Abstract
Context
Age-related declines in immune system function, including vaccine responsiveness, are well established. Dietary and lifestyle factors have been investigated in human clinical trials and observational studies for their effects on vaccine response.
Objective
The review intended to assess dietary and lifestyle factors that can modulate vaccine response in a population aged 55 years or older or in a population with an average age of 55 years or older.
Design
The research team performed a narrative review of studies occurring up until May 2021 by searching electronic PubMed databases.
Results
The review findings suggest that two factors may have clinically relevant effects on vaccine response: regular aerobic exercise and psychological environmental stressors, in particular caregiving stress, which studies have consistently found can have a positive and negative effect or association, respectively. In addition, micronutrients used in combination as well as microbiome-targeted interventions show mostly promising results. Other factors may yet be relevant but very few studies have been done.
Conclusions
Heterogeneity of study design, small sample sizes, and other challenges mean that strong conclusions remain elusive. Further study is needed as well as improvements in study design. However, there are indications that certain dietary and lifestyle factors influence vaccine effectiveness.
Age-related declines in immune system function, including vaccine responsiveness, are well established. Vaccine efficacy, particularly in older adults, is of heightened importance in the context of the SARS-CoV-2 immunization programs and against a background of other vaccine-modifiable illnesses in the population, such as influenza. The global pandemic that SARS-CoV-2 has caused has renewed interest in the aging immune system and vaccine efficacy in older adults.
Older adults are at a higher risk for infectious disease and related adverse effects due to multiple factors that negatively impact immune-system function as people age. These factors are collectively referred to as immunosenescence and include thymic involution, decreased T- and B-cell production, alterations in immune cell signaling, systemic inflammation, and chronic infections.1
Age-related immune dysfunction is associated with worsened vaccine response. Influenza vaccines, for example, provide 70%-90% protection against the virus for younger adults; however, the efficacy range drops to 17% to 51% in adults aged over 65 years.2 This age-related decline in vaccine efficacy is generally measured as both a decrease in initial antibody response and diminished vaccination longevity.3 Yanez et al and Levin et al found that COVID-19 mortality rates increase sharply for individuals aged 55 and older and increased even more so for those aged 65 or older.4,5
Dietary and lifestyle interventions have shown promise in improving the immune response to vaccines and have the benefits of carrying little, if any, evidence of harm.6 Human clinical trials and observational studies have investigated dietary and lifestyle factors for their effects on vaccine response for adult populations aged 55 years and older, but no existing reviews have evaluated the strength of evidence for comprehensive dietary and lifestyle interventions specifically for that age group.
The dietary and lifestyle factors examined in this review include: (1) micronutrients—vitamins A, D, E, and zinc singularly and in combinations with other nutrients; (2) food groups—fruit, vegetable and dairy consumption; (3) botanical medicines; (4) microbiome-targeted interventions—probiotics, prebiotics, synbiotics; (5) dehydroepiandrosterone (DHEA); (6) physical resilience, activity and exercise—frailty, physical activity levels, fitness, acute and longer term aerobic exercise, and acute resistance training; (7) psychological factors—environmental stressors, stress management, and mood interventions; (8) sleep; and (9) time of day of vaccine administration.
For many of these factors, very few studies have occurred, and the quality of the evidence and the studies’ results are mixed. The current review intended to assess dietary and lifestyle factors that can modulate vaccine response in a population aged 55 years or older or in a population with an average age of 55 years or older.
Methods
The research team performed a narrative review of studies occurring up until May 2021 by searching electronic PubMed databases.
Results
Table 1 provides a summary of reported results for dietary and lifestyle factors. Supplementary material consisting of summaries of each of the studies reported in the sections below is available online in a table format.
Table 1.
Summary of Findings by Category of Dietary or Lifestyle Factor. In the Vaccine Outcome column, significant indicates significant positive or negative effects on or association with vaccine response for at least one vaccine strain or subgroup, and not significant indicates no significant effect on or association with vaccine response. Supplementary material consisting of summaries of each of the studies reported in the sections below is available online in a table format.
| Category | Vaccine Outcome | Findings |
|---|---|---|
| Single micronutrients |
Significant, 5 studies: Goncalves-Mendes et al, 201914 Zitt et al, 201215 Meydani, 199719 Duchateau et al, 198124 Kreft et al, 200025 Not significant, 3 studies Sundaram et al, 202112 Harman & Miller, 198620 Provinciali et al, 199823 Braga et al, 201526 |
Beneficial associations or effects reaching significance:
Negative effect reaching significance:
|
| Combination micronutrients |
Significant, 4 studies: Girodon et al, 199927 Wouters-Wesseling et al, 200228 Langkamp-Henken et al, 200430 Lankamp-Henken et al, 200631 Not significant, 1 study: Bunout, 200429 |
Beneficial effects reaching significance:
|
| Food groups |
Significant, 3 studies: Gibson et al, 201232 Freeman et al, 201033 Schaefer et al, 201834 |
Beneficial effects reaching significance: |
| Botanical medicine |
Significant, 2 studies: Saiki et al, 201335 Vidal et al, 201237 Yutani et al, 201336 |
Beneficial effects reaching significance:
No effect:
|
| Probiotics |
Significant, 4 studies: Maruyama et al, 201642 Boge et al, 200948 Bosch et al, 201250 Akatsu, Arakawa et al, 201343 Not significant, 3 studies: Akatsu, Iwabuchi et al, 201351 Puyenbroeck et al, 201249 Namba et al, 201052 |
Beneficial effects reaching significance: No significant effects: |
| Prebiotics |
Significant, 4
studies: Lomax et al, 201554 Langkamp-Henken et al, 200430 Langkamp-Henken et al, 200631 Negishi et al, 201358 Not significant, 1 study: Bunout et al, 200257 |
Beneficial effects reaching significance:
|
| Synbiotics |
Significant, 1 study: Akatsu et al, 201659 Not significant, 3 studies: Nagafuchi et al, 201560 Bunout et al, 200429 Przemska-Kosicka et al, 201661 |
Beneficial effect reaching significance:
|
| DHEA |
Significant, 1 study: Degelau et al, 199765 Not significant, 2 studies: Araneo et al, 199763 Danenberg et al, 199764 |
Beneficial effect reaching significance:
|
| Physical resilience, activity, and exercise |
Significant, 10 studies: Yao et al, 201172 Bauer et al, 201775 Kohut et al, 200276 Schuler et al, 200377 Choon Lim Wong et al, 200978 Araujo et al, 201579 Keylock et al, 200780 Woods et al, 200982 Kohut et al, 200483 Ranadive et al, 201467 Not significant, 6 studies: Moehling et al, 201873 Moehling et al, 202074 Hayney et al, 20148 Long et al, 201269 Bohn-Goldbaum et al, 202068 Edwards et al, 201570 |
Beneficial associations or effects reaching significance: No significant associations or effects: |
| Psychological factors |
Significant, 9 studies: Kielcolt-Glaser et al, 199686 Vedhara, 199987 Glaser et al, 200089 Phillips et al, 200690 Moynihan et al, 200491 Ayling et al, 201892 Vedhara et al, 200385 Irwin et al, 200793 Yang et al, 200894 Not significant, 4 studies: Segerstrom et al, 200888 Phillips et al, 200690 Haney et al, 201484 Ayling et al, 201995 |
Negative associations or effects reaching significance: Positive associations or effects reaching significance: No significant associations or effects: |
| Sleep |
Not significant, 1 study: Ayling et al, 201892 |
No significant association:
|
| Morning vs afternoon vaccine administration | Significant, 2 studies: Long et al, 2016105 Phillips et al, 2008104 |
Beneficial effects reaching significance |
Abbreviations: BGF, bifido growth factor; DHEA, dehydroepiandrosterone; FOS, fructooligosaccharides; GOS galacto-oligosaccharides; JTT, Juzentaihoto; RDA, recommended dietary allowance.
Micronutrients
Several micronutrients play an important and recognized role in immune function, including adaptive immunity.7,8 Inadequate nutrient intake is common in older adults and includes vitamins A, B12, D, E, K, calcium, iron, and zinc.9 In addition, due to impaired nutrient absorption with age and conditions such as atrophic gastritis, some nutrients may become deficient despite adequate intakes.10
Vitamin A
Vitamin A, as an all-trans retinoic acid, plays an essential role in immune responsiveness, promoting the differentiation of T and B cells as well as many other functions. Nearly all studies of vitamin A and vaccine responsiveness have occurred in combination with routine childhood vaccinations in less-developed countries where vitamin A deficiency is common, and results have been mixed.11
To the best of the current research team’s knowledge, no studies have examined the effects of a vitamin-A intervention on vaccine response in older populations. One study with 205 adults aged 65 years and older, none of whom were vitamin A or E deficient, found no association between prevaccination levels of serum retinol and decreased hemagglutination-inhibition responses to a trivalent influenza vaccine (TIV).12
Vitamin D
Vitamin D has immunomodulatory effects, and Dror et al found a positive association between vitamin-D deficiency and the incidence and severity of infectious diseases, including seasonal influenza, hepatitis, and Covid-19.13 However, the effects of vitamin-D supplementation on vaccine responsiveness are unclear.
In a small randomized, controlled trial (RCT), 38 deficient volunteers aged over 65 years, with serum 25-(OH)D levels of <30 ng/mL), received vitamin-D supplementation of six doses of 100 000 IU every 15 days for three months prior to an influenza vaccination.14 The study found no statistically significant improvement in antibody production, despite increasing average serum 25-(OH)D levels to 44.3 ± 8.6 ng/mL (P < .001). In addition, the study found that seroconversion was significantly lower for the H3N2 influenza strain, at 36.8% and 42.1% for the vitamin D group and the control group, respectively (P < .05).
Effects may also be different in immunocompromised individuals and for yet other vaccinations. Patients with impaired renal function are immunocompromised, due both to the effects of end-stage renal disease on the host’s defensive mechanisms and to dialysis therapy. In addition, vitamin D deficiency is highly prevalent in individuals with chronic kidney disease (CKD).
In a trial of 200 patients with CKD, 125 males and 75 females with a mean age of 64 years, an 25-(OH)D concentration below 10 ng/mL was associated with a greater likelihood of a lack of response to a hepatitis B vaccination (P = .011) and with a reduced likelihood of seroconversion (P = .011) or seroprotection (P = .034).15 However, chronic inflammation, as is present in CKD and many other noncommunicable diseases, is also associated with both reduced serum 25-(OH)D levels16 and a weakened response to vaccines.17 This raises the possibility of a potential indirect, noncausative relationship between vitamin-D status and vaccine response in the context of chronic disease.
Vitamin E
Vitamin-E supplementation that is above currently recommended intake levels has been shown to delay immunosenescence in older adults;18 however, strong evidence for its direct effects on vaccine response is as yet lacking. Several review articles have cited a randomized, double-blind, placebo-controlled trial in 89 healthy individuals aged 65 years and older with serum vitamin E levels of <27.9(mol/L).19 Participants in the intervention group’s were assigned 60, 200, or 800 mg/d of supplemental vitamin E in the form of synthetic all rac-alpha-tocopherol in soybean oil.
After five months, all intervention groups showed a greater, delayed-type, hypersensitivity skin response to the hepatitis B vaccine, and the 200 mg/d intervention group showed a greater antibody response, compared to that of the control group, at six-fold and three-fold, respectively. The researchers also found improved antibody titers to tetanus vaccine in the 200 mg/d group but not in the other groups. Vitamin-E supplementation showed no effects for diphtheria vaccination and no change in immunoglobulin levels or number of T cells or B cells.
