To the Editor: I have been interested in the coverage by themedia of the studies of intradermal influenza vaccination byBelshe et al.1 and Kenney et al.2 (Nov. 25 issue). We had quitesimilar findings — albeit without a control group —over 50 years ago.3
Thomas H. Weller, M.D. 56 Winding River Rd. Needham, MA 02492
References
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]
Weller TH, Cheever FS, Enders JF. Immunologic reactions following the intradermal inoculation of influenza A and B vaccine. Proc Soc Exp Biol Med 1948;67:96-101.
To the Editor: In comparisons of intradermal and subcutaneousroutes of inoculation, an important control is often omitted— namely, the comparison of equal doses of vaccine deliveredby the two routes. This deficiency plagues the otherwise excellentstudies of influenza vaccine by Belshe et al. and Kenney etal. An editorial in the same issue appears under the subtitle"Can Less Be More?"1 Yes, it can — in a primed population.And in an immunologically "virgin" population (as in the pandemicof 1957) with a double-antigen change in the virus, it can atleast be equal, as was shown by McCarroll and me in a reportpublished in the Journal during that pandemic.2
Therefore, given the prospects of a pandemic or a vaccine shortageand the greater ease of subcutaneous injection of vaccine, futurestudies should compare apples with apples — without theassumption that either the booster or the priming effects ofsmall doses of vaccine are dependent on the injection site,rather than the amount of vaccine given.
Edwin D. Kilbourne, M.D. New York Medical College Valhalla, NY 10595 ekilbourne{at}snet.net
References
La Montagne JR, Fauci AS. Intradermal influenza vaccination -- can less be more? N Engl J Med 2004;351:2330-2332. [Free Full Text]
McCarroll JR, Kilbourne ED. Immunization with Asian-strain influenza vaccine: equivalence of the subcutaneous and intradermal routes. N Engl J Med 1958;259:618-621. [Medline]
To the Editor: As a hospital epidemiologist supporting massimmunization of health care workers against influenza, I welcomethe recent studies in the Journal concluding that lower dosesof intradermal influenza vaccine are equally immunogenic withthe traditional intramuscular doses in younger, healthy adults.One cannot help but wonder, however, whether the findings ofthese studies were available to the Centers for Disease Controland Prevention (CDC) in early October 2004 (one month beforethe publication of the articles), when it advised against usingpartial doses of the recommended dosages of inactivated influenzavaccine1 and instead recommended the use of live attenuatedinfluenza vaccine (FluMist) in most health care workers. Unfortunately,data on the safety of the live attenuated vaccine in healthcare settings — with regard to transmission to susceptiblepatients — are lacking, the practice is not supportedby the product label,2 and such use is not approved by the Foodand Drug Administration. Until safety data on the use of liveattenuated influenza vaccine in health care settings becomeavailable, it would seem that the immunization of health careworkers with reduced-dose injectable influenza vaccine wouldbe preferable to the use of live attenuated vaccine during periodsof vaccine shortage.
Farrin A. Manian, M.D., M.P.H. St. John's Mercy Medical Center St. Louis, MO 63141 manianfa{at}aol.com
References
Questions & answers: 2004-05 flu season. Atlanta: Centers for Disease Control and Prevention, January 18, 2005. (Accessed February 17, 2005, at http://www.cdc.gov/flu/about/qa/0405season.htm.)
Dr. Belshe and colleagues reply: The study by Dr. Weller andhis coworkers, conducted more than 50 years ago, foreshadowedmany of the results of the recently published studies of intradermalinfluenza vaccine. Dr. Weller used a bivalent influenza A andB vaccine administered intradermally at 1/50th of the usualdose and observed serum antibody increases of 3.6-fold for influenzaA and 2.9-fold for influenza B.1 He also noted the local inflammatoryresponses that were seen in our more recent study.2 Dr. Kilbournecorrectly points out that low-dose intramuscular vaccine inprimed persons might have yielded responses equivalent to thoseobserved after the administration of low-dose intradermal vaccine.3We agree that more definitive studies comparing the dose–responserelationships of intradermally and intramuscularly administeredinfluenza vaccine will be important to assess the potentialbenefits of intradermal immunization. These studies should includeevaluation of the cell-mediated immune responses, as well asmucosal immune responses, in primed persons who receive intradermalvaccine.
