Sunday, April 17, 2011

Unforgiving Numbers & Pandemic Vaccines

 

 

 

# 5499

 

 

In my last blog (see WHO Video: A Vaccine Story) I highlighted a short film from the World Health Organization (WHO) that showed their efforts to distribute roughly 78 million doses of pandemic vaccine to 77 developing countries.

 

While a laudable accomplishment, those numbers fell well short of what was initially hoped for (see WHO: Deploying Donated Vaccine As Soon As November  and  ECDC: Global Vaccine Goals And Realities).

 

They also fall far short of what would be needed should another – more virulent – pandemic virus emerge in the near future. 

 

Some of the obstacles faced by this vaccine distribution project were reported in last month’s IHR Review Committee Report On The Pandemic Of 2009 (reparagraphed for readability):

 

Despite the ultimate deployment of 78 million doses of pandemic influenza vaccine to 77 countries, numerous systemic difficulties impeded WHO’s ability to achieve a timely distribution of donated vaccines.

 

Negotiations over legal agreements with  manufacturers were protracted and in some cases unsuccessful. Excessive complexity in donor and recipient agreements hindered timely execution.

 

Obtaining regulatory approvals, dealing with liability concerns over vaccine used in recipient countries,  assuring maintenance of the cold chain throughout vaccine distribution and securing plans for local vaccine administration added to the delays.

 

These difficulties proved daunting in the midst of a pandemic; some could have been reduced by more concerted  preparation and arrangements in advance of a pandemic.

 


You’ll notice that this reports states that `some’ of these problems could have been reduced by better preparation. 

 

`Some’ . . . but certainly not all.

 

In recommendation # II of the above IHR report, the authors urge that the WHO:

 

Set up advance agreements for vaccine distribution  and delivery

In concert with efforts by Member States, and building on existing vaccine distribution systems, WHO should set up advance agreements with appropriate agencies and authorities in Member States, vaccine manufacturers and other relevant parties that would facilitate approval and delivery of pandemic vaccines to low-resource countries, to increase equity in supply and support advance planning for administration of vaccines.

 

 

And indeed, a step in this direction came this week when the WHO and member states agreed on a framework for the sharing of virus samples (see CIDRAP On Virus-sharing, Pandemic Vaccine Access).

 

The newly brokered deal reportedly reserves a percentage of vaccine production for developing nations in exchange for access to virus samples.

 

But in a world of nearly 7 billion people - all of whom would be at risk from a virulent and fast moving novel pandemic virus - our ability to manufacture and (just as importantly) distribute a pandemic vaccine in a timely fashion remains severely limited.

 

And frankly, most of these limitations are far beyond the control of the World Health Organization, or any other organization, agency, or government.

 

It is really a matter of unforgiving numbers.

 

Numbers that start with billions of people at risk from a novel virus, and end with the number of doses of vaccine that can be delivered in a short period of time.

 

Using current egg-based technology it takes about 6 months from the time a virus is identified to the time that the first vaccines begin to roll off the assembly line.

 

And that assumes the virus grows well.

 

During that period of time, as we saw in 2009, a pandemic virus can easily spread around the globe largely negating the benefits of a vaccine.

 

Newer technologies, such as cell-based technology (see Lancet: Efficacy, Safety & Immunogenicity Of Cell Based Vaccine), hold some promise to shave a month or two off these times (if widely adopted), but would do little to reduce the many of the other difficulties of distribution.

 

One of the most vexing problems – particularly in developing nations - is the maintenance of a `cold chain’, where vaccines must be continually stored at 35° to 46°F (2° to 8°C).

 

Places without reliable electricity are particularly problematic.  Research on Shelf Stable Vaccines for influenza are ongoing, but we aren’t there yet. 

 

But even if the vaccines (and syringes and other necessary supplies) were available, simply administering vaccines to billions of people (many of whom may require two doses a month apart) over a matter of a few months is a daunting, perhaps even impossible task.