Two other trials have shown no improved antibody response to vaccines associated with vitamin-E status or supplementation. Sundaram et al’s study with 205 adults aged 65 years or older found that vitamin E status, assessed as serum vitamin E, wasn’t associated with prevaccination and postvaccination influenza protection, as measured by hemagglutination inhibition (HAI) responses.12 However, none of the participants in that study were vitamin-E deficient.
Harman and Miller gave 103 patients at chronic-care facilities vitamin-E supplementation at either 0 mg, 200 mg, or 400 mg per day, beginning one month before vaccination for six months. The researchers found that the supplementation had no effect on serum titers to a polyvalent influenza vaccine, including when evaluating only a subset of patients older than 69 years.20
One caution, however, is that one large randomized, placebo-controlled trial has suggested an increased risk of prostate cancer in men taking 400 IU/d of rac-alpha-tocopheryl acetate, equivalent to 180 mg/d of RRR-alpha-tocopherol.21 This finding has yet to be explained mechanistically but may be related to selenium status, polymorphisms in vitamin E and selenium-related genes, negative effects on the balance of other vitamin-E tocopherols and tocotrienols, and/or to the synthetic form of vitamin E used. No studies to the current research team’s knowledge have yet evaluated the effects of natural forms of supplemental alpha-tocopherol as well as other tocopherols and tocotrienols in the vitamin-E family on vaccine response.
Zinc
Older adult populations can have a reduced zinc status, and Prasad has shown that supplementation to improve that status can improve measures of immune function and reduce susceptibility to infections.22 Trials using zinc supplementation to affect vaccine responses, as well as those investigating potential associations between zinc status and vaccine response, have had mixed results across all age groups, including for older adults.
One study of 384 individuals aged 64 to 100, with a mean age of 82 years, found that neither 400 mg/d zinc sulfate nor 400 mg/d of zinc sulfate plus 4 g/d of arginine, starting at 15 days prior to influenza vaccination, improved the antibody response.23 Sundaram et al reported that zinc status wasn’t related to prevaccination or postvaccination influenza protection for adults aged 65 years or older, 20 percent of whom had low serum zinc levels of <70 μg/dL.12
Conversely, in a small RCT with 30 participants over 70 years old, Duchateau et al reported that 220 mg of oral zinc sulfate BID for one month prior to a tetanus vaccination could significantly improve antibody response.24 In addition, a small study with 16 chronic hemodialysis patients, with a mean age of 65 years, found that the response to a diphtheria vaccination was significantly associated with serum zinc levels, with responders showing similar serum zinc levels as age-matched controls, and nonresponders having a significantly decreased serum zinc level.25
More recently, Braga and colleagues performed a study with older individuals undergoing chemotherapy for colon cancer, with 25 participants in a chemotherapy-Zn group who had a mean age of 63.0 ± 15.0, and 32 participants in a control group, who had a mean age pf 61.0 ± 13.0.26 Those researchers found that 70 mg/d of zinc sulfate for 16 weeks after a pneumococcal vaccine led to a trend toward better seroconversion in the intervention group than in the control group, although the trend didn’t reach significance.
In addition, those researchers reported that zinc supplementation appeared to protect against antibody decline during chemotherapy, as indicatedby the comparable vaccination responses of individuals undergoing chemotherapy who received zinc supplementation compared to healthy controls who also received zinc supplementation, at 62% and 68%, respectively.
Studies of the effects of other singularly used micronutrients are lacking in general and especially in older age groups.
Micronutrients in combination
Researchers have conducted several studies with older-adult populations using combinations of micronutrient vitamins and minerals, some with additions such as probiotics, prebiotics, and antioxidant flavonoids, with mixed results. These studies have tended to report more positive effects than those using interventions of single nutrients, suggesting that micronutrients in combination and in context with other immunomodulatory factors may have more benefit.
In a double-blind RCT with 725 older adults aged 65 years or older, the researchers assigned participants to one of four groups receiving an oral daily supplement for 2 years: (1) trace elements—20 mg zinc and 100 μg of selenium; (2) vitamins—6 mg of beta carotene (provitamin A), 15 mg of vitamin E as alpha-tocopherol, and 120 mg of vitamin C; (3) both trace elements and vitamins; or (4) a placebo.27 Serological protection following the influenza vaccination was higher in the groups receiving trace elements and trace elements plus vitamins than in the other groups (P < .05), while the vitamins-only group achieved lower protection than other groups, including the control group (P < .05). However, the vitamins-only group did experience a nonsignificant lower incidence of respiratory infections compared with the control group (P = .06).
Wouters-Wesseling et al conducted a small trial with 19 older adults aged 65 and older, with a mean age 84 years.28 The intervention group received a nutritional supplement containing between 30% and 160% of the US recommended dietary allowance of vitamins and minerals as well as antioxidants and 250 kcal energy—comprising 14% protein, 40% fat, and 46% carbohydrate—twice daily for 7 months. They experienced a statistically significant improvement in mean fold increase—the ratio of the TIV’s postvaccination titer level to the prevaccination level—in antibody titers against the influenza A H3N2 strain but not for H1N1 or influenza B Yamanashi/166/98—as compared with controls.
In a study of 60 healthy older adults aged 70 years and older, half received a nutritional formula, in addition to their regular diet daily for twelve months.29 The formula included 120 IU of vitamin E, 3.8 mcg of vitamin B12, 400 mcg of folic acid, 10 billion CFU of Lactobacillus paracasei (NCC 2461), 6 g of fructo-oligosaccharide prebiotics as well as 480 kcal energy—comprising 26% protein, 23% fat, and 51% carbohydrate. The participants received influenza and pneumococcal vaccines at four months. No difference was observed in seroconversion between the groups.
In an RCT with 66 adults aged 65 years and older, the intervention group received a supplement for 183 days of 8 oz/d of an experimental nutritional formula (EXP).30 The supplement contained multiple vitamins and minerals, beta-carotene, taurine, carnitine, omega-3 fats, medium-chain triacylglycerol, and fermentable oligosaccharides (prebiotics). Participants in the control group consumed a standard, liquid nutritional formula matched for macronutrient ratios but with far fewer micronutrients and none of the additional bio active components in the EXP formula. All participants were vaccinated on day 15 ± 2 with a TIV. In the intervention group, 87% responded to the H3N2 strain, with a fourfold increase in antibody titer at the end of the period, compared with 41% of the control group (P = .012). Significant differences weren’t noted for the other influenza strains.
The same research group conducted a similar study published two years later, an RCT with 92 adults aged 65 years and older, with a mean age of 83.86 years, in which the intervention group consumed 240 mL/d of the EXP formula for 4 weeks prior to the TIV and for 6 weeks after it.31 The researchers found a greater likelihood of postvaccination H1N1 antibody titers of >1:100 (43%) in the EXP group as compared to those of the control group (23%), who consumed a standard, liquid nutritional supplement (P=.047).
Food Groups
Fruits and vegetables
Fruits and vegetables contain phytonutrients and fibers that may modulate immune responses, although to the current research team’s knowledge, only one clinical study has evaluated them directly in older adults.
In a trial of 83 healthy older adults aged 65-85 years, the antibody response to a pneumococcal vaccine improved in participants who consumed ≥5 portions of fruits and vegetables for 16 weeks as compared to the control group who ate ≤2 portions per day (P = .005).32 Vaccines were administered at 12 weeks. At baseline, all participants had had a low fruit-and-vegetable consumption, at ≤2 portions per day. The study found no increases in the antibody response to a tetanus vaccine, which the researchers had concurrently administered.
Dairy
Two studies have found that dairy components, such as whey protein, can have immunomodulatory effects. In Freeman et al’s randomized, double-blind pilot study of 17 healthy older adults, the intervention group received 5g of whey protein TID, for 4 weeks before and 4 weeks after a pneumococcal vaccine.33 That group had higher antibody responses than those of the control group to all strains except two, and in particular, to the four more-virulent strains.
In Schaefer et al’s study with 21 participants 63 to 94 years of age, the intervention group received 6 g of UV-treated, raw-milk powder BID for 4 weeks before and 4 weeks after a DTaP vaccine.34 That group’s tetanus antibodies increased significantly more than the control group’s did. Both Freeman et al’s and Schaefer et al’s studies used low-isoflavone soy protein as the control treatment.
Botanical Medicines
Botanical medicines encompass a large group of naturally occurring plant compounds in either a whole or an extract form. Researchers have studied very few for their effects on vaccine efficacy in older adults.
In an unblinded RCT with 90 older adults aged 65 or older at four care centers in Japan, the intervention group received a traditional Japanese Kampo medicine, Juzentaihoto (JTT), which has been approved for medical use in Japan.35 JTT consists of 10 herbs, including Astragalus membranaceus root, Cinnamomum cassia bark, Panax ginseng root, and Glycyrrhiza uralensis root, and therefore, contains a wide variety of active phytonutrients and fibers.
The JTT group consumed 3.75 g of JTT, two times daily, from 4 weeks before to 24 weeks after a TIV. Hemagglutination-inhibition titers were significantly higher against H3N2 in the intervention group at 8 weeks after vaccination (P = .0229), and the increase in titers between week 4 and week 24 was significantly greater than those of the control group (P =.0468). No significant differences were noted for titers against the H1N1 and B/Brisbane/60/2008 strains.
Patients with advanced pancreatic cancer in Yutani et al’s study received a personalized peptide vaccination.36 In the intervention group, 28 participants, with a median age of 66 and a range of 50-83 years, received 15 mg/d of JTT for 35 days during the first cycle of vaccinations. The 29 control group participant’s median age was 65, with a range of 45-79 years, and they received the same vaccination without the JTT treatment. The JTT didn’t significantly alter the intervention group’s vaccine responses as compared to those of the control group, despite appearing to prevent deterioration in the condition of the intervention group’s participants.
To the current research team’s knowledge, researchers have studied very few other botanical compounds in the context of vaccine response in older adults. The team found only a study with 150 older adults aged 65-70 years that used Chinese wolfberry, a herb used in Traditional Chinese Medicine and better known in Western cultures as goji berry.37 The herb was in the form of 13.7g/d of a dietary lacto-wolfberry supplement, containing 530 mg/g of wolfberry fruit, and the researchers found that it could significantly enhance immunoglobulin G (IgG) levels and seroconversion rate after an influenza vaccination.
Microbiome-targeted Interventions
The understanding of the complex role that the microbiome plays in immunity is continuously evolving, but existing evidence suggests that gut microbes and their metabolites play a significant role in the immune response of aging adults.38 Several studies in younger adults also have indicated that broad-spectrum antibiotic use, which indiscriminately targets bacterial populations, may negatively affect vaccine response.39,40
The related mechanisms of action have yet to be fully defined but may include interference with pathogenic organisms and the alteration of pathogen-associated molecular patterns; changes in microbial metabolites, such as short chain fatty acids; modulation of intercellular tight junctions; increases in mucin and defensin production; and modulation of signaling pathways.38
Human trials in older adults have used probiotics, prebiotics, or a mix thereof—synbiotics—to investigate their roles in vaccine efficacy. A systematic review of 12 RCTs with 688 participants found that use of prebiotic and probiotic supplements resulted after vaccination in 13.6% to 20% higher levels of antibody titers for influenza hemagglutination inhibition in adults.41 While that review included adults of all ages, in 15 of the 20 reviewed studies, participants were part of populations with mean ages of 55 years or older, and in 12 of the 20 studies, they were part of populations of adults aged 75 years or older. Although the review found a significant amount of heterogeneity in the existing research, the results suggest that microbiome-targeted interventions may be a promising area for continued research and clinical interventions.
Probiotics
Existing evidence for probiotic modulation of vaccine response in older adults aged 55 years and older is inconsistent. Researchers have completed RCTs using probiotic interventions in the context of vaccines in older adults of up to 100 years of age, many of whom lived in long-term care facilities (LTCFs) and some of whom received enteral feeding.
