Flu Fighters
Brendan Maher
Tuesday, 01 July 2008 20:44 UTC
Media interest may seem to have cooled, but experts are as worried as ever about an impending avian-influenza (H5N1) outbreak in humans quickly becoming a pandemic. A vaccine stockpile may prove to be invaluable for stemming the death toll.
This week in a Commentary in Nature, Tadataka Yamada, Alice Dautry and Mark Walport urge the vaccine research and development community not to become complacent about this important issue. Although their respective institutions — the Bill & Melinda Gates Foundation, the Pasteur Institute and the Wellcome Trust — are working with other parties to develop new resources and collaborative opportunities to provide vaccines where they may be needed most (the developing world), the authors say a wider community response is also needed.
In a related Commentary, Steven Salzberg calls for greater transparency in the viral-strain selection process for the human influenza vaccine. The vaccine for the 2007–2008 season failed for predictable and, says Salzberg, avoidable reasons. If the process remains closed, and researchers are denied access to sequencing data used in the selection process, future vaccine failures could be more dramatic and deadly.
What do you think? Can a pre-pandemic vaccine curb a major catastrophe? And are the cooperative attitudes that Yamada, Dautry and Walport advocate exactly the kinds of things that are lacking from efforts to develop seasonal flu vaccines?
Updated 09 July 2008 19:50 UTC
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Replies
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Greetings all!
Am I missing something, or does it seem odd to you, that countries are talking about stockpiling vaccines for HP H5N1 influenza that only last 18 months on the shelf ignoring genetic drift of the influenza?
I understand, also to have any effect, the vacines for HP H5N1 influenza have to be given in two doses separated by a month, prior to facing any possible HP H5N1 influenza exposure in the community.
Why not start vaccinating? I also understand, the vaccine being stockpiled against a pandemic influenza outbreak is all clade 1, a specific genetic type of HP H5N1 influenza. Most of the recent human infections were running clade 2 when samples were available for typing and were published. The vaccine of clade 1 was not protective at all against clade 2, but prior vaccinations with two doses of clade 1 vaccines increased the efficacy of a single dose of clade 2 vaccine to the point where a single dose of clade 2 was protective against clade 2 HP H5N1.
Point of information, also I understand, that Japan is no longer just stockpiling vaccines but starting to vaccinate health care and necessary services workers, first in a small test program and then if all goes well, using all their vaccines before they expire on the shelves.
I am also pleased to hear the experts expect casualties only in the tens of millions from an HP H5N1 influenza pandemic without widespread pre-pandemic vaccination. With death rates from the HP H5N1 currently running 61% to 80+% depending on the country and strain with the best intensive care available, one might expect casualties into hundreds of millions if not in the billions if the pandemic hits as badly as the 1918 influenza pandemic and health care facilities become hugely overwhelmed.
Sincerely,
Janice Guidotti, M.D. -
Janice, you’re not missing anything – your point is quite accurate. Yes, the stockpiling of H5N1 vaccines doesn’t make a whole lot of sense, given what we know about the rapid genetic drift of the virus. And as you point out, it has already split into several clades (sub-strains), and a vaccine against one may have little efficacy against another.
I think that what we’re witnessing is an attempt by some governments to demonstrate that they’re doing something to prepare for a flu pandemic – even if what they’re doing is completely ineffective. This happens all too often. The US government has also been stockpiling Tamiflu, which is almost completely worthless as a method of preventing or even slowing the spread of avian flu. The makers of Tamiflu (Roche) don’t mind at all, of course.
What our governments can and should do is launch a crash program to create vaccines using non-egg based methods. This could allow us to get a new vaccine – if a pandemic strain appears – into production in a matter of weeks. In the meanwhile, we just have to hope that a pandemic doesn’t happen.
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Media interest in flu is erratic and always needs to be critically assessed, as set out by Debra Blakely in her 2007 book, Mass Mediated Disease: A Case Study Analysis of Three Flu Pandemics and Public Health Policy. The Nature leader, “The long war against flu” (10 July 2008) is quite right that “as long as H5N1 continues to be present in animals, that risk [of a human flu pandemic] persists” and is “inevitable.”
Unfortunately, as the H5N1 virus continues to circulate in chickens, ducks and turkeys the possibility of a genetic reassortment of the virus becomes greater. Perhaps the greatest danger is that pigs will serve as mixing vessels for a new strain of the virus that has the capability to reach the lower part of the human respiratory system (which the present H5N1 virus happily does not have). There is a need to unify human and veterinary medicine in relevant research, especially as the virus is most likely to mutate in the thousands of “wet markets” of Southeast Asia where live chickens, ducks and pigs are sold to keen buyers.
Steven Salzberg is quite correct that it would be a great idea to “launch a crash program to create vaccines using non-egg based methods.” However, such a program would require extensive financial and research co-operation between international organizations, national governments and the pharmaceutical industry. Perhaps this need for cell-based vaccines would be an excellent project for the Bill & Melinda Gates Foundation’s Global Health Program, the Pasteur Institute and the Wellcome Foundation to tackle together to get ready for a coming flu pandemic whose timing and casualties remain unknown.
