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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 9 2911-2914
Copyright © 1997 by The Endocrine Society

Original Studies

Dehydroepiandrosterone Treatment Is Not Beneficial to the Immune Response to Influenza in Elderly Subjects1

H. D. Danenberg, A. Ben-Yehuda, Z. Zakay-Rones, D. J. Gross and G. Friedman

Department of Medicine (H.D.D., A.B-Y., G.F.), Geriatric Unit, Hadassah University Hospital, Ein-Karem; Department of Virology (Z.Z-R.), Hebrew University - Hadassah Medical School; Department of Endocrinology and Metabolism (D.J.G.), Hadassah University Hospital, Ein-Karem, Jerusalem, Israel

Address correspondence and requests for reprints to: H. D. Danenberg, Department of Medicine, Hadassah University Hospital, Ein-Karem, Jerusalem POB 12000, Israel 91120.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background. Dehydroepiandrosterone (DHEA) is a native steroid with an immunomodulating activity that was suggested to counterregulate some phenomena of immunosenescence. Recently, it was shown to reverse the age-associated decline of immune response against influenza vaccine in aged mice. The present study was designed to evaluate the effect of DHEA on the immunization of elderly volunteers against influenza.

Methods. Seventy-one elderly volunteers age 61–89 yr were enrolled in a prospective randomized, double-blind study to receive either DHEA (50 mg qd p.o. for four consecutive days starting two days before immunization) or placebo. Antibody response to the vaccine was measured before and 28 days after vaccination.

Results. DHEA treatment significantly increased serum DHEA-sulfate (DHEA-S). No enhancement in established immunity was observed. A significant decrease in attainment of protective antibody titer (1:40 or higher) against the A/Texas strain in subjects with nonprotective baseline antibody titer was recorded following DHEA treatment compared with placebo (52% vs. 84%, P < 0.05). Baseline DHEA-S serum levels were inversely related to attainment of immunization in DHEA-treated subjects. Influenza-like morbidity during the winter was low in the study group with no difference between the DHEA and placebo groups.

Conclusions. Although highly effective in aged rodents, a short course of DHEA treatment did not improve the age-related declined response to immunization against influenza in human subjects. Higher baseline DHEA-S levels are not predictive of better immunization against influenza in the elderly.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ELDERLY persons are at increased risk for hospitalization and death from influenza (1). Today, influenza prophylaxis depends upon the annual administration of an inactivated, trivalent influenza vaccine tailored each year to specific current strains of the influenza virus. Vaccination of the elderly population reduces the risks of pneumonia, hospitalization and death during epidemics (2). However, while highly effective in young, healthy adults, a decline in the ability to mount protective immune response following vaccination was observed in the elderly (3, 4). This age-related decline results from dysregulation of the immune system, known as immunosenescence. It is characterized by disturbed cytokine production in response to antigens, a decline in T lymphocytes function, a decreased number of naive T cells, and decreased production of antibodies against antigens (5, 6). However, efforts to enhance anti-influenza immunization in the aged focus mainly on improving the immunogenicity of the vaccine, rather than on improving the altered immune response (7, 8, 9).

Dehydroepiandrosterone (DHEA) is an abundantly secreted, weak androgenic adrenocortical steroid hormone. Concentrations of DHEA and its sulfatic ester (DHEA-S) decline after the third decade of life, reaching in the elderly 10–20% of the peak level (10). It has been suggested that this age-related decline might be involved in major consequences of aging, including the aging of the immune system (11). Treatment of aged mice with DHEA reversed some of the phenomena typical of immunosenescence, including age-related changes in cytokine production and the defective immunization (11, 12).

Recently we have shown that treatment of aged mice by a single injection of DHEA increased their immune response to influenza vaccination. The age-associated decline in antibody production was reversed and the mice were protected against a challenge by a live influenza virus (13).

The present study was designed to examine the effect of DHEA treatment on vaccination of elderly persons against influenza.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The study protocol was reviewed and approved by the appropriate local review board, and all participants gave written informed consent. Retired personnel of the Hadassah Medical Organization, functionally independent, age 60 or older were immunized during the autumn of 1995 with a single dose of an inactivated trivalent split influenza vaccine (Fluvirin, Evans Medical, Leatherhead, England). The concentration of hemagglutinin per single dose (0.5 mL) of each component was 15 µg of A/Johannesburg/33/94 (H3N2), A/Texas/36/91 (H1N1), and B/Harbin/7/94. Sera were collected two days (first day of taking adjunctive drug) before vaccination and four weeks later. All sera were frozen upon collection and kept at -20 C until use.

