Saturday, August 30, 2014

Case from Guinea went to Dakar, Senegal and lied about exposure. Took bus and stopped in 2 health care facilities. Contact tracing now going on in Senegal. Spoke with Tom Frieden who is in Liberia. Trying to get him to appreciate that giving VSV Ebola vaccine as post-exposure prophylaxis (PEP) is risky due to the induction of cytokines by the live VSV, which might actually enhance the acquisition upon exposure since cytokine dysregulation plays a negative and potentially positive role in Ebola virus disease. He wants to pre-position VSV vaccine for PEP and TKM drug (siRNA – not yet is phase 1) at all Ebola treatment Units (ETUs). I understand the desire to protect the CDC and other health care workers on the front lines, but we must be concerned about giving drugs/PEP vaccines BEFORE they have even been in the earliest Phase 1 trials. Yesterday CDC evacuated a WHO worked who had a low risk needle stick (clean needle through potentially contaminated gloves) and they gave the person TKM drug and wanted to give VSV, but could not get it. That is why he now wants to pre-position it. See below my e-mail to Tom Frieden sent to him on Sunday, August 31 while he was in Liberia: Tom: I am including a few attachments: 1) 2 slides (from Nancy Sullivan who does our pre-clinical Ebola studies) that summarize the issue of "cytokine dysregulation" in Ebola disease and potentially following vaccination; 2) 2 reprints (referred to in the 2 slides) on the types of cytokine responses in Ebola disease and following vaccination with different vaccine platforms; and 3) the Heinz Feldmann paper with which you are familiar and which shows that in the monkey model of Ebola virus disease, the VSV Ebola vaccine used as post exposure prophylaxis (PEP) protected 50% of the monkeys from lethal challenge with Ebola if administered 20-30 minutes following the challenge. Getting back to our discussion and your question concerning the issue of any risk of administering VSV as PEP, I certainly would not characterize the inflammation following VSV vaccine administration as "cytokine storm". It certainly induces inflammation and can cause fever. Note that the only human to my knowledge who received this vaccine was the laboratory worker in Germany who had a needle stick injury and she got a fever following vaccination. Inflammation that results in fever will virtually always induce secretion of cytokines of various sorts. Since VSV in the NewLink vaccine is a replicating virus, it will almost certainly induce the secretion of cytokines. The reason that this might be important is that a whole array of cytokines are important in the pathogenesis of Ebola virus disease. It certainly can kill you (advanced cytokine storm) and it is almost certainly involved in protection and recovery from Ebola infection. It is a delicate balance that we do not fully understand. At this time, we are unclear about the positive versus negative effects of cytokine secretion (or call it dysregulation) related to the precise cytokines in question and the timing of their secretion vis-à-vis Ebola infection (see first bullet in the first of 2 slides in the first attachment. In my mind, this does not mean that one should not provide VSV as PEP for your people (or others); however, if administered to them, it should be made clear to the recipients that 1) VSV Ebola vaccine provided 50% protection in monkeys if given 20-30 minutes following exposure. I would mention that monkey models are somewhat different from human Ebola (see 3rd and 4th bullet of 2nd slide in first attachment) and so direct extrapolation to humans should be made with caution at this point in time; and 2) importantly, the vaccine recipients should clearly understand that there is a theoretical possibility that the VSV, due to the complexities of the cytokine dysregulation that accompanies Ebola infection and the perturbation of this cytokine network that might occur with a live virus vaccine (VSV) that induces inflammation and fever, might actually cause them harm by disturbing their normal inflammatory/immune response to Ebola infection. If they understand these caveats, then it would be their choice to receive the vaccine with informed consent. Finally, as you certainly know better than anyone, the FDA will have to be involved in the approval of allowing this pre-positioning and potential use of an experimental vaccine by whatever is the appropriate regulatory mechanism. I hope that this information is helpful to you in your deliberations about PEP. I look forward to discussing these issues with you. Best regards, Tony -----Original Message----- From: Frieden, Thomas (Tom) (CDC/OD) Sent: Sunday, August 31, 2014 3:49 AM To: Fauci, Anthony (NIH/NIAID) [E] Subject: Cytokine I had heard of cytokine storm with tekmira but not with VSV. Can you confirm? Did MSNBC