| UPDATE Dec 1, 2009: Follow-up on anaphylaxis in this diary, Oil-Based Adjuvants and Mechanisms for Increased Risk of Anaphylaxis
Old FW hands may remember me saying I was an accidental blogger. It all started with me trying to explain something to someone, thinking I was just going to post a couple of comments, to clarify a few things, and that would be it. Of course, you know it didn't quite work out that way ;-D. I think the most rewarding - also the most addictive - part of writing on this forum is the sheer amount of knowledge you gain, either learning from others, or trying to answer a question, to share something that you know. Or at least you think you know. Until you start to double check, just to be sure, and you find yourself chasing one interesting lead after another, going deeper and deeper, and, before you know it, you've disappeared down a gigantic warren of rabbit runs (with Hat-Tip to beehiver!)...
Which was what happened to me the other day. ;-p Someone sent me a link and a question ("is this normal?"). I clicked on that link, and, thinking I ought to check my numbers before I replied, decided to invoke the powers of google. And then I was just gone. Of course, not being a rabbit, by the time I found my way out and finally saw daylight again, I discovered 3 days had gone by, but I'd learned so many things that now my new problem is trying to condense it all down to something sensible and which actually answers the question that was asked!! |
So, the basic question posted to me was, is this normal?
B.C. sees spike in severe reactions to flu shot
As Canadian health officials assured the public that the pandemic H1N1 vaccine is as safe as the seasonal flu shot, at least one province is reporting almost double the rate of severe allergic reactions.
British Columbia Centre for Disease Control said it is probing why residents suffered anaphylaxis at a higher rate compared with the previous five seasonal-flu-vaccination programs, suggesting it could be because some people received H1N1 and the seasonal flu shot simultaneously.
It will be several more weeks before B.C. officials can definitively attribute the spike in the rate - 2.2 per 100,000 doses distributed, compared to 1.2 per 100,000 doses. None of the 18 anaphylaxis reactions in B.C. resulted in death.
If you want the short answer, here it is. No, it isn't normal, for either of those numbers. The risk of anaphylaxis after unadjuvanted seasonal flu vaccination is very low, in the order of 1 in a million vaccinations (Public Health Agency of Canada 2002), not 1.2 per 100,000. So, 2.2 per 100,000 represents a 20 fold increase, not a 2-fold increase. Something is going on, if those 18 people did have anaphylactic reactions to the vaccine. And, as if to support my point, right on cue, GSK announces they are pulling a batch of vaccines suspected of causing severe allergic reactions at the even more alarming rate of 1 per 20,000!!
That's it. That's the short answer.
If you want the long one, make yourself a cup of, well, something nice ;-D, pull up a chair, and I'll give you a short tour of what I found on my subterranean forays..
So, there have been at least 18 cases of anaphylaxis in BC, after vaccination with the AS03-adjuvanted H1N1 vaccine. I say 'at least' because the vaccination campaign is far from over, plus there is no clear indication in that article what the cut-off date was for that count. And because the story just keeps on growing. Like here: Adverse reactions to H1N1 vaccine showing
At an Ottawa news conference, Dr. David Butler-Jones, Canada's chief public health officer, said the death involved an elderly person who went into a severe allergic reaction after receiving the vaccine, the Canwest News Service reported Wednesday.
and here:
http://thechronicleherald.ca/N... ...three people have been treated for anaphylactic shock since vaccinations began in the province....So far in Nova Scotia, 203,000 people have been vaccinated. Those people are in priority groups such as pregnant women, children under five and those under 65 with health conditions.
also here:
http://www.sott.net/articles/s... As of Nov. 16, there have been 88 adverse reactions in Manitoba to H1N1 vaccine, of which seven were considered serious. Five of those have been confirmed as anaphylactic reactions.
According to CBC News, by Nov 12, 200,000 people had been vaccinated in Manitoba, so we are talking about 2.5 per 100,000 vaccinations, about the same as the figures given for BC.
We've always known that if you vaccinate enough people, you're going to get adverse reactions, which may or may not be related to or caused by the vaccine. There are, however, few adverse reactions that are so unmistakably related to vaccination, than immediate allergic reactions. The most serious allergic reaction is anaphylaxis, which is characterized by (Anaphylaxis case definition, Brighton Collaboration):
- sudden onset
- rapid progression
- involvement of 2 or more organ systems, and
- often accompanied by skin changes
Anaphylaxis is dangerous because the severe forms can be life threatening, sometimes in a matter of minutes, due to respiratory obstruction from swelling of the throat, and/or shock from sudden cardiovascular collapse.
