Vaccine Investigations.....Raw Data Thread

[Commonground]

I'm putting this here, so I can study what I have gathered. These are all excerpts. I think, right now, before I study this, that there is going to be a greater delay in the Seasonal Flu vaccines.



Glaxo Has Pandemic Swine Flu Orders Totalling 440 Million Shots
October 6, 2009 02:08 EDT

Oct. 6 (Bloomberg) -- GlaxoSmithKline Plc received 22 government orders for pandemic swine flu vaccine since Aug. 4, bringing the total to 440 million shots. The U.K. drugmaker will start shipping the first supplies this week.
http://www.bloomberg.com/apps/news?pid=20601202&sid=ahEa7KNOxFvQ



Swine Flu Vaccine APPROVED
09/15/09

Then about 45 million doses should arrive around Oct. 15, followed by more shipments each week.
The government has ordered 195 million doses...
http://www.huffingtonpost.com/2009/09/15/swine-flu-vaccine-approve_n_287526.html



FDA Approves Vaccine for 2009-2010 Seasonal Influenza
July 20, 2009

The U.S. Food and Drug Administration today announced that it has approved a vaccine for 2009-2010 seasonal influenza in the United States.
The six vaccine brand names and manufacturers 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.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm172772.htm


U.S. orders lots more swine flu vaccine
Sept. 21, 2009
bringing the nation's eventual total to 251 million doses.

The government on Monday ordered an extra 27.3 million doses from Sanofi Pasteur of France, which produces flu shots at its Swiftwater, Pa., factory. It also ordered 29 million more doses of the nasal-spray version of swine flu vaccine, MedImmune LLC's FluMist.

The news came as health officials announced Monday that while people 10 and older are protected by one dose of swine flu vaccine, children 9 and younger almost certainly will need two.
http://www.msnbc.msn.com/id/32956901/ns/health-swine_flu/


Seasonal flu vaccine delivery delayed
September 18, 2009

?Unfortunately, we have recently learned . . . that the scheduled delivery for the remaining doses of seasonal flu vaccine will not be as accelerated as originally anticipated, due to prioritization of [swine flu] vaccine and other challenges,??

?Every flu season has challenges, and this one is not without its challenges,?? said Donna Cary, a spokeswoman for the biggest maker of seasonal vaccine, Sanofi Pasteur. ?We thought we had accommodated for that, but in addition to the low yielding ?B? strain, we?re also producing the pandemic vaccine, and producing both in one year limits our flexibility in scheduling shipments.??

Massachusetts, one of the biggest government buyers of flu vaccine in the nation, had placed orders for 880,000 seasonal flu doses. So far, the state has distributed close to 400,000 doses to doctors and clinics, and 100,000 more are expected in about a week, said John Auerbach, state commissioner of public health.

...Joe Quimby, a spokesman for the US Centers for Disease Control and Prevention. ?But all of the 115 million doses of seasonal influenza vaccine are on schedule for distribution in the states by mid-November.??
http://www.boston.com/news/local/ma...8/seasonal_flu_shot_delivery_delayed_in_mass/


Demand for swine-flu vaccine puts seasonal-flu clinics on hold
September 26, 2009

Seasonal-flu clinics scheduled for parts of southern New Jersey have been postponed as the vaccine's manufacturers concentrate on developing a vaccine for the H1N1 influenza virus, better known as swine flu.

Diamond said the county received about 50 percent of its entire order before the season began. The county was told by the seasonal flu vaccine's manufacturer, Sanofi Pasteur, that the company "is having problems fulfilling its orders as a result of interruptions caused by the production of the H1N1 vaccine," a release from the county states.

The federal government wanted 114 million doses of the seasonal flu vaccine produced among five manufacturers. Sanofi Pasteur is the largest seasonal flu vaccine manufacturer this year, expecting to produce 50.5 million doses in total, Sanofi spokeswoman Donna Cary said.
http://www.pressofatlanticcity.com/...cle_c1d8cc86-c0b3-5f32-9813-6dfde1c70524.html

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

discussion always welcome

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

Tally of SF doses

10/6 - 440 million
9/21 - 251 million
9/15 - vaccine approved
9/15 - 195 million


8/4 - Orders received for GlaxoSmithKline
10/6 - GlaxoSmithKline starts shipping first supplies

Seasonal Flu:
The six vaccine brand names and manufacturers 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.

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

Are all these companies that are producing the seasonal flu vax, also producing the SF vax?

If not, there should not be a delay. You would have to know what the contract specs are for each company on their individual allotment.

Is it normal protocal to order vaccine from a company BEFORE it gets approved?

We have more than doubled our orders since 9/15 for SF vax.

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

Is it normal protocal to order vaccine from a company BEFORE it gets approved?

MedImmune Receives U.S. Government Order for Additional 29 Million Doses of Nasal Spray Vaccine for 2009 H1N1 Influenza
September 21, 2009
GAITHERSBURG, MD, Sept. 21 ? MedImmune announced today that the U.S. Department of Health and Human Services (HHS) has placed an order for an additional 29 million doses of its live attenuated influenza vaccine (LAIV) against the 2009 H1N1 influenza virus. This brings HHS orders to date to more than 40 million vaccine doses, with a total cumulative contract value of approximately $453 million. Previous HHS orders for approximately 13 million doses of LAIV for the 2009 H1N1 strain were placed in May and July.

MedImmune?s development of LAIV for this strain of H1N1 began at the end of April, when the company received the novel virus from the U.S. Centers for Disease Control and Prevention (CDC). Enough bulk vaccine to fill all orders placed by HHS has already been manufactured and about 3.4 million doses have been released by the FDA.
http://pressroom.medimmune.com/pres...-nasal-spray-vaccine-for-2009-h1n1-influenza/

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

Med Immune
September 21st

This is Med Immune's third contract since the spring and summer, when the federal health department ordered a total 13 million doses from the local biotech, which is owned by London-based Astra Zeneca PLC. Also on Monday, the federal government ordered an extra 27.3 million doses of the H1N1 flu vaccine from Sanofi Pasteur of France, which produces flu shots at its factory in Swiftwater, Pa, bringing the U.S. eventual total to 251 million doses.
Earlier this year, the federal Centers for Disease Control and Prevention (CDC) said the government had ordered a total of 195 million doses of the H1N1 flu vaccine from five companies including the above-mentioned two.



http://news.xinhuanet.com/english/2009-09/22/content_12093548.htm

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

Are all these companies that are producing the seasonal flu vax, also producing the SF vax?

Bolded are also producing SF vax:

Seasonal Flu:
The six vaccine brand names and manufacturers 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.

