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Swine Flu Global Medical Research.org Discussion Andre Berro, MPH, CPH Public Health Advisor at the Centers for Disease Control and Prevention (CDC)
As public health professionals work around the clock to control the swine flu outbreak, what kind of research ideas/data collection would you like respondants to incorporate as they respond?Sent in my personal capacity. ...............  Aamer Fattah Technical, Quality & Development Consultant; Medical Scientist; MLC, National Australia Bank Thanks for this critical query, Andre. I would be specifically interested in up-to-date mortality and morbidity data, specifically regarding risk factors that result in increased susceptibility of an affected individual i.e. prolonged course, greater mortality risk, etc. Quantitative data would be ideal i.e. to facilitate subsequent analyses, although I appreciate that it may be early days. I note I am a medical scientist qualified in clinical virology - happy to contribute further where indicated. ---------- 
Robert Malone, MD, MS Consultant, Vaccines and Biologics at RWMaloneMD.com Hello Andre:
I had posted this info (below) on some of the other groups and have sent out through my personal network, but I do not think that I posted it to this group. I will also write separately in response to your query topic. FYI, I am based just north of Atlanta, and have just returned from spending the last two weeks in DC at the world and NFID vaccine conferences. I have three clients who are deeply involved in responding to this issue- Focus Diagnostics, C-PERL, and Accelovance, and also have many contacts within the government and biotech firms who are responding to this situation. I think that I have insights which may be of use to the CDC. Please feel free to contact me directly (770 735 1549) if you wish to speak further. best wishes robert ---------- Robert Malone, MD, MS Consultant, Vaccines and Biologics at RWMaloneMD.com
Vaccines and Biotechnology
(US) 770 735 1549
http://www.linkedin.com/in/rwmalonemd
http://www.rwmalonemd.com/ Dear Colleague: FYI, Dr. Jose Santos is formerly director of the Mexican national immunization program and perhaps the most senior and highly respected pediatric infectious disease physician in Mexico. He has been very closely involved in helping to manage the emerging situation in Mexico. I thought that the information below might be of particular interest to you. In the interest of rapid communication on this topic, please forward as appropriate. Dr. Santos is open to considering potential consulting if this would be useful to you. Best wishes robert .........................
From: Jose Ignacio Santos <jisantosp@gmail.com>
Robert, this is the most recent update
To date, there have been over 2500 suspected cases with influenza-like illness (ILIS) and 159 deaths. The PCR techniques for diagnosis of this virus have just been established in Mexico, with the help of CDC and the people from Manitoba, Canada. There are 49 confirmed cases, of which 7 have died. Theree is now now an established a network of the hospitals in Mexico City to define the burden of the disease that includes the number of consults to the ER, hospitalizations and deaths. ERs are now loaded with patients that seek medical care. From these, 24% meet the criteria of ILIS; 10% of them are hospitalized, with 1.2% deaths. In this recently established network, although deaths occurred in the 20-45 years of age group, there have been predisposing conditions in the subjects, such as morbid obesity, diabetes, autoimmune diseases. However, we don’t have information on the causes of death of the majority of cases that have occurred before and out of this recently established network. There are many questions that arise from this epidemic. This virus doesn’t seem to be associated with a high mortality such as that observed with avian flu viruses that occurred in south Asia. It is important to define the actual cause of death of these patients to determine the risk factors for severe illness, and also to define the pathogenesis of this infection, the pre-existing immunity to swine flu H1N1 virus, to find whether the cause of severe disease and death is related with cytokine storm, among other important questions that are arising, and of course the research for the development of a vaccine is guaranteed.
