic author, contracting officer's representative for several SBIR contracts, and as Independent Research Monitor for the upcoming Phase 1 study. In addition, WRAIR will play a role in performance of immunological assays."
Snyder hopes that by utilizing the SBIR program in this development effort, his team will be able to determine if PaxVax, a small business, can develop and manufacture a vaccine that is equally as safe and effective as the current one, and if this innovation can result in overall cost savings and risk reduction. Much of this "innovation" lies in the actual manufacturing of the vaccine, which currently is being produced using the same technology from the 1960's, albeit successfully.
By incorporating state-of-the-art processes into production, Snyder believes this switch should help lower the per-dose cost, which is now approximately $150. PaxVax was ultimately chosen as SBIR contractor because of its prior experience in working with multiple strains of Adenovirus.
Among the potential risks that prompted USAMMDA to begin its search for a new Adenovirus Vaccine product is the fact that the current manufacturer could stop production at any time, after the end of its current delivery contract. Also, the essential biological materials of the present vaccine, the Type 4 and Type 7 Adenoviruses, are produced overseas in Scotland, and Snyder's team would like to bring this process to the U.S. going forward. PaxVax intends to produce these critical materials in its home state of California.
Another interesting aspect of the new development process being established by PaxVax is the method of removing water from virus preparations. Currently, water is removed by the process of lyophilization, which involves exposure of frozen viruses to a lengthy set of combinations of temperature and reduced pressure. MPAV Prototype A is being manufactured using this method, whereas MPAV Prototype B, which is in early process development, will use a spray drying method to remove water. Spray drying is more rapid than lyophilization and can produce a free-flowing powder, which lyophilization does not. However, only actual experience in manufacturing and testing will reveal the pros and cons of spray drying as applied to Adenovirus Types 4 and 7.
The current form of Adenovirus Vaccine is given in two tablets, one for Type 4 and one for Type 7. These tablets are made by compressing viruses and inactive ingredients to form an inner core, and then performing a second compression with additional inactive ingredients to protect the core against the organic solvents that are used to deliver an enteric coating to the tablets. This enteric coating protects the viruses from stomach acid but allows the tablet to dissolve once it encounters the small intestine.
Needless to say, the two-step tableting process is extremely critical, as well as costly, and PaxVax is working to develop a way of delivering the Type 4 and 7 Adenoviruses in a capsule instead of a tablet. While MPAV Prototype A will consist of two capsules, MPAV Prototype B will combine both Type 4 and Type 7 in one capsule, which actually provides another engineering challenge – but again, Prototype B is presently in the early stages of process development.
Said Snyder, "Of course, one capsule will be much easier to distribute and ingest than two tablets, but we still have a way to go before we reach that point, although we're quite hopeful."
Snyder acknowledged and praised the U.S. Army Medical Research Acquisition Activity, which has been handling the multiple contracts put in place in support of this effort. He went on to explain that although the SBIR program is helping to fund development of this vaccine, the Prototype B vaccine is receiving financial support from the U.S. Army's Manufacturing Technology Program, also known as ManTech.
"ManTech is providing $5 million in funding for the early development of MPAV Prototype B," he said. "Without this support, we might not have Prototype B, which is actually very interesting and may eventually offer the greatest potential for production cost savings [due to spray drying and single-capsule form]."
Although MPAV Prototype A is ready to be tested in a Phase 1 clinical study, Snyder believes that Prototype B will be ready for clinical study in early 2018, after PaxVax has finished development of the spray-drying process.
"Both prototypes will hopefully be tested before Milestone B," he said, "and we could have the clinical study results for both Prototypes A and B by late 2018. At that time, PaxVax should have more manufacturing data, on a small scale, in order to make cost projections for [DOD] decision making. Then, we could move into scale-up and Phase III studies."
If this process goes smoothly, and if funding permits, Snyder believes the MPAV product could be ready for FDA licensing by 2021, and available for distribution to military trainees in 2022. He also noted that the availability of funding from the Defense Production Act Title III program would help maintain an aggressive development schedule.
"The execution of DPA Title III funding requires Presidential approval, and with the recent change in administration, we hope this does not slow down the approval process," said Snyder.
Considering all that is going into the manufacturing of the Adenovirus Vaccine by both the current and potential supplier working with this crucial product, one thing certainly remains clear: the safety of our Warfighters throughout all military branches is the primary focus of this important effort.
In the same vein, the work being conducted by Snyder and his team at USAMMDA's PSPMO, and members of the Integrated Product Team beyond the PSPMO, highlights the tremendous commitment of the men and women of an organization dedicated to developing and delivering quality medical capabilities to protect, treat and sustain the health of Service Members worldwide. In light of this, USAMMDA remains the premier developer of world-class military medical capabilities and will continue its mission to provide critical products, drugs and devices that help bolster our nation's military forces.