Several of those studies used heat-killed species to increase the safety profile, although with mostly negative results.42,43 Studies with positive outcomes have predominantly occurred in Mediterranean countries, Spain and France. Traditional diets in those regions are typically rich in microbiome-supportive dietary factors, including prebiotic fibers, such as vegetables and legumes, and fermented foods, such as kefir, olives, and capers.44 It’s unclear what role diet-related, baseline microbiome characteristics may have played in those studies, and future research is needed to elucidate potential connections.
In their systematic review, Yeh et al suggested that live-probiotic interventions, including those discussed above, are relatively safe in older adults, because the clinical trials that they reviewed reported no cases of sepsis related to live probiotics.41 However, several studies have reported individual cases of probiotic-related sepsis involving live probiotics, including from supplementation with Lactobacillus rhamnosus GG, Bacillus clausii, and Saccharomyces boulardii, in immunocompromised older adults45 and in those with comorbidities, including diabetes46 and C. difficile infections.47
Researchers have studied specific probiotic strains in the context of TIV vaccinations, as follows:
Lactobacillus paracasei (heat-killed)
A small RCT with 42 adults aged 65 and older, with a mean age 87.15, in a LTCF in Japan examined the use of 10-billion CFU/day of the heat-killed Lactobacillus paracasei MCC1849, taken 3 weeks before and 3 weeks after a TIV vaccination.42 The researchers found that the probiotic significantly improved the intervention groups antibody response to type A/H1N1 and B antigens but only for the very small subset of 11 adults aged 85 and older with a mean age of 90.8 years.
In another very small trial with 15 participants from a similar population, with a mean age of 76 years, the intervention group used 10 billion CFU/day of heat-killed Lactobacillus paracasei MoLac-1. The study found that the probiotic’s use 3 weeks before and 4 weeks after the TIV didn’t significantly improve antibody response. However a significant increase occurred in the group’s hemagglutination-inhibition titers for all three strains (A/H1N1, A/ H3N2, B) compared to baseline, which was only seen to A/H3N2 in the control group.43
Lactobacillus casei
Two studies, both sponsored by the probiotic’s formulators, have looked at varieties of live Lactobacillus casei that are commonly found in the commercially available, fermented-milk drinks Actimel (L. casei DN-114001, Danone Research, Palaiseau Cedex, France) and Yakult (L. casei Shirota, Yakult Honsha Co., Ltd.).
A sizeable RCT with 222 older adults living in LTCFs in France, aged 70 or older with a mean age of 84.64, evaluated the benefits of Lactobacillus casei DN-114001 in the form of two bottles per day of the Actimel fermented-milk drink, 4 weeks before and 9 weeks after the TIV.48 That study found significant improvements in the intervention group’s antibody response, for the B strain only.
By contrast, a large RCT with 737 older adults in LTCFs in Belgium, aged 65 or older with a mean age 84, evaluated the benefits of 2 bottles per day of the Lactobacillus casei in the Shirota fermented-milk drink, for a total of 13-billion CFUs.49 The intervention group started using the probiotic 3 weeks before a TIV and continued the use for a total of 176 days. The study found that the probiotic didn’t significantly improve the intervention group’s antibody response. Of note, participants in the study were overweight, with a mean body mass index (BMI) of 28.
Lactobacillus plantarum
A 2012 study with 60 older adults aged 65-85 years who were living in LTCFs in Spain compared a high dose of 5 billion CFU/day and a low dose of 500 million CFU/day of live Lactobacillus plantarum CECT 7315/7316.50 The probiotic supplier also sponsored this study, which found a significant increase in IgA antibodies in both the high- and low-dose groups as compared with the levels of the control group. Participants in the high-dose group also had a significant increase in IgG antibodies and a nonsignificant trend toward an increase in IgM antibodies.50
Bifidobacterium longum
Two small clinical trials occurred in LTCFs in Japan, Akatsu et al’s51 with 45 older adults and Namba et al’s52 with 27 older adults, aged 65 years or older and with mean ages of 81.7 and 86.7 respectively. Both used Bifidobacterium longum BB536 for the interventions. Akatsu et al found significant increases in antibodies specific to the H1N1 strain when using Bifidobacterium longum BB536 at a dosage of 100 billion CFU/day, 50 billion BID, for 4 weeks before and 8 weeks after the vaccination.51
Namba et al’s earlier trial used 100 billion CFU/day of the same strain, 2 weeks before and 3 weeks after the vaccination for all participants, followed by 14 weeks of either a continued probiotic supplementation at the same dose or a discontinuation of probiotic supplementation. The study found no significant difference in the improvements in antibody response between the groups. The intervention did, however, increase natural killer (NK)-cell activity for both groups and reduce influenza cases and fevers in those continuing probiotic supplementation over the 14-week continuation of the probiotic.
Prebiotics
Prebiotics are carbohydrates that are resistant to human digestion and absorption and that increase the growth of beneficial bacteria that ferment these fibers to produce metabolites known to positively impact human health.53 Researchers have conducted prebiotic studies in the UK, US, and Chile, and diets typical in some of these regions, especially in the UK and US, tend to be otherwise relatively low in prebiotic fibers. To date, researchers have mostly conducted prebiotic studies in free-living participants with a mean age of 55 years of less.54-56 Existing evidence suggests that some types of prebiotics, including Beta 2-1 fructans and Mekabu Fucoidan, may beneficially impact the response to TIV, pneumococcal, and tetanus vaccines in older adults.
Beta 2-1 Fructans
A small, supplier-sponsored RCT with 49 otherwise healthy older adults, aged 45-63 years and with a mean age of 55, gave the intervention group 8g/day of a mixture of 50% long-chain inulin and 50% oligofructose, commercially available as Orafti Synergy 1 (Beneo Orafti), beginning 4 weeks before and continuing until 4 weeks after vaccination. The prebiotic TIV’s antibody response significantly improved but only for the H3N2 strain.54
Langkamp-Henken et al conducted two studies that found small, strain-specific improvements in the TIV’s antibody response in older adults, aged 65 and older who were living in LTCFs.30,31 The researchers used a combination nutritional formula (EXP), which this article discusses above under Micronutrients in Combination. It included fructo-oligosaccharides (FOS) as one of the many components. As a result, it’s difficult to ascertain the contribution of the FOS to the positive results that these studies found.
In contrast, a small study included 43 free-living older adults, aged 70 years and older with a mean age of 75.73, who were enrolled in a national nutritional supplementation program in Chile.57 The study found no benefits for 6g/day of a prebiotic mixture containing FOS, 70% raftilose and 30% raftiline, which is commercially available as Prebio 1 (Nestec, Ltd., Vevey, Switzerland), on the response of TIVs or pneumococcal vaccines. Of note, the prebiotic intervention commenced only one week prior to the vaccination, and all participants in this trial received two vaccinations at the same time.
Mekabu Fucoidan
Negishi et al’s study with 70 older adults, 60 years of age and older with a mean age of 87, consumed 300mg/day of mekabu fucoidan, which is commercially available as Riken Mekabu Fucoidan (Riken Vitamin).58 It’s a fucose-rich, sulphated polysaccharide derived from seaweed, and the intervention group received it beginning 4 weeks prior to vaccination, together with 300mg/day of indigestible dextrin, which is commercially available as Fibersol-2 (Matsutani Chemical Industry).
Antibody titers against all three strains of influenza targeted with TIVs were higher after the prebiotics use. However, only B-strain titers were significantly higher, and they maintained that significance at 5 weeks and 20 weeks, with P = .038 and P = .047, respectively.58
Synbiotics
Synbiotics are probiotics and prebiotics administered in combination. Although clinical approaches often combine probiotic and prebiotic interventions, relatively few good-quality studies have investigated synbiotic interventions in the context of vaccine efficacy for older adults. Most of the existing studies that used synbiotic interventions in older adults have found no benefits for them; however, the sample sizes were small and potential confounding factors were present.
A small study of 23 bedridden older adults receiving enteral feeding in Japan used an enteral formula that included a combination of milk products fermented with heat-treated, lactic-acid bacteria, 4 g/day of galacto-oligosaccharide (GOS), and 0.4 g/day of bifidogenic growth stimulator (BGS).59 Its use began 4 weeks before and continued for 6 weeks after the TIV. The synbiotic significantly improved the H3N2 antibody response compared to a standard enteral formula.
A follow-up study, conducted to correct for baseline differences in the original study’s groups, found no significant increase in antibody response; however, the intervention group maintained enhanced A/H1N1 antibody titers for a significantly longer period than the control group did.60
Similarly, Bunout et al conducted a 2004 study among free-living older adults in Chile, who were part of a national nutritional program.29 The researchers found no significant improvement in antibody response to TIV with the addition of Lactobacillus paracasei (NCC 2461) and 6 g of FOS to a multinutrient formula but did find significant increases in NK-cell activity and lower rates of infection.
More recently, a 2016 RCT in the UK, comparing a group of younger adults 18-35 years of age to older adults 60-85 years of age, found no benefits for a synbiotic intervention with 10 billion CFU/day of Bifidobacterium longum bv. infantis (CCUG 52486) and 8g/day of gluco-oligosaccharide.61
DHEA
DHEA is an endogenously-produced steroid hormone, also available as a dietary supplement, with immunomodulatory activity. DHEA levels can fall with age in both men and women, sometimes to as little as 10-20% of levels in young individuals.62 Although none are recent, several studies have examined supplementation with dietary DHEA for older adults and its effects on vaccine responsiveness. The studies have varied with respect to administration, oral compared to injections, with only a subcutaneous injection showing significant improvements in outcomes.
In an RCT with 66 men over the age of 65,63 treatment with 50 mg of DHEAs orally BID for 4 consecutive days, starting at 2 days prior to a tetanus booster vaccination, didn’t provide any statistically significant benefit in immunological response compared with the control, 50 mg BID of corn starch. Most of the study’s participants had a previous history of tetanus vaccine and protective levels of antibody titers had been detectable prior to the study’s initiation.
In a double-blind, controlled trial, 71 adults aged 61-89 years in the intervention group received 50 mg/d of DHEA orally for 4 consecutive days, starting 2 days prior to receipt of the influenza vaccine, but the DHEA failed to improve the response to immunization.64 In addition, in participants without protective antibody titers at baseline, the DHEA treatment appeared to reduce seroprotection following vaccination (P <.05).
In yet another double-blind RCT, 78 adults aged 73-90 years, together with 20 younger controls, received a single 7.5-mg dose of subcutaneously-injected DHEAs administered concurrently with an influenza vaccine.65 The study found improved antibodies to the H3N2 strain but only in participants with low prevaccination titers and lower DHEAs levels.
The impact of short-term DHEA treatment, therefore, remains unclear, and no investigation has occurred on the effects of longer-term DHEA treatment—greater than 4 days—or of repletion on vaccine effectiveness.
Physical Resilience, Activity, and Exercise
This section reviews associations of vaccine response with frailty phenotype, physical activity levels, and fitness levels as well as trials investigating aerobic exercise and resistance-training interventions. Evidence, both from observational and interventional studies, suggests that regular, habitual, aerobic exercise, physical activity, and increased fitness levels aid vaccine response and may blunt age-related declines in vaccine efficacy.66
Evidence for the effects of frailty have been mixed, despite the inclusion of activity and fitness measures in its evaluation. Furthermore, acute exercise interventions have shown almost no benefits for vaccine response in older adults to date.67-70
Frailty phenotype
The defined characteristics of Fried et al’s frailty phenotype, indicators of frailty in older adults, include: (1) weakness—grip strength, (2) slowness—walking speed, (3) self-reported exhaustion, (4) unintentional weight loss of 10 lbs in the past year, and (5) low physical activity in kcals/week at the lowest quintile.71 The scale considers older adults with three or more of these characteristics to be frail and those having one or two indicators to be prefrail.