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Robert Malone, MD, MS Consultant, Vaccines and Biologics at RWMaloneMD.com
Vaccines and Biotechnology
(US) 770 735 1549
http://www.linkedin.com/in/rwmalonemd
http://www.rwmalonemd.com/
Andre: 1) Regarding the info that we need, updated info on any signs of GBS in infected patients and info on morbidity/mortality incidence is critical to those planning for development and deployment of vaccines under emergency use authorization. AS you know, the GBS incidence with the prior swine flu vaccine deployment resulted in some real PR damage to the vaccine community and cost the (then) CDC director his job. Vaccine developers need GBS incidence/risk assessment data ASAP to help plan for how we will manage the clinical development/safety monitoring/Emergency use authorization planning as we develop our product develop plans for response to this situation. 2) Accurate info on projected deployment timelines for the major manufacturers is also critical. 3) My USG colleagues tell me that DHS and DHHS have not been "playing nice in the sandbox" with each other, and DHS has taken over management consequent to the situation with the delay in confirmation of the secretary for DHHS. This is a problem. Key planning and response expertise resides in BARDA, and they need to have a greater role. 4) Since Dr. Jose Santos has been in DC for the last two days, I tried to hook him up with BARDA so that they could capture his knowledge of the current situation in Mexico (which is extensive and detailed). They have indicated that they have no interest in speaking to him. I find this remarkable. Perhaps the CDC might wish to connect with him? 5) In their nearsightedness (or ignorance), DHS has only contacted the major manufacturers about development/deployment of vaccine. Their supply lines and manufacturing are very egg-centric and all are currently engaged in manufacturing for next seasons product. The timelines for deployment of H1N1(2009) swine vaccine based on their production lines are VERY optimistically projected by Janet N as September. I am very skeptical of their ability to meet this timeline, and even if they do we still have distribution and deployment lag time which will be significant. This will leave the "key personnel"/medical/first responder personnel vunerable to what is anticipated to be a second wave pandemic anticipated for October-December. We need a solution for the first responder (as per the BARDA pandemic planning documents). The small biotechs who are my client base have solutions which can meet this more abbreviated timeline, but none of these employ licensed manufacturing processes. However ALL vaccine solutions will have to be deployed under EUA- majors and small biotech. Somehow we need to get the attention of the USG decision makers that the small biotech firms (Novavax, protein sciences, Vaxin, Nanobio for example) can probably address the need for vaccine to be deployed under EUA on an accelerated timeline for dosing the first responder population. For example, Vaxin can deploy 100M doses (bulk vaccine) involving a recombinant AdV intranasal (two Ph1 studies completed) product within 90 days. Manufacturing using very well established processes at 500l scale using PerC6- the best characterized cell-based manufacturing platform! 6) Here in N America, we are very focused on our need for vaccine, but the PAHO and emerging asian countries have no solution either, and face the potential for political unrest unless they can come up with a solution. Even if the USG does not want to engage the small biotech in deploying a vaccine solution, the small biotechs could help address the challenges in the emerging and underdeveloped countries, but the pathways for export of "experimental" vaccine product (for use under something modeled after EUA) from US into those countries is not clear. 7) If you have time to look at the EUA guidance and FDA SOP, they are very nebulous. This is good in one sense, as it allows the FDA/DHHS quite a bit of flexability. It is also a problem for planning, as no-one can really sort out what they need to do to plan for rollout of vaccine under EUA. It would be very helpful if CBER could issue some sort of draft guidance or "points to consider" document to help clarify their expectations. Please feel free to contact me directly if you wish to discuss one on one. I can also drive down to CDC to meet in person if you wish. Best wishes robert 770 735 1549
rwmalonemd@gmail.com ----------- Aamer Fattah Technical, Quality & Development Consultant; Medical Scientist; MLC, National Australia Bank Robert, Thanks for your recent postings - excellent insights. In reference to GBS and specifically the 1976 outbreak: do we know what (confirmed or theorised) caused GBS at the time? If at hand, what was the mortality rate for GBS sufferers? More importantly, is there any risk that new vaccines (i.e for the current outbreak/potential pandemic) may cause GBS? I'd appreciate any insights you might provide. ---------- Robert Malone, MD, MS Consultant, Vaccines and Biologics at RWMaloneMD.com
Vaccines and Biotechnology
(US) 770 735 1549
http://www.linkedin.com/in/rwmalonemd
http://www.rwmalonemd.com/ Aamer: Please see the following JAMA article from the time, which I believe provides an excellent entre into the data concerning this topic- JAMA. 1980 Jun 27;243(24):2490-4.
Guillain-Barré syndrome in recipients of A/New Jersey influenza vaccine.
