Elsevier

Vaccine

Volume 29, Issue 16, 5 April 2011, Pages 2865-2873
Vaccine

Antibody and Th1-type cell-mediated immune responses in elderly and young adults immunized with the standard or a high dose influenza vaccine

https://doi.org/10.1016/j.vaccine.2011.02.017Get rights and content

Abstract

A comparative analysis of antibody and cell-mediated immune responses was performed in ambulatory medically stable elderly and young adults who received the standard-dose of trivalent inactivated influenza vaccine, containing 15 μg of hemagglutinin (HA) per virus strain, or a high-dose vaccine containing 60 μg HA per virus strain. Among the elderly, the high dose vaccine induced greater HAI (hemagglutination inhibition) and virus neutralization antibody titers than the standard dose vaccine. These responses, however, did not achieve the magnitude of those induced by the standard dose vaccine in young adults. Vaccine-specific circulating T cells producing IFN-γ were detected in the elderly and young adults following immunization. However, there were no significant differences in the IFN-γ responses among groups. On the other hand, the standard dose vaccine in the elderly resulted in the highest proportion of complete non-responders who failed to elicit either an HAI or an IFN-γ response. This study provides further evidence that a higher dose vaccine for the elderly may result in enhanced immune responses which are predicted to improve protection although still of lower magnitude than those induced in younger healthier individuals.

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.

Section snippets

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)

  • A.M. Palache et al.

    Influenza vaccines: the effect of vaccine dose on antibody response in primed populations during the ongoing interpandemic period. A review of the literature

    Vaccine

    (1993)
  • J.E. McElhaney et al.

    Antibody response to whole-virus and split-virus influenza vaccines in successful ageing

    Vaccine

    (1993)
  • R. Pyhala et al.

    Vaccination-induced HI antibody to influenza A(H1N1) viruses in poorly primed adults under circumstances of low antigenic drift

    Vaccine

    (1993)
  • K.A. Brokstad et al.

    Cross-reaction but no avidity change of the serum antibody response after influenza vaccination

    Vaccine

    (1995)
  • D.M. Murasko et al.

    Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly

    Exp Gerontol

    (2002)
  • W.W. Thompson et al.

    Mortality associated with influenza and respiratory syncytial virus in the United States

    JAMA

    (2003)
  • K.L. Nichol et al.

    Effectiveness of influenza vaccine in the community-dwelling elderly

    N Engl J Med

    (2007)
  • D. Rivetti et al.

    Vaccines for preventing influenza in the elderly

    Cochrane Database Syst Rev

    (2006)
  • P.A. Gross et al.

    The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature

    Ann Intern Med

    (1995)
  • C.W. Potter et al.

    Determinants of immunity to influenza infection in man

    Br Med Bull

    (1979)
  • F.L. Ruben et al.

    A new subunit influenza vaccine: acceptability compared with standard vaccines and effect of dose on antigenicity

    J Infect Dis

    (1972)
  • S.R. Mostow et al.

    Inactivated vaccines. 1. Volunteer studies with very high doses of influenza vaccine purified by zonal ultracentrifugation

    Postgrad Med J

    (1973)
  • H. Matzkin et al.

    Accidental tenfold overdose of influenza vaccine: a clinical and serological study

    Isr J Med Sci

    (1984)
  • P.A. Gross et al.

    Immunization of elderly people with high doses of influenza vaccine

    J Am Geriatr Soc

    (1988)
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