Antibody and Th1-type cell-mediated immune responses in elderly and young adults immunized with the standard or a high dose influenza vaccine
Introduction
Influenza virus infections represent one of the leading causes of morbidity and mortality in the elderly; >90% of annual influenza-associated mortality occurs among those 65 years of age and older [1]. Although annual vaccination is the primary method of preventing influenza infection, the effectiveness of the currently approved influenza vaccines in the elderly is lower than in healthy young adults [2], [3], [4], [5], [6]. One explanation for the poor responses to the vaccine among the elderly is a phenomenon termed immunesenescence, which is described as a progressive, slow and steady decline in the function of the immune system during aging [7].
Virus-specific antibodies measured by hemagglutination inhibition (HAI) have been traditionally associated with protective immunity against influenza [8]. Although assessments of antibody responses to influenza vaccines in the elderly has yielded conflicting results [9], aging has been associated with reduced hemagglutinin (HA) antibody [10] as well as reduced cell-mediated immune (CMI) responses to influenza vaccines [11].
One promising approach to improve the protection afforded by influenza vaccines in older adults is to increase the amount of antigen contained in each vaccine dose. Until recently, influenza vaccines approved for use in the elderly contained 15 μg of HA from each of three annually selected virus strains. However, a high dose influenza vaccine (60 μg of HA/virus strain) was approved for use in adults age ≥65 years on December 23, 2009. Several studies have shown that vaccine formulations containing higher dosage levels of HA can be administered safely and induced greater HAI antibody responses in the elderly [12], [13], [14], [15], [16], [17], [18], [19].
A recent multi-site influenza Phase 2 clinical trial in elderly adults, in which our group participated, showed significantly higher HAI and virus neutralization (VN) antibodies for all three vaccine virus strains among recipients of the high dose influenza vaccine in comparison to those that received the standard dose [20]. An important aspect that was not addressed in that study, however, was how the responses induced by the influenza vaccine in the elderly compare in both quality and magnitude with those of young healthy adults, particularly whether the high dose vaccine is able to achieve the levels of responses elicited by young adults.
We report here the immunogenicity of a trivalent, inactivated influenza vaccine administered to healthy ambulatory elderly adults using the standard dose (15 μg HA of each virus strain) or a high-dose (60 μg HA per virus strain) formulation, in comparison to young adults who received the standard-dose vaccine. The immunological outcome measures were HAI, VN, and HA-specific serum IgG and IgA levels. We also investigated the induction of CMI by measuring the frequency of IFN-γ-secreting T cells in peripheral blood.
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Participants and study design
Forty-nine healthy, independently living elderly (≥65 years) volunteers participating in a multi-center influenza vaccine trial [20] during April 11–22, 2005 agreed to participate in a substudy (described herein) to further characterize the immune responses induced by the trivalent inactivated split-virus influenza vaccine (TIV) administered in the standard or an experimental high-dose formulation. For comparison, 15 young adults (18–40 years) were enrolled and vaccinated, under an independent
Demographics
The demographic characteristics of the vaccine recipients are summarized in Table 1. Forty-nine medically stable elderly volunteers (65–85 years, mean age 74 years) were enrolled in the study (no subjects were terminated early); 25 were male and all elderly subjects were white, non-Hispanic. Twenty-six elderly subjects received the standard-dose vaccine (ES cohort) and 23 received the high-dose vaccine (EH cohort) (Fig. 1). Fifteen medically stable young adult volunteers (20–40 years, mean age
Discussion
The public health importance of the effects of aging on influenza vaccine responses has become increasingly more evident as the global elderly population continues to dramatically rise. Development of effective influenza vaccines targeted specifically to this high-risk group remains a high priority. The protection elicited by a successful influenza vaccine for the elderly will likely need both humoral and cellular-mediated immunity, requiring full engagement of the host immune system. However,
Acknowledgments
The authors thank Yu Lim and Mardi Reymann, CVD Applied Immunology Section, for their outstanding technical support and Steven Bowen and Melissa Hayes, Department of Microbiology and Immunology, for their contribution to this work. We also acknowledge Dr. Linda Lambert, Chief of the Respiratory Diseases Branch at DMID, NIAID. This work was funded by NIH, NCRR grant K12-RR023250 (WHC), NIA grant P30-AG028747 (WHC), and NIAID contracts N01-AI85342, N01-AI25461 and N01-AI-800001 (WHC, AC, RE, MBS,
References (49)
- et al.
Efficacy and effectiveness of influenza vaccines in elderly people: a systematic review
Lancet
(2005) - et al.
A meta-analysis of effectiveness of influenza vaccine in persons aged 65 years and over living in the community
Vaccine
(2002) - et al.
Vaccination in the elderly: an immunological perspective
Trends Immunol.
(2009) - et al.
Antibody induction by influenza vaccines in the elderly: a review of the literature
Vaccine
(1989) - et al.
Antibody response to influenza vaccination in the elderly: a quantitative review
Vaccine
(2006) - et al.
Responses to influenza vaccination in different T-cell subsets: a comparison of healthy young and older adults
Vaccine
(1998) - et al.
Antibody response after influenza immunization with various vaccine doses: a double-blind, placebo-controlled, multi-centre, dose–response study in elderly nursing-home residents and young volunteers
Vaccine
(1993) - et al.
Improvement of the immunoglobulin subclass response to influenza vaccine in elderly nursing-home residents by the use of high-dose vaccines
Vaccine
(1993) - et al.
Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects
Vaccine
(2007) - et al.
Vaccination in the elderly: an immunological perspective
Trends Immunol
(2009)
Influenza vaccines: the effect of vaccine dose on antibody response in primed populations during the ongoing interpandemic period. A review of the literature
Vaccine
Antibody response to whole-virus and split-virus influenza vaccines in successful ageing
Vaccine
Vaccination-induced HI antibody to influenza A(H1N1) viruses in poorly primed adults under circumstances of low antigenic drift
Vaccine
Cross-reaction but no avidity change of the serum antibody response after influenza vaccination
Vaccine
Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly
Exp Gerontol
Mortality associated with influenza and respiratory syncytial virus in the United States
JAMA
Effectiveness of influenza vaccine in the community-dwelling elderly
N Engl J Med
Vaccines for preventing influenza in the elderly
Cochrane Database Syst Rev
The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature
Ann Intern Med
Determinants of immunity to influenza infection in man
Br Med Bull
A new subunit influenza vaccine: acceptability compared with standard vaccines and effect of dose on antigenicity
J Infect Dis
Inactivated vaccines. 1. Volunteer studies with very high doses of influenza vaccine purified by zonal ultracentrifugation
Postgrad Med J
Accidental tenfold overdose of influenza vaccine: a clinical and serological study
Isr J Med Sci
Immunization of elderly people with high doses of influenza vaccine
J Am Geriatr Soc
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