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

Med Immune
September 21st

This is Med Immune's third contract since the spring and summer, when the federal health department ordered a total 13 million doses from the local biotech, which is owned by London-based Astra Zeneca PLC. Also on Monday, the federal government ordered an extra 27.3 million doses of the H1N1 flu vaccine from Sanofi Pasteur of France, which produces flu shots at its factory in Swiftwater, Pa, bringing the U.S. eventual total to 251 million doses.
Earlier this year, the federal Centers for Disease Control and Prevention (CDC) said the government had ordered a total of 195 million doses of the H1N1 flu vaccine from five companies including the above-mentioned two.



http://news.xinhuanet.com/english/2009-09/22/content_12093548.htm

As usual, numbers are not the same.....

Sanofi Pasteur:
September 21st

The company also said Monday that it had received a new order from the U.S. Department of Health and Human Services to produce the equivalent of 27.3 million doses, bringing the total U.S. order to 75.3 million doses from the drug maker, the news service said.

http://www.nlm.nih.gov/medlineplus/news/fullstory_89614.html

 

[Vibrant62]

Re: Vaccine Orders -

Re: Vaccine Orders -

Do we have any idea of vaccine orders by country/ manufacturer anywhere - I have been trying to find out this information, not least because there seems to be a lot of spin over the numbers... there is also the interesting question of what happens to next years seasonal vax if manufacturers are still churning out pandemic vaccination - or this could be put into the trivalent seasonal manufacture - but if this is the case, what happens to the pandemic vaccine orders that remain outstanding? They will need to make a decision on this relatively soon, as seasonal/ trivalent manufacture should start by January

It would be interesting to get a handle on this...

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

They started producing the Seasonal Flu Vaccine earlier this year....but they still ran into production output problems this Fall.

Seasonal Flu Vaccine Shipping Early
Thursday, August 06, 2009

TRENTON, N.J. - The swine flu pandemic is spurring makers of seasonal flu vaccines to ship them to the U.S. market well ahead of schedule, and supplies are tightening as distributors and others snap up vaccine vials.

The top U.S. supplier of flu vaccine, Sanofi Pasteur, stopped taking orders for 10-dose vials of Fluzone, which make up about 60 percent of its production, on June 19, spokesman Len Lavenda said Wednesday.

"Last year, we had them available through Thanksgiving," Lavenda told The Associated Press. "That's a huge difference."

Sanofi, Novartis AG and GlaxoSmithKline PLC all have begun shipments of seasonal flu vaccine earlier than usual, with Glaxo and Novartis both starting shipments Wednesday and Sanofi on July 27. Novartis said it was starting "weeks ahead of schedule;" Sanofi is about two weeks early, and Glaxo is a little ahead of its normal mid-August start.

Swine Flu Pandemic Increases Demand

The companies cite expectations of increased demand due to concerns about the global swine flu pandemic, plus the need to clear the deck for making swine flu vaccine. Also, doctors and clinics will face quite a challenge in trying to vaccinate patients first against seasonal flu and then give what is expected to be a series of two shots against swine flu.

Despite the early shipments and apparent heavy demand, there is no need for people who want a seasonal flu vaccine to panic, said Dr. Henry Bernstein, a member of the American Academy of Pediatrics' committee on infectious diseases.

"I think there's going to be a more than adequate supply to administer the vaccine to everyone that wants it," Bernstein said.

When swine flu, or novel H1N1 influenza, first surfaced this spring, flu vaccine makers said they were worried about being able to make enough of two different vaccines, one against the new strain and one against the three strains of seasonal flu expected to circulate.

Companies Rising to the Challenge

But the companies appear to have risen to the challenge - although Glaxo has had technical problems that will reduce its expected production from about 27.5 million to 20 million doses.

Sanofi Pasteur of Swiftwater, Pa., part of French drug giant Sanofi-Aventis SA, had a little luck this year: It just got a new manufacturing plant in Swiftwater, in the Pocono Mountains, approved in May. Instead of closing the older one for a planned renovation, it has been running both factories "24 hours a day, seven days a week," Lavenda said, noting the company has hired about 200 additional workers there and is looking for more for the two plants.

"One is making seasonal [vaccine] and the other is making H1N1" concentrate in bulk, he said.

Production of the H1N1 vaccine began back in June, after the Centers for Disease Control and Prevention supplied manufacturers with virus samples needed to begin growing the H1N1 virus in eggs. Once the federal government tells vaccine makers the exact dose to be in each shot, it can be packaged into vials or syringes and labeled for shipment, Lavenda said.

Sanofi Pasteur is producing about 50 million doses for the U.S. market, the same as last year.

Switzerland's Novartis started production earlier than usual this year, according to spokeswoman Beth Birke.

'Accelerated Efforts Tremendously'

"We have accelerated our efforts tremendously," Birke said in an e-mail, increasing resources "to ensure seasonal supply and our ability to expeditiously switch over to H1N1."

The company plans to supply 30 million doses of its Fluvirin vaccine.

GlaxoSmithKline started shipping its Flulaval vaccine Wednesday and will soon start shipping another one called Fluarix. It had a lower-than-expected yield of one of the vaccine strains, and has had to tell customers it can't fill all their orders.

One is Henry Schein PLC, believed to be the largest supplier to doctors' offices. Schein now expects to get 9 million instead of 13 million doses, but Executive Vice President Steven Paladino said it may try to get more later in the season.

"We've seen very strong demand from our customer base," he said, citing awareness of swine flu.

Nasal Spray Vaccine

MedImmune, an AstraZeneca PLC subsidiary that sells a nasal spray seasonal flu vaccine, started shipments on July 28, about normal for the company. It plans to distribute about 10 million doses.

The Food and Drug Administration said Wednesday it has cleared a total of 70 lots of flu vaccine, made by five different manufacturers, for distribution. Lots typically range from 500,000 to 600,000 doses each, meaning roughly 38.5 million doses already have been cleared. About 120 million doses are expected to be available this year.

Dr. Jonathan Temte, a family physician at the University of Wisconsin at Madison and a member of the federal Advisory Committee on Immunization Practices, said much of the flu vaccine supply is routinely ordered early in the year, but he thinks large HMOs, university clinics and drugstore chains have been making big orders to get patients in early.

Doctors, other providers and schools will have to work together and start seasonal flu vaccines in August or September, ahead of the usual schedule of October or November, to handle the logistical difficulties of two types of flu vaccines, Temte said.

"We don't know how to ratchet up the system" to do that, he said.

http://www.cbn.com/cbnnews/healthscience/2009/August/Seasonal-Flu-Vaccine-Shipping-Early/

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

Sanofi Pasteur
August 6th

Sanofi Pasteur started shipping on July 27th. 2 weeks earlier than usual.
They stopped taking orders on June 19th, for their Fluzone, which makes up 60% of their production.
Last year they took order until Thanksgiving.
Produces 50 million doses for the US. Same amount they produced last year.

