The following uses the US as its model but the information applies to all countries. Please feel free to add to this ongoing dialog. Many numbers are used in this article and they do change in time.

Too Little, Too Late or Too Much, Too Soon?

The Swine Flu Vaccine Quandary

Richard Price
Barbara Price
ASA/CBMTS

          Of major concerns to the ASA and CBMTS group of professionals, in over 125 countries, are possible pandemics and the resulting medical repercussions that may overwhelm each country's hospital and medical infrastructure, as well as civil services. Emergency and disaster medical planning for these situations are mandated for all, whether the situations are caused by war or terrorist or nature.

          Have our actions, our collective response for the new 2009 H1N1 Influenza A virus been too little, too late or too much, too soon? We will look at background, funding committed, questions raised, and remaining problems. We will also look at what other countries are doing and what the international vaccine developers/producers are doing on the business side of vaccines and other flu medications.

Background:

          The Department of Health and Human Services (HHS) in the US, and the Ministries of Health in other countries, work with and agree on the following for an overview or background for H1N1.

          The emergent 2009 H1N1 influenza virus is a novel virus with a proven major pandemic potential.

          For review purposes - vaccines are made from a virus or bacteria (referred to as an antigen), which cause the human body's immune system to develop antibodies against that specific virus or bacteria. Adjuvants may be added to a vaccine to help generate a stronger immune response with less vaccine needed. GSK believes that the addition of an adjuvant would also help to continue to provide protection even if the influenza strain were to drift slightly.

          When the 2009 H1N1 strain was isolated and identified as a novel influenza virus, work began to prepare a virus reference strain. This is standard practice when new influenza strains are discovered, where a clinical sample of the virus is mixed with another influenza virus to develop a new virus that has some properties of the novel virus, plus the ability to grow in chicken eggs. This work creates an influenza vaccine using conventional methods. When the virus reference strain is ready, it is made available to influenza vaccine manufacturers to create a master virus seed used in making the vaccine.

Swine Flu Vaccine and Antiviral Production Basics

          All major, and most smaller, vaccine producers are working 24/7 now and the major questions are who will be able to get what amount of vaccine or vaccine product and in what time frames? As Dr. Barbara Price pointed out in the ASA 09-3 on June 26, "... the concern is that when drugs are needed in a severe pandemic, where will the drugs go first? Will the population of the country in which the company is headquartered really permit drugs, intermediates, active pharmaceutical ingredients, or end product, to be shipped to another country before its own population is taken care of? Also will the EU permit shipments to outside of Europe before the needs of its 27 members are met?"

          Dramatically, since this note was posted in the ASA Newsletter, many others have asked the same question - including members of the US Congress. From an Associated Press release on 16 July "Experts warn that during a global epidemic, which the world is in now, governments may be under tremendous pressure to protect their own citizens first before allowing companies to ship doses of vaccine out of the country. That does not bode well for many nations, including the US, which typically makes only 20 percent of the seasonal flu vaccines it uses, or the UK, where all of its flu vaccines are produced abroad..." Experts say politicians would not be able to withstand the pressure. "The consequences of shipping vaccine to another country when your own people don't have it would be devastating," added David Fedson, a retired vaccine industry executive. About 70 percent of the world's existing flu vaccines are made in Europe, and only a handful of countries are self-sufficient in vaccines. The US has limited flu vaccine facilities, and because factories can't be built overnight, there is no immediate fix to boost vaccine supplies.

          To ensure Swine Flu vaccine is available as soon as possible, the European Medicines Agency is accelerating the approval process for the H1N1 flu vaccine by allowing companies to skip the normal initial testing in large numbers of people. Countries such as the UK, Greece, France and Sweden say they'll start using the vaccine as quickly as possible after approval and receipt of the vaccine product. The World Health Organization's flu chief warned of the potential dangers of untested vaccines, although he stopped short of outright criticizing Europe's approach. He pointed out that the safety of vaccines can not be compromised.

