Key Point

The intradermal influenza vaccine can use less than one quarter of the amount of antigen currently needed for one adult intramuscular dose without sacrificing immunogenicity, although it appears to be more effective in younger recipients.

NEW YORK CITY—The unexpected shortage of influenza vaccine in the United States this year has generated renewed interest in alternative routes of administration that could immunize the most people using a smaller dose. One such method—already in use with vaccines against rabies and hepatitis B—is intradermal administration.

The skin has a large number of dendritic cells that are responsible for recognizing and defending against foreign microbes. Thus, vaccines introduced directly into the skin elicit a fairly strong immune response but use less than one quarter of the antigen in a traditional intramuscular vaccine.

Two recent studies compared the safety and efficacy of an intradermal influenza vaccine versus an intramuscular vaccine, both in patients younger than 60 and in those 60 and older. The intradermal vaccine was as effective as the intramuscular vaccine in recipients younger than 60, but the immune response to both vaccines was mitigated in older patients.^1,2

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.

In both studies, immunogenicity was assessed via serum samples collected at baseline and after 21 days.

VACCINES HAVE SIMILAR IMMUNOGENICITY IN YOUNGER PATIENTS

In the St. Louis study, there was no significant difference between vaccine groups in hemagglutination inhibition (HAI) titers to any of the antigens. However, in the older age-group, the frequency of seroconversion was less than 30% with either the intramuscular or the intradermal vaccine. Additionally, in those older than 65, only the response to the type A (H3N2) strain was significantly lower in the intradermal group compared to the intramuscular group.

The reasons for the lower response in the elderly were not clear. The authors speculated about the possibility of the older group having high titers to begin with—in which case the vaccine would not elicit a strong immune response.

In the Belgian study, there was no measurable difference between routes of administration, except for the type A (H3N2) strain—which induced a significantly greater response in the intradermal group. In this patient group, seroconversion rates at 21 days ranged from 66% to 82% with the intramuscular route, compared to 78% to 82% with the intradermal route. The HAI responses achieved in both groups on day 21 were high and similar.

Overall, in the St. Louis study, the intradermal vaccine provided protective levels of antibodies, but the intramuscular vaccine induced higher levels. Obviously, higher titers are more desirable, but the authors pointed out that even the quantities of antigen used in the current intramuscular vaccine provide 40% to 90% protection—depending on patient age. In other words, a strong immune response is never guaranteed, even with the intramuscular vaccine.

VACCINATION LOWERS INFLUENZA-RELATED HOSPITALIZATION RATES IN THE ELDERLY

Although the immune response was low in the elderly, vaccination offers this group protection against hospitalization for influenza-related illness, rather than protection against the virus alone. An editorial commentary highlighted the importance of this finding, noting that more than 90% of influenza-related deaths in the US occur among those older than 65.³

To examine the protective effect of the influenza vaccine in the elderly, Dutch researchers conducted a population-based cohort study of community-dwelling individuals who were 65 and older.⁴ The study tracked cumulative exposure to the influenza vaccine from 1996 through 2002. The annual vaccination rate for this age-group was 64% in 1996 and 74% in 1999. Of 26,071 eligible individuals, 5,095 never received an influenza vaccine. Overall, any vaccination was associated with a 22% lower risk of death. Any revaccination reduced risk of death by 24%. During epidemics, revaccination reduced mortality risk by 28%, compared with first vaccination only.

According to the study results, one death was prevented for every 302 vaccinations or 195 revaccinations. Compared with patients ages 65 to 69 at baseline, revaccination reduced mortality to a much greater extent in those who were older than 70 at baseline. The authors reported that these results support annual influenza vaccination not only for elderly people with comorbidities but also for the healthy elderly and for those 80 and older.

NOW IS THE TIME TO USE NEW TECHNOLOGIES

The administration technique for an intradermal vaccine is more difficult to master than that for an intramuscular vaccine, but once it is learned, trained personnel should have a high rate of success using it. In times of vaccine shortage, having an intradermal preparation available could help immunize at-risk groups.¹ It could also increase the vaccine supply by a factor of about five.

The Belgian study was carried out with healthy young adults, in whom the intradermal vaccine elicited immune responses that were at least equivalent—if not superior—to those obtained from the intramuscular vaccine.

The authors of the St. Louis study pointed out that serum antibody provides protection against influenza. They went on to explain that in times of vaccine shortage (such as the present) “intradermal vaccination of healthy young persons with reduced dose inactivated influenza vaccine could be considered in order to stretch vaccine supplies.”¹

The skin is an effective site for delivery of vaccines, noted the Belgian study authors, who used the example of the smallpox vaccine to illustrate its effectiveness.

“Intramuscular injection of vaccine bypasses the skin’s immune system and delivers influenzavirus and other antigens into tissue that has no important resident population of antigen-presenting cells.”²

The authors of the editorial also observed that different vaccination routes would increase vaccine availability during shortages. Thus, continued research as well as timely approval of new routes of administration are essential. “Technological innovation, such as the use of new vaccines delivered by the intradermal route, offers great promise to change and improve on current immunization strategies. It is our responsibility to pursue these and other approaches in order to advance our ability to meet the inevitable challenges of emerging and reemerging infectious diseases, particularly influenza.”³

—Gale Jurasek

References
1. Belshe RB, Newman FK, Cannon J, et al. Serum antibody responses after intradermal vaccination against influenza. N Engl J Med. November 3, 2004. [epub ahead of print].
2. Kenney RT, Frech SA, Muenz LR, et al. Dose sparing with intradermal injection of influenza vaccine. N Engl J Med. November 3, 2004. [epub ahead of print].
3. La Montagne JR, Fauci AS. Intradermal influenza vaccination—can less be more? N Engl J Med. November 3, 2004. [epub ahead of print].
4. Voordouw ACG, Sturkenboom MCJM, Dieleman JP, et al. Annual revaccination against influenza and mortality risk in community-dwelling elderly persons. JAMA. 2004;292:2089-2095.

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