Saturday, May 18, 2019

Manufacturing Pandemic Flu Vaccines: Easier Said Than Done











  • Buried Lede Alert: Japanese Pharmaceutical Company Daiichi Sankyo unable to fulfill its obligation to produce H5N1 vaccines for 40 million people in the time allotted


#14,074


The cliché in most fictionalized pandemic movies, TV shows, and books  (excluding zombie movies and post-apocalyptic works) is that - when all hope seems lost - a highly effective experimental vaccine is miraculously formulated and is then quickly distributed to the world's population, thereby saving the day.
These Deus ex machina resolutions have been used for thousands of years to tidy up seemingly impossible situations in the final act.  In order to guarantee a satisfying ending, the Cavalry must always arrive in the nick of time.
In a rare and bold move, last year Johns Hopkins presented a day-long pandemic table top exercise (see CLADE X: Archived Video & Recap), which provided a sobering look at a plausible pandemic where hundreds of millions of people could die, many from indirect causes.
While a vaccine was promised early on, and expected to begin rolling off the production line`within six months', that initial vaccine turned out to be a failure.
If you don't have the time to watch the (highly recommended) entire 8 hour exercise, I would urge you to at least view the 5 minute wrap up video. It will give you some idea of the possible impact of a severe - but not necessarily `worst case' - pandemic.

Recap Video

In the spring of 2009, a new swine-origin H1N1 virus emerged from (presumably) Mexican pigs, and in a remarkable achievement, a pandemic vaccine was formulated, manufactured, and made available (in limited quantities) within six months. 
But this was a simple strain change, involving an H1N1 virus - not some exotic avian flu strain - or worse, a non-influenza virus. 
But even so, things did not go quite as well as planned.

In May of 2009, several weeks after the emergence of the novel H1N1 virus,  Dr. Marie-Paule Kieny, director of the WHO's Initiative for Vaccine Research, estimated  (via CIDRAP Experts to discuss swine flu vaccine decision May 14) global vaccine production as:
. . . .  somewhere between 1 billion and 2 billion doses in a year, based on an estimated seasonal vaccine capacity of about 900 million doses. Current world population is more than 6 billion.

"Being conservative, we think there'll be at least between 1 and 2 billion doses," she said.
An even more aggressive manufacturing projection came from a May document called Recommendations of the Strategic Advisory Group of Experts (SAGE) on Influenza A (H1N1) vaccines.
For influenza A (H1N1), it is estimated that up to 4.9 billion doses could be produced over a 12‐month period after the initiation of full scale production if: 
  1. There is a vaccine yield equivalent to that routinely obtained for seasonal vaccine and the use of the most dose‐sparing formulations. 
  2. In this situation, there is a potential access for the UN of supplies of up to 400 million doses.

In the end these manufacturing goals were not met (see 2010's ECDC: Global Vaccine Goals And Realities), as the yield from the seed virus proved less than anticipated and the use of adjuvants – to reduce the amount of antigen needed per shot – was met with public resistance.


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Luckily for the world, the 2009 H1N1 pandemic was relatively mild, the vaccine was a relatively simple `strain change' with seasonal H1N1, and it did not - as originally feared - require two shots 30 days apart to convey protection.
None of this is to disparage the usefulness of the vaccine, or the efforts that went into producing it, but by the time the shot was widely available in the United States and Europe, the crisis was about over.
In order to shave time off the manufacturing of a pandemic vaccine, the WHO, CDC, and others analyze emerging novel viruses and have selected dozens over the years to turn into a candidate vaccine virus (CVV) (see CDC: Making a Candidate Vaccine Virus For HPAI Avian Flu).

Since H5N1 emerged in 2003, more than three dozen H5 CVVs have been selected by WHO for development. While it can be expensive, having a proven CVV already tested and approved can save months of valuable time if mass production and distribution of a vaccine is ever required.
Similarly there are currently 14 H7N9 CVVs, and 7 H9N2 CVVs either developed or in the pipeline.  Other novel viruses, including swine variant H1 and H3 viruses, have CVVs as well.
But, as we've seen before, having a Candidate Vaccine Virus is still a far cry from having a safe and effective vaccine, and farther still from having a vaccine manufactured in quantity (see The Long Road To An H7N9 (or Any Other Pandemic) Vaccine).

All of which brings us to a small press release yesterday from the Japanese pharmaceutical manufacturer Daiichi Sankyo Company, Limited, which in 2011 received a contract from the Japanese government to supply H5N1 vaccines for 40 million people in the time frame allotted (6 months) under the Japanese Ministry of Health, Labour and Welfare’s pandemic plan.

After 8 years, and an extension (granted in 2014), Daiichi Sankyo has formally apologized - and returned some of the initial grant money - for being unable to fulfill the terms of the contract.


Tokyo, Japan (May 17, 2019) – Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) announced today that the Company has been unable to fulfill its obligation to build a scheme to supply vaccines for 40 million people in the time allotted under the Japanese Ministry of Health, Labour and Welfare’s cell culture vaccine production facility capacity building project, which is a part of the Ministry’s second initiative for H5NI vaccine development and production capacity building grant. After being selected for the project, Daiichi Sankyo had been engaged in preparations to build a scheme to supply vaccines from August 2011 to March 31, 2019.
        (SNIP)
It was discovered in the development phase that higher doses are needed than expected when designing facilities, and they have addressed to increase the vaccination yield and improve the facilities.
However, they have been unable to build a scheme capable of supplying vaccines for 40 million people in 6 months by March 31, 2019, the extended time limit for the initiative, and the scheme built is now capable of supplying vaccines for approximately 23 million people. Daiichi Sankyo sincerely apologizes for having been unable to build the required scheme in the timeframe allotted.
       (SNIP)
Daiichi Sankyo and Daiichi Sankyo Biotech will make efforts toward maintaining and managing a scheme that will be fully capable of supplying the required quantity of H5NI influenza vaccine necessary for when a pandemic breaks out, and will contribute to the health of people in Japan.

This illustrates that producing a pandemic flu vaccine in quantity, and in a timely manner - even when we are not hampered by an active pandemic - is easier said than done.
Non-influenza vaccines are even tougher to develop. 
Despite 16 years of research, there is still no commercially available SARS vaccine. Seven years after MERS emerged in the Middle East a vaccine remains elusive (see Middle East Respiratory Syndrome Vaccine Candidates: Cautious Optimism), and twenty years after its discovery, a Nipah vaccine is still in the works.
And of course, none of this takes into account the logistics (and politics) of distributing vaccine doses as lots are released, and actually delivering them to the arms of the public. 
While a pandemic vaccine might be available in limited quantities for a second or third wave, most people will have to get by without its protection for a year or longer (see CDC: 2018 Interim Guidance On Allocating & Targeting Pandemic Influenza Vaccine).

Although a vaccine may be vital to end a pandemic, the adoption of NPIs' - Non-pharmaceutical Interventions - will be critical to reduce the impact while we wait for its arrival (and for countries unlikely to see a vaccine at all).

The CDC’s Nonpharmaceutical Interventions (NPIs) webpage defines NPIs as:
Nonpharmaceutical interventions (NPIs) are actions, apart from getting vaccinated and taking medicine, that people and communities can take to help slow the spread of illnesses like influenza (flu). NPIs are also known as community mitigation strategies.
While telling people to wash their hands, cover their coughs, avoid crowds, and stay home while sick may seem like an inadequate response to a pandemic - they and other more disruptive measures like school closures, cancellation of public events, etc. - may prove to be our most powerful weapons in the opening months of a pandemic.
 






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