Sanofi Pasteur
September 18th

“Every flu season has challenges, and this one is not without its challenges,’’ said Donna Cary, a spokeswoman for the biggest maker of seasonal vaccine, Sanofi Pasteur. “We thought we had accommodated for that, but in addition to the low yielding ‘B’ strain, we’re also producing the pandemic vaccine, and producing both in one year limits our flexibility in scheduling shipments.’’

Sanofi Pasteur
September 26th

Diamond said the county received about 50 percent of its entire order before the season began. The county was told by the seasonal flu vaccine's manufacturer, Sanofi Pasteur, that the company "is having problems fulfilling its orders as a result of interruptions caused by the production of the H1N1 vaccine," a release from the county states.
The federal government wanted 114 million doses of the seasonal flu vaccine produced among five manufacturers. Sanofi Pasteur is the largest seasonal flu vaccine manufacturer this year, expecting to produce 50.5 million doses in total, Sanofi spokeswoman Donna Cary said.

They stopped taking orders as of June 19th. It wasn't the "interruption" caused by H1N1 vaccine....it could be because they could not meet the quota by June 19th, due to a low yield of the "B" strain.....

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

GlaxoSmithKline update: Government orders for pandemic (H1N1) 2009 vaccine


Issued: Tuesday 06 October 2009, London, UK
GSK is committed to supporting governments and health authorities around the world respond to the pandemic (H1N1) 2009 influenza strain.
The company today provided an update on orders received for its pandemic (H1N1) adjuvanted vaccine.

On the 4th August, GSK confirmed that it had contracts in place to supply 291 million doses of the vaccine and had a variety of agreements in place with the US Government to supply pandemic products worth $250 million.
-snip-
First supplies of the vaccine will be shipped to governments during the week commencing 5th October. Shipments of the vaccine will be delivered in both the fourth quarter of 2009 and the first half of 2010.
The vaccine deliveries are contingent on a number of factors including government import/export regulations, regulatory approvals, approvals for outsourced packaging and filling as well as testing required by reference laboratories.
-snip-
http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10104.htm


APPENDIX B
H1N1 COUNTERMEASURES STRATEGY AND
DECISION-MAKING FORUM
DETAILED REPORT
PANDEMIC INFLUENZA WORKING GROUP (PIWG)
NATIONAL BIODEFENSE SCIENCE BOARD
JULY 2009

Excerpt:
Manufacturers? Vaccine Development Plans
GlaxoSmithKline?Bruce Innis, M.D.
The H1N1 vaccine that GSK proposes to manufacture is monovalent and incorporates a vaccine strain recommended by WHO. The standard dose is 3.75 micrograms of hemaglutination administered twice, 21 days apart. The antigen comes in a 10-dose vial with a thimerosal preservative and is mixed before injection with AS03, a tocopherol based emulsion adjuvant system also presented a 10-dose vial. The adjuvant is manufactured in Belgium and the United States; the antigen is manufactured in Dresden
(D) and Quebec (Q); the processes differ depending on the location.
GSK?s Dresden-manufactured H5N1 vaccine is approved in the European Union (EU), Australia, Singapore, Malaysia, and Hong Kong. GSK plans to submit the QH5N1/

AS03 vaccine for approval in Canada and the United States in 2009. The company has clinical data from 3,500 adults, ages 18?93 years, and a safety summary from approximately 9,900 adults, including completed studies with the Dresden vaccine. GSK believes the data are sufficient to support use of the H1N1/AS03 vaccine under an EUA and eventually licensure.

Clinical data suggest that the Dresden- and Quebec-manufactured H5N1 antigens plus adjuvant have equivalent immunogenicity. Current plans permit GSK to initiate clinical trials of a Dresden-produced H1N1 pandemic vaccine several weeks before trials of the Quebec product. Dr. Innis noted that early data from the Dresden vaccine can guide emergency use of the Quebec product. The H5N1 vaccine is highly immunogenic in children and adults and even in the elderly, despite prior TIV vaccination. These responses greatly exceed the thresholds for seroconversion mandated by CBER in its guidance.

The correlates of immunity against pandemic influenza A are unknown. Therefore, GSK has investigated the effect of its adjuvant on cell-mediated as well as humoral immunity. The company?s evidence shows that the adjuvanted H5N1 vaccine generates better T and B cell memory than unadjuvanted vaccine.

Immunization with the H5N1 vaccine is protective. In ferrets administered a range of doses of adjuvanted vaccine or control vaccine on days 0 and 21 and challenged 4 weeks later, all the controls died, and 22/23 animals receiving the adjuvanted vaccine survived. Moreover, the adjuvanted vaccine reduced the amount of virus in the subjects? lung tissue by at least 3.5 logs compared with controls. Immunity elicited by the H5N1 vaccine protects against severe disease and is likely to reduce virus shedding, potentially reducing virus transmission.

Although two doses of vaccine are required, the GSK H5N1/AS03 vaccine can be administered as two injections in separate extremities at a single visit and still achieve protection. This approach saves both time and antigen.

Vaccine with the AS03 adjuvant is a new product, and GSK has made unparalleled efforts prelicensure to evaluate its safety. The company has compiled safety data from adults in eight completed trials of H5N1/AS03 vaccine manufactured in Quebec or Dresden. Subjects were followed for 6 months after vaccination. Rates of medically attended and serious adverse events were comparable between the vaccine and controls. The total number of adverse events with adjuvanted vaccine is slightly higher than the total for controls because of increased reports of reactogenicity during the days immediately following vaccination. These events were predominantly mild and transient. There was no escalation with the second dose, and compliance in receiving the second dose was above 95%.
GSK agreed with CBER to query the data for a list of 120 immune-mediated diseases, called adverse events of special interest (AESIs). There were 16 AESIs in the H5 group and one among the controls (p > 0.2).
GSK ran the same query on a pooled database of 11,721 subjects enrolled in five clinical trials of TIV conducted by GSK since 2004. Comparing the data demonstrates that the events reported more than once in the H5 group also appear in the TIV control group. These data provide no evidence for an association of any single event or of this class of events with the H5N1/AS03 vaccine.

GSK?s safety summary supports a favorable risk-benefit profile for AS03-adjuvanted influenza vaccines and additional trial data are forthcoming. GSK has investigated two reports of asymptomatic autoimmune hepatitis. In case 1 (a child) the condition existed before vaccination and is in remission following treatment. In case 2 (an adult), the condition resolved spontaneously, and experts have cast doubt on the diagnosis.

Since September 2008, GSK has been following a cohort of 43,000 elderly subjects vaccinated with TIV/AS03 or control, and their safety data are being reviewed by an Independent Data Monitoring Committee. GSK recently expanded the pooling of safety data to include recipients of any influenza vaccine with AS03. Results from this analysis of 20,500 adults exposed to AS03 will become available in July.