Observational studies in older adults that measured associations between the Fried et al’s frailty phenotype and TIV response have been mixed. Yao et al conducted a study of 71 community dwelling, older adults, aged 72-95 with a mean age of 84.5.72 Those researchers found that a significant step-wise decrease occurs in antibodies to all three influenza strains, with non-frail participants having the highest levels, followed by prefrail, and frail participants having the lowest levels.
However, another study found that Fried et al’s frailty phenotype was positively associated with antibody response to TIV but only in a subset of older adults aged 50-64 years and not in those aged 65 years or older.73 More recently, a study of 168 older adults, aged 65-83 years with a mean age 71.5 years, found no associations between Fried et al’s frailty phenotype and antibody response to TIV but did find significant differences in the peripheral-blood mononuclear cells between the frail and non-frail groups.74 The findings of that study suggested that frailty may contribute to other markers of immune response in older adults74; however, further elucidation of these connections requires more research.
One study illuminated how physical activity levels, as a component of frailty, may be an important predictor of TIV antibody response. A study of 76 community-dwelling, older adults aged 70-93 found no overall significant effects for Fried et al’s frailty phenotype on antibody titers.75 However, a significantly lower antibody response occurred to both the H3N2 and B strains in the subset of participants with the lowest levels of physical activity.
Physical activity levels
Higher physical activity levels, independent of frailty phenotype, are generally associated with improvements in response to TIV in older adults. One study, with 56 participants aged 62 years or older, found an association between enhanced immune response to TIV, including both increased antibodies and peripheral-blood mononuclear cells, and high activity levels of at least 20 mins of vigorous exercise, 3 times per week.76 Another small study of 30 older adults, aged 67-91 years with a mean age of 81, found that participants with the highest levels of physical activity had significantly improved antibody response to the H3N2 strain only.77
Furthermore, researchers have found that activity levels can influence B-cell function and antibody persistence in older women. A small study conducted with 56 Singaporean Chinese, older adult women aged 65 or older, used a wristband to monitor their activity for 14 days after the TIV. The study found that higher rates of activity were associated with improvements in markers of both innate and adaptive immunity, including higher antibody levels for influenza B after the second vaccination.78
Fitness levels
Research has shown that fitness levels correlate with TIV antibody response in older adults. De Araujo et al examined the benefits of levels of fitness activities that included moderate and intense activity for a group of 61 older adult males aged 65-85 years.79 The researchers measured the levels using a physical activity questionnaire and a treadmill test measuring the maximum amount of oxygen the body can use (VO2 max) during exercise. They found that both moderate and intesnse activity levels were associated with an improved antibody response to TIV.
A smaller study of 26 older adults aged 60-76 years found that high levels of fitness, as measured by the VO2 max, were associated with an improved antibody response to TIV and a T helper cell 2 (Th2)-skewed response to tetanus toxoid vaccine.80
Aerobic exercise interventions—longer-term
Studies have generally shown that interventions of longer-term, moderate aerobic exercise can have a positive impact on vaccine response in older adults. A recent systematic review on the benefits of exercise in older adults concluded that prolonged, moderate aerobic exercise can improve immune response to both influenza and pneumococcal vaccines.81 A RCT of 144 healthy older adults, with a mean age of 69.9 years, compared 45-60 minutes of moderate cardiovascular exercise three times per week, at 60-70% of maximal oxygen uptake, with flexibility and balance training at <20% maximal oxygen uptake.82 The activities began 4 months prior to TIV and continued afterward for a total of 10 months. While the flexibility training had no significant impact on vaccine response, the cardiovascular intervention group had 30-100% significantly increased seroprotection that was variant dependent.
Similarly, in a small RCT, 27 older adults aged 64 or older performed aerobic exercise at 65-75% of the heart rate reserve for 25-30 mins, 3 days per week.83 The exercise commenced one month after the first vaccination and continued for 13 months, with a second vaccination given at 10 months. The study found that the exercise significantly improved antibody response to the H1N1 and H3N2 strains after a TIV.
Not all studies found a benefit, however. One RCT examined TIV response with older adults, aged 50 and older with a mean age of 59.84 For the interventions, the researchers evaluated the effects of 8 weeks of 2.5-hr, weekly group sessions, plus 45 minutes daily of at-home exercise, with 47 participants, or meditation, with 51 participants. The study found no significant improvements in antibody response for either intervention group as compared to that of a control group with 51 participants.
Hayney et al found that the 2009-2010 TIV had a high effective rate in older adults.84 The researchers suggested that the effective rate may have influenced the ability of the exercise intervention to significantly affect results. In addition, the participants in the study took part in the supervised exercise intervention only once per week, compared to the studies above that showed benefits for a supervised exercise intervention of 3 times per week.
Aerobic exercise interventions—acute
Two studies found little-to-no benefit for aerobic exercise immediately prior to vaccination. A small RCT of 59 adults, aged 55-75 years with a mean age of 67, found that acute, moderate aerobic exercise at 55-65% of the maximum heart rate for 40 minutes immediately before receiving TIV didn’t improve the antibody response of the male participants.67 Women in that study had a significantly higher antibody response to the H1N1 strain following exercise compared to the men, although the researchers suggested that the finding may have been due to lower H1N1 prevaccination titers in the women among the exercise group’s participants.
Another RCT that compared 60 younger adults with a mean age of 22 with 60 older adults with a mean age of 57.5 found that 45 mins of brisk walking immediately prior to receipt of a pneumococcal vaccine or TIV at a half dose had no significant improvements in antibody response in either group.69
Resistance training interventions—acute
Similar to the studies on acute aerobic interventions, studies of acute resistance training on vaccine response in older adults have found no benefits. A recent, small RCT with 46 older adults with a mean age of 73.4 found that 45 minutes of acute resistance exercise—5 sets with 8 repetitions—immediately prior to TIV had no significant impact on antibody response or on the development of flu-like symptoms at 6 months postvaccination.68
An earlier, small RCT with 46 older adults with a mean age of 73 found that upper- and lower-body, resistance training immediately prior to the TIV, at 60% intensity with one repetition maximum, had no significant effects on antibody response or on the development of flulike symptoms at 6 months postvaccination.70 Research is lacking regarding the potential effects of longer-term, resistance-training programs on vaccine response in older adults.
Psychological Factors
This section reviews associations of vaccine response with environmental stressors as well as trials investigating stress management and mood interventions. Evidence, both from observational and intervention studies, suggests that psychological factors influence the immune system’s innate and adaptive responses, although few robust RCTs have occurred, and the ones that have occurred had high levels of heterogeneity in their target populations and the interventions used. While some researchers have suggested that cortisol is the primary mediator of psychological effects on vaccine response, other studies, albeit not in older populations, have found no between-group differences in cortisol despite observing differences in vaccine response according to measures of psychological stress.85
Environmental stressors
The majority of studies conducted in the older-adult population that have looked at the effects of environmental stressors on vaccine response have examined the role of caregiver, assumed to confer higher levels of emotional stress. Kiecolt-Glaser et al performed a comparison of 32 caregivers for Alzheimer’s patients matched to 32 controls.86 In that study, fewer caregivers demonstrated influenza-vaccine responsiveness to any one of the three vaccine strains, defined as a fourfold or more increase in antibody titers, than controls did (P = .02). Only 12 of the 32 caregivers met this response criterion compared with 21 of the 32 controls.
In a similar comparison of 50 caregivers of Alzheimer’s patients with a median age of 73 years and 67 controls with a median age of 68 years, the mean scores of emotional distress were higher in caregivers at all time points as was the level of salivary cortisol.87 In addition, only 16% of the caregivers responded to one or more of the strains targeted by the TIV compared with 39% of controls, a difference that reached statistical significance (P = .007). However, in a later study, caregiver status wasn’t associated with antibody response to any strain of viruses targeted by TIVs.88 This latter study comprised 14 caregivers in the intervention group and 30 non-caregivers in the control group.
While those studies have investigated the effects of caregiver stress on influenza-vaccine response, Glaser et al looked at its effect on response to pneumococcal vaccines.89 They found that spousal caregivers of dementia patients initially exhibited a similar vaccine response to controls at 2 weeks and one month after vaccination. However, their protection declined more rapidly over time, with a significantly-reduced antibody response to vaccination at both 3 and 6 months postvaccination than either former caregivers or non-caregiver controls.
The effects of other environmental psychological influences have also been investigated in association studies. Phillips et al looked at bereavement for 184 participants with a mean age of 75 years, specifically the loss of a spouse or relative within the year prior to the study.90 The study found that bereavement was associated with significantly lower antibody responses to TIV compared to the controls. Specifically, differences in the antibody means were -0.6 (95%CI -0.30 to -0.02) for the A/Panama strain and -0.21 (95%CI -0.34 to -0.09) for the B/Shangdong strain. Those researchers also found that being married and having higher marital satisfaction was associated with significantly higher antibody responses to the A/Panama strain. Social-support measures, such as network size or the functional social support score, weren’t related to vaccine response in that study.
In another study of 37 older adults living in a nursing home, higher levels of self-reported social support, including having a significant other, family, and/or friends, were positively associated with prevaccination influenza titers but negatively associated with post-TIV titers for the NC and HK strains.91 Measures of perceived stress were also negatively correlated with prevaccination, but not postvaccination, titers to the NC and HK strains.
Participants in Ayling et al’s study were 138 community-dwelling adults, aged 65-85 years with a mean age of 72.87.92 Across a six-week observation period, with TIV administered after 2 weeks of observation, a positive mood, and especially a positive mood on the day of vaccination, were significantly associated with achieving H1N1 seroprotection but not seroprotection to other strains.
Stress management and mood interventions
A few clinical trials have employed a diverse set of psychological interventions to look for potential effects in vaccine response in older adults, with promising outcomes. In a controlled study, Vedhara et al provided 70 caregiver and non-caregiver, older adults with cognitive behavioral stress management at one hr per week for 8 weeks.85 The intervention group had a mean age of 75 years and the control group 71 years.
The researchers administered the influenza vaccine 2-3 weeks after the final intervention session. The seroresponse was significantly greater in the intervention caregivers as compared to the caregiver controls. In addition, no significant difference existed between the response of the intervention caregivers compared to that of the non-caregiver controls, implying that the intervention could reverse the negative effect of caregiving on vaccine response.
Two separate studies investigated the influence of Tai Chi practice on vaccine response, both with beneficial effects. In one RCT, 112 adults aged 59-96 years, with a mean age of 70, were randomly assigned to either a westernized version of Tai Chi group, with 40 minutes of practice 3 times per week, or an control group receiving health education that incorporated 16 didactic presentations on a range of health themes for 16 weeks, followed by a varicella zoster vaccine.93 Participants in the Tai Chi group exhibited greater cell-mediated immunity, as measured by peripheral-blood mononuclear cells, specifically CD4+CD45RO+ T cells or memory T cells, than did the health education group (P < .05), with the immunity increasing at nearly twice the rate of the health education groups (P < .001).
A second study with 50 older adults, with a mean age of 80 in the intervention group and 75 in the control group, used a combination of Tai Chi and Qigong meditation, with sessions lasting one hour 3 times per week for 20 weeks.94 The researchers administered the influenza vaccine during the first week of the intervention or control period. The antibody titers at 3 and 20 weeks, but not at 6 weeks, postvaccination were significantly higher in the intervention group.
By comparison, other studies have found no improvement in vaccine response following psychological interventions. Hayney et al’s study, which included 149 adults with no prior experience of meditation who were over 50 years of age, used a mindfulness-based, stress-reduction intervention.84 The intervention group’s mean age was 60 and the control group’s was 58.8. The intervention consisted of weekly 2.5 hr group sessions using meditation and 45 minutes of home practice each day for 8 weeks. The study found no significant improvement in antibody response to the TIV administered at week 6.
