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Age, Dose, and Sex Effects on Immune Responses

Renata J. M. Engler, MD; Michael R. Nelson, MD, PhD; Mary M. Klote, MD; Mark J. VanRaden, PhD; Chiung-Yu Huang, PhD; Nancy J. Cox, PhD; Alexander Klimov, PhD, ScD; Wendy A. Keitel, MD; Kristin L. Nichol, MD; Warner W. Carr, MD; John J. Treanor, MD; for the Walter Reed Health Care System Influenza Vaccine Consortium

Arch Intern Med. 2008;168(22):2405-2414.

Background  Optimal public health strategies for managing influenza vaccine shortages are not yet defined. Our objective was to determine the effects of age, sex, and dose on the immunogenicity of intramuscular trivalent inactivated vaccine (TIV).

Methods  Healthy adults aged 18 to 64 years, stratified by age (18-49 and 50-64 years) and sex, were randomized to receive full- or half-dose TIV. Hemagglutination inhibition titers against vaccine antigens were measured before and 21 days after immunization. A primary outcome of noninferiority was defined as a difference of less than 20% in the upper 95% confidence interval (CI) of the proportion of subjects with strain-specific hemagglutination inhibition antibody titers of 1:40 or higher after vaccination. Secondary outcomes included geometric mean titers, after vaccination side effects, and occurrences of influenza-like illnesses.

Results  Among previously immunized subjects (N = 1114) receiving half- vs full-dose TIV (age, 18-49 years, n = 284 [half] and n = 274 [full]; and age 50-64 years, n = 276 [half] and n = 280 [full]), CIs for proportions of subjects with hemagglutination inhibition antibody titers of 1:40 or higher excluded substantial reduction for all antigens in the 18- to 49-year age group and for B/Shanghai/361/2002 (B) and A/Fujian/411/2002 (A/H3N2) in the 50- to 64-year age group. Geometric mean titer in the female 18- to 49-year age group exceeded male responses for all strains: responses to half-dose TIV that were comparable with male full-dose responses for A/New Caledonia/20/99 (A/H1N1) antigen, 25.4 (95% CI, 20.9-30.9) vs 25.6 (95% CI, 21.3-30.9); A/H3N2 antigen, 60.8 (95% CI, 50.8-72.7) vs 44.1 (95% CI, 37.6-51.8); and B antigen, 64.4 (95% CI, 53.9-76.9) vs 60.7 (95% CI, 51.4-71.7) (findings were similar for the 50- to 64-year age group). Some injection site and systemic reactions (myalgias and/or arthralgias [P < .05], headache [P < .001], and impact of fatigue [P < .05]) were significantly lower in men. The relative risk of medical visits and hospitalizations for influenza-like illnesses were similar in the half- and full-dose groups regardless of age.

Conclusions  Antibody responses to intramuscular half-dose TIV in healthy, previously immunized adults were not substantially inferior to the full-dose vaccine, particularly for ages 18 to 49 years. Significantly higher geometric mean titer responses in women were identified for all ages, regardless of dose or influenza strain. Half-dose vaccination may be an effective strategy for healthy adults younger than 50 years in the setting of an influenza vaccine shortage.

Trial Registration  clinicaltrials.gov Identifier: NCT00283283

Author Affiliations: Allergy-Immunology Department, Walter Reed Army Medical Center, Washington, DC (Drs Engler, Nelson, and Klote); National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (Drs VanRaden and Huang); Influenza Branch, Centers for Disease Control and Prevention, Atlanta, Georgia (Drs Cox and Klimov); Baylor College of Medicine, Houston, Texas (Dr Keitel); VA Medical Center and Department of Medicine, University of Minnesota Medical School, Minneapolis (Dr Nichol); Allergy and Asthma Associates of Southern California, Mission Viejo (Dr Carr); and Infectious Diseases Unit, Department of Medicine, University of Rochester, Rochester, New York (Dr Treanor).

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