The planned clinical development of H1N1 vaccine with AS03 includes at least 13 trials of D- or Q-H1N1 vaccine in the United States and Canada or in Europe, with over 5,000 children and adults exposed to adjuvanted vaccine. The trials performed under an investigational new drug application (IND) are all randomized, blinded trials using antigen-only vaccine as a control. The adjuvanted vaccine will be evaluated simultaneously in children and adults. The trials will evaluate the benefit of the adjuvant in terms of dose-sparing, efficacy, and immunogenicity compared with antigen-only vaccine, and the two-dose, one-visit schedule. The possibility of interference between TIV and the pandemic vaccine will be evaluated when these products are coadministered or given sequentially. GSK will assess whether AS03 can overcome interference and will also confirm the equivalent immunogenicity between D and Q products. GSK will rapidly expand the safety database for this new vaccine. By December, the Company anticipates that 4,340 subjects will have been exposed to H1N1/AS03 in a GSK trial.

Because the use of a novel adjuvant raises questions that can be addressed best by long-term follow up, GSK is discussing with HHS the need for a large, simple safety study involving, for instance, 40,000 persons who would be followed for up to two years after vaccination.
If a potency reagent is available in early August, the product could be ready for clinical trials in early September, and the first data would be available in November. Pilot data from GSK's smaller trials in Europe, including interim analyses after administration of dose 1 (in a 2-dose schedule), could be available somewhat earlier, in October.

http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf


http://www.gsk.com/media/pandemic-flu.htm

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

APPENDIX B
H1N1 COUNTERMEASURES STRATEGY AND
DECISION-MAKING FORUM
DETAILED REPORT
PANDEMIC INFLUENZA WORKING GROUP (PIWG)
NATIONAL BIODEFENSE SCIENCE BOARD
JULY 2009

Production Options....
Excerpt:

NOVEL H1N1 VACCINE STRATEGY H1N1 Vaccine Strategy
—Robin Robinson, Ph.D., BARDA

Dr. Robinson said a convergence of events led to the development of the National Strategy for Pandemic Influenza: the H5N1 virus reemerged, and surprising results from clinical studies showed that the H5 vaccine developed would not protect 90% of the people. Hurricane Katrina exposed significant gaps in disaster response planning and capacity. Having only one manufacturer to produce seasonal influenza vaccine (for the 2004–2005 season) demonstrated what a vaccine shortage would be like. With all of these events happening in the early part of the decade, and 29 years after the 1976 swine influenza epidemic, Congress passed PAHPA and established BARDA to develop countermeasures. The Federal effort was energized with a new plan, funding, and a critical mass of people dedicated to addressing the potential for a pandemic.

The National Strategy describes two critical goals for use of vaccines for pandemic influenza:

Goal #1: Establish and maintain a dynamic prepandemic influenza vaccine stockpile available for 20 million persons (2 doses/person).

Goal #2: Provide pandemic vaccine to all U.S. citizens within 6 months of a pandemic declaration (600 million doses).

Previous planning assumptions set a total production goal of 100 million doses of vaccine for a pandemic. Now, however, the expectation is to produce 600 million doses. Dr. Robinson said the key question is, “What do you want and when?” The production capacity for 2009 is much different than in 2005, so BARDA has had to adjust its vaccine distribution planning. The strategic approach for H5N1 vaccine included some flexibility; going forward, as clinical studies provide more information, it will be important to be able to make changes.

The FDA may consider licensing vaccines that do not include adjuvants as the virus strain changes. Adjuvants that do not achieve licenses would need to be approved by the FDA under and emergency use authorization (EUA); pending information on how they would be used, who would receive them, and how they mitigate morbidity and mortality. The FDA has created templates and “pre-EUA” packages to speed up the process.
The key decision points for the Federal vaccine enterprise continue to be: what type of vaccine will be used, whether vaccines will include thimerosal as a preservative, whether adjuvant will be used, and how adverse event safety monitoring will be undertaken after immunization.

Dr. Robinson described three production options:
Plan A—vaccine with no adjuvant; Plan B—vaccine with one adjuvant; and Plan A/B—use of vaccine with and without adjuvant, as available.

He noted that planning assumes a resurgence of H1N1 on September 15, with the first vaccine available in October. According to projections, manufacturers could provide 150 million doses of a vaccine with no adjuvant (Plan A) in October, and 80 million doses per month from November through March.

With Plan B, 312 million doses of adjuvanted vaccine would be available in October, 160 million doses in November, and 120 million doses in December. Dr. Robinson said such a large supply could overwhelm the system under the current planning assumptions, so it would be necessary to revise the strategy.

The combination plan (Plan A/B) would allot some antigen-only vaccine for special populations, such as children, early in the season. Others could receive adjuvanted vaccine if they give informed consent. The amount of vaccine available would be similar to that in Plan B.

Vaccine may take the form of a nasal spray, prefilled syringes, or 10-dose vials of antigen and 10-dose vials of adjuvant that could be combined manually. The total vaccine output by manufacturer is projected as follows:
. Novartis: 45.7%
. Sanofi Pasteur (vial plus syringe): 26.4%
. CSL: 18.7%
. MedImmune (nasal spray): 5.8%
. GlaxoSmithKline (GSK): 3.4%

-snip-

Discussion (paraphrased)1

Tim Gallagher: Do you anticipate an increased demand for seasonal influenza vaccine?

Dr. Robinson: We’ve taken that into account, and the amount of seasonal vaccine may reflect an increased demand.

Kathy Neuzil, M.D., M.P.H.: I would like to see this strategy applied to seasonal influenza. I think the theme of today is that we can’t look at H1N1 in isolation but rather should look at how it intersects with seasonal influenza in terms of immunogenicity, distribution, antigenicity, etc.

Dr. Robinson: We are working with manufacturers, talking with CDC and others, engaging in meetings like this and others, but the clock is ticking, and we need to decide soon. Some manufacturers have not finished production of their seasonal influenza vaccine yet, but it’s not interfering now. It would take another level of coordination, but it’s worth discussing further.

Dr. Neuzil: The Advisory Committee on Immunization Practices (ACIP) has worked hard to evaluate risk groups and has included more people in its seasonal influenza vaccine recommendations. This will be the first year of full implementation of our recommendations for pediatric patients. It’s important to be careful about messaging, especially if there are different target groups. There is potential for confusion—there’s always confusion about vaccines. Our compromise with the American Academy of Pediatrics was to recommend that children get two doses of seasonal influenza vaccine in the first year that they are vaccinated. Does H1N1 vaccine count toward that? Should they get two doses of seasonal vaccine also? You can see how the decision on H1N1 will affect our implementation.