As noted above, Ayling et al found that a positive mood was associated with improved H1N1 seroprotection. In a second study, a single-blind RCT, with 103 older adults aged 65-85 years, the same researchers subsequently found no improved vaccine response for an intervention of a 15-minute video package, intended to induce positive mood, that occurred immediately prior to quadrivalent influenza vaccination.95 However, they did note a possible trend toward significance of a greater effect size in the intervention group.
Sleep
While multiple studies in younger and middle-aged adult populations of 40-60 years have indicated that sleep duration and quality can have a significant impact on vaccine response,96-100 the current research team found only one associational study with older adults with a mean age of 55 years or older. A cohort study of 138 older adults aged 65-85 years found no association between sleep duration and antibody response.92 The researchers measured the effects based on self-reported sleep duration, as recorded using psychosocial and behavioral measures 2 weeks before and 4 weeks after TIV vaccination. Further research into the effects of sleep duration and quality in older adults seems warranted.
Time of Day of Vaccine Administration
Various components of the immune system fluctuate in a circadian fashion.101 Preclinical studies have suggested that immune cells, including both B cells and T cells, have a circadian clock that may play a role in modulating vaccine response.102,103 Circadian rhythms also influence other immune-system regulating factors, such as cytokines and cortisol.104 As a result, interest is ongoing in the relationship between vaccine timing and vaccine efficacy in older adults.
Two human clinical trials have looked at the impact of vaccination timing for older adults. A large cluster, randomized trial included 276 older adults aged 65 and older, who received the TIV either in the morning between 9 and 11 am or in the afternoon between 3 and 5 PM.105 The study found that those who received the vaccine in the morning had significantly better antibody responses to the H1N1 A and B strains but not to the H3N2 strain.
Some earlier data suggest that the effects of time of day and vaccine response may be gender-influenced. A 2008 nonrandomized trial of 89 older adults, aged 65 and older with a mean age of 73.1, found that morning administration of the TIV significantly improved antibody response to the H1N1 A strain but only for males.104 This measurement was part of a study that also looked at the response of younger adults to Hepatitis A vaccination and found a similar time of day and gender interaction.104 Those researchers suggested that diurnal variations in cytokines and cortisol may have gender-related immune effects.104
Discussion
While the current review indicates that an interest exists in understanding the potential connections between diet and lifestyle and vaccine efficacy, research methodologies have been heterogeneous with respect to the type, dosage, and timing at pre- or postvaccination of interventions that also varied significantly. The results have been highly mixed, and researchers have studied only a few factors to an extent that suggests potential effects. The current research team found that the evidence suggests a positive clinical effect for regular aerobic exercise implemented before vaccine administration. In addition, the evidence consistently suggests that psychological environmental stressors, such as caregiving, can have a negative effect on vaccine efficacy.
Studies looking at other categories have generally been lacking in number, making conclusions elusive. Yet, given the increasing evidence of the influence of diet and lifestyle on immune health as well as the ongoing public and individual health challenges in navigating emerging infectious diseases, the current research team suggests that reason exists to continue to evaluate these connections, especially in vulnerable, older age groups.
Other promising factors have demonstrated a potential to influence vaccine efficacy in studies with other age groups or in preclinical studies, including colostrum, melatonin, beta-glucans, larch arabinogalactans, lectins, saponins, quercetin, curcumin, astragalus root, and Coriolus mushroom.55,106-113 As research continues, however, several challenges exist related to study heterogeneity, confounding factors, and assessment measures that will likely need to be addressed.
First, the majority of studies in older-adult populations have evaluated interventions in the context of TIV, and significantly less evidence is available with respect to other vaccine types. However, vaccine type might make a significant difference to an intervention’s outcome. For example, oral vaccines, such as those for polio, cholera, typhoid fever, or rotavirus, because they use live-attenuated versions of viruses that replicate in the gastrointestinal tract, may be more likely to elicit an immune response that interacts with the intestinal microbiome.114 Furthermore, no studies have as yet investigated dietary and lifestyle effects on mRNA-based vaccine technology or COVID-19 vaccines.
In addition, variations in baseline characteristics between the studies’ populations, such as prior exposure to wildtype infections, history of antibiotic use, diet that is more or less nutrient dense prebiotic fiber and/or fermented food intake, nutrition status, microbiome composition, and habitual exercise may contribute to the diversity in outcomes. Gender differences and gene status, such as Vitamin-D-receptor polymorphisms, may also affect outcomes.115-116
A recent review of studies in younger participants suggests that obesity may also have a negative impact on vaccine response.117 The combination of low BMI and low psychological distress has been associated with improved vaccine response in older adults, making BMI another relevant baseline measure to collect.88 Furthermore, researchers have studied older adults in different environments, including free-living and LTCF settings.
It’s worth noting that some researchers have suggested the influence of persistent, chronic infections, and potentially, associated immunological phenotypes, over vaccine response in older adults. One of the RCTs reported in the Synbiotics section in this article observed that the study’s control group had significantly lower rates of immunosenescence—CD28- CD57+ helper T cells—and cytomegalovirus (CMV) infection, which the researchers argued may have impacted the results.61 An in-vitro follow-up study by the same group found that poor vaccine response in older adults, but not in younger adults, was associated with CMV seropositivity.118
The type of control used may also inadvertently impact immune function and a study’s results. Several studies have used corn starch or maltodextrin, which contain prebiotic fiber that can alter the gastrointestinal microbiome. These studies include those with interventions that targeted the microbiome in the digestive tract.54,57,58 Other controls have included noncaloric drinks, which may contain artificial sweeteners, such as aspartame, that may have negatively affected the immune homeostasis and microbiome status.119
Finally, while the great majority of studies on vaccine efficacy focus on antibody response as the primary outcome, other potential indicators of immunoprotection, such as T-cell mediated immunity, may also be relevant in older adult populations.120
Conclusions
Despite the presence of significant heterogeneity and potentially confounding factors, clinical research conducted to date shows promise in the ability of several dietary and lifestyle factors to influence vaccine response in older adults. Notably, reasonable early evidence indicates that regular aerobic exercise and psychological environmental stressors, such as caregiver stress, may lead to clinically relevant alterations, positive and negative, respectively, in vaccine response. Those two factors have had the most extensive research attention to date.
Most studies looking at micronutrients in combination, probiotics, and prebiotics, have reported improved vaccine response. However, significant heterogeneity exists across studies in terms of the type of micronutrient combination, probiotic, or prebiotic chosen, and some probiotic studies reported conflicting results using the same strain. The number of studies conducted on any one nutrient, food group, or botanical intervention as well as on DHEA, sleep, or time of day of vaccine administration is very small.
Further research and refinements in study design are needed to strengthen these preliminary conclusions, expand the evidence base for factors where very few studies exist, and to explore additional potential factors that may impact vaccine efficacy in this age group.
Supplementary Material
Table S1.
Micronutrient Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Vitamin A | n/a | n/a | n/a | 65+ years, n=205. Not considered vitamin A deficient | TIV | No association between vitamin A status and vaccine responsea | Sundaram et al12 |
| Vitamin D | 100000 IU every 15 days | 3 months prior to vaccination | Placebo supplementation, not specified | 65+ years, n=38, serum 25-(OH)D<30 ng/mL | TIV | No improvement in antibody response. Significant negative response for H3N2b | Goncalves-Mendes et al14 |
| Vitamin D | n/a | n/a | n/a | Mean age 64 years. n=200 patients with CKD |
Hepatitis B | <10 ng/mL 25-(OH)D associated with reduced seroconversion and seroprotectionb | Zitt et al15 |
| Vitamin E | 60, 200, or 800 mg/day all racalpha-tocopherol in soybean oil | 5 months prior to vaccination | Soybean oil only | 65+ years; serum vitamin E < 27.9 μmol/L n=89 |
Hepatitis B Diphtheria | Vitamin E group showed greater delayed-type hypersensitivity response to Hep B vaccine. 200 mg/d group had greater antibody response to Hep B vaccineb No difference in response to diphtheria vaccine No change in T cell or B cell level | Meydani et al19 |
| Vitamin E | n/a | n/a | n/a | 65+ years; not considered vitamin E deficient n=205 |
TIV | No association between vitamin E status and vaccine responsea | Sundaram et al12 |
| Vitamin E | 200 or 400 mg/day | 1 month prior to and 5 months after vaccination | Placebo identified as “0 mg vitamin E” | 24-104 years; patients of a chronic care facility n=103 |
TIV | No improvement in vaccine response in whole population or in those older than 69a | Harman et al20 |
| Zinc | 400 mg/day zinc sulfate, or 400 mg/day zinc sulfate plus 4 g/day arginine | 15 days prior to vaccination | Vaccine only | 64-100 years; mean age 82 n=384 |
TIV | No improvement in vaccine responsea | Provinciali et al23 |
| Zinc | n/a | n/a | n/a | 65+ years; 20 percent had low serum zinc <70 μg/dL n=205. |
TIV | No association between zinc status and vaccine responsea | Sundaram et al12 |
| Zinc | 220 mg zinc sulfate BID 440mg total daily dose | 1 month prior to vaccination | Vaccine only | 70+ years n=30 |
Tetanus | Significant improvement in antibody response to vaccineb | Duchateau et al24 |
| Zinc | n/a | n/a | Two control groups - one was young blood donors <30 years, the other age-matched elderly individuals >70 years | Mean age 65; n=16 (intervention), n=21 (controls >70), n=20 (controls <30) |
Diphtheria | Non-responders to vaccine had significantly decreased serum zinc levelsb | Kreft et al25 |
| Zinc | 70 mg/day zinc sulfate alongside chemotherapy | 16 weeks after vaccination | Control-placebo, control-Zn, and chemo-placebo groups. Control group consisted of non-cancer patients. Placebo was wheat starch capsules. | Mean age 63; undergoing chemotherapy for colon cancer (chemo-Zn group) n=57 |
Pneumococcal | Non-significant trend towards better seroconversion in the chemo-Zn group and protected against antibody decline during chemotherapya | Braga et al26 |
| Combination Micronutrients | Either (1) 20 mg zinc and 100 μg selenium daily; (2) 6 mg beta carotene (vitamin A precursor), 15 mg alpha tocopherol (vitamin E), 120 mg vitamin C daily; or (3) supplements from (1) and (2) combined daily. | 2 years, with vaccination at 15-17 months | Calcium phosphate and microcrystalline cellulose | 65+ years n=725 |
TIV | Significantly improved serological protection in groups (1) and (3) compared to control. Group (2) achieved significantly lower seroprotection, though nonsignificantly lower incidence of respiratory infection, compared to controlb | Girodon et al27 |
| Combination Micronutrients | Multivitamin and mineral with 30-160% US RDA plus antioxidants and 250 kcal energy (14% protein, 40% fat, 46% carbohydrate) dosed BID | 7 months, with vaccination at 6 months | Noncaloric placebo drink (ingredients not specified) | 65+ years; mean age 84 n=19 |
TIV | Significantly improved serological protection for H3N2 but not other strainsb | Bunout et al29 |
| Combination with Micronutrients | Nutritional formula that included 120 IU vitamin E, 3.8 mcg vitamin B12, 400 mcg folic acid, 10 bn CFU Lactobacillus paracasei (NCC 2461), 6 g fructo- oligosaccharide prebiotics and 480 kcal energy (25% protein, 23% fat, 51% carbohydrate) daily | 12 months, with vaccination after 4 months | No nutritional supplementation | 70+ years n=60 |
TIV and pneumococcal | No improvement in vaccine responsea | Bunout et al29 |
| Combination with Micronutrients | 8 oz liquid multivitamin and mineral plus beta-carotene, taurine, carnitine, omega- 3 fatty acids, medium chain triglycerides and fermentable oligosaccharides (prebiotics) daily | 183 days with vaccination on day 15 ± 2 | 8 oz of an isonitrogenous/isoenergetic standard liquid nutritional formula (brand unspecified) 77% maltodextrin 23% sucrose | 65+ years, mean age 82-84 n=66 |
TIV | Significantly improved serological protection for H3N2 but not other strainsb | Langkamp-Henken et al30 |
| Combination with Micronutrients | 240 mL liquid multivitamin and mineral plus beta-carotene, taurine, carnitine, omega-3 fatty acids, medium chain triglycerides and fermentable oligosaccharides (prebiotics) daily | 4 weeks prior to, and 6 weeks after vaccination | 240mL of an isonitrogenous/isoenergetic standard liquid nutritional formula (brand: EnsurePlus, Abbott Laboratories) 0% FOS 77% maltodextrin | 65+ years; mean age 81-85. n=92 |
TIV | Significantly improved serological protection for H1N1 but not other strainsb | Langkamp-Henken et al31 |
aNo significant effect on/association with vaccine response
bSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
Table S2.