 

Despite these known obstacles, in the three years leading up to the 2009 Pandemic we saw a number of optimistic projections of global vaccine production. 

 

The trouble with these forecasts, even when you label a projection a `best-case’ scenario, is that most people will come to expect that result.

 

In September of  2006 the WHO released their Global Action Plan (GAP) for vaccine production titled:

 

Global pandemic influenza action plan to increase vaccine supply [pdf 510kb]

 

One of their short-term objectives was stated as having enough vaccine to immunize 2 billion people within the first 6 months of an influenza outbreak.

 

image

 

In October of 2007, the WHO released an optimistic assessment of vaccine manufacturing prospects by the year 2010 (see Projected supply of pandemic influenza vaccine sharply increases) that stated:

 

Experts now anticipate that global production capacity will rise to 4.5 billion pandemic immunization courses per year in 2010.

 

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, gave a more measured estimate (via CIDRAP Experts to discuss swine flu vaccine decision May 14) of global vaccine production; somewhere between 1 billion and 2 billion doses in a year.

 

But at almost the same time, a far more aggressive manufacturing projection came from 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.

 

 

Things did not go nearly as well as projected and as you can see by the chart below, the actual global production of pandemic vaccine fell well short of these estimates.

 

image

In all fairness, the yield from the seed virus proved less than anticipated and the use of adjuvants – planned to help reduce the amount of antigen needed per shot – was met with public resistance.

 

On the plus side (and this isn’t well appreciated), the vaccine that was eventually produced came off the assembly line a few weeks sooner than expected (albeit in small quantities), and has proven to be both safe and effective.

 

Which has to be viewed as a considerable victory for all parties involved, even if the ultimate number of doses produced was less than hoped.

 

The irony of all of this is that delays in getting the vaccine deployed, negative publicity about the vaccine, and the perception by the public that the H1N1 virus was relatively `mild’ led to many doses of the H1N1 vaccine to go unused.

 

The next time, however, we may not be as lucky. 

 

Vaccines remain one of our best defenses against the seasonal influenza virus, but the reality is that during a pandemic, vaccines are not going to be a panacea.

 

They will be in short supply - in all probability for the duration of the crisis.

 

Richer countries will no doubt see vaccines sooner, and in greater quantity, than will poorer nations.  But even economically advantaged, vaccine-producing countries may not see vaccines soon enough, or in great enough quantity, to blunt a pandemic outbreak.

 

For most of the world’s population, the use of NPIs (Non Pharmaceutical Interventions) will be their first and for many: only – protection against an emerging pandemic virus.

 

NPI’s can be as simple as hand hygiene, covering your coughs, and avoiding crowds, or can involve the use of personal protective barriers like N95 or surgical masks, latex or vinyl gloves, and eye protection.

 

School closures, public education, staying home when sick, and engineered barriers to avoid exposure are also examples of NPIs.

 

None of which is to suggest that vaccines shouldn’t be a priority, or that we shouldn’t be investing in greater production capacity. 

 

We should. 

 

Vaccines will save lives during a severe pandemic, and help stop its spread; once they can be deployed.

 

But getting them into the arms of billions of people is a enormously complex task.  

 

One that – despite the best efforts of the World Health Organization, the HHS, CDC, and other public health agencies – would be unreasonable to expect will come about flawlessly or without delays.

 

For more on the difficulties of producing a pandemic vaccine, we turn to Maryn McKenna.

 

Three and a half years after she first wrote it, there is probably no better overview of the problems inherent in the creation, production, and distribution of a vaccine than her award winning 7-part series the Pandemic Vaccine Puzzle which she penned in 2007 for CIDRAP.

 

Part 1: Flu research: a legacy of neglect
Part 2: Vaccine production capacity falls far short
Part 3: H5N1 poses major immunologic challenges
Part 4: The promise and problems of adjuvants
Part 5: What role for prepandemic vaccination?
Part 6: Looking to novel vaccine technologies
Part 7: Time for a vaccine 'Manhattan Project'?
Bibliography

 

Well worth revisiting.

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