Dr. Pavia: Given the data needed to make recommendations, and what’s been done in clinical trials so far, the concept of priming patients for seasonal influenza and novel H1N1 adds another level of complexity.

[Unidentified]: Can we reach the goal of 600 million doses?

Dr. Robinson: We have been able to cobble together with the manufacturers the capacity to get that.

[Unidentified]: When does the six-month clock start? October?

Dr. Robinson: May. That’s our assumption. On May 22, the Secretary put the pandemic influenza money toward vaccine development.

[Unidentified]: Is it possible to get more product before October?

Dr. Robinson: Maybe we could have some in July, but what amount of antigen should it contain? How much adjuvant? We could make blind decisions, but we want science informing us where possible.



1 This and subsequent discussions paraphrase the questions and comments of the participants. This document does not represent a verbatim transcript.
http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

From Post #1:

The U.S. Food and Drug Administration today announced that it has approved a vaccine for 2009-2010 seasonal influenza in the United States.
The six vaccine brand names and manufacturers 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.

APPENDIX B
H1N1 COUNTERMEASURES STRATEGY AND
DECISION-MAKING FORUM
DETAILED REPORT
PANDEMIC INFLUENZA WORKING GROUP (PIWG)
NATIONAL BIODEFENSE SCIENCE BOARD
JULY 2009
Excerpt:

Manufacturers’ Vaccine Development Plans

Novartis Vaccines and Diagnostic—Rino Rappuoli, Ph.D.
Dr. Rappuoli said Novartis has been working on pandemic influenza since 1999. The company plans to begin trials of an H1N1 vaccine with and without adjuvant in late July or early August. Studies will include about 4,000 children and adults ranging in age from six months to over 65 years. Data analysis should be completed by October or November, but preliminary data may be available sooner. Data from influenza cell culture trials in Europe may be available in September.

Novartis’ adjuvant, Mf59, has been licensed for use in Europe since 1997 as part of a seasonal influenza vaccine, and 45 million commercial doses have been distributed. It provides protection against drifted strains. Data comes from 120 studies involving more than 200,000 subjects, including a database of pediatric patients.

After one dose, Mf59 stimulates strong response from helper B cells and T cells. Boosting with Mf59 induces a protective immune response against all H5N1 isolates in seven days.

H5N1-plus-Mf59 prepandemic vaccine increases antibody production when compared to unadjuvanted vaccine and so reduces the amount of antigen needed. It also demonstrates cross-reactivity against most H5N1 subclades that have caused human disease, and Novartis has seen cross-coverage when Mf59 is combined with seasonal influenza vaccine. After a primary vaccine is administered, a booster dose can be given 6-8 years later and demonstrate protection in 7 days. The prepandemic vaccine has a favorable safety profile and a growing clinical database that includes children as young as six months.

The combined safety data for Mf59 provided to FDA include 25,000 cases compared with normal influenza vaccine. Adverse events are all local reactions that resolve quickly. Novartis is currently conducting a 3-year trial in Italy of 150,000 elderly people. The pharmacovigilance database from that study includes spontaneous reports after 40 million doses and has revealed no safety signals for selected adverse events.

Novartis is producing a cell-culture based H1N1 vaccine at its facility in Germany and is working with HHS to build a plant in North Carolina. With the addition of the North Carolina plant, Novartis will have the capacity to produce 150 million doses. Novartis is planning to have commercial production of prepandemic vaccine, adjuvant, and seasonal influenza vaccine in 2012.

Novartis’ influenza cell culture (Optaflu) demonstrated efficacy of 84% against vaccine-like virus strains when compared with placebo. Adjuvanted influenza cell culture H5N1 vaccine is both antigen- and adjuvant-dose-sparing. Novartis has limited capacity to produce this product, but it can still be available quickly.

Dr. Rappuoli concluded that Novartis has had an ongoing partnership with HHS to develop an H5N1 vaccine. It is working to develop a novel H1N1 vaccine for current pandemic in adjuvanted and unadjuvanted formulations, with potential use of Mf59 potential for dose sparing and cross-protection.

http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

From Post #1

The U.S. Food and Drug Administration today announced that it has approved a vaccine for 2009-2010 seasonal influenza in the United States.
The six vaccine brand names and manufacturers 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.

APPENDIX B
H1N1 COUNTERMEASURES STRATEGY AND
DECISION-MAKING FORUM
DETAILED REPORT
PANDEMIC INFLUENZA WORKING GROUP (PIWG)
NATIONAL BIODEFENSE SCIENCE BOARD
JULY 2009

Manufacturers? Vaccine Development Plans

MedImmune, LLC?Raburn Mallory, Ph.D.
Dr. Mallory explained that the FluMist A (H1N1) is a monovalent live attenuated 6:2 reassortant vaccine. It will be delivered intranasally via a unit-dose AccuSpray device at 0.2 mL per dose (0.1 mL in each nostril). It contains no preservative or adjuvants.

The vaccine dose is fixed on the basis of clinical efficacy studies conducted with MedImmune?s trivalent seasonal influenza vaccine, FluMist, at 106.5-7.5 FFU (fluorescent focus units). Lower doses resulted in lower efficacy in one study, and higher doses are constrained by sporadic fever rates and the manufacturing process. While no correlate of protection (e.g., seroprotective hemagglutination inhibition assay [HAI] titers) has been identified, vaccination generates a broad immune response including cellular, humoral and mucosal responses.

MedImmune conducts an annual study to incorporate new influenza strains into FluMist and the FluMist A (H1N1) studies are based on this design.

Two concurrent, placebo-controlled, clinical studies are planned to evaluate the attenuation of the new influenza A (H1N1) vaccine; one in adults ages 18?49 years (n = 300 subjects) and one in children ages 2?17 years (n = 300 subjects). The subjects in the studies will receive two doses approximately one month apart. Investigators will evaluate fever rates and serum immune responses after each dose and also look at solicited symptoms and adverse events.
Initiating the studies depends on selection of the final master virus seed, which Dr. Mallory expected to occur shortly. The clinical studies will begin in August and initial safety data will be available about 1 month after the first patients are enrolled. The annual strain change procedure that MedImmune usually follows with CBER would allow for vaccine approval based on this safety data. Immunology data could be available beginning in October, which may be late in terms of the planned distribution of the vaccine.

http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

APPENDIX B
H1N1 COUNTERMEASURES STRATEGY AND
DECISION-MAKING FORUM
DETAILED REPORT
PANDEMIC INFLUENZA WORKING GROUP (PIWG)
NATIONAL BIODEFENSE SCIENCE BOARD
JULY 2009


Manufacturers? Vaccine Development Plans
excerpt:
Sanofi Pasteur?James Matthews, Ph.D.
Dr. Matthews said Sanofi Pasteur is doing parallel work on H1N1 vaccine in Europe and the United States. The company has been working on a clinical development plan for the United States since the end of April. It is currently negotiating with CBER on proposed trial designs. CBER has asked the company to expand the number of subjects in the clinical trials (from 1,500 to 3,100 children and adults), limit the number of formulations tested, and place less emphasis on the adjuvanted formulations. Sanofi Pasteur?s proposed protocol would have provided some data by mid-October, but accommodating CBER?s requests will affect the timeline of studies and availability of data.