Food Group Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Fruits and vegetables | ≥ 5 portions of fruits and vegetables per day | 16 weeks with vaccination at 12 weeks | ≤ 2 portions per day | 65-85 years n=83 |
Pneumococcal Tetanus | Significantly improved antibody response to pneumococcal but not tetanus vaccines.a | Gibson et al32 |
| Dairy | 5g whey protein TID 15g total daily dose | 4 weeks before and 4 weeks after vaccination | 5g low isoflavone soy protein TID | 60+ years n=17 |
Pneumococcal | Improved antibody response to the majority of strains and to all four more virulent strains.a | Freeman et al33 |
| Dairy | 6g UV-treated raw milk powder BID 12g total daily dose | 4 weeks before and 4 weeks after vaccination | 6g/d low isoflavone soy protein BID | 63-94 years n=21 |
DTaP | Significantly improved antibody to tetanus but not other vaccines.a | Schaefer et al34 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
Table S3.
Botanical Medicine Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| JTT (Kampo) | 3.75 g JTT formula containing astragalus, cinnamon, Panax ginseng, licorice and others BID Total daily dose 7.5g | 4 weeks before and 24 weeks after vaccination | No supplementation | 65+ years n=90 |
TIV | Significantly increased antibody titers for H3N2 but not other strainsa | Saiki et al35 |
| JTT (Kampo) | 15 mg JTT formula containing astragalus, cinnamon, Panax ginseng, licorice and others daily | 35 days during first cycle of vaccinations | No supplementation | 50-83 year; median age 66 Advanced pancreatic cancer patients undergoing peptide vaccination n=57 |
Personalized peptides based on HLA typing and IgG titers | No significant change in vaccine responseb | Yutani et al36 |
| Chinese wolfberry (Goji berry) | 13.7 g lacto-wolfberry supplement containing 530 mg/g wolfberry fruit, 290 mg/g bovine skimmed milk, 180 mg/g maltodextrin daily | 1 month before and 2 months after vaccine | 13.7 g/d placebo containing 290 mg/g bovine skimmed milk, 200 mg/g maltodextrin, 476 mg/g sucrose, and 34 mg/g colorants. | 65-70 years n=150 |
TIV | Significantly increased total and influenza-specific antibody levelsa | Vidal et al37 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup;
bNo significant effect on/association with vaccine response
Table S4.
Probiotic Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Lactobacillus paracasei MCC1849 (heat-killed) | 10 billion CFU/day in jelly | 3 weeks before and 3 weeks after vaccination | Control jelly without probiotics | 65+ years; mean age 87 residents of long-term care facility n=42 Subgroup 85+ years; mean age 90.8; n= 11 only | TIV | Improved antibody response to H1N1 and B strains in subgroup 85+ years onlya | Maruyama et al42 |
| Lactobacillus paracasei MoLac-1 (heat-killed) | 10 billion CFU/day in jelly | 3 weeks before and 4 weeks after vaccination | Control jelly without probiotics | 65+ years; mean age 76; residents of long-term care facilities n=15 |
TIV | No significant improvement in antibody response between groupsb Significant increase in HAI titers against all three strains compared with baseline. In the control group, only HAI titers to A/H3N2 increased significantly. | Akatsu et al43 |
| Lactobacillus casei DN-114001 | Actimel drink 100mg BID (Lactobacillus dosage unspecified) Total daily dose 200mg | 4 weeks before and 3 weeks (pilot) or 9 weeks (confirmatory) after vaccination | Non-fermented milk drink | 70+ years; residents of long-term care facilities Pilot study mean age 82 (intervention); 85 (control) years. n=86 Confirmatory study mean age 85 (intervention); 84 (control) years. n=222 |
TIV | Confirmatory study: significantly greater increase in antibodies against B strain. For other strains, the increase was also greater than control but did not reach significance3 Pilot study: insignificant trend towards improvement | Boge et al48 |
| Lactobacillus casei ssp. Shirota | Yakult drink containing 6.5 billion CFU, BID Total daily dosage 13 billion CFU | 3 weeks before vaccination and continuing for a total of 176 days | Non-fermented milk drink | 65+ years, mean age 84; residents of long-term care facilities n=737 | TIV | No significant change in vaccine responseb | Van Puyenbroeck et al49 |
| Lactobacillus plantarum CECT 7315/7316 | Low dose group: 500 million CFU/day High dose group: 5 billion CFU/day Consumed in a base of 20 g powdered skim milk | 3 months, starting 3-4 months after vaccination | 20 g powdered skim milk | 65-85 years; residents of long-term care facilities n=60 | TIV | Significant improvement in influenza-specific IgG with high dose, and in influenza-specific IgA with both high and low doses. Nonsignificant higher IgM levels in high dose groupa | Bosch et al50 |
| Bifidobacterium longum BB536 | 50 billion CFU BID Total daily dosage 100 billion CFU | 12 weeks, with vaccination at week 4 | Powder consisting mainly of dextrin | Mean age 81.7 years; fed by enteral tube feeding n=45 | TIV | Significant improvement in antibody response to H1N1 strain at week 6, but not for other strains. Nonsignificant increase in serum IgAa | Akatsu et al51 |
| Bifidobacterium longum BB536 | 500 billion CFU/day | All participants consumed the dose daily for 5 weeks (Phase 1), with vaccination at week 3. Thereafter, one group continued the probiotic supplement daily for 14 weeks (Phase 2), and the other group discontinued supplementation. | Discontinuation of probiotic supplement after week 5. | Mean age 86.7 years; residents of long-term care facilities n=27 | TIV | No significant difference in antibody response between groupsb NK cell activity, and bactericidal activity of neutrophils, increased significantly for both during Phase 1. Those with the extended probiotic regimen had significantly reduced influenza cases and fever during Phase 2. | Namba et al52 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup;
bNo significant effect on/association with vaccine response
Table S5.
Prebiotic Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Long-chain inulin 50% and oligofructose 50% mixture (brand: Orafti Synergy 1) | 8g/day | 4 weeks before vaccination and continuing for 4 weeks after | 4g/day maltodextrin | 45-63 years; mean age 55 (54.98) n=43 |
TIV | Significant improvement in antibody response to H3N2 strain and significant increase in vaccine specific IgG1a | Lomax et al54 |
| Combination with FOS (9%) 71% maltodextrin 20% sucrose | 8 oz liquid multivitamin and mineral plus beta-carotene, taurine, carnitine, omega- 3 fatty acids, medium chain triglycerides and fermentable oligosaccharides (prebiotics) daily | 183 days with vaccination on day 15 ± 2 | 8 oz of an isonitrogenous/isoenergetic standard liquid nutritional formula (brand unspecified) 77% maltodextrin 23% sucrose daily | 65+ years; mean age 82-84 n=66 |
TIV | Significant improvement in antibody response to H3N2 but not other strainsa | Langkamp-Henken et al30 |
| Combination with FOS (9%) 71% maltodextrin | 240 mL liquid multivitamin and mineral plus beta-carotene, taurine, carnitine, omega- 3 fatty acids, medium chain triglycerides and fermentable oligosaccharides (prebiotics) daily | 4 weeks prior to, and 6 weeks after, vaccination | 240mL of an isonitrogenous/isoenergetic standard liquid nutritional formula (brand: EnsurePlus, Abbott Laboratories) 0% FOS 77% maltodextrin daily | 65+ years; mean age 81-85 n=92 |
TIV | Significant improvement in antibody response to H1N1 but not other strainsa | Langkamp-Henken et al31 |
| Raftilose 70% and raftiline 30% mixture (brand: Prebio 1) | 6g/day In addition to a nutritional supplement providing 15 g protein and 50% of vitamin daily reference values. | 28 weeks, with vaccination at week 2 | 6g/day maltodextrin In addition to a nutritional supplement providing 15 g protein and 50% of vitamin daily reference values. | 70+ years; mean age 75.73 n=43 |
TIV and Pneumococcal | No significant difference in antibody response between groupsb | Bunout et al57 |
| Mekabu fucoidan (brand: Riken Mekabu Fucoidan); and Indigestible dextrin (brand: Fibersol-2) | 300 mg/day mekabu fucoidan plus 300 mg/day dextrin | 4 weeks prior to vaccination | 600mg/day indigestible dextrin | 60+ years; mean age 87 years n=70 |
TIV | aSignificant improvement in antibody response to B strain. Nonsignificant improvement in antibody response to other strainsa | Negishi et al58 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
bNo significant effect on/association with vaccine response
Table S6.
Synbiotic Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Fermented milk (containing Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus) + Bifido growth factor (BGF) and Galacto-oligosaccharides (GOS), as part of a multi- nutrient formula (enteral feeding) | Enteral formula with lactic acid bacteria (dose unspecified), plus 4 g GOS and 0.4 g BGF daily | 10 weeks, with vaccination given at week 4 | Similar enteral formula without lactic acid bacteria, GOS and BGF | Mean age 77.8 (intervention), 84.5 (control); fed by enteral tube feeding n=23 | TIV | Significant improvement in antibody response to H3N2. In addition, antibodies to H1N1 and H3N2 were maintained longer in the intervention groupa | Akatsu et al59 |
| Fermented milk products (Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus) + Bifido growth stimulator (BGS) and Galacto-oligosaccharides (GOS), as part of a multi- nutrient formula (enteral feeding) | Enteral formula with lactic acid bacteria (dose unspecified), plus 0.4g/100kcal GOS and 1.65ug/100kcal BGS daily | 14 weeks, with vaccination given at week 4. | Similar enteral formula without lactic acid bacteria, GOS and BGS | 60+ years; mean age 80; fed by enteral tube feeding n=24 | TIV | No significant improvement in antibody response. Intervention group had significantly lower B strain antibodiesb However, intervention group A/H1N1 antibodies were maintained for longer than control. | Nagafuchi et al60 |
| Lactobacillus paracasei (NCC 2461) + fructooligo-saccharides (FOS) as part of a multi-nutrient formula | Nutritional formula that included 120 IU vitamin E, 3.8 mcg vitamin B12, 400 mcg folic acid, 10 bn CFU Lactobacil-lus paracasei (NCC 2461), 6 g fructo-oligosaccharide prebiotics and 480 kcal energy (25% protein, 23% fat, 51% carbohydrate) daily | 12 months, with vaccination after 4 months | No nutritional supplementation | 70+ years; participants had “low socioeconomic status” n=60 | TIV and pneumococcal | No significant improvement in antibody responseb Increased innate immunity (NK activity) and lower rates of infection. | Bunout et al29 |
| Bifidobacterium longum bv. infantis CCUG 52486 + gluco-oligosaccharide (Gl-OS) | Bifidobacterium 10 billion CFU/day, Gl-OS 8g/day | 8 weeks, with vaccination after 4 weeks | 9g/day maltodextrin | 60-85 years n=112 |
TIV | No significant improvement in antibody responseb | Przemska-Kosicka et al61 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup;
bNo significant effect on/association with vaccine response
Table S7.
