A vaccine's little helpers
The Sanofi-Pasteur H5N1 vaccine was a bust because it took too much viral antigen to produce a protective effect, and that in only a little over half the recipients. The obvious thing to do next is add adjuvants, additional materials that boost the potency of the viral material. The vaccine giant GlaxoSmithKline (GSK) is now beginning clinical trials in Germany and Belgium with a low dose vaccine containing adjuvants (reported by Helen Branswell, Canadian Press)
Historically, the first adjuvant was tapioca, added to diphtheria or tetanus toxoid in 1925. In 1926 it was discovered that aluminum salts were effective and these alum adjuvants are still the only licensed vaccine adjuvants in the United States. However there are also "natural adjuvants" present in the heterogeneous mixtures of killed organisms comprising many vaccines. The natural adjuvants are an assorted mixture of tiny amounts of active exotoxins and endotoxins not removed in the older vaccine making processes. Ironically, the use of modern methods of genetic engineering to produce purified viral proteins has also reduced their immunogenicity, perhaps because the natural adjuvants from killed whole virus vaccines are missing.
How do adjuvants work? Researchers have made progress understanding this in the last 20 years, but there is still much to learn. The earliest idea was that alum adjuvants worked by associating with the antigen and making it hang around longer at the injection site, thus allowing more interaction with the immune cells that process it and present it to lymphocytes. We now believe there are also effects on the processing and delivery of the antigen. Adjuvants can also affect the immune system's chemical signaling system (cytokines) which then modulate its response. There is still no consensus about how alum adjuvant works, despite its long use in vaccines.
In its new trials, GSK is proposing to test four doses of viral antigen, ranging from 3.75 µg to 30 µg. In the unadjuvanted vaccine just reported in the New England Journal of Medicine (post here), a little more than half those receiving the highest dose of 90 µg achieved protective levels of antibody and required two doses. This would require twelve times the vaccine production capacity we now use for seasonal flu, a capacity that is already inadequate. Thus using doses at or even a fraction of the current12 15 µg used for seasonal flu would be a breakthrough. An earlier pilot study with conventional alum adjuvant done by Sanofi suggested that 30 µg, twice, might be sufficient for protection, but this is still fivefour times the dose now used in conventional flu vaccine. There is no reason to expect that the GSK alum adjuvanted trial will differ, but we shall see.
So in addition, GSK plans to test a novel adjuvant, which they will not identify except to say it is not their proprietary adjuvant, MPL (monophosphoryl lipid A). That raises safety and licensing questions. There is always a risk that the added benefits for immunogenicity provided by an adjuvant will be balanced by some adverse reaction. The most likely would be increased frequency of pain and tenderness at the injection site, granulomas or sterile abscesses there. (A granuloma is a non-specific inflamatory reaction appearing as a reddened, raised bump. They are usually not serious.) Malaise, fever and other systemic reactions are also seen and not uncommon. However, the immune system is complicated and sometimes reacts in unexpected ways. Phase I and II clinical trials are mainly designed to test the safety of a vaccine, with or without adjuvants.
Another way to increase potency ("spare antigen") is through the use of intradermal (ID) injection. Instead of injecting the vaccine deep into the shoulder muscle (IM), the vaccine is injected within the skin surface. This produces a little bubble or bleb of liquid in the skin which absorbs quickly. Many people are familiar with tuberculin skin tests which are done this way. ID injection uses a different and smaller syringe and needle than IM, is slightly more difficult to administer (but an unskilled worker can learn it in less than 15 minutes), and probably would be less comfortable for children than an IM injection. But evidence suggests there is a substantially greater immune response to ID versus IM administration (see a previous post here), so combined with adjuvant this would seem to be a natural next step. We know of no ID trials of H5N1 vaccine underway, however. The disappointing early efforts do not mean we are up against a wall. A natural way forward seems clear, of which the GSK adjuvanted trials are one step. Cell culture vaccines and ID trials may be just over the horizon.
But all these steps take time. We got a very late start despite the fact that this problem has been visible to public health experts for years, if not decades. The late start is a reflection of the low priority national leaders have for the most fundamental of security issues, the security of being healthy and not sick. Letting our public health systems fall into disrepair and our tools dwindle and rust away is a result of failed leadership, a failure that in the US encompasses both Democratic and Republican administrations but which has reached new heights of incompetency, blindness and outright stupidity in the administration of George W. Bush.