          Vaccine producers were initially getting much less product from growing the virus in eggs. The UK supposedly has developed a fix that will help decrease this production deficit. Another cause of worry is that the H1N1 flu appears to be much more virulent than seasonal flu. It appears to replicate in throat and lungs and cause more lung damage.

Tamiflu and Relenza antiviral drugs and resistance

          Although Tamiflu resistance has been found in normal seasonal flu cases, as well as a few Swine Flu cases, resistance to Relenza has only been found in the lab. But virologists worry that resistance in the lab could mean that antiviral-resistant viruses could spread rapidly around the world.

          Reference Tamiflu - actual virus resistant cases are a very minute number in comparison to the numbers of treatment regimens provided and used; however, the massive overuse of Tamiflu, which occurred in normal flu outbreaks, as well as an ill-conceived use as a preventative for early stage cases of Swine Flu, could in itself create an earlier resistance.

Swine Flu related pharmaceutical expenditures and commitments - US

          Within the US the HHS has committed funds for production of a bulk supply of antigen and adjuvant for use in vaccines for the 2009 H1N1. Vaccines produced become a part of the national stockpile of pandemic preparations. The HHS set aside 8.5 billion dollars for pandemic vaccines in preparation for a serious pandemic challenge. Of this amount, almost two billion have now been obligated to the giants of the vaccine industry, which unfortunately for the US, are primarily either located in or have their headquarters in off-shore locations. Funding by the HHS, or other agencies as noted, has been distributed as follows:

1. Astra Zeneca (UK) subsidiary Medimmune (US) - $300,000,000 for new vaccine order on 13 August plus $61,008,000 on 09 July for Bulk Virus Concentrate/FFF, plus $32,293,397. on 26 May to supply Influenza Vaccine for US Armed Forces and Federal Civil Agencies, plus $90,000,000 on 22 May for Bulk Vaccine Antigen
   (total = $483,301,397)
2. Glaxo Smith Kline (UK) - $38,000,000 for bulk vaccine antigen and $144,000,000 for Oil-in-Water Bulk Adjuvant on 22 May, plus $71,400,000 on 09 July for Oil-in-Water Bulk Adjuvant. (total = $253,400,000)
3. Novartis (Switzerland) - on 22 May for $150,000,000 for Bulk Vaccine Antigen and $139,000,000 for Oil-in-Water Bulk Adjuvant and $346,334,450 for Bulk Vaccine Antigen and $343,810,470. on 09 July. (total = $979,144,920)
4. Sanofi-Pasteur (sanofi-adventis-Paris, France) -$191,000,000 on 22 May for Bulk Vaccine Antigen, plus $12,368,596. on 26 May to supply influenza vaccine for US Armed Forces and Federal Civil Agencies, plus $61,425,000 on 09 July for Bulk Vaccine Antigen. (total = $264,793,596)
5. CSL Biotherapies, (Australia). $180,000,000 on 22 May for Bulk Vaccine Antigen (total = $180,000,000)

plus the following related buys:

1. Roche (Switzerland) 110,000 bottles of anti-viral drug Tamiflu (Oseltamiver Phosphate) for the H1N1 Virus; $2,212,600. (US Dept. of State)
2. AVI BioPharma, Corvallis, Oregon. Analyze H1N1 sequence, determine appropriate targets and identify lead and back-up candidate drugs and manufacture development grade material in sufficient quantities for planned animal tests and perform animal studies for lead and back-up candidate drugs; $5,100,000 on 22 June (DTRA-Ft. Belvoir)
3. Mystic Pharmaceuticals Inc., Austin, Texas. Commercialize technology for a precision and non-invasive drug delivery platform with intranasal and ophthalmic applications for vaccine delivery for biodefense and public health countermeasures; $1,560,000 on 07 May (Texas State Emerging Technology Fund-Austin)
4. Protein Sciences Corporation, Connecticut. Advanced development of recombinant influenza virus vaccines; $34,514,547 plus options (not to exceed $147,000,000) on 22 July. (BARDA/ASPR/DHHS)