The company has proposed to drop one of its non-adjuvanted formulas from its studies; also, it may not study children ages 10?17 years, as CBER believes data from other age groups can be extrapolated for this age group. CBER has proposed longer safety follow-up monitoring and more complicated laboratory testing for safety assessment, as well as intensive follow up for any adults who receive the adjuvant. Dr. Matthews predicted that the final trial design will represent a hybrid of the various proposals.

Sanofi Pasteur is focused on a timeline that will produce clinical data quickly so that vaccine could be available as early as January 2010. Trials would begin as early as mid-August and include a placebo group. Timelines are based on commercial production schedules. One key assumption is that vaccine will be formulated on the basis of comparability data. The company does not expect to have fully calibrated reagents until the end of August or early September.

The current plan is to produce the needed material for clinical study in the next few weeks, file an IND in July, and begin enrolling patients in August. The 21-day HAI serology results would be available in mid-October, and booster data in November and December. Data on adjuvanted vaccine would be available in early 2010.

http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

Sanofi Pasteur: Seasonal Flu Vaccine Delayed In U.S.

October 01, 2009
NEW YORK (AP) -- The largest U.S. supplier of seasonal flu vaccines said it is running behind on shipping those vaccines -- partly because of the crunch to produce millions of doses of the swine flu vaccine.
The pharmaceutical company Sanofi Pasteur said it has shipped more than half of the 50.5 million doses of seasonal flu vaccine order by U.S. health care providers. But the company has sent notices to customers indicating that additional doses may be delayed.
Company spokeswoman Donna Cary said it could be November before some customers get the rest of their orders.
The delay already has forced some doctor's offices to turn away parents seeking season flu vaccines for their infants and toddlers and caused some public health offices to cancel scheduled community vaccination clinics.
"We understand it does create an inconvenience for some people who wanted to hold their seasonal influenza campaigns earlier," Cary said. "We apologize for that, but we're doing every thing we can."
The federal Centers for Disease Control and Prevention said Sanofi Pasteur had alerted it a while ago that it may need to delay shipments, but the federal agency did not learn the details until Thursday, said spokesman Tom Skinner.
The delay isn't surprising nor cause for big concern, Skinner said, because about 70 million of the nation's expected 114 million doses already have been delivered and vaccinations started unusually early. October is the traditional time when seasonal flu vaccine clinics open.
"Vaccine, while it's coming out, may not be coming out to some of the providers when they thought they were going to get it," Skinner said. But, "it's coming, and people may have to be patient and persistent in inquiring about when they can get it."
Sanofi Pasteur, the Swiftwater, Pa.-based vaccines division of the French drug-maker Sanofi-Aventis SA, is producing about 45 percent of seasonal influenza vaccine, making it the largest of the country's five suppliers.
-snip-
http://www.manufacturing.net/News-Sanofi-Pasteur-Seasonal-Flu-Vaccine-Delayed-In-US-100109.aspx





Sanofi Pasteur Announces Results of U.S. Clinical Trials in Adults Following One Dose of Influenza A (H1N1) Vaccine
Date:10/1/2009

LYON, France and SWIFTWATER, Pa., Oct. 1 /PRNewswire/ --Sanofi pasteur, the vaccines division of the sanofi-aventis Group [snip] announced today an interim analysis of data from clinical trials of the U.S. licensed Influenza A (H1N1) 2009 Monovalent vaccine in adults 18 years through 64 years of age and over the age of 65 years.


These data indicate that a single 15 mcg dose of sanofi pasteur's Influenza A (H1N1) 2009 Monovalent vaccine, administered to adults, including the oldest study participants, induces a robust antibody response 21 days post-vaccination that is considered protective. These data from a placebo controlled study of 849 adults help confirm preliminary data from a few vaccine recipients 10-days post immunization reported from another study by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH).



"The development of an A (H1N1) vaccine and the efficient execution of clinical trials to evaluate the safety and immunogenicity of this vaccine demonstrate the tremendous achievements that can occur when public and private sectors work collaboratively to address public health challenges," said Wayne Pisano, President and Chief Executive Officer of sanofi pasteur. "The independent clinical trials conducted by NIH and sanofi pasteur provide a rich data set that can be utilized to make informed decisions on vaccine administration. In addition, the consistency of findings among these separate independent trials will help build public confidence in the vaccine."
Sanofi pasteur began clinical trials in the U.S. on August 6 to test the immunogenicity and safety of its Influenza A (H1N1) 2009 Monovalent vaccine. Clinical trials are being conducted in adults 18 years of age and older, including a group 65 years of

http://www.bio-medicine.org/medicin...ose-of-Influenza-A--28H1N1-29-Vaccine-5153-1/
'/>"/>

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

From Post #1

The U.S. Food and Drug Administration today announced that it has approved a vaccine for 2009-2010 seasonal influenza in the United States.
The six vaccine brand names and manufacturers 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.

APPENDIX B
H1N1 COUNTERMEASURES STRATEGY AND
DECISION-MAKING FORUM
DETAILED REPORT
PANDEMIC INFLUENZA WORKING GROUP (PIWG)
NATIONAL BIODEFENSE SCIENCE BOARD
JULY 2009
excerpt:

Manufacturers? Vaccine Development Plans

CSL Limited?Jillian Bennet
Ms. Bennet said CSL licensed an influenza vaccine in the United States in 2007 and is currently fulfilling FDA postmarket study requirements for that product (Afluria). CSL is the only influenza vaccine manufacturer in the Southern Hemisphere. Its product is an egg-derived, classical, inactivated vaccine.

In the United States, Afluria is available in a thimerosal-free prefilled syringe and in a multidose vial. The antigen is manufactured in Australia, and CSL has fill-and-finish capacity in Australia and Germany. The company has applied for FDA approval to open a fill-and-finish plant in the United States.

CSL is on track to meet the forecast requirements for seasonal influenza vaccine in the United States. For its H1N1 vaccine, CSL is doing strain evaluation. The seed lot has been selected, and the company is inoculating its first load of eggs. CSL has the capacity to produce excess antigen that could be shipped to the United States after it meets the needs of Australians and others in the Southern Hemisphere. Regarding reagent viability, Ms. Bennet said CSL would like to talk with FDA about an early-release protocol similar to that described by Dr. Matthews.

