Effect of zinc or zinc plus arginine supplementation on antibody titre and lymphocyte subsets after influenza vaccination in elderly subjects: a randomized controlled trial

Age and Ageing, Nov, 1998 by Mauro Provinciali, Alessio Montenovo, Giuseppina Di Stefano, Mauro Colombo, Laura Daghetta, Marco Cairati, Claudio Veroni, Roberto Cassino, Fabrizio Della Torre, Nicola Fabris

Abstract

Objective: to evaluate whether oral supplementation with zinc or zinc/arginine increases the antibody response to influenza vaccine or modulates the lymphocyte phenotype in elderly subjects.

Design: a randomized controlled trial with two supplemented groups and one control group.

Setting: a community nursing home.

Participants: 384 subjects aged 64-100 (mean age 82 years) examined in three separate studies.

Intervention: oral supplementation with zinc (400 mg/day) or zinc plus arginine (4 g/day) for 60 days starting 15 days before influenza vaccination. The control groups received vaccine only.

Measurements: haematological and nutritional indices, antibody titre against influenza viral antigens, lymphocyte phenotype.

Results: supplementation with zinc or zinc plus arginine increased zinc plasma concentrations restoring the age-related impairment in zinc concentrations to values found in younger people. The antibody titre against influenza viral antigens was not increased in zinc or zinc/arginine supplemented groups in comparison with subjects receiving vaccine alone. The number of CD3, CD4 or CD8 lymphocytes was not affected by zinc or zinc/arginine supplementation.

Conclusion: prolonged supplementation with zinc or zinc/arginine restores zinc plasma concentrations but is ineffective in inducing or ameliorating the antibody response after influenza vaccination in elderly subjects.

Keywords: immune response, influenza vaccine, randomized controlled trial, zinc

Introduction

Influenza is a major cause of morbidity and mortality world-wide, with most of the serious complications occurring in the elderly population and particularly in individuals living in high-density environments, such as nursing homes [1, 2]. Annual vaccination against the influenza viruses is recommended for older people but the protection offered by standard influenza vaccination in preventing illness is low in elderly nursing home subjects [3]. Influenza vaccination is not very effective in conferring adequate antibody protection in elderly subjects [2, 4, 5]. One of the main causes of this low antibody response is age-related impairment in immune functioning with thymus involution and decline in various peripheral immune functions. Advancing age is also associated with reduced immune responsiveness to foreign antigens, particularly to those that are T cell-dependent, such as influenza viral antigens [6].

One way to improve the immunological responses to vaccination is by enhancing antibody responses with immuno-potentiating substances [7], particularly for those whose endogenous levels are reduced with advancing age. Either thymic hormones [8], interleukin-2 [9] or other immunomodulants [10, 11] can increase the serum antibody response to influenza viral antigens in elderly subjects, particularly in very old subjects.

We were interested in improving antibody response to influenza vaccine using zinc and arginine, two immunopotentiating agents.

Zinc plays a crucial role in the development and maintenance of immune competence [12]. Zinc metabolism is altered during ageing and a reduction of serum zinc concentrations is commonly found in healthy old age, and particularly in institutionalized elderly people [13, 14]. Furthermore, zinc turnover is altered in trauma, exercise, inflammation and with tumours and burn injury [12].

Zinc deficiency produces rapid and severe depression of immune function. Hypoplasia of the thymus, decrease of T lymphocyte number, reduction of T-helper lymphocyte function and of the cytotoxic activity of natural killer (NK) cells occur in humans and animals [12, 15, 16]. The zinc-induced immune impairment has been associated with Down's syndrome, cystic fibrosis, acrodermatitis enteropathica, sickle cell anaemia, AIDS and leukaemia [12]. In most cases, zinc treatment reversed the immune deterioration in these diseases [12, 17]. Stimulation of both T cells and B-lymphocytes, as well as NK cell activity, antibody formation and intracellular killing of parasites is triggered or enhanced by zinc supplementation [18-20]. Similarly, various age-related immune deteriorations have been corrected by increasing the reduced zinc concentrations [17]. Increased antibody response to tetanus toxoid vaccination occurs in healthy elderly people after zinc supplementation, but no beneficial effects on the antibody formation to influenza virus vaccine was found in a previous study [21, 22].

Arginine is a basic amino acid with immuno-modulating effects [23, 24]. It restores several immune indices that are decreased during ageing: oral arginine supplementation in old age restores the reduced thymic endocrine activity [25], improves peripheral immune efficiency (such as mitogen responses and NK activity) and increases the percentage of peripheral blood T-helper lymphocytes [26].

Some immunomodulating effects of either zinc or arginine are exerted directly on lymphocytes, although an indirect action through the modulation of endogenous cytokine production has also been demonstrated [27, 28].