          Recognize that with all of the US orders (above), plus other countries' orders (below), and with WHO tallying a manufacturing capacity of 94,000,000 doses per week starting in mid-October, based on estimates from 25 drug companies, the world may be in trouble if the pandemic does hit when expected. FiercePharma/Vaccine reports that reality has set in and the major makers report serious delays, with a new yield projection that is less than half of the original estimate. The manufacturers are keeping the stiff upper lip and all say they expect to deliver on time - or near on time. They collectively do not see bulk deliveries prior to October. And that is the earliest that testing can commence in the US, i.e., upon receipt of the bulk vaccine and adjuvant, which then must be bottled, packaged and delivered.

Asked if the Swine Flu virus could mutate, which could render ineffective the vaccines currently being prepared, Albert Garcia, an epidemiologist and flu vaccine specialist with Sanofi, said:"All flu viruses mutate and this happens very slowly. The H1N1 virus is being monitored. For the moment, it is continuing to progress but its virulence is still what it was a few weeks ago."

Other countries' efforts in pharmaceuticals and vaccine development/delivery/distribution in-country:

1. Australia. To provide for an additional 1,600,000 courses Relenza treatment for possible flu pandemic; $33,700,000 on 29 May to GlaxoSmith Kline, Australia. On 29 May the Government also ordered 10,000,000 H1N1 vaccine doses from CSL Ltd., Melbourne. According to FierceVaccines, Australia ordered 21,000,000 doses of Swine Flu vaccine from CSL on 20 August and plans the world's first mass vaccination campaign to get underway in a matter of weeks. The first shipment of 2,000,000 doses will have gone out the week of 24 August with pregnant women, the chronically ill and health workers at the front of the line.
             Another CSL order includes providing Novel A (H1N1) influenza vaccine antigen in bulk form to be manufactured in CSL's facilities in Parkville, Victoria Australia and destined for the US; $180,000,000 on 22 May - DHHS Washington.
2. Brazil. According to XinHua, Brazil has ordered 18,000,000 doses of Swine Flu vaccine and will start producing their own Swine Flu vaccine (30,000,000 doses) in October 2009 which will be based on virus samples provided by the WHO in early August, this year.
3. Canada. 50,400,000 doses Swine Flu Vaccine; $400,000,000 on 05 August to GlaxoSmithKline (Hq in UK) for manufacture at the GSK facility in Ste-Foy, Quebec, Canada. (Public Health Agency of Canada)
4. China. On 19 June China ordered 4,000,000 doses H1N1 vaccine from Sinovac Biotech. In a 21 August update China's Health Minister Chen Zhu says China will be able to produce enough influenza A(H1N1) vaccines for 65 million people by the end of this year. This is 5% of the populace. Vaccines will be first carried out among high risk groups and vulnerable people such as medics, the elderly and children.
   
5. Croatia. Has ordered 21,000,000 Swine Flu doses.
6. Czech Republic. Plans to contract with Novartis for initial vaccines for 2.5 million people.
   
