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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:M563-M566 (2002)
© 2002 The Gerontological Society of America

Effect of a Complete Nutritional Supplement on Antibody Response to Influenza Vaccine in Elderly People

Wendeline Wouters-Wesselinga, Marja Rozendaala, Marieke Snijderb, Yvo Grausa, Guus Rimmelzwaanc, Lisette de Grootb and Jacques Bindelsa,b

a Department of Clinical Nutrition and Therapeutic Diets, Numico Research B.V., Wageningen, The Netherlands.
b Department of Human Nutrition and Epidemiology, Wageningen University, The Netherlands.
c Department of Virology, Erasmus University, Rotterdam, The Netherlands.

Wendeline Wouters-Wesseling, Numico Research B.V., P.O. Box 7005, 6700 CA Wageningen, The Netherlands E-mail: wendeline.wouters-wesseling{at}numico-research.nl.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. The impact of influenza infection on morbidity and mortality in the elderly population can be severe. Influenza vaccination is not very effective in this age group, which is potentially related to impaired nutritional status. We investigated the effect of a 7-month nutritional supplementation on antibody response to influenza vaccine in elderly people.

Methods. Nineteen subjects aged 65 years and older with a body mass index of 25 kg/m2 or less were studied. Subjects received a complete liquid nutrition supplement containing energy, vitamins, and minerals, including enhanced levels of antioxidants or noncaloric placebo drink for 7 months. Antibody titers to influenza strains A/Sydney/5/97 (SY), A/Beijing/262/95 (BE), and B/Yamanashi/166/98 (YA) before and 28 days after vaccination were measured. Age, gender, weight, height, serum albumin, serum prealbumin, hemoglobin, and serum vitamin E at baseline were registered.

Results. Mean fold increase upon vaccination for SY was significantly larger in the supplement group (2.76 ± 0.66) compared to the placebo group (1.91 ± 0.66). These differences were not observed for YA (1.73 ± 0.31 vs 1.19 ± 0.18) and BE (4.40 ± 2.63 vs 5.76 ± 3.34). For all three strains, there was no significant difference between groups in protective antibody levels (HI titer >=40) after vaccination.

Conclusions. We conclude that provision of a complete liquid nutrition supplement including enhanced levels of antioxidants may have a beneficial effect on antibody response to influenza vaccination in the elderly population. Further confirmation of these findings and their clinical consequences should be the subject of a larger study.

THE impact of influenza infection on morbidity and mortality in the elderly population can be severe. Therefore, vaccination of elderly people (and other risk groups) is recommended. However, influenza vaccination has limited effectiveness in this age group (reviewed by Webster (1)) due to the fact that vaccination does not always result in protective serum antibody titers. An explanation for this is that, with aging, there is a decreased function of the immune system, mainly related to a decline in T-cell-mediated immunity. This is a multifactorial phenomenon affecting the number of T-cells, T-cell subset composition, and biological functions including lymphocyte proliferation and cytokine production (2). A strong correlation exists between the serum hemagglutination-inhibiting (HI) antibody titers to influenza viruses and clinical protection against infection (3). In healthy, well-nourished elderly people, only a small decline in immune function with aging is observed (4), which may mean that impaired immune function in elders is potentially related to comorbidity and/or impaired nutritional status. Therefore, it may be possible to improve the antibody response after influenza vaccination by nutritional intervention and reduce influenza-related morbidity and mortality.

The effect of a variety of nutritional supplements on antibody response to influenza vaccine has previously been investigated (5)(6)(7)(8)(9)(10). Supplements contained either vitamins (7), minerals (9), or both (5)(6)(10), or were in the form of a complete liquid nutrition supplement (8). Most studies were performed either with elderly people living in nursing homes or long-stay hospital wards (7)(8)(9)(10). Only two studies have been performed with noninstitutionalized elders (5)(6). In some studies, positive effects were found (5)(6)(8)(10), whereas other studies did not reveal effects on antibody response to influenza vaccination (7)(9). It is of interest that, in the studies describing positive effects on the antibody response, a combination of nutrients was used. It seems that a combination of vitamins and minerals or a complete liquid nutrition supplement has the highest potential to improve the antibody response to influenza vaccination.

