Vaccine Investigations

[Commonground]

Posts #'s 2, 3, 4 & 5, are summaries on each vaccine.

The information taken from various threads here: http://www.flutrackers.com/forum/showthread.php?t=127421
This thread contains numerous articles regarding the current vaccines for H1N1A (Swine Flu).

 

[Commonground]

Re: Vaccine Investigations

This is a whole summary of Sanofi-Aventis SA. Done in a time-line. I do not have a more recent Working Group Document. This Document is dated July, 2009. I don't know about the problem of two articles for September 21, one specifying an order of 27.3 million doses...the other, specifying an order of 56 million. I feel that the age group of 10-17 was dropped from the studies, as is mentioned in the working document, the October 1st article clearly states the age groups in the study.

Sanofi-Aventis SA
[Article dated: 5/26]
-Received $190 million order from HHS.

-Order was issued under an existing pandemic stockpile contract between Sanofi Pasteur & U.S. Gov, that allows HHS to purchase vaccines for viruses with pandemic potential.

-Order provides for bulk vaccine & related activities.

-Dosage requirements are yet to be determined.

-Clinical trials to begin in August.

-Commercial scale production planned for June, following FDA certification of a working seed.



-Previously they developed & licensed the first pre-pandemic vaccine for H5N1.



July Working Group Document

The total vaccine output by manufacturer is projected as follows:

Sanofi Pasteur (vial plus syringe): 26.4%

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.



Another Discussion from working 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.



Another Discussion from the working document:



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.



- Sanofi-Aventis, which has a contract to provide 75.3 million doses of its H1N1 vaccine to the U.S. government, is making all of its product at a new plant in Swiftwater, Pennsylvania.



- 9/21 - Gov’t ordered an extra 27.3 million doses on 9/21.



- 9/21 - HHS orders an additional 56 million doses of vaccine

- The U.S. Department of Health and Human Services ordered an additional 56 million doses of vaccine for the 2009 H1N1 flu from MedImmune and Sanofi Pasteur. HHS used approximately $438 million in existing funds for the purchase. The additional vaccine purchase will help to ensure that anyone who wants a vaccine will be able to obtain one when the vaccine becomes available.





9/29 - Sanofi CEO says vaccine shipments began

- Sanofi's U.S. contract had called for an initial delivery by Oct. 15. She didn't specify how many doses were being shipped

Tuesday.



- FDA approved new Penns. facility on a timely basis, plant produces good yields of vaccine.



- Older Sanofi-Aventis plant in Swiftwater is producing seasonal flu vax.



- 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,"



- 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,



- No other company currently makes influenza vax in the United States.



October 1st

- 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).

- 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





Seasonal Flu Vaccine



October 1st

- 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.



- 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.

 

[Commonground]

Re: Vaccine Investigations

This is a whole summary of MedImmune LLCs FluMist. Done in a time-line. I do not have a more recent Working Group Document. This Working Document is dated July, 2009.

Medimmune LLC’s FluMist

- Live attenuated influenza vaccine

- Also makes Seasonal Flu Vaccine- Development of LAIV begain at end of April, when company received novel virus from the CDC.

- Government contract for 40 million doses.

- The total vaccine output by manufacturer is projected as follows:

. MedImmune (nasal spray): 5.8%

From July Working Group document:

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.


Discussion in same document:

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.



9/17

-FDA Approves H1N1 Vaccines, Paving Way For Large-Scale U.S. Vaccination Campaign - approves Medimmune.



9/21

- Receives order from U.S. Gov. for additional 29 million doses. - Makes HHS orders to date of more than 40 million.

- Previous order was for 13 million doses of LAIV placed in May and July.


Week of 9/27

- Delivered 5 million doses in past week to McKesson Corp.

- Approved for people 2-49, not recommended for those w/underlying conditions.



This may explain the $56 million:

The U.S. Department of Health and Human Services ordered an additional 56 million doses of vaccine for the 2009 H1N1 flu from MedImmune and Sanofi Pasteur.

 

[Commonground]

Re: Vaccine Investigations

This is a whole summary of GlaxoSmithKline. Done in a time line. I do not have a more recent Working Group Document. This Working Document is dated July, 2009.

GlaxoSmithKline

July Pandemic Influenza Working Group Document

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.



Pandemic Influenza Working Group Document

The total vaccine output by manufacturer is projected as follows:

. GlaxoSmithKline (GSK): 3.4%


Discussion* From July Planning Document:

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.

* This and subsequent discussions paraphrase the questions and comments of the participants. This document does not represent a verbatim transcript.



7/20

- 7/22 confirmed contract for 195 million doses of its pandemic (H1N1) 2009 adjuvanted influenza vaccine, and had a variety of agreements in place with the US Government to supply pandemic products worth $250 million.

- Since that date, nine government contracts have been signed for a further 96 million doses of the vaccine. This now brings the total number of doses ordered for GSK’s adjuvanted vaccine to 291 million.