7. Egypt. According to Egypt's Deputy Health Minister on 08 August, Egypt ordered 5,000,000 doses Swine Flu vaccine when the vaccine becomes available. This is sufficient for 2,500,000 (3.1%) of its 80,000,000 inhabitants - if two doses per individual are required.
8. France. According to Health Minister Roselyne Bachelot, France ordered 94,000,000 doses with option orders for another 44,000,000 doses of the H1N1 vaccine for $1,400,000,000 on 17 July. The orders are split between Sanofi-Adventis, GlaxoSmithKline and Novartis. France also ordered 28,000,000 doses A/H1N1 Influenza Vaccine to be manufactured in Val de Reiul, France; $ not provided on 25 July to Sanofi Pasteur, Paris. (French Ministry of Health)
9. Germany. Will start distributing the A/H1N1 flu vaccine in September and over fifty million people are expected to receive it. The German Health Ministry has said all Germans can take the vaccine voluntarily and the cost of the vaccine in 2009 will reach 600,000,000 Euros. The vaccine will first go to priority groups like chronically ill, pregnant women and health workers. Germany has purchased 50,000,000 doses and reserved another 82,000,000. 12,000 cases of A/H1N1 flu have been reported in the country, but there have been no related deaths.
10. Greece. Expects to vaccinate entire population - has ordered 8,000,000 doses from Novartis, GSK and Sanofi. Expects to order 16,000,000 more doses from the same 'big' three and has programmed 40,000,000 Euros for this effort.
11. Israel. The government has determined that Israel must have its own manufacturing facilities to ensure delivery of required doses. Some feel that any country where vaccines are produced will take care of its own needs first and countries without manufacturing capabilities will have to stand in line for their requirements. However, recognizing that vaccine manufacturing is not magic and that without current facilities, Israel is talking with Novartis, GSK, Sanofi, Baxter and Medimmune. Prime Minister Netanyahu has now ordered (29 July) $120,000,000 of the Swine Flu vaccine - enough vaccine for each inhabitant (6,250,000 ) to be vaccinated. The Prime Minister also is ordering that stockage of antiviral Tamiflu coverage to 35% of the population. (WHO recommends minimum of 25%)
12. Italy. Plans to vaccinate about 8,600,00 people, 15 per cent of the population, including medical personnel and other essential service personnel as well as those with chronic diseases with the H1N1 shot by the end of this year.
    
13. Netherlands. According to Dutch Health Minister Ab Klink, the Netherlands has ordered 34,000,000 vaccine doses against Swine Flu - enough for entire population.
14. New Zealand. 300,000 Doses Swine Flu Vaccine for New Zealand; $ not provided on 07 July to Baxter International Inc., Deerfield, Illinois USA (Hq) via Baxter Healthcare, New Zealand.
15. Qatar. Has ordered 500,000 doses Swine Flu vaccines from the World Health Organisation
16. Saudi Arabia. Has ordered 4,000,000 doses Swine Flu vaccine
17. Slovenia. Will buy 1,300,000 doses this year from the GlaxoSmithKline (UK) and Novartis (Switzerland) and will buy 400,000 doses in January 2010. for a total of $19,910,000 Slovenia will also buy 140,000 of GSK's Relenza treatments.
18. Switzerland. According to World Radio Switzerland - Switzerland will be among the first wave of countries to receive the H1N1 (Swine Flu) vaccine once it becomes available. There are 10 countries that are included in the first batch of deliveries, which are set to go out between September and October.
19. United Arab Emirates (UAE). Vaccination against swine flu will be mandatory and free of charge for all 630,000 students of private and public schools in the UAE when schools open in September, the director general of the Ministry of Health, Dr Ali Bin Shakar, has said.
20. United Kingdom. The UK had contracts signed with Baxter (72,000,000 doses) and GSK (60,000,000) and which were supposed to kick in when WHO announced Phase 6. And then on May 15, the UK government placed separate orders for a combined 90,000,000 doses (with no numbers breakdown by company). When the WHO announced the phase change, on June 11, these orders for 90,000,000 doses were superseded by the earlier contracts for 132,000,000 doses of vaccines. Because of yield problems, the UK was told by Baxter their orders would be arriving with less than expected doses. The UK, being amongst the most aggressive in the world with its determination to fight the Swine Flu, is continuing to work on plans for a nationwide vaccination campaign to cover the entire population.