Anaphylaxis after vaccination is thankfully very rare, in the order of about 1 in a million vaccinations (Bohlke 2003, Nokleby 2006, Nakayama 2007, Pool 2002) and even less with the unadjuvanted seasonal flu vaccine (CDC 2009). The only exception in recent years seems to be Gardasil where in Australia they found the risk to be 2.6 per 100,000 doses (as compared to 0.1 per 100,000 for meningococcal vaccine), which was unusual enough that the investigators felt compelled to write a paper about it (Brotherton 2008). Anyway, here's a good overview of anaphylaxis risk, with data from around the world (Brotherton 2008)
There are other studies cited in that paper, eg with enhanced surveillance or school programs, but those did not find any cases of anaphylaxis with the flu vaccine, so they are not shown here. As for data from Canada, here's what I found:
Infuenza vaccine-associated adverse events: results of passive surveillance: Canada 2001-2002
During the 2001-2002 influenza season, a total number of 9,842,601 doses of influenza vaccine were distributed to health care providers in Canada, although the exact number of doses administered is unknown.
The serious adverse events reported were anaphylaxis (9 per 10 million doses distributed), Guillain-Barré syndrome (1 per 3 million doses distributed), convulsions (1 per 3 million doses distributed), paralysis (1 per 2.5 million doses distributed), and meningitis/encephalopathy (1 per 3 million doses distributed).
So there you have it, 1 in a million. Official Canadian figures. Granted it was for one year only, but given the abundance of data (above) I see no reason to believe the background risk of anaphylaxis in Canada from the seasonal flu vaccine should differ substantially from other countries or from that year. Which means that if the cases are confirmed, the risk of anaphylaxis from the adjuvanted vaccine may be 20 times higher than unadjuvanted seasonal flu vaccines, and not double, as suggested by Canadian officials and GSK.
In general, for the seasonal flu shot, the chief culprit for allergic reactions is thought to be ovalbumin, the main protein found in egg white. There are regulatory requirements as to the maximum allowable amount in a vaccine (Nasser 2009). Variations in the amount of ovalbumin can account for some variations in anaphylaxis risk from batch to batch, which is probably why they decided to recall one batch of vaccine. We don't know how many of those cases, eg in BC, did receive a dose from that particular batch, and I haven't come across any reports in the literature, of particularly bad batches of flu vaccines causing a 20-times increase in risk, so many questions still remain open, and we'll just have to wait and see what happens in the next few weeks.
In addition, for any new pharmaceutical product, there is always the question of whether the new formulation changes the risk profile. One example involves the substitution of polysorbate and glycine for human serum albumin, as excipients for stability, in the formulation of erythropoietin or EPO from 1 manufacturer, which resulted in a massive increase in a rare form of anemia called pure red cell aplasia or PRCA in patients on dialysis. Since this appeared to be specific to one product (Eprex) which was not licensed in the US, the difference in incidence of the disease between patients who received different preparations soon became very striking (Schellekens 2005)
While the jury is still out (Locatelli 2007) as to the exact mechanism involved in EPO-associated PRCA, this one change to a supposedly inactive component of the formulation also resulted in cases of anaphylaxis, which on investigation turned out to be caused not by EPO itself, but by the polysorbate in the preparation instead (Steele 2005). Indeed, hypersensitivity due to excipients like polysorbate may be more common than we think eg in multivitamin preparations given to pregnant women (Coors 2005) or in penicillin (Grims 2006). Excipients are easily overlooked in investigation, since false-positive skin tests to the whole preparation (eg penicillin), can cause clinicians to draw the wrong conclusion (eg penicillin sensitivity) unless patients are tested specifically for such excipients (Grims 2006)
So, the story is complex. As I look into possible mechanisms for increased risk of anaphylaxis beyond ovalbumin content, there just seems to be an endless number of rabbit-holes that reveal new and interesting revelations. At this point, there are a few suspects which are not mutually exclusive, that I hope to achieve enough interim closure to post about, if the trend of increased anaphylaxis risk continues. In the meantime, if this is all due to just one batch, by whatever mechanism, we should see the incidence of anaphylaxis return to the normal range of 1 in 1 million vaccinations soon. Since anaphylaxis is pretty easy to spot and very likely to be reported, it should become obvious in the coming weeks, whether such increase in cases has stopped or continues. Stay tuned.
UPDATE Dec 1, 2009: Follow-up on anaphylaxis in this diary, Oil-Based Adjuvants and Mechanisms for Increased Risk of Anaphylaxis |