We, therefore, investigated the effect of a 7-month nutritional supplementation with a liquid nutrition supplement with enhanced levels of antioxidants on the HI antibody response to influenza vaccine in residents of homes for elderly people.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
This randomized, double-blind, placebo-controlled study was part of a larger study performed from May through November 1999. Subjects aged 65 years or older with a body mass index (BMI; weight/height2) <=25 were eligible to participate. Nineteen elderly people of this larger study (10 supplement, nine placebo) could be included in the substudy as they consented to both influenza vaccination and blood draw and had adequate compliance with the supplement. The study was approved by the institutional review board of Wageningen University, and all subjects gave informed consent.

Subjects received nutritional supplementation with a supplement containing between 30 and 160% of the United States recommended daily allowance of vitamins and minerals, with enhanced levels of antioxidants and 250 kcal energy twice daily for 7 months. Per 100 ml, the supplement included 100 kcal (0.42 MJ), 3.5 g protein, 4.5 g fat, 11.4 g carbohydrates, 1.8 g fiber, 32 mg Na, 220 mg K, 16 mg Cl, 160 mg Ca, 160 mg P, 40 mg Mg, 3.6 mg Fe, 7.2 mg Zn, 1.2 mg Cu, 1.6 mg Mn, 0.3 mg F, 16 µg Mo, 34 µg Se, 14 µg Cr, 60 µg I, 96 µg RE vitamin A, 1.2 mg carotenoids, 100 mg vitamin C, 5.2 µg vitamin D, 28 mg-{alpha}-TE vitamin E, 32 µg vitamin K, 0.75 mg vitamin B1, 0.75 mg vitamin B2, 5.6 mg NE niacin, 1.8 mg pantothenic acid, 1 mg vitamin B6, 192 µg folic acid, 2.1 µg vitamin B12, 28 µg biotin, 1.2 mg coenzyme Q10, and 7.6 mg flavonoids. Influenza vaccine (Influvac®99, containing vaccine strains A/Sydney/5/97[H3N2] [SY], A/Beijing/262/95[H1N1] [BE], and B/Beijing/184/93-like [B/Yamanashi/166/98] [YA]) was administered in October, 6 months after start of the nutritional intervention. A fasting blood sample was taken after 6 months of supplementation immediately prior to vaccination and 1 month after vaccination (11). Antibody response to each strain was measured in serum by hemagglutination inhibition (HI) test following standard procedures using turkey erythrocytes and four HA-units of the virus (12)(13) at the University Medical Center, Rotterdam. A HI titer >=40 was considered protective (14). Mean fold increase of antibody titers was calculated as ratio of postimmunization titer to preimmunization titer. Vaccination history of the previous 3 years was registered. Chronic diseases and number of medications taken were also registered. At baseline, albumin and prealbumin were analyzed by Synchron Clinical System CX4CE using kits 442765 and 445855, respectively (Beckman Instruments, San Ramon, CA), by Analytical Biochemical Laboratory (Assen, The Netherlands). Vitamin E was measured by the method of Stump (15) using a plasma ethanol dilution of 1/10 and a triple hexane extraction. Hemoglobin was analyzed according to Riggs (16).

Antibody titers are reported as mean (ln antibody titer). One-tailed t test for mean changes and analysis of variance was performed using SPSS for Windows 10.0 (SPSS Inc., Chicago, IL). Wilcoxon's signed rank test was applied for mean fold increase in titer after vaccination, and Fisher exact test was used for comparison of the number of protected subjects between groups.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
Table 1 reports baseline characteristics of the study participants. No differences between groups were observed in baseline parameters.


