Current issues of ACP Journal Club are published in Annals of Internal Medicine


Intradermal injection of reduced-dose influenza vaccine was immunogenic in young adults


ACP J Club. 2005 May-Jun;142:69. doi:10.7326/ACPJC-2005-142-3-069

Related Content in this Issue
• Companion Abstract and Commentary: Intradermal injection of reduced-dose influenza vaccine was highly immunogenic in persons ≤ 60 years of age but less so in persons > 60 years

Clinical Impact Ratings

GIM/FP/GP: 5 stars

Allerg & Immunol: 5 stars

Infectious Disease: 5 stars

Source Citation

Kenney RT, Frech SA, Muenz LR, Villar CP, Glenn GM. Dose sparing with intradermal injection of influenza vaccine. N Engl J Med. 2004;351:2295-301. [PubMed ID: 15525714]



Is an intradermal injection of one fifth the standard intramuscular dose of a commercial influenza vaccine as immunogenic as the standard-dose intramuscular injection in young adults?


Design: Randomized controlled trial.

Allocation: Unclear allocation concealment.*

Blinding: Unblinded.*

Follow-up period: 42 days.

Setting: A hospital in Antwerp, Belgium.

Patients: 100 persons 18 to 40 years of age (mean age 31 y, 66% women) who were free of clinically important abnormalities in their medical history or on physical examination, serum chemical analysis, hematologic analysis, or urinalysis.

Intervention: Intradermal injection of 0.1 mL of trivalent influenza vaccine containing ≥ 3 µg of hemagglutinin antigen per strain (n = 50), or intramuscular injection of 0.5 mL of vaccine containing ≥ 15 µg of hemagglutinin antigen per strain (n = 50). The influenza virus strains were those recommended by the World Health Organization for the 2003 to 2004 season: A/New Caledonia/20/99 IVR-116, A/Panama/2007/99 Resvir-17, and B/Shangdong/7/97 (a B/Hong Kong/330/2001–like strain).

Outcomes: Immunogenicity of the vaccines assessed at 21 and 42 days with hemagglutination inhibition (HAI): The response for the A/New Caledonia, A/Panama, and B/Hong Kong strains was assessed by calculating geometric mean titers, fold increases in titer (geometric means of the ratio of the antibody titer after vaccination to the antibody titer on day 0), seroconversion rate (percentage of persons with increase in HAI titers ≥ factor of 4 after vaccination), and seroprotection rate (percentage of persons with HAI titer ≥ 1.40 after vaccination).

Patient follow-up: 100% (intention-to-treat analysis).

Main results

The intradermal and intramuscular groups did not differ in HAI response or fold increase in titer for the A/New Caledonia or B/Hong Kong strains on day 21. The intramuscular group had a better response to the B/Hong Kong strain on day 42 (Table). The intradermal group had better response to the A/Panama strain on days 21 and 42 (Table). The intradermal and intramuscular groups did not differ for seroconversion rate (ranges at d 21, 78% to 82% vs 66% to 82%) or seroprotection rate (ranges at d 21, 84% to 100% vs 94% to 100%). Local reactions were more common in the intradermal group but were mild and transient.


An intradermal injection of one fifth the standard intramuscular dose of a commercial influenza vaccine had a response similar to or better than that of a standard-dose intramuscular injection for 3 World Health Organization–recommended strains in young adults.

*See Glossary.

Source of funding: National Institutes of Health.

For correspondence: Dr. G.M. Glenn, Iomai, Gaithersburg, MD, USA. E-mail

Table. Reduced-dose intradermal vs standard-dose intramuscular influenza vaccination†

Strain Day Geometric mean titer (95% CI) CI for ratio of geometric mean P value
Intradermal Intramuscular
A/Panama 21 431 (291 to 640) 201 (143 to 282) 28 to 79‡ < 0.001
42 373 (256 to 544) 171 (123 to 238) 28 to 76‡ < 0.001
B/Hong Kong 42 147 (113 to 192) 253 (181 to 353) 112 to 264§ < 0.04

†CI defined in Glossary.
‡Favors intradermal injection.
§Favors intramuscular injection.