DHEA Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| DHEA | 50 mg BID DHEAS (oral) 100mg total daily dosage | 4 days, starting 2 days prior to vaccination | 50 mg corn starch BID Total daily dose 100mg | Males 65+ years n=66 |
Tetanus booster | No significant change in vaccine responsea | Araneo et al63 |
| DHEA | 50 mg BID DHEA (oral) 100mg total daily dosage | 4 days, starting 2 days prior to vaccination | Not specified | 61-89 years n=71 |
TIV | No significant change in vaccine responsea Possible negative effect on vaccine response in individuals without baseline protective antibody titers. | Danenberg et al64 |
| DHEA | 7.5 mg subcutaneous DHEAS | Single dose concurrent to vaccination | Vaccination only | 73-90 years n=78 Control group consisted of adults <40 years |
TIV | Significantly improved serological protection for H3N2 in those with low pre-vaccination titers and lower DHEAS levels, but not other strainsb | Degelau et al65 |
aNo significant effect on/association with vaccine response
bSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
Table S8.
Physical Resilience, Activity & Exercise Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Frailty phenotype | n/a | n/a | n/a | 72-95 years; mean age 84.5 n=71 |
TIV | Non-frail phenotype associated with improved antibody responsea | Yao et al72 |
| Frailty phenotype | n/a | n/a | n/a | 50+ years+, mean age 62.3 n=106 |
TIV | No significant improvement in vaccine response for non-frail phenotypeb Frail phenotype associated with improved antibody response in 50-64 year group only. | Moehling et al73 |
| Frailty phenotype | n/a | n/a | n/a | 65-83 years; mean age 71.5 n=168 |
TIV | Non-frail phenotype not associated with improved antibody response (but there were differences in PBMCs)b | Moehling et al74 |
| Physical activity levels (as component of frailty phenotype) | n/a | n/a | n/a | 70-93 years n=76 |
TIV | Participants in the normal (compared to low) physical activity subgroup had significantly better vaccine response to H3N2 and B strainsa | Bauer et al75 |
| Physical activity levels | n/a | n/a | n/a | 62+ years n=56 |
TIV | High activity levels (regular, vigorous exercise at least 20 mins. 3 times per week) associated with improved antibody response and PBMCsa | Kohut et al76 |
| Physical activity levels | n/a | n/a | n/a | 67-91 years; mean age 81 n=30 |
TIV | Highest level of physical activity associated with improved antibody response (H3N2 strain only)a | Schuler et al77 |
| Physical activity levels | n/a | Vaccination at month 0 and month 20 with activity levels monitored for 2 weeks post vaccination | n/a | Females 65+ years n=56 |
TIV | Higher rates of walking associated with higher influenza B antibodies and H1N1 HAI titersa | Wong et al78 |
| Fitness levels | n/a | n/a | n/a | Males 65-85 years n=61 |
TIV | Both moderate and intense fitness levels (VO2 max) associated with significantly improved antibody response at both 6 weeks and 6 monthsa | de Araújo et al79 |
| Fitness levels | n/a | n/a | n/a | 60-76 years n=26 ‘ |
TIV Tetanus toxoid | High fitness (VO2 max) associated with significantly higher influenza H1N1 and B strain antibodies, and Th2-skewed IgG2 tetanus toxocoid at 6 weeks, plus a trend towards higher infleunza B strain antibodies at 6 months.a | Keylock et al80 |
| Regular moderate aerobic exercise | Building up to 45-60 mins cardiovascular exercise (60-70% maximal oxygen uptake) three times per week (supervised) | 4 months prior to vaccination and continuing for a total of 10 months | Flexibility exercise program | Sedentary adults; 69.9 mean age n=144 |
TIV | Significantly improved seroprotection in the cardiovascular exercise intervention group (30-100% depending on variant), compared to flexibility exercise groupa | Woods et al82 |
| Regular moderate aerobic exercise | Building up to 25-30 mins aerobic exercise (65-75% of heart rate reserve) three times per week (supervised) | 4 weeks post first vaccination and continued for 13 months, with a second vaccination at 10 months | Control participants instructed to continue current level of physical activity/inactivity | 64+ years;, mean age 70 (intervention), 73 (control) n=28 |
TIV | Significantly improved antibody response for H1N1 and H3N2 strainsa | Kohut et al83 |
| Regular moderate aerobic exercise | 45 mins. per/day (independent) + 2.5 hour/wk group sessions Moderate intensity (Borg’s Rating of Perceived Exertion) | 6 weeks before and 2 weeks after vaccination | Assigned to wait-list | 50+ years; mean age 59 n=149 |
TIV | No significant change in vaccine responseb | Hayney et al84 |
| Acute moderate aerobic exercise | 40 mins 55-65% max. heart rate | Immediately prior to vaccination | No exercise | 55-75 years; mean age 67 n=55 (32 women and 23 men) |
TIV | Significantly improved antibody response at 4 weeks to H1N1 strain only in women (even after covarying for baseline value differences)a No significant change in vaccine response in men. No significant change in seroprotection (40+ HI titre) in either group. | Ranadive et al67 |
| Acute brisk walking | 45 mins at least 55% max. heart rate | Immediately prior to vaccination | No exercise (site quietly for 45 mins prior to vaccination) | 50-64 years; mean age 57.5 n=60 |
Pneumococcal (full dose) TIV (half dose) | No significant change in TIV responseb Pneumococcal IgM strains (pn1, pn4, pn18c) were significantly lower in the intervention group compared to controls. | Long et al69 |
| Acute resistance training | 45 mins. 5 sets; 8 reps; 2 minutes rest in between sets Moderate intensity (60% one repetition max) | Immediately prior to vaccination | No exercise (30 min. seated rest) | 65+ years; mean age 73.4 n=46 |
TIV | No significant change in vaccine responseb Control participants higher rates of mild symptoms (48h post vaccination). | Bohn-Goldbaum et al68 |
| Acute resistance training | Upper and lower body resistance exercises (60% one repetition max) | Immediately prior to vaccination | No exercise | Mean age 73 n=46 |
TIV | No significant change in vaccine responseb Control participants higher rates of adverse events (48h post vaccination). | Edwards et al70 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
bNo significant effect on/association with vaccine response
Table S9.
Psychological Factors and Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Caregiver stress | n/a | n/a | Non-caregiver controls | Mean ages 73.12 (caregivers to Alzheimer’s disease patients) and 73.30 (controls) n=64 | TIV | Caregivers met criteria for vaccine response significantly less frequently than controlsa | Kiecolt-Glaser et al86 |
| Caregiver stress | n/a | n/a | Non-caregiver controls | Median age 73 (caregivers to Alzheimer’s disease patients) and 68 (controls) n=117 | TIV | Caregivers met criteria for vaccine response significantly less frequently than controlsa Scores of emotional distress and salivary cortisol were higher in caregivers than controls. | Vedhara et al87 |
| Caregiver stress | n/a | n/a | Non-caregivers | Mean age 73.43 (caregivers) and 75.03 (controls) n=44 |
TIV | No significant difference in vaccine responseb | Segerstrom et al88 |
| Caregiver stress | n/a | n/a | Former caregivers and non-caregivers | Mean age 68.09 (caregivers), 72.46 (former caregivers), 69.54 (controls) n=52 |
Pneumococcal | Caregivers had similar antibody response at 2 weeks and 1 month post-vaccination but reduced antibody response at 3 and 6 monthsa | Glaser et al89 |
| Bereavement Marital status Social support structures | n/a | n/a | n/a (all participants completed the questionnaires) | Mean age 75, n=184 (80 men, 104 women) |
TIV | Bereavement within last year associated with lower antibody response to A/Panama and B/Shangdonga Being married and having higher marital satisfaction associated with greater antibody response to A/Panama. Social support measures were not related to vaccine response. | Phillips et al90 |
| Social support structures | n/a | n/a | n/a (all participants completed the questionnaires) | Mean age 84; residents of long-term care facility n=37 | TIV | Higher levels of social support structures were significantly positively correlated with pre-vaccination titers, but negatively associated with some post-vaccination titers. Perceived stress was negatively associated with some pre-vaccination titersa | Moynihan et al91 |
| Positive mood | n/a | n/a | n/a (all participants received the same evaluation) | Mean age 72.87 n=138 |
TIV | Positive mood on day of vaccination and across 6-week observation period significantly positively associated with H1N1 seroprotection rate. But not for other strainsa | Ayling et al92 |
| Cognitive behavioural stress management | 1 hr per week for 8 weeks | Vaccine administered 2-3 weeks after final intervention session | No intervention. Both caregivers and non-caregivers were included in the control group and analyzed separately | Mean age 75 years (intervention) and 71 (control). n=70 |
TIV | Significant improvement in caregiver vaccine response with intervention, compared with caregiver controls. Intervention appeared to restore reduced seroresponse of caregivers to match that of non-caregiver controlsa | Vedhara et al85 |
| Tai Chi | Tai Chi group: 40 min 3 times per week for 16 weeks | Vaccine administered at the end of intervention | Health Education group: 16 general health presentations | Mean age 69.6 (intervention) and 70.2 (control) n=112 |
Varicella zoster | Tai Chi group had significantly improved measures of cell-mediated immunity compared to health education groupa | Irwin et al92 |
| Tai Chi/Qigong combination | 1 hr 3 times per week for 20 weeks | Vaccine administered during first week of intervention | Continue routine activities for 20 weeks | Mean age 80 (intervention) and 75 (control) n=50 |
TIV | Significant increase in antibody titers in intervention group at 3 and 20 weeks, but not at 6 weeksa | Yang et al94 |
| Meditation/Mindfulness | 45 mins. per/day (independent) + 2.5 hour/wk group sessions | 6 weeks before and 2 weeks after vaccination | Assigned to wait-list (control) or exercise intervention arm | Mean age 60 (intervention), 59 (control) No prior meditation experience n=149 |
TIV | No significant change in vaccine responseb | Hayney et al84 |
| Mood-enhancement | 15-minute video intended to induce positive mood | Vaccination immediately after watching video | Matched neutral control video | 65-85 years n=103 |
Influenza (quadrivalent) | Non-significant improvement in intervention groupb | Ayling et al95 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
bNo significant effect on/association with vaccine response
Table S10.
Sleep Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) |
Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Sleep Duration Observational | n/a | n/a Psychosocial measures taken two weeks before and four weeks after vaccination. | n/a | 65-85 years n=138 |
TIV | No association between self-reported sleep duration and antibody responsea | Ayling et al92 |
aNo significant effect on/association with vaccine response
Table S11.
Time of Day of Vaccine Administration Modulation of Vaccine Efficacy
| Dosage | Timing | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Morning vs afternoon vaccine administration | n/a | Group 1AM (9-1 lam), Group 2 PM (3-5 pm) vaccination | n/a | 65+ years n=276 |
TIV | AM vaccination significantly improved antibody response to the H1N1 A & B strains only, compared to PM vaccinationa | Long et al105 |
| Morning vs afternoon vaccine administration | n/a | Group 1 AM (8-11 am), Group 2 PM (1-4pm) vaccination | n/a | 65+ years; mean age 73.1 n=89 (38 men) |
TIV | AM vaccination improved antibody response to the H1N1 A strain in males only, compared to PM vaccinationa | Phillips et al104 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
Footnotes
Authors’ Disclosure Statement
The authors declare that they have no conflicts of interest related to the study.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1.