- Discussions continue with governments for further supplies of the vaccine.

- First supplies of the vaccine will be available to governments from September onwards, with shipments expected in the second half of 2009 and early 2010.

- The vaccine will comprise antigen of the recently isolated Pandemic (H1N1) 2009 influenza strain and also contain GSK's proprietary adjuvant system AS03.

-An adjuvant system can be added to the antigen at time of administration.



9/17

FDA Approves H1N1 Vaccines, Paving Way For Large-Scale U.S. Vaccination Campaign

- The application for GlaxoSmithKline PLC's vaccine is still being considered (Dooren/Favole, 9/15).


10/6

- starts shipping first supplies of vaccine during week 10/5

- shipments will be delivered in both the fourth quarter of 09 and first half of 2010
- Received 22 gov. orders since August 4th, bringing total to 440 million shots.

-45 million shots should arrive around October 15.

-Gov has ordered 195 million doses



Seasonal Flu 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.


[I need to do more on this area...I don't even have a date for this excerpt...]

 

[Commonground]

Re: Vaccine Investigations

This is a whole summary of Novartis Fluvirin. Done in a time line. I do not have a more recent Working Group Document. This Working Document is dated July, 2009.


Novartis Fluvirin A(H1N1)

July Pandemic Influenza Working Group Document

The total vaccine output by manufacturer is projected as follows:

. Novartis: 45.7%



July Pandemic Influenza Working Group Document

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.



Discussion - July Pandemic Influenza Working Group Document

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.



Discussion - July Pandemic Influenza Working Group Document
Dr. Belshe: It’s not unreasonable to pick a default dose—say, 15 mcg with no adjuvant—and use it for adults. For children, we could use live vaccine and we know the dose. For those not eligible, we could study alternatives. That approach gets you a long way. CDC showed that if you vaccinate 70% of kids with live attenuated vaccine, you reduce community burden by 99%. We should consider more creative use of two vaccine types.

Dr. Robinson: I agree with the use of the FluMist product, but the manufacturer has a small capacity. They are struggling to get enough. They expect to have about 6.4 million doses by the end of August. The limitations are not in the capacity to produce the bulk product but are inherent in the production of the delivery device.

Dr. Belshe: You could use live vaccine as drops. NIH has conducted several studies with drops.

Dr. Tsai: Novartis’ adjuvant has been studied in children. One study in Finland included children 6–36 months, and it found that a single dose led to seroprotective responses to the H3N2 strain. Some adults responded similarly to adjuvanted H9N2 vaccine. There is evidence that in people naive to antigen, the adjuvant promotes good response after one dose.

Dr. Pavia: In closing, I want to summarize what I’ve heard today. We have some assumptions we’re getting comfortable with:

There will be significant disease this fall, mild to moderate at least. . We are not locking into a vaccination program, but we need to work on our

assumptions. . Children are likely to be heavily affected and also an amplifier of disease. . A late decision and late vaccine may be worse than no vaccine. Some options

may lead to a safe vaccine at a point when it’s useless. We must abandon that approach and move back to an early vaccine strategy. . Some decisions will be made with limited data and some with no data.
9/15

- Washington Post reports on warnings made by WHO Director-General Margaret Chan during a WHO regional meeting in Copenhagen Tuesday of the devastating toll the H1N1 virus could have on developing nations.


9/17

FDA Approves H1N1 Vaccines, Paving Way For Large-Scale U.S. Vaccination Campaign

- approves Novartis


9/25

- includes the adjuvant MF59®,

- can elicit protective antibody levels with a lower dose, just 7.5 micrograms of viral antigen versus 15 micrograms in non-adjuvanted vaccines, potentially resulting in greater vaccine supply.

- received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA). The positive opinion clears the way for European Union approval in all 27 Member States as well as in Iceland and Norway.

- The CHMP opinion follows the September 15 US Food and Drug Administration (FDA) approval of the Novartis Fluvirin Influenza (A)H1N1 2009 monovalent vaccine.

- plans to begin delivery of its Fluvirin A(H1N1) monovalent vaccine to the U.S. market by early October.

- Novartis already started first deliveries of pandemic vaccines under quarantine to governments in Europe – just 3 months after WHO declaration of the pandemic – despite the initially low yields with the current production seed strain provided by the World Health Organization (WHO).

- We recently received a need seed strain from the WHO and are working diligently to improve the yields, while continuing with the production process, to make as much vaccine available as quickly as possible.


9/29

- The government hopes by the end of the year to acquire a total of 250 million doses from Sanofi and four other vaccine makers -- the MedImmune division of AstraZeneca Plc, Australia's CSL Ltd, GlaxoSmithKline Plc and Novartis AG.

- Novartis AG (NVS) began shipping its H1N1 vaccine for distribution in the U.S. on Sunday, a spokesman said.

10/6

- Completes shipment to US for Seasonal Flu Vaccine.