The US has laid waste two other countries (Iraq and Afghanistan) while we have simultaneously left our own country and people open to attack by a virus with no ideology, no political party and no mercy. For those of you who don't like us to inject "politics" into a public health discussion, we suggest you think about it again. If we'd had even a five year head start we'd be so much farther ahead. Then consider why we aren't and why there is a good chance H5N1 will beat us to the finish line.
The finish line.
Historically, the first adjuvant was tapioca, added to diphtheria or tetanus toxoid in 1925. In 1926 it was discovered that aluminum salts were effective and these alum adjuvants are still the only licensed vaccine adjuvants in the United States. However there are also "natural adjuvants" present in the heterogeneous mixtures of killed organisms comprising many vaccines. The natural adjuvants are an assorted mixture of tiny amounts of active exotoxins and endotoxins not removed in the older vaccine making processes. Ironically, the use of modern methods of genetic engineering to produce purified viral proteins has also reduced their immunogenicity, perhaps because the natural adjuvants from killed whole virus vaccines are missing.
How do adjuvants work? Researchers have made progress understanding this in the last 20 years, but there is still much to learn. The earliest idea was that alum adjuvants worked by associating with the antigen and making it hang around longer at the injection site, thus allowing more interaction with the immune cells that process it and present it to lymphocytes. We now believe there are also effects on the processing and delivery of the antigen. Adjuvants can also affect the immune system's chemical signaling system (cytokines) which then modulate its response. There is still no consensus about how alum adjuvant works, despite its long use in vaccines.
In its new trials, GSK is proposing to test four doses of viral antigen, ranging from 3.75 µg to 30 µg. In the unadjuvanted vaccine just reported in the New England Journal of Medicine (post here), a little more than half those receiving the highest dose of 90 µg achieved protective levels of antibody and required two doses. This would require twelve times the vaccine production capacity we now use for seasonal flu, a capacity that is already inadequate. Thus using doses at or even a fraction of the current
So in addition, GSK plans to test a novel adjuvant, which they will not identify except to say it is not their proprietary adjuvant, MPL (monophosphoryl lipid A). That raises safety and licensing questions. There is always a risk that the added benefits for immunogenicity provided by an adjuvant will be balanced by some adverse reaction. The most likely would be increased frequency of pain and tenderness at the injection site, granulomas or sterile abscesses there. (A granuloma is a non-specific inflamatory reaction appearing as a reddened, raised bump. They are usually not serious.) Malaise, fever and other systemic reactions are also seen and not uncommon. However, the immune system is complicated and sometimes reacts in unexpected ways. Phase I and II clinical trials are mainly designed to test the safety of a vaccine, with or without adjuvants.
Another way to increase potency ("spare antigen") is through the use of intradermal (ID) injection. Instead of injecting the vaccine deep into the shoulder muscle (IM), the vaccine is injected within the skin surface. This produces a little bubble or bleb of liquid in the skin which absorbs quickly. Many people are familiar with tuberculin skin tests which are done this way. ID injection uses a different and smaller syringe and needle than IM, is slightly more difficult to administer (but an unskilled worker can learn it in less than 15 minutes), and probably would be less comfortable for children than an IM injection. But evidence suggests there is a substantially greater immune response to ID versus IM administration (see a previous post here), so combined with adjuvant this would seem to be a natural next step. We know of no ID trials of H5N1 vaccine underway, however. The disappointing early efforts do not mean we are up against a wall. A natural way forward seems clear, of which the GSK adjuvanted trials are one step. Cell culture vaccines and ID trials may be just over the horizon.
But all these steps take time. We got a very late start despite the fact that this problem has been visible to public health experts for years, if not decades. The late start is a reflection of the low priority national leaders have for the most fundamental of security issues, the security of being healthy and not sick. Letting our public health systems fall into disrepair and our tools dwindle and rust away is a result of failed leadership, a failure that in the US encompasses both Democratic and Republican administrations but which has reached new heights of incompetency, blindness and outright stupidity in the administration of George W. Bush.
The US has laid waste two other countries (Iraq and Afghanistan) while we have simultaneously left our own country and people open to attack by a virus with no ideology, no political party and no mercy. For those of you who don't like us to inject "politics" into a public health discussion, we suggest you think about it again. If we'd had even a five year head start we'd be so much farther ahead. Then consider why we aren't and why there is a good chance H5N1 will beat us to the finish line.
The finish line.
posted by Revere at
4/01/2006 08:36:00 AM
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