Note: France, Sweden and the UK will begin their vaccine treatments as soon as supplies arrive. The US, which had expected to have 40,000,00 doses on hand in October, has a very cautious approach to vaccine development and administration, which although worthy in concept - may expose over 100,000,000 Americans to the pandemic.

and the individual industries and the business side of flu antiviral drugs and flu vaccines:

1. Baxter International Inc., US, has taken orders from five countries, including the UK, Ireland and New Zealand, for a total of 80,000,000 doses of H1N1 vaccine and will not take any more orders. They are maxed out on production capability. Although manufactured in the US, Baxter's Swine Flu vaccine, Celvapan, will not be sold within the US because with the laboriously slow US FDA approval process - Baxter's vaccine has not been approved for US distribution.
2. BioCryst, US, with Japan partner Shionogi have tested and report that their Swine Flu therapy Peramivir is proving to be very similar in results with the product of choice (to date) Tamiflu.
3. Biota Holdings, Australia, discovered zanamivir (Relenza), the first-in-class neuraminidase inhibitor for the treatment and prevention of influenza. Zanamivir is licensed to GSK and marketed as Relenza. GSK is responsible for the production, marketing and sales of Relenza. Biota plans to return $20,000,000 to its shareholders, after finding it has an overabundance of capital because Relenza sales increased dramatically.
4. CSL Ltd., Australia, has a contract to supply 21,000,000 doses to the Australian government and an order from the US for $180,000,000 of antigen and has orders from Singapore as well.
5. GlaxoSmithKline (GSK), UK, maker of the antiviral Relenza has taken orders for an additional 128,000,000 treatments. Sales have also increased from $5,000,000 last year to orders reaching $95,000,000+ this year. GSK had taken orders from nine governments for an added 96,000,000 vaccine doses and they are now committed to meeting 25 requests for 291,000,000 Swine Flu vaccine doses. They are also in discussions with over 40 countries. GSK with a possible $4,000,000,000+ in orders, is saying that although they expect to start shipping in September, they are unsure how quickly vaccine can be produced to fulfill their orders. GSK has recalled 160 of its earlier 'downsized' employees for positions at its French production facility. By mid-July GSK had already received orders for more than 195,000,000 vaccine doses and was in discussions with up to 50 more countries. GSK says it will donate 50,000,000 doses Swine Flu vaccine to the WHO for use in poorer countries. GSK has invested some 2,500,000 over the past few years in developing the technology and capacity for production of a pandemic vaccine and pandemic meds. Analysts believe that GSK will receive and fulfill some $5,000,000,000. in sales this pandemic flu season.
6. Medimmune, US, (subsidiary of AstraZeneca, UK) uses a nasal spray as delivery for its vaccines both regular flu as well as Swine Flu and feels it can produce 200 million Swine Flu doses - only problem is that it may be limited to delivery of 40 million doses because of not having enough spray devices. Medimmune's vaccine is made from the flu virus and has a stronger immune response. The required doses are also less in volume than normal neutralized virus.
7. Merck, US, almost as a side issue, may see a substantial increase in orders for their Pneumovax - Merck's pneumonia vaccine. Heart specialists are recommending their patients take the shot in hopes of avoiding the riskiest complication of the flu - pneumonia. This is particularly true in one third of the pneumonia-flu deaths, which are linked to the s. neumoniaea strain.
8. Novartis, Switzerland. The US has ordered $979 million worth of bulk vaccine and Novartis' adjuvant. Half of Novartis' vaccines being tested are grown in chicken eggs, the traditional way of making flu vaccines, while the other half use a new cell-based technology. Of special note is that Novartis did begin shipment of its 30,000,000 doses of seasonal flu vaccine (Fluvirin) to the US a few weeks early.
9. Roche, Switzerland, is looking at boosting Tamilflu sales by testing to see if larger doses for longer periods would boost effectiveness (and profits). Roche has donated 100,000 Tamiflu regimens for H1N1 treatment to the Government of India as H1N1 rapidly spreads throughout India.
10. Sanofi Pasteur, France, world's largest vaccine manufacturer, will make 28,000,000 doses in country (France) with a possibility of an optional 28,000,000 more.

          The problem for all could be in the shipping out of vaccines from manufacturing facilities of any manufacturer in any country across any borders, during a serious pandemic. If the country of manufacture feels it internally needs that vaccine product - forget all contracts to the contrary - they are very easily broken - and this is a FACT.

