Monday, December 19, 2005

Is the flu vaccine problem only skin deep?

In an earlier post on the relatively disappointing results from the H5N1 vaccine trials with alum adjuvant, a commenter (Joseph B.) asked about another way to stretch the vaccine, intradermal administration. It was an excellent question. Here is the rationale for this technique.

Skin, unlike muscle, is well supplied with dendritic cells (specialized immune cells that process and present antigen). If dendritic cells are given the opportunity to process the viral antigen in vaccine, we might be able to use far less than for conventional intramuscular injection, which, while slightly easier to perform, essentially by-passes an important immunologic organ (the skin) and is thus inefficient.

Last year during a vaccine shortage, caused by half of the US vaccine supply going down the crapper because of contamination in Chiron Corporation's UK vaccine facility, intradermal administration was tried in Belgium and at St. Louis University Medical Center.
One study—supported by a grant from GlaxoSmithKline—was conducted at St. Louis University and recruited 238 participants: 130 men and women ages 18 to 60 and 108 who were 60 or older. Each age-group was further divided to receive either the intramuscular influenza vaccine (69 in the younger group and 50 in the older group) or the intradermal vaccine (61 in the younger group and 58 in the older group). The intradermal vaccine was administered using a tuberculin syringe and needle and contained approximately 40% of the antigen needed for one 0.5-mL dose of the intramuscular vaccine. Both of the vaccines contained one strain of influenza type A (H1N1), type A (H3N2), and a type B virus.

The other study was conducted by Iomai Corporation—a company that develops transcutaneous vaccines. The investigators used data from a larger Belgian study of influenza vaccination in healthy men and women. The researchers used results from the open-label, randomized portion of the study that evaluated different routes of administration for their safety and efficacy. In this study, the intradermal vaccine contained 20% of the antigen in the intramuscular vaccine. One hundred patients ages 18 to 40 were enrolled (50 in each group), and both groups received a vaccine that included two type A (H1N1 and H3N2) viruses and two type B viruses. (
Protection was assayed by determining the extent to which serum prevented the virus's usual ability to clump (hemagglutinate) red blood cells after three weeks. There were some differences between the IM and ID groups in one age group, the over 65 year olds, where the ID vaccine response was lower than the IM group in St. Louis but higher than the IM group in the Belgian study. Overall, titers were higher for the IM group but both groups had comparable in their ability to produce protective antibody titers.

The recently reported adjuvanted vaccine stretched supplies by a factor of three over conventional seasonal flu vaccine, but since the H5N1 vaccine required a twelve-fold greater amount of antigen spread over two doses a month apart, the current vaccine production capacity still would be cut by three-quarters. Intradermal injection provided up to a five fold improvement in seasonal vaccine use. It isn't clear whether it could be combined with adjuvant for a still greater increase, but in any event it seems the intradermal route is worth looking at. Intradermal injection uses different needles and a different technique, but it isn't hard to learn. It took me about five minutes to learn it for TB skin testing when I was a medical student.

The pity of all this is that we took so long to get started on this when the problem was visible years ago. With a properly functioning federal public health establishment (one that doesn't screw up flu vaccine supplies every year), we could have known the answers to some of these questions by now. (Every time I say something like this a commenter complains I am making a partisan swipe at the Bush Administration. Yes, I am. Because they deserve it.)

The St. Louis studies were reported in the New England Journal of Medicine on November 3, 2004, the Belgian studies in JAMA. 2004;292:2089-2095.