CSL has completed manufacture of its required antigen for the Northern Hemisphere; production of extra antigen would occur in June and July. The company is in a good position to make additional H1N1 antigen, though the projections for producing more antigen assume that CSL will receive approval to begin operations in a U.S. fill-and finish plant.

CSL is planning two trials of H1N1 vaccine. The company is located in the epicenter of the influenza pandemic in Australia, where it is currently winter and the middle of the typical influenza season. In the United States, pending FDA approval, CSL would begin trials under an IND in pediatric and adult populations (including evaluation of a thimerosal-free vaccine in children ages 6 months to 3 years). The study would compare a placebo against vaccine in three formulations (7.5 mcg, 15 mcg, or 30 mcg). The vaccine would be given in two doses, 21 days apart. Safety would be assessed 21 days after each dose, with monthly assessment for up to 6 months. The study would monitor for serious adverse events of new-onset chronic disease. CSL is determining whether it could prospectively review immunogenicity and safety data after each dose. Ms. Bennet wondered whether a placebo should be used in pediatric populations, which might impede recruitment, and whether using a licensed seasonal influenza vaccine instead of placebo would be an acceptable alternative.

Ms. Bennet compared the planned CSL studies in the United States and Australia. In Australia, enrollment would stratify adults ages 18?64 years in an attempt to identify people who were exposed to the 1957 epidemic. The Australian study is only exploring two vaccine formulations (15 mcg and 30 mcg doses). The Australian study will look at both hemaglutination inhibition (HI) and microneutralization (MN) titers, while the U.S. study would look only at the former. Monthly follow-up would be more intensive in the United States. The Australian study would not be conducted under an IND, but the data would be provided to the FDA.
In Australia, adult patient enrollment would begin in July and pediatric enrollment in August; in the United States, enrollment for both children and adults would begin in August. Interim analysis following the first dose could begin in September in Australia and in October in the United States. Ms. Bennet hoped analysis following the second dose could be concurrent in both countries. She added that pediatric recruitment takes a long time and she anticipated that pediatric data from either the United States or Australia would not be available until late November to mid-December.

http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

I copied different discussions throughout the document. This is one of them:

Same Document:
APPENDIX B
H1N1 COUNTERMEASURES STRATEGY AND
DECISION-MAKING FORUM
DETAILED REPORT
PANDEMIC INFLUENZA WORKING GROUP (PIWG)
NATIONAL BIODEFENSE SCIENCE BOARD
JULY 2009

Discussion
Dr. Pavia: I?m gratified to see the investments in basic research on safety for the future; will any of that investment be useful this fall?

Dr. Hackett: We have nothing like a chip or gene that can help you identify whom not to vaccinate, but there are investigators looking at special populations and generating data. You could get preliminary information from them on special populations.

Dr. Pavia: If Dr. Salmon asked, could you identify the top 10 conditions for which we need baseline rates on, e.g., diseases or adverse events?

Dr. Hackett: That?s a good question. We are always concerned that when you trigger B cells could they respond to existing antigens as auto-antigens? That?s one priority. For special populations, we are concerned about people who have had transplants and people with autoimmune disease or primary immune deficiency. Those are some groups to look at, but we can?t have that data by this fall.

Gus Birkhead, M.D., M.P.H.: Given the historical context, we need to address GBS. The potential for the issue of adverse events to blow up is very large. Vaccine safety is an even bigger issue now; there are children not getting vaccinated for measles or haemophilus influenza type b, despite the risk of death. Could the record of adjuvant use in Europe be informative in terms of signals? They must have experience, having dispensed 45 million doses.

Dr. Pavia: There is a list of adverse events.


Dr. Quinlisk: From a State health department perspective, we may be giving seasonal influenza vaccine, the first dose of H1N1 vaccine, and a second dose of H1N1 vaccine, treating people sick with H1N1, and tracking adverse events. We can?t handle that with our current capacity, but, if this treatment plan is supposed to work, we need to do all of that.

http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf

 

[Commonground]

Re: Vaccine Orders -

Re: Vaccine Orders -

Yet another discussion....same document....

Discussion
Dr. Neuzil: What I?m hearing is that five companies are working on vaccines, and they are testing multiple doses or multiple combinations of antigen and adjuvant in multiple age groups. We could end up with many different vaccines, and that complicates policy issues. How will decisions about licensing be made? Do we have a definition of success? Will the focus be on individual response, like the correlation with HAI antibody, or on population responses? Could there be a lower threshold to cover more people, or do we need a consistent approach to ensure more reliable coverage? We also have to consider distribution issues.

Dr. Pavia: I?m hearing that licensing should take into account public health as well as individual concerns, which is different from what we usually do.

Bob Belshe, M.D.: Two companies are addressing the epidemiology of priming by previous H1 infection. That will tell us at what age you only need one dose and what that dose should be. Kids ages 10?17 years were initially proposed for study but are now out of the Sanofi Pasteur study, but I disagree. That could be a critical age group. Kids under 9 years probably are not primed, but those over 10 might be. Sanofi and CSL should put that age group back in their studies and consider the age at which priming might occur. The only vaccine for which we know the dose is live vaccine, but there are few plans to acquire that. We could vaccinate children and adults, then challenge them with live vaccine as a surrogate to get efficacy data quickly. All the plans seem too late for a fall epidemic. We need to accelerate so we can have at least first-dose data by the end of August.

Dr. Pavia: Are all of the manufacturers studying coadministration with seasonal influenza vaccine?

[Unidentified]: We?ve been asked.

Ms. Bennet: We have, too, but in the initial studies, we?re not sure what dose to combine. We will probably address that in the next stage.

Dr. Pavia: To deal with the complexity of these studies, consider involving the people who will analyze the data early on. I don?t think that?s the usual path. Usually VRBPAC and ACIP are not involved in study design. Could that smooth the process?

Dr. Modlin: VRBPAC analyzes data that FDA brings to it; FDA analyzes what the manufacturer provides. We are not part of the process early. I share the concerns of others that there are lots of options, but we have a likely pandemic possibly coming soon. We should identify the most important questions to answer quickly and focus on them, such as the populations most likely to be affected most severely. I?d like us to prioritize the questions.

Dr. Pavia: Yes?we should consider that.