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  		Table 1. Baseline Characteristics of Elderly Study Participants (Mean ± SD)

 
Antibody titers specific for the three vaccine strains after vaccination for placebo and supplement group before and after vaccination are given in Fig. 1. Before vaccination, titers for BE were lower in the placebo than in the supplement group (2.9 ± 1.0 vs 3.9 ± 1.0) (p = .055) but did not differ for SY (4.9 ± 1.5 vs 4.4 ± 1.0) (p = .427) and YA (5.3 ± 1.6 vs 5.3 ± 0.8) (p = .923). The increase in titer after vaccination was significant in the placebo group for BE (p = .015) but not for SY (p = .071) and YA (p = .418). For the supplement group, the increase was significant for all three strains (p = .002, p = .015, and p = .013, respectively). The changes in titer were significantly different between supplement and placebo groups for SY (p = .096) and YA (p = .068) but not for BE (p = .760). Analysis of variance was performed on the difference in titer before and after vaccination, correcting for titer before vaccination, which resulted in a similar effect.



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  		Figure 1. Differences in mean titers (ln(titer) ± SD) for the influenza strains A/Sydney/5/97 (SY), A/Beijing/262/95 (BE) and B/Yamanashi/166/98 (YA) for placebo and supplement groups after vaccination in elderly people (p values for t test of changes between groups).

 
Table 2 reports the mean fold increase in titer postvaccination and the number of subjects with a protective titer (>=40) before and after vaccination.


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  		Table 2. Mean Fold Increase in Antibody Titers and Number of Protected Individuals (Titer >=40) Before and After Vaccination in Elderly People

 
A large number of subjects had a protective titer already before vaccination. There was no significant difference in the number of protected individuals before and after vaccination between treatment groups. The mean fold increase was significantly larger in the supplement group for SY (p = .048) but not for BE (p = .780) and YA (p = .091). A fourfold rise in titer, which is a criterion for an adequate effect of vaccination, could be detected only in a few subjects (SY: one placebo, one supplement; BE: one placebo, one supplement, YA: one supplement).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
We have described that increased rises in influenza vaccine-induced antibody titer against two of the three influenza vaccine strains after nutritional supplementation. No significant differences in the number of protected individuals were observed between the supplement and placebo groups.

This report contains a per-protocol analysis of subjects who did not drop out of the larger study and who had adequate compliance with the supplementation for 7 months. This may have induced a selection bias leading to exclusion of subjects who were more frail (i.e., did not feel up to blood draw or vaccination or had intercurrent illness that led to cessation of participation in the trial). This observation is sustained by the fact that baseline characteristics of the subjects did not reveal a status of severe undernourishment. As a consequence, stronger effects may have been observed if a more frail and undernourished population had been studied. The high prevalence of adequate titers before vaccination reduced the potential for finding effects of supplementation. Explanations for this could be a study group without impaired antibody response or the vaccine composition for the study year, containing very similar strains to previous years, which led to high prevaccination antibody levels. The reason for the relatively small (50%) titer increases after vaccination in our study may be the fact that, in the previous year, a similar cocktail of strains was used. However, specifically for YA, the level of protection was largely adequate before vaccination. A bias in our results due to influenza infection circulating in the community cannot be expected, as no such epidemic was reported at the time of the study.

As the influenza vaccination substudy was dependent on the season of completion of the trial, we could study only a limited number of participants. The calculated required number of subjects per group needed for significance based on the observed effect sizes was 33, 25, and 85 for SY, YA, and BE, respectively.

The increase in titer rises found in our study was relatively small compared to studies with nutritional supplementation by Chandra and Puri (5)(6). They used a supplement containing a range of micronutrients in levels comparable to our study and reported a fourfold increase in titer for a larger number of subjects in the supplemented group compared to the placebo group and an increase in geometric mean antibody titer (5). In a later study (6), the same authors found an increase in geometric mean titer after supplementation. However, Lesourd and colleagues (8) reported an increase of about 30% in antibody titer, which is similar to our study. Mean fold increases reported by Girodon and colleagues (10) after supplementation were even smaller than in our study (an increase of about 20%). In their study, the number of protected individuals remained low even after intervention, and the number of protected individuals before vaccination was not reported. In general, the data of studies on nutritional supplementation often report different calculations of titers, which complicates comparisons.