The study was conducted in a double-blind manner. Participants were randomly assigned to receive either DHEA or placebo capsules. DHEA (Akzo, Oss, Holland) capsules of 50 mg were administered once daily in the morning for a total of four sequential days starting two days before vaccination.

Serum DHEA-S and cortisol levels were measured before the study in all subjects by specific radioimmunoassays (DPC, Los-Angeles, CA.). Measurements were repeated 24 h after administration of the second dose in every sixth participant.

Antibody level studies were performed in a standard microtiter assay for hemagglutination-inhibiting (HAI) antibodies. Serum was treated with receptor-destroying enzyme (RDE) (Sigma, St. Louis, MO) overnight, heat-inactivated (56 C for 30 min), and its capacity to inhibit the agglutination of chicken red blood cells by influenza hemagglutinin was determined as described previously (14).

The following parameters were used for expression of humoral immune response: a) Log2 of HAI antibodies before and four weeks after vaccination, b) mean-fold increase of HAI titer after vaccination, c) proportion of subjects showing protective titer,i.e. HAI antibody titer at least 1:40.

Side-effects of the vaccination regimen and flu-like morbidity during the following winter were recorded by telephone-based interview at days 7, 28, and 120 after vaccination.

Statistical analysis of the significance between baseline and postimmunization titers was determined by the paired t test. Differences in elicitation of protective HAI antibody titer were determined using Fisher’s exact test.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 71 subjects were enrolled and randomized to treatment. The characteristics of the subjects according to treatment assignment are shown in Table 1Go. Randomization resulted in an even distribution of recorded parameters including base-line health status. All enrolled subjects completed the study and were available for follow-up 4 months after vaccination.


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  		Table 1. Base-line characteristics of the study subjects

 
Baseline DHEA-S levels were similar in both groups. DHEA-S levels measured 24 h after the second dose was administered were five- to ten-fold increased in the DHEA treatment group while unchanged in the placebo group. Post-treatment DHEA-S levels (mean ± SD) were 7.4 ± 2.6 in DHEA treated subjects (n = 5), and 1 ± 1 in the placebo group (n = 6).

Local adverse effects to the influenza vaccine were recorded in three subjects of the DHEA group and two of the placebo group. Systemic (flu-like) reactions to the vaccine were reported by one subject in each group. Five subjects reported improved well-being, both mental and physical, during the week of vaccination. All five received DHEA.

Following exclusion of subjects with baseline protective titers pre- and post-immunization titers, mean-fold increase (MFI) in titer, and the ability to raise HAI antibody titer to protective levels were compared (Table 2Go). Higher post-immunization levels and MFI’s were recorded in the placebo group against the two influenza A strains. However, no statistical significance appeared in these parameters. No difference was observed against the influenza B. Accomplishment of protective titers against all three influenza strains was higher in the placebo-treated group, with significantly higher response against the A/Texas strain.


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  		Table 2. Pre- and postimmunization antibody status of DHEA and placebo-treated subjects with nonprotective baseline antibody titers

 
We further studied the relation between serum baseline DHEA-S and cortisol levels and the achievement of immunization in susceptible subjects (baseline HAI antibodies titer <40). No correlation was found between DHEA-S levels and attainment of protective titers in the placebo group (Table 3Go). However, in DHEA-treated subjects, higher baseline DHEA-S levels were related to diminished immunization (Table 3Go). Baseline cortisol levels were similar in the two groups and between subjects who attained and did not attain immunization (data not shown).


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  		Table 3. DHEA-S baseline levels in subjects with nonprotective baseline antibodies titer

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This placebo-controlled, double-blind, randomized clinical trial studied the effect of DHEA treatment on the immunization of elderly subjects against influenza. Preliminary studies in an aged-mice model were very promising (13): a single parenteral dose of DHEA reversed the marked decline in humoral response, conferring protection from exposure to live influenza virus.

Such results were not found in humans. In accordance with previous studies (3, 15), the immune response of the elderly to influenza vaccine was indeed incomplete, with protective rates in susceptible subjects treated with placebo ranging between 25% against the B/Harbin strain and 84% against the A/Texas. However, the results in DHEA-treated subjects were even more disappointing with protection ranging between 31–52%. A significantly lower attainment of protective immunity against the A/Texax strain was observed in the DHEA group. Thus, DHEA treatment elicited decreased immune response against the H1N1 influenza strain. We can further speculate that the lack of statistical significance favoring placebo over DHEA in the two other strains is possibly due to the small number of subjects in our study.