Influenza causes annual epidemics that are associated with excess morbidity and mortality in high-risk persons and excess antibiotic use, medical visits, and work days lost in healthy persons. Our main weapon against this predictable battle is immunization, which is offered each fall in targeted campaigns to persons at high risk for serious complications (e.g., underlying pulmonary disease) or their caregivers. In recent years, a few jurisdictions have embarked on universal influenza vaccine programs, but most public health programs target subpopulations and encourage, rather than recommend, influenza vaccine in healthy persons. The fragility of the influenza vaccine system became clear in the 2004−2005 season, with the withdrawal of 1 of the 2 suppliers of inactivated influenza vaccine to the U.S. market. This cut the national vaccine supply in half and precipitated heroic efforts by the public health community to ensure the most vulnerable persons received the available vaccine (1, 2).

The unexpected shortage this year is not the only reason that creative solutions are required to ensure an adequate, secure supply of efficacious influenza vaccines. Certain populations, particularly the elderly and the immunocompromised, do not mount vigorous immune responses to available vaccines. Protection from disease varies over time, depending on the match between circulating and vaccine strains, the host's experience with the virus, and the immunogenicity of the product. A need exists to prepare for the next pandemic of influenza in which ≥ 30% of the population could become ill. Consequently, many attempts have been made to improve influenza vaccines, such as different adjuvants to enhance immunogenicity, different formulations of vaccine (e.g., live attenuated and inactivated subunit) and different routes of antigen delivery (e.g., intranasal, intramuscular, and intradermal).

In the studies by Belshe and Kenney and their colleagues, low doses of inactivated influenza vaccines, licensed for intramuscular injection, were delivered to healthy participants by the intradermal route. This route of antigen delivery is known to engage the dendritic cell, a potent antigen-presenting cell located in peripheral tissues that links the innate arm of the immune system with the cellular and humoral arms (3). Dendritic-cell–based vaccination strategies have been explored for several infectious agents and have become an exciting new pathway for vaccine development and immune intervention.

Before large phase III efficacy trials are done, the candidate vaccines must succeed in phase I and II trials. The trials by Kenney and Belshe and colleagues evaluated immunogenicity rather than efficacy, and standard serologic correlates of vaccine protection were used as outcome measures. Both trials showed that intradermal administration of lower doses of inactivated vaccine compared favorably with standard doses of their intramuscular counterparts.

Much more must be learned about this new method of vaccine delivery before it enters clinical practice. We need to know more about the immunogenicity of intradermal vaccination in high-risk persons, particularly older adults, immunocompromised patients, and children. While the adverse events were confined to transient local injection site complaints, only larger trials would identify less common events and estimate their frequency with some precision. Devices that ensure intradermal administration of vaccine will need to be considered in future research. In both trials, a visible wheal was taken as confirmation that intradermal injection occurred; Belshe and colleagues used a disk that limited skin penetration, while Kenney and colleagues used a method similar to administration of a Mantoux test. These and other considerations will need to be included in the design of larger randomized controlled efficacy trials of intradermally administered influenza vaccines. These studies provide evidence that such studies are worth pursuing.

Joanne M. Langley, MD
Dalhousie University
Halifax, Nova Scotia, Canada


1. Updated interim influenza vaccination recommendations—2004-05 influenza season. MMWR Morb Mortal Wkly Rep. 2004;53:1183-4. [PubMed ID: 15614237]

2. Treanor J. Weathering the influenza vaccine crisis. N Engl J Med. 2004;351:2037-40. [PubMed ID: 15492296]

3. Moll H. Antigen delivery by dendritic cells. Int J Med Microbiol. 2004;294:337-44. [PubMed ID: 15532992]