We conclude that provision of a complete liquid nutrition supplement containing enhanced levels of antioxidants may have a beneficial effect on antibody response to some influenza vaccine strains in the elderly population and, therefore, may improve the induction of protective immunity. Further confirmation of these findings and their clinical consequences should be the subject of a larger study.


   Acknowledgments
 
The study was sponsored by Numico Research B.V. We thank Stichting De Stromen, Rotterdam, for cooperating in subject recruitment and Jeanette Gallas from the GGD Rotterdam for her excellent assistance in the study.

Received November 28, 2001

Accepted April 15, 2002


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

  1. Webster RG, 2000. Immunity to influenza in the elderly. Vaccine 18: (16) 1686-1689. [Medline]
  2. Chakravarti B, Abraham GN, 1999. Aging and T-cell-mediated immunity. Mech Ageing Dev 108: (3) 183-206. [Medline]
  3. Gross PA, Hermogenes AW, Sacks HS, Lau J, Levandowski RA, 1995. The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature. Ann Intern Med 123: (7) 518-527. [Abstract/Free Full Text]
  4. Krause D, Mastro AM, Handte G, Smiciklas-Wright H, Miles MP, Ahluwalia N, 1999. Immune function did not decline with aging in apparently healthy, well-nourished women. Mech Ageing Dev 112: (1) 43-57. [Medline]
  5. Chandra RK, Puri S, 1985. Nutritional support improves antibody response to influenza virus vaccine in the elderly. BMJ (Clin Res Ed) 291: (6497) 705-706.
  6. Chandra RK, 1992. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet 340:1124-1127. [Medline]
  7. Harman D, Miller RW, 1986. Effect of vitamin E on the immune response to influenza virus vaccine and the incidence of infectious disease in man. Age 9:21-23.
  8. Lesourd B, Favre-Berrone M, Thiollet M, et al. 1990. Action immunostimulante d'une supplementation orale complete chez des sujets ages denutris. Age & Nutrition 1:41-51.
  9. Provinciali M, Montenovo A, Di Stefano G, et al. 1998. 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 Ageing 27: (6) 715-722. [Abstract/Free Full Text]
  10. Girodon F, Galan P, Monget AL, et al. 1999. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. Arch Intern Med 159: (7) 748-754. [Abstract/Free Full Text]
  11. Gross PA, Russo C, Teplitzky M, Dran S, Cataruozolo P, Munk G, 1996. Time to peak serum antibody response to influenza vaccine in the elderly. Clin Diagn Lab Immunol 3:361-362. [Abstract]
  12. Palmer DF, Dowdle WR, Coleman MT, Schild GC. Hemagglutination inhibition test. In Advanced Laboratory Techniques for Influenza Diagnosis: Procedural Guide. Atlanta, GA: US Department of Health, Education and Welfare; 1975:25–62.
  13. Masurel N, Ophof P, de Jong P, 1981. Antibody response to immunization with influenza A/USSR/77 (H1N1) virus in young individuals primed or unprimed for A/New Jersey/76 (H1N1) virus. J Hyg (Lond) 87: (2) 201-209.
  14. Couch RB, Kasel JA, 1983. Immunity to influenza in man. Annu Rev Microbiol 37:529-549. [Medline]
  15. Stump DD, 1984. Simultaneous determination by high-performance liquid chromatography of tocopherol isomers, alpha-tocopherol quinone, and cholesterol in red blood cells and plasma. J Chrom 306:377-382.
  16. Riggs A, 1981. Preparation of blood hemoglobins of vertebrates. Methods Enzymol 76:5-29. [Medline]



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