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Greetings Steven and Robert and others:
The clades of HP H5N1 type A influenza or AI for short, represent something like strains. A single clade has one genome. Various mutations may be included in the clade subtypes. So for example clade 1.2 would be more closely genetically related to clade 1.1.3 than to clade 2.2.2. The clades represent some attempt to measure the distance in genetic diversity between various samples of a virus. The clade differences do not always indicate differences in cross reaction to antibodies or vaccines. A single clade will react the same to the same antibodies no matter where captured, but clade 1.1.3 may cross react more strongly with an antibody to say a clade 2.2.2 than to a clade 1.2. The antibody reactions, infectivity of various clades, contagiousness and morbidity caused still have to be defined in laboratory tests. It is likely clade 2.2.2 will react more like clade 2.2.3 than clade 1.2, to a given antibody but that is not guaranteed at all.
The stockpiling of Tamiflu is another not totally wise choice either I understand. Tamiflu’s shelf life is reported to be five years, better than the vaccines, but not unlimited. It has looked to be effective in the field in the recent Indian outbreak as none of the government employees culling AI infected chickens taking Tamiflu were reported to have become infected. There are however, distressing reports of numerous strains of flu acquiring resistances to Tamiflu quite quickly.
The current human vaccines developed by Sanofi-Pasteur are, I believe, already not grown in chicken eggs but in a patented cell line. The HP H5N1 influenza was so lethal to chickens and chicken eggs, sufficient quantities of antigen to make any vaccine could not be produced in chicken eggs I understand. I do believe this cut down on the amount of months it takes to produce vaccines against new strains, but I do believe it would still take months following capture of a new strain of AI, such as in a pandemic, to produce any sizable batch of vaccines.
I am not working in the field, but have read a bit about it. My reading led me to think pre-pandemic vaccination is still the best option.
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Greetings all – a great forum!
Pardon me if I am wrong, but isn’t the reason that currently circulating flu variants are not so dangerous, and the reason that single-dose vaccines work, because of prior exposure of the bulk of the population?
Meaning that vaccination with even a mismatched H5N1 HA or full vaccine would serve to ameliorate the severity of subsequent infection, AND limit onward spread?
All the more reason, then, to introduce pre-emptive vaccination? As someone living in a developing country with more than a passing interest in vaccines and immunity, I know I would be happy to use even an experimental H5N1 vaccine!
Ed Rybicki
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Apropos of which…I have a detailed post on this and other matters pertaining to flu vaccination at ViroBlogy.
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There really are two separate parts to Ed’s long question. First most currently circulating flu variants are much less lethal than the HP H5N1 currently circulating in Asia, Europe, and Africa. The HP H5N1, or AI, was named HP for highly pathogenic, meaning very lethal. It is lethal in about 100% of cases in chickens. Other strains of flu are usually much milder than that. There is a strain of H5N1 influenza circulating in North American birds that was termed an LP H5N1, for low pathogenic, which is nowhere near as dangerous to birds or people. The AI is just a more lethal strain of flu.
The seasonal flu’s most of us just shrug off after a week can also be quite lethal. Flu kills about 30,000 Americans every year. But as a percentage, seasonal flu has a very low percentage of lethal cases.
Both people and birds usually develop totally protective antibodies after one exposure to a strain of flu. You never get the same strain twice.
Flu vaccines cause the body to make the same kind of protective antibodies using parts of killed viruses or a weakened strain of the virus depending on which vaccine for seasonal flu you get. A single dose of a vaccine provides protective antibodies in adults because they have exposure to similar viruses or prior vaccinations. Babies get multiple doses of seasonal flu vaccines when first vaccinated. Since very few people have ever been exposed to any H5N1 influenza, and the H5N1 is very different from other types of flu, most people need two doses about a month apart of vaccine to H5N1 to make enough antibodies to protect them from an H5N1 influenza.
I don’t know of any reports of people who had an HP H5N1 vaccine who were actually exposed to HP H5N1, yet. I understand Japan is offering the vaccine to workers who would be involved in culling chickens sick or dead of HP H5N1 and inspecting imported birds.
There is no guarantee an HP H5N1 vaccine mismatched to a circulating HP H5N1 pandemic will do anybody any good at all. Vaccines for seasonal influenza mismatched to circulating viruses frequently do not prevent infection or even make it milder unless the circulating virus is quite close to the vaccine type.
However, there have been reports after two vaccinations a month apart with vaccine for clade 1 HP H5N1, a single vaccination with clade 2 HP H5N1 vaccine produces a higher antibody response that is in the level to be protective against clade 2. Additionally, the antibodies to clade 1 rise after a following vaccination against clade 2. So the prior doses of an H5N1 mismatched against a pandemic virus can improve both the response time and protection of a vaccine against a pandemic virus. I don’t know if there is any broad based protection, as the seasonal vaccines do not seem to provide a broad based protection.
Hong Kong has reported that some vaccinated chickens can acquire HP H5N1, and shed the virus after being vaccinated but without dying. Whether this represents a failure of the vaccine or a mismatched vaccine and virus type is not clear. I never read a report about the amount of virus shed. I haven’t yet read of any humans infected after the HP H5N1 virus was found in a random check of a chicken market in Hong Kong. However, the chickens may have all appeared well, and if there were any human infections they may have been missed as none of the patients would have reported a history of having been exposed to sick or naturally dead chickens. Vietnam also vaccinates chickens, and reports no infections in farmers handling chickens that have been vaccinated.
And although there has never been any of the HP H5N1 found in my hemisphere, I agree with Ed and would be interested in taking any available vaccine for HP H5N1.
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