Wellington Sun, M.D.: My views do not necessarily reflect the views of CBER, but we?ve had ongoing discussion in the vaccine office about the options. The approach we took was to look at the potential urgency and identify the most efficient way to get clinical data that policymakers need to make decisions on vaccine. So, we may have many formulas that work. From the agency?s perspective, I think we?ll apply the standards outlined in our guidance: HAI level, seroconversion rates, and protection rates. The studies are not large enough to allow for comparison of all the available vaccine. At some point, we will have to prioritize the vaccines, and ACIP and VRBPAC will be helpful there.
Why did we drop ages 10?17 from the Sanofi studies? If this group is at high risk, we need to revisit that decision, but our thought was that we could extrapolate from adults and from younger kids. Regarding the progression of data for decision-making, adaptive
design of clinical studies may not be viable for some clinical trials, but results of a trial
from one company using antigen only could apply to immunogenicity for another trial.
The need for some mechanism to organize data for policy development is not a regulatory
issue. We have wrestled with the timing issues, and we?re trying to abbreviate the
timelines. We welcome your ideas to fix that issue.
Finally, is the context of TIV?that?s why we?re concerned about concurrent vaccine.
We hope to get information from coadministration studies.

Dr. Pavia: What?s the most important thing to fix?

Dr. Neuzil: Given concerns about coadministration or sequential administration, when do you anticipate administering the seasonal vaccine?

Dr. Innis: That?s less of a problem than you might imagine. About 90% of seasonal vaccine will be released in September, and novel H1N1 will probably not be ready by then. If it?s coming from BARDA, it will be later. We can talk about abbreviated release protocols, but vaccine trials should represent the commercial product that will be used in the whole population. There will be very limited data on which to base licensure of novel H1N1 vaccine if unadjuvanted or an Emergency Use Authorization if adjuvanted ?the earliest post-dose-1 data would be out in October, and that could lead to distribution of formulated and filled product from the National Stockpile as late as December and January. So, there probably won?t be much coadministration. As for sequential administration, data show there can be interference. Subjects with a history of prior TIV
vaccination who got unadjuvanted H5N1 vaccine in the clinical trial for licensure, as described by the CBER reviewer to the VRBPAC, did not respond well at all.

Dr. Rappuoli: There are some data on H5N1 with adjuvant coadministered with seasonal vaccine that showed no interference, but we don?t know yet about H1N1.

Dr. Innis: I think adjuvant abates some of the interference.

Dr. Mallory: Data for our seasonal influenza vaccine will go to FDA in July. I think early administration of seasonal vaccine is the best strategy.

Dr. Belshe: Novartis has a product online already. You should just put that in a few adults and look for antibodies. That would be very helpful in deciding what to do with the first batches of vaccine. For live vaccine, we need a little safety data on post-dose-1 in adults and kids. I?m distressed about data not being available until October. We need it now.

Dr. Pavia: Do we have the capacity to run assays for all the trials in a way that provides data FDA can use?

Dr. Innis: Manufacturers who are licensed in Europe do annual registration studies in about 100 individuals, and even with no delays, it still takes about 30 days, with a 1-dose vaccination schedule, to get data you can share. We can?t go faster and we?re limited. GSK will be doing a small but early H1N1 vaccine study in adults designed like an annual registration trial to provide pilot data as rapidly as possible, in Belgium.

Dr. Matthews: We do serology studies internally in the United States. It depends on the size of the study, so that?s why we kept it fairly small. With 3,000 subjects, it would be difficult to handle lots of samples.

Dr. Mallory: MedImmune will also be performing serology in-house. If the live vaccine is held to the same standard for immunogenecity that CBER has proposed for inactivated vaccines (TIV), it is unlikely to meet that standard.

Ms. Bennet: Serology depends on the availability of reagents. We have a lab in the U.S. that validates, but that depends on providing reagents. We are frustrated in Australia by WHO?s decision to debate a containment level before we could work with seeds.

Theodore Tsai, M.D., M.P.H.: With the release of a cell-culture-based vaccine lot, we?re going to clinical trials, with and without adjuvant, in Germany, and we expect to see results in September.

Dr. Edwards: It?s not clear that HAI is the best assay. More functional assays may be needed.

Gerald Quinnan Jr., M.D.: I have not been involved in the discussions that occurred regarding this issue previously. However, it is worth noting that this is an extraordinary time and extraordinary measures may be needed. In concert with this theme I raise the question whether we should consider moving now to replace the H1N1 component in the trivalent vaccine with the novel H1N1 component. It is highly likely that people of most ages will respond well to 15 mcg doses of the novel antigen, and it is not clear why there need to be clinical trials before proceeding to use that dose. Moreover, inclusion of the novel antigen in the trivalent vaccine will increase the likelihood that people who need the trivalent vaccine will get vaccinated against the novel strain, and that vaccine with the novel strain will be available to them early in the season. If subsequent clinical trials demonstrate a need for a second dose in some of those people, we could develop a recommendation to do that. If that's feasible, it should be considered.

Industry representatives (all): It?s too late to reformulate seasonal vaccine with the novel H1N1 strain.

Dr. Pavia: What?s the difficulty with HI assays? Dr. Katz: It?s not that they don?t work, but comparing them with MN assays and looking for a cross-reactive response?the MN assays gave higher titers and demonstrated greater seroconversion compared with HI. There may be receptor-binding differences that underestimate the antibody. I encourage manufacturers to use a functional assay like MN. All the manufacturers have well-validated assays for seasonal vaccine and H5N1, but it?s difficult to compare between groups because they all have their own assays. So WHO developed a standard human antibody for H5N1, and there?s already a discussion about the need for one for H1N1 to better understand the similarities and differences.

Ms. Bennet: When FDA approached us, they asked if we would keep sera samples from our studies so someone could analyze all the sera.

Dr. Pavia: Is there any plan to do that?

Dr. Robinson: All the samples will go to NIH for comparability studies.

Dr. Hayden: I support Dr. Belshe. Look at the antibody responses early on, as early as 7 days, to examine effects of priming. The efforts to develop WHO reference antibody for H5N1 serologic testing took over a year; we can?t wait that long. What information do we have from HAI and MN in persons with natural pandemic H1N1 infection? These data are needed to help understand responses to candidate vaccines.

Dr. Katz: There are ongoing studies, and we?re waiting for convalescent serum. If we encouraged follow-up serology, we would have to find a way to get follow-up sera from infected people.

[Unidentified]: We face an awkward situation in the fall. We?ll be pushing seasonal vaccine and expecting H1N1 outbreaks, and we will have to tell people the vaccine we?re giving them will not protect against H1N1. We need a comprehensive strategy that includes messaging and anticipates this awkward situation.

Dr. Pavia: Here are my takeaways: The plan for developing vaccine is complicated and will involve multiple products that are different, so there?s a plea for clarifying goals and endpoints and perhaps involving more analysts in the planning stages. Everyone is nervous about timelines and much can go wrong. It?s important to identify who can be protected with one dose. There are concerns about the effect of the disease and vaccine on young people. We should use early data to adapt studies as we go, maintaining flexibility.

http://www.hhs.gov/aspr/conferences/nbsb/nbsb-h1n1forum-sum-090617.pdf