Added Notes:

• The US DHHS is providing $350,000,000 to US States to prepare for the Swine Flu. An example Virginia will get $8,800,000 for hospital and public health preparedness.
  
• On 06 May 2009 the FDA announced that Sanofi's new $150,000,000 vaccine production facility had been licensed for vaccine production. This is Sanofi's 145,000-square-foot manufacturing facility in Swiftwater, Pennsylvania.
  
• 18 Aug. WHO announces that orders from Northern Hemisphere countries for the Swine Flu vaccine have surpassed 1,000,000,000 doses. WHO earlier had said that the major producers could possibly produce 94,000,000 doses per week, starting in mid-October.
  
• 22 Aug. China notes that a single dose Swine Flu vaccine may be sufficient.
  
• 22 Aug. Bloomberg says Australia, Germany, UK and US have commenced Swine Flu vaccine trials in China.
  
• The US CDC reports that for the seasonal flu season of 2007/08, 140,600,000 doses vaccine were produced and this was up from the 120,900,000 vaccine doses produced for the previous flu year 2006/2007. And interestingly, only 61 million doses were produced in the 2004/2005 flu season.
  
• Five manufacturers were prime in these previous years (above): Sanofi, GSK, Novartis, CSL and Medimmune. Earlier in this report we provided these same five names - as prime for the 2009/2010 flu season - with the added production burden of Swine Flu vaccines.
  
• The 2009/2010 seasonal flu vaccine contains the following flu strains most likely to be circulating:
  
• an A/Brisbane/59/2007 (H1N1)-like virus.
  
• an A/Brisbane/10/2007 (H3N2)-like virus.
  
• a B/Brisbane/60/2008-like virus.
  
• The US FDA said the six manufactured seasonal flu vaccines for 2009-2010 are: Afluria, CSL Limited; Fluarix, GlaxoSmithKline Biologicals; FluLaval, ID Biomedical Corporation; Fluvirin, Novartis Vaccines and Diagnostics Limited; Fluzone, Sanofi Pasteur Inc.; and FluMist, MedImmune Vaccines Inc.

Too much too soon or too little too late: big questions

          The US has ordered over 200,000,000 doses of the Swine Flu vaccine. If the ordered vaccine works, and it has yet to be fully tested, and if the virus does not mutate into a more dangerous form - these orders for 200,000,000 doses would not be considered too much too soon. Would these orders be considered too little too late?

          If we found that more than one dose per individual were needed, and we had problems with receipt and distribution of product - both very big realities - we could be faced with having the "correct" vaccine but only enough vaccine for less than 50% of the population. We have to recognize that timing may only permit less than 25% of the population to be vaccinated in time, if receipt of product is stretched out over several months.
Assuming the correct formulation, receipt and distribution of product in a timely manner is the biggest hurdle - as indicated in previous paragraph. Upon receipt the vaccine must be tested, packaged and distributed - without glitch - which has yet to happen in any program at any time in any country.

          The testing and delay of vaccination may require the Secretary of the Department of Health and Human Services (HHS) to issue temporary emergency use authorizations (EUAs) in accordance with the Project BioShield Act - see page 18, second paragraph, of this ASA issue. In essence the EUA would permit distribution and use of vaccines without prior FDA approval and before complete testing and certification as to efficacy and safety.

          ASA/CBMTS applauds the efforts of the BARDA/ASPR/DHHS staff of professionals as well as the professionals in all countries who are attempting to prepare and respond to the possible Swine Flu pandemic - and, hopefully minimize its impact on the world populace.

For our Congressional readers, hopefully this is a wake up call and lessons learned on the consequences of permitting the industrial base of the most basic industries to be, or forced to be, off-shore because of supposed competitiveness. Let whomever - own, but keep the industry base at home.

For FDA - wake up.

This discussion will continue.

For the Professional in Government and Industry with an interest in Nuclear, Biological and Chemical Defense, Disarmament and Verification; Emergency and Disaster Medical Planning; Industrial Health and Safety; and Environmental Protection