Our study was preliminary, and the results should not be consideredas definitive evidence that vaccination by the intradermal routewill provide protection at the level currently provided by licensedinfluenza vaccines; larger studies to demonstrate the noninferiorityof antibody responses after intradermal immunization, as comparedwith intramuscular immunization, and perhaps even vaccine-efficacystudies may be needed to elucidate the potential benefits oflow-dose intradermal vaccination. We do not expect that recommendingbodies such as the Advisory Committee on Immunization Practices(ACIP) would embrace this strategy without further data. Incontrast, live attenuated vaccine has been studied extensivelyin adults and has been shown to be efficacious in this population.The ACIP recommendations preferentially recommending it forhealthy persons such as health care workers in order to conservetrivalent influenza vaccine seemed quite reasonable in the faceof a shortage of inactivated vaccine.
Robert B. Belshe, M.D. Saint Louis University St. Louis, MO 63110 belsherb{at}slu.edu
John Treanor, M.D. University of Rochester Rochester, NY 14642
Gary Dubin, M.D. GlaxoSmithKline Biologicals King of Prussia, PA 19406
References
Weller TH, Cheever FS, Enders JF. Immunologic reactions following the intradermal inoculation of influenza A and B vaccine. Proc Soc Exp Biol Med 1948;67:96-101.
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]
Treanor J, Keitel W, Belshe R, et al. Evaluation of a single dose of half strength inactivated influenza vaccine in healthy adults. Vaccine 2002;20:1099-1005. [CrossRef][Medline]
Drs. Glenn and Kenney reply: Our report on intradermal influenzavaccination has brought to light some additional, older studieson the potential value of intradermal immunization.1,2 Althoughthey are informative, these early studies lacked relevant controls,were performed with monovalent vaccine, or used assays thatwere indicative but crude in comparison with those availabletoday. The goal of our trial was not to compare doses, but ratherto compare the responses — in a well-controlled studywith the use of a highly reproducible immunoassay — toa modern trivalent influenza vaccine administered intradermallywith as little as one fifth the normal dose of the availablecommercially licensed product.3 We found a similar responsewith the two routes; statistically significant superiority wasdemonstrated for one strain as compared with the full intramusculardose.
To move beyond these findings and make a general recommendation,a large, well-controlled, formal equivalence trial is neededto generate adequate data on safety and immunogenicity in severalage groups. Although physicians may have elected to give influenzavaccine intradermally this year on the basis of the recent data,we recommend that this larger data set be generated quicklyto support a public health recommendation for a dose-sparingstrategy, particularly given the potential for pandemic influenza.
We disagree with Dr. Manian's contention that the CDC mishandledthe information on dose-sparing vaccination this past fall,since it is this agency's duty to make sound policy recommendations,which must be based on larger efficacy and equivalence studies.In contrast, there is a tremendous amount of data on the safetyof the live attenuated influenza vaccine. Although health careworkers were asked to avoid severely immunocompromised patientsafter vaccination, in accordance with the package insert, theavailable safety data suggest that the CDC acted wisely in themidst of a supply crisis.
Dr. Kilbourne rightly points out that more should be learnedabout reduced-dose strategies. Treanor et al. recently studiedhalf-dose intramuscular immunization against influenza and foundreduced immune responses for all three strains, although theyargue that these differences are not clinically significant.4Finally, we point out that the more permanent problem and principalunmet need in annual influenza immunization remains the vaccine'srelatively poor immunogenicity in elderly persons, leading tosignificant but substandard protection in the most susceptiblepopulation. The most lasting lesson from our recent data isthe confirmation that the skin is a highly desirable immuneenvironment for the delivery of vaccines. Targeting the skinmay allow investigators to devise strategies for both dose sparingand improved immunogenicity in the elderly, as we have recentlyshown.5
Gregory M. Glenn, M.D. Richard T. Kenney, M.D. Iomai Gaithersburg, MD 20878 gglenn{at}iomai.com
References
Weller TH, Cheever FS, Enders JF. Immunologic reactions following the intradermal inoculation of influenza A and B vaccine. Proc Soc Exp Biol Med 1948;67:96-101.
McCarroll JR, Kilbourne ED. Immunization with Asian-strain influenza vaccine: equivalence of the subcutaneous and intradermal routes. N Engl J Med 1958;259:618-621. [Medline]
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]
Treanor J, Keitel W, Belshe R, et al. Evaluation of a single dose of half strength inactivated influenza vaccine in healthy adults. Vaccine 2002;20:1099-1105. [CrossRef][Medline]
Frech SA, Kenney RT, Spyr CA, et al. Improved immune responses to influenza vaccination in the elderly using an immunostimulant patch. Vaccine 2005;23:946-950. [CrossRef][Medline]
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