Marks JS, Halpin TJ. In late 1976, when 32% of the eligible population of Ohio received the A/New Jersey influenza (swine flu) vaccine, systematic contact of neurologists was used to evaluate the possible association of Guillain-Barré syndrome (GBS) with receipt of the vaccine. The overall rate of GBS was significantly higher among vaccine recipients (13.3/10(6)) than in nonrecipients (2.6/10(6)). Peak time of onset was two to three weeks after receiving the vaccine, and cases among vaccinees were less likely to have a history of antecedent infection than were cases in unvaccinated persons. Even when the effect of one highly associated vaccine lot was removed, an elevated risk of GBS remained in vaccinees regardless of manufacturer or vaccine type (bivalent or monovalent). Systematic surveillance is needed for rare serious reactions from all vaccines. ----------- Robert Malone, MD, MS Consultant, Vaccines and Biologics at RWMaloneMD.com
Vaccines and Biotechnology
(US) 770 735 1549
http://www.linkedin.com/in/rwmalonemd
http://www.rwmalonemd.com/ I believe that there were +/- 500 excess cases of GBS attributed to the vaccine with about 25 deaths due to complications of GBS. If you look back at the history of what happened, you can appreciate that info on morbidity, mortality, and transmissibility of this strain are critical to determinations of the strategy for use of H1N1 (2009) swine vaccine under emergency use authorization. The pivotal question is whether we need to do a safety trial in healthy normal adults with interim safety data analysis at 4-5 weeks prior to full implementation of vaccination, or whether some sort of very active safety surveillance would be adequate. This would potentially have to be done for each vaccine manufacturer. The sample size to detect excess GBS post vaccination (above normal incidence of GBS) would be quite large- something like 8,000 subjects or more. ---------- Aamer Fattah Technical, Quality & Development Consultant; Medical Scientist; MLC, National Australia Bank Thanks again, Robert. I have quickly reviewed the JAMA article you suggested and have since located several more. Whilst GBS mortality and morbidity data appear readily available, I will research further to attempt to clarify the potential underlying causes of GBS and other neurological complications in individual patients (e.g. neurotoxic, idiosyncratic, correlated with underlying comorbdity, genetic variation, a combination of factors, etc.) I encourage other group members to join the discussion and contribute relevant insights. As you say, this is a critical question and once answered, has the potential to significantly mitigate the risk of complications that might result from a new vaccine. ---------- Robert Malone, MD, MS Consultant, Vaccines and Biologics at RWMaloneMD.com
Vaccines and Biotechnology
(US) 770 735 1549
http://www.linkedin.com/in/rwmalonemd
http://www.rwmalonemd.com/ Hi again, Aamer:
I posted a response to your email concerning your most recent comment, but it does not seem to have been able to make its way thorough linked in processes. I am unaware of any risk predictor for GBS other than prior GBS.. If there were such, CBER would be requiring that we employ such a screening criteria for subjects participating in clinical vaccine (and particularly influenza vaccine) clinical trials, and I have never seen any such exclusion criteria other that past history of GBS. Obviously, identification of such a risk factor which might be screened for prior to vaccination would be enormously helpful. Assuming that this is antigen-specific having to do with some epitope of biological immune response aspect of the Swine H1 (as increased risk of GBS existed independent of manufacturer) I do not know if the actual incidence of GBS in patients infected with the prior swine influenza was higher than background. If so, then we might expect to see GBS cropping up in Mexico as the case incidence moves past 1 million patients- and it appears to currently be in the thousands so it would be unlikely that we would see a GBS case at this point. Hence my original comment that we really need Epi on incidence of GBS in this outbreak!
----------- Robert Malone, MD, MS Consultant, Vaccines and Biologics at RWMaloneMD.com
Vaccines and Biotechnology
(US) 770 735 1549
http://www.linkedin.com/in/rwmalonemd
http://www.rwmalonemd.com/ Regarding the global epidemiology of this emerging pandemic, and the risk of tamiflu resistance emerging- If we assume that the poorly characterized seasonal characteristics of influenza infection will impact on geographic/temporal distribution of this virus, then it seems likely that infection in N American/N Hemisphere populations will die out this summer, but that the virus will continue to infect and spread throughout the southern hemisphere over the next six months. If we assume liberal use of tamiflu during that time, then there would appear to be a risk of tamiflu resistance developing during the course of the southern hemisphere spread. Thus it seems a reasonable risk that the northern hemisphere may be subjected to infection with a tamiflu-resistant strain next fall. Therefore, development and deployment of a vaccine in the northern hemisphere before the flu season kicks off next fall/winter would seem to be imperative even though the virus is currently susceptible to tamiflu. In other words, in the Northern hemisphere we need to prepare for the virus as it is likely to be next fall, not as it currently is. Ongoing assessment for emergence of resistant virus during the course of S hemisphere infection will be critical!
------------------ Malcolm Barth
Senior Research Protection Analyst at Analytical Services, Inc.
I think it would appropriate for public health professionals and scientists to gather data on possible differences in the immune interactions with the virus and human host in mexico and other countries. I think it is vital to establish reasons for any differences for the rates of mortality different people around the world that are infected with this virus. Other factors that may specific to different populations around the world should also be considered.
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