A recently published study examined the efficacy of DHEA-S treatment as an adjuvant for influenza vaccine in 67 elderly subjects (16). Although not statistically significant, a trend in favor of DHEA-S was observed in immunization to all three components of the influenza vaccine (16). The major difference between that study and ours is the shorter 2-day regimen and the use of DHEA-S instead of DHEA. The prolonged increased plasma levels of DHEA-S in our DHEA-treated subjects probably precludes the difference in DHEA formulation as an explanation for the difference. We cannot conclude whether a shorter regimen is preferable. Based on two studies that showed an immunomodulating effect for DHEA in which longer periods of treatment were sustained (17, 18), a 4-day regimen seemed a reasonable and clinically applicable alternative for checking the above alternative.

The inverse correlation between baseline DHEA-S levels and immunization rate in DHEA-treated subjects adds further evidence to our findings that increasing DHEA-S levels does not improve, and may even harm, immunization against influenza in humans.

DHEA-induced decrease in immunization could be the result of augmented IL-2 production by CD4+ cells (19). IL-2, by increasing the production of interferon-{gamma}, enhances the clearance of viral particles. This prevents a proper presentation of antigen to the naive T cells (20), which are already decreased in number in the elderly (6). Therefore, induction of rapid viral clearance may make DHEA treatment beneficial in viral infection, but may jeopardize immunization.

Numerous data concerning the therapeutic ability of DHEA in age-related diseases such as atherosclerosis (21) and cancer (22, 23) were collected from studies in mammals and rodents. Reversal of immunosenescent phenomena and augmentation of the age-associated decline in immunization were repeatedly observed in mice (11, 12, 13). Why weren’t these results reproduced in the present study? The adrenal glands of rodents are incapable of synthesizing DHEA, with undetectable levels of circulating DHEA (24). Thus, no age-associated decline in DHEA production is found in mice, and therefore extrapolating the results of murine DHEA studies to humans is not obvious. Moreover, mice were treated with pharmacological doses of the drug that, if repeated in humans, would be well above 100 g/day per subject, thus violating our requirement for physiologic replacement therapy. The incomplete age-associated decline of the humoral response in humans, compared with the almost total decline observed in mice renders difficult the interpretation of immunosenescence studies in rodents with respect to the human situation. However, it may be possible that DHEA can boost primary immune responses, as observed in mice, and fails to enhance secondary immune responses that follow influenza vaccination in humans.

The minimal adverse effects of the vaccine are comparable to other studies in elderly populations (25). The self-reported, improved well-being following DHEA treatment was previously reported by Morales et al. (26). In that study, 67% of the men and 84% of the women recipients of DHEA (50 mg for 6 months) reported such a sensation. In the present study, only 15% of the DHEA-treated volunteers reported improved well-being compared with none of the placebo-recipients. Nevertheless, taking into account the short 4-day treatment period, the present results are in keeping with the cited results.

The notion that DHEA is the "fountain of youth" has apparently been scientifically substantiated in three respects: DHEA’s age-associated decline; epidemiological studies suggesting that higher DHEA-S levels confer increased longevity (27); and numerous animal studies that convincingly demonstrated beneficial effects of DHEA administration in preventing atherosclerosis (19), cancer (20), and immunosenescence (12). These led to administration of DHEA to aged men and women (28) despite the lack of established beneficial effects. The present study did not confirm its base-line hypothesis that a short course of DHEA combined with influenza vaccine is effective as an adjuvant therapy in an elderly population. Moreover, it may even be detrimental to immunization. Therefore, until further data on the beneficial and adverse effects of DHEA is collected in clinical trials, caution should be used in dispensing DHEA.


   Footnotes
 
1 This study was supported by Grant S/3229 from the Israeli Ministry of Health to H.D.D. and a grant from H.J. Leir to G.F. Back

Received April 7, 1997.

Revised June 9, 1997.

Accepted June 11, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  23. Ratko TA, Detrisac CJ, Mehta RG, et al. 1991 Inhibition of rat mammary gland chemical carcinogenesis by dietary dehydroepiandrosterone or a fluorinated analogue of dehydroepiandrosterone. Cancer Res. 51:481–486.[Abstract/Free Full Text]
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