To the Editor: Treanor et al. (March 30 issue)1 conducted awell-designed study of a poor vaccine produced by methods thatare used in the labor-intensive manufacture of conventionalinactivated influenza vaccine. This subvirion influenza A (H5N1)vaccine induces a hemagglutinin-dominant immunity that is susceptibleto failure resulting from antigenic changes.2,3,4 It is notpossible to predict how closely related the H5 subtype of hemagglutininis to influenza A/Vietnam/1203/2004 and how protective the immunitywill be against an emerging pandemic strain. Two 90-µgdoses of the vaccine (which is 12 times as great as the doseused in the conventional influenza vaccine4) induced significantimmune responses in 54 to 58 percent of subjects. However, thepurchase and stockpiling of this vaccine are wasteful of scarcehealth care dollars. Money would best be directed at researchon the use of adjuvants, alternative techniques for producingrecombinant H5 hemagglutinin, and the addition of other influenzaproteins (e.g., neuraminidase, eM2, and conserved T-cell epitopes)to broaden the immune response against influenza. Updating productioncapabilities with a shift in vaccination methods could allowfor flexibility in the choice of antigen and decreased productiontime.
Bert E. Johansson, M.D., Ph.D. 819 Mt. Kisco Rd. Armonk, NY 10504
Ian C. Brett, B.S. State University of New York at Stonybrook, School of Medicine Stonybrook, NY 11794
References
Treanor JJ, Campbell JD, Zangwill KM, Rowe T, Wolff M. Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine. N Engl J Med 2006;354:1343-1351. [Free Full Text]
Johansson BE, Kilbourne ED. Influenza vaccine strain selection: equivalence of two antigenically distinct haemagglutinin variants of 1989 H3N2 influenza A virus in protection of mice. Vaccine 1992;10:603-606. [Medline]
Kilbourne ED, Smith C, Brett I, Pokorny BA, Johansson B, Cox N. The total influenza vaccine failure of 1947 revisited: major intrasubtypic antigenic change can explain failure of vaccine in a post-World War II epidemic. Proc Natl Acad Sci U S A 2002;99:10748-10752. [Free Full Text]
Couch RB, Kasel JA, Gerin JL, Schulman JL, Kilbourne ED. Induction of partial immunity to influenza by a neuraminidase-specific vaccine. J Infect Dis 1974;129:411-420. [ISI][Medline]
To the Editor: Regulatory factors encourage trials that useconventional approaches, such as intramuscular injection ofegg-derived hemagglutinin without adjuvants, as reported byTreanor et al., but the threat of an influenza pandemic shouldexpedite the acceptance of new strategies. As of January 24,2006, 28 vaccines against avian or pandemic influenza were registeredat the International Federation of Pharmaceutical Manufacturersand Associations (IFPMA), of which 19 vaccines were againstthe H5N1 subtype.1 Of those vaccines, none have been investigatedwith the use of intradermal delivery, which has already provedto be effective at reducing to just 3 µg per dose theamounts of hemagglutinin required for the induction of theoreticallyprotective antibody titers against the H3N2 and H1N1 subtypesamong subjects between the ages of 18 and 60 years.2,3 Furthermore,none of the vaccine trials listed by the IFPMA use less than1.7 µg of hemagglutinin.1 Even if those trials succeed,there will be the scaling-up hurdles pointed out by Poland inhis accompanying editorial.4 If the hemagglutinin dose remainsa limiting factor, vaccines that are produced by reverse geneticsand culture of mammalian cells should be thoroughly investigated,including those delivered epidermally.5
Belshe RB, Newman FK, Cannon J, et al. Serum antibody responses after intradermal vaccination against influenza. N Engl J Med 2004;351:2286-2294. [Free Full Text]
Kenney RT, Frech SA, Muenz LR, Villar CP, Glenn GM. Dose sparing with intradermal injection of influenza vaccine. N Engl J Med 2004;351:2295-2301. [Free Full Text]
Poland GA. Vaccines against avian influenza — a race against time. N Engl J Med 2006;354:1411-1413. [Free Full Text]
Drape RJ, Macklin MD, Barr LJ, Jones S, Haynes JR, Dean HJ. Epidermal DNA vaccine for influenza is immunogenic in humans. Vaccine (in press).
The editorialist replies: I agree with Focosi that in view ofa pandemic influenza threat, we must develop new techniquesand strategies for the rapid production of new candidates forpandemic vaccines. However, we need to be cautious about theapplication of results of studies of various delivery methods(such as intradermal injection) and doses of seasonal vaccinesto new influenza antigens. This caveat reinforces the need forcareful, parallel tracks of ongoing clinical research studiesregarding dose, delivery, and concomitant adjuvant agents fornew influenza-vaccine candidates. As I pointed out in my editorial,a variety of candidates — including vaccines administeredwith adjuvant, peptide-based vaccines, and vaccines developedwith adenovirus vectors — deserve consideration in orderto meet the terrible threat of pandemic influenza. Furthermore,the testing and clinical trials of viable candidates shouldoccur in parallel, rather than in serial studies, in order toexpedite the compilation of results.
Gregory A. Poland, M.D. Mayo Clinic College of Medicine Rochester,MN 55905
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