Micronutrient Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Vitamin A | n/a | n/a | n/a | 65+ years, n=205. Not considered vitamin A deficient | TIV | No association between vitamin A status and vaccine responsea | Sundaram et al12 |
| Vitamin D | 100000 IU every 15 days | 3 months prior to vaccination | Placebo supplementation, not specified | 65+ years, n=38, serum 25-(OH)D<30 ng/mL | TIV | No improvement in antibody response. Significant negative response for H3N2b | Goncalves-Mendes et al14 |
| Vitamin D | n/a | n/a | n/a | Mean age 64 years. n=200 patients with CKD |
Hepatitis B | <10 ng/mL 25-(OH)D associated with reduced seroconversion and seroprotectionb | Zitt et al15 |
| Vitamin E | 60, 200, or 800 mg/day all racalpha-tocopherol in soybean oil | 5 months prior to vaccination | Soybean oil only | 65+ years; serum vitamin E < 27.9 μmol/L n=89 |
Hepatitis B Diphtheria | Vitamin E group showed greater delayed-type hypersensitivity response to Hep B vaccine. 200 mg/d group had greater antibody response to Hep B vaccineb No difference in response to diphtheria vaccine No change in T cell or B cell level | Meydani et al19 |
| Vitamin E | n/a | n/a | n/a | 65+ years; not considered vitamin E deficient n=205 |
TIV | No association between vitamin E status and vaccine responsea | Sundaram et al12 |
| Vitamin E | 200 or 400 mg/day | 1 month prior to and 5 months after vaccination | Placebo identified as “0 mg vitamin E” | 24-104 years; patients of a chronic care facility n=103 |
TIV | No improvement in vaccine response in whole population or in those older than 69a | Harman et al20 |
| Zinc | 400 mg/day zinc sulfate, or 400 mg/day zinc sulfate plus 4 g/day arginine | 15 days prior to vaccination | Vaccine only | 64-100 years; mean age 82 n=384 |
TIV | No improvement in vaccine responsea | Provinciali et al23 |
| Zinc | n/a | n/a | n/a | 65+ years; 20 percent had low serum zinc <70 μg/dL n=205. |
TIV | No association between zinc status and vaccine responsea | Sundaram et al12 |
| Zinc | 220 mg zinc sulfate BID 440mg total daily dose | 1 month prior to vaccination | Vaccine only | 70+ years n=30 |
Tetanus | Significant improvement in antibody response to vaccineb | Duchateau et al24 |
| Zinc | n/a | n/a | Two control groups - one was young blood donors <30 years, the other age-matched elderly individuals >70 years | Mean age 65; n=16 (intervention), n=21 (controls >70), n=20 (controls <30) |
Diphtheria | Non-responders to vaccine had significantly decreased serum zinc levelsb | Kreft et al25 |
| Zinc | 70 mg/day zinc sulfate alongside chemotherapy | 16 weeks after vaccination | Control-placebo, control-Zn, and chemo-placebo groups. Control group consisted of non-cancer patients. Placebo was wheat starch capsules. | Mean age 63; undergoing chemotherapy for colon cancer (chemo-Zn group) n=57 |
Pneumococcal | Non-significant trend towards better seroconversion in the chemo-Zn group and protected against antibody decline during chemotherapya | Braga et al26 |
| Combination Micronutrients | Either (1) 20 mg zinc and 100 μg selenium daily; (2) 6 mg beta carotene (vitamin A precursor), 15 mg alpha tocopherol (vitamin E), 120 mg vitamin C daily; or (3) supplements from (1) and (2) combined daily. | 2 years, with vaccination at 15-17 months | Calcium phosphate and microcrystalline cellulose | 65+ years n=725 |
TIV | Significantly improved serological protection in groups (1) and (3) compared to control. Group (2) achieved significantly lower seroprotection, though nonsignificantly lower incidence of respiratory infection, compared to controlb | Girodon et al27 |
| Combination Micronutrients | Multivitamin and mineral with 30-160% US RDA plus antioxidants and 250 kcal energy (14% protein, 40% fat, 46% carbohydrate) dosed BID | 7 months, with vaccination at 6 months | Noncaloric placebo drink (ingredients not specified) | 65+ years; mean age 84 n=19 |
TIV | Significantly improved serological protection for H3N2 but not other strainsb | Bunout et al29 |
| Combination with Micronutrients | Nutritional formula that included 120 IU vitamin E, 3.8 mcg vitamin B12, 400 mcg folic acid, 10 bn CFU Lactobacillus paracasei (NCC 2461), 6 g fructo- oligosaccharide prebiotics and 480 kcal energy (25% protein, 23% fat, 51% carbohydrate) daily | 12 months, with vaccination after 4 months | No nutritional supplementation | 70+ years n=60 |
TIV and pneumococcal | No improvement in vaccine responsea | Bunout et al29 |
| Combination with Micronutrients | 8 oz liquid multivitamin and mineral plus beta-carotene, taurine, carnitine, omega- 3 fatty acids, medium chain triglycerides and fermentable oligosaccharides (prebiotics) daily | 183 days with vaccination on day 15 ± 2 | 8 oz of an isonitrogenous/isoenergetic standard liquid nutritional formula (brand unspecified) 77% maltodextrin 23% sucrose | 65+ years, mean age 82-84 n=66 |
TIV | Significantly improved serological protection for H3N2 but not other strainsb | Langkamp-Henken et al30 |
| Combination with Micronutrients | 240 mL liquid multivitamin and mineral plus beta-carotene, taurine, carnitine, omega-3 fatty acids, medium chain triglycerides and fermentable oligosaccharides (prebiotics) daily | 4 weeks prior to, and 6 weeks after vaccination | 240mL of an isonitrogenous/isoenergetic standard liquid nutritional formula (brand: EnsurePlus, Abbott Laboratories) 0% FOS 77% maltodextrin | 65+ years; mean age 81-85. n=92 |
TIV | Significantly improved serological protection for H1N1 but not other strainsb | Langkamp-Henken et al31 |
aNo significant effect on/association with vaccine response
bSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
Table S2.
Food Group Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Fruits and vegetables | ≥ 5 portions of fruits and vegetables per day | 16 weeks with vaccination at 12 weeks | ≤ 2 portions per day | 65-85 years n=83 |
Pneumococcal Tetanus | Significantly improved antibody response to pneumococcal but not tetanus vaccines.a | Gibson et al32 |
| Dairy | 5g whey protein TID 15g total daily dose | 4 weeks before and 4 weeks after vaccination | 5g low isoflavone soy protein TID | 60+ years n=17 |
Pneumococcal | Improved antibody response to the majority of strains and to all four more virulent strains.a | Freeman et al33 |
| Dairy | 6g UV-treated raw milk powder BID 12g total daily dose | 4 weeks before and 4 weeks after vaccination | 6g/d low isoflavone soy protein BID | 63-94 years n=21 |
DTaP | Significantly improved antibody to tetanus but not other vaccines.a | Schaefer et al34 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
Table S3.
Botanical Medicine Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| JTT (Kampo) | 3.75 g JTT formula containing astragalus, cinnamon, Panax ginseng, licorice and others BID Total daily dose 7.5g | 4 weeks before and 24 weeks after vaccination | No supplementation | 65+ years n=90 |
TIV | Significantly increased antibody titers for H3N2 but not other strainsa | Saiki et al35 |
| JTT (Kampo) | 15 mg JTT formula containing astragalus, cinnamon, Panax ginseng, licorice and others daily | 35 days during first cycle of vaccinations | No supplementation | 50-83 year; median age 66 Advanced pancreatic cancer patients undergoing peptide vaccination n=57 |
Personalized peptides based on HLA typing and IgG titers | No significant change in vaccine responseb | Yutani et al36 |
| Chinese wolfberry (Goji berry) | 13.7 g lacto-wolfberry supplement containing 530 mg/g wolfberry fruit, 290 mg/g bovine skimmed milk, 180 mg/g maltodextrin daily | 1 month before and 2 months after vaccine | 13.7 g/d placebo containing 290 mg/g bovine skimmed milk, 200 mg/g maltodextrin, 476 mg/g sucrose, and 34 mg/g colorants. | 65-70 years n=150 |
TIV | Significantly increased total and influenza-specific antibody levelsa | Vidal et al37 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup;
bNo significant effect on/association with vaccine response
Table S4.
Probiotic Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Lactobacillus paracasei MCC1849 (heat-killed) | 10 billion CFU/day in jelly | 3 weeks before and 3 weeks after vaccination | Control jelly without probiotics | 65+ years; mean age 87 residents of long-term care facility n=42 Subgroup 85+ years; mean age 90.8; n= 11 only | TIV | Improved antibody response to H1N1 and B strains in subgroup 85+ years onlya | Maruyama et al42 |
| Lactobacillus paracasei MoLac-1 (heat-killed) | 10 billion CFU/day in jelly | 3 weeks before and 4 weeks after vaccination | Control jelly without probiotics | 65+ years; mean age 76; residents of long-term care facilities n=15 |
TIV | No significant improvement in antibody response between groupsb Significant increase in HAI titers against all three strains compared with baseline. In the control group, only HAI titers to A/H3N2 increased significantly. | Akatsu et al43 |
| Lactobacillus casei DN-114001 | Actimel drink 100mg BID (Lactobacillus dosage unspecified) Total daily dose 200mg | 4 weeks before and 3 weeks (pilot) or 9 weeks (confirmatory) after vaccination | Non-fermented milk drink | 70+ years; residents of long-term care facilities Pilot study mean age 82 (intervention); 85 (control) years. n=86 Confirmatory study mean age 85 (intervention); 84 (control) years. n=222 |
TIV | Confirmatory study: significantly greater increase in antibodies against B strain. For other strains, the increase was also greater than control but did not reach significance3 Pilot study: insignificant trend towards improvement | Boge et al48 |
| Lactobacillus casei ssp. Shirota | Yakult drink containing 6.5 billion CFU, BID Total daily dosage 13 billion CFU | 3 weeks before vaccination and continuing for a total of 176 days | Non-fermented milk drink | 65+ years, mean age 84; residents of long-term care facilities n=737 | TIV | No significant change in vaccine responseb | Van Puyenbroeck et al49 |
| Lactobacillus plantarum CECT 7315/7316 | Low dose group: 500 million CFU/day High dose group: 5 billion CFU/day Consumed in a base of 20 g powdered skim milk | 3 months, starting 3-4 months after vaccination | 20 g powdered skim milk | 65-85 years; residents of long-term care facilities n=60 | TIV | Significant improvement in influenza-specific IgG with high dose, and in influenza-specific IgA with both high and low doses. Nonsignificant higher IgM levels in high dose groupa | Bosch et al50 |
| Bifidobacterium longum BB536 | 50 billion CFU BID Total daily dosage 100 billion CFU | 12 weeks, with vaccination at week 4 | Powder consisting mainly of dextrin | Mean age 81.7 years; fed by enteral tube feeding n=45 | TIV | Significant improvement in antibody response to H1N1 strain at week 6, but not for other strains. Nonsignificant increase in serum IgAa | Akatsu et al51 |
| Bifidobacterium longum BB536 | 500 billion CFU/day | All participants consumed the dose daily for 5 weeks (Phase 1), with vaccination at week 3. Thereafter, one group continued the probiotic supplement daily for 14 weeks (Phase 2), and the other group discontinued supplementation. | Discontinuation of probiotic supplement after week 5. | Mean age 86.7 years; residents of long-term care facilities n=27 | TIV | No significant difference in antibody response between groupsb NK cell activity, and bactericidal activity of neutrophils, increased significantly for both during Phase 1. Those with the extended probiotic regimen had significantly reduced influenza cases and fever during Phase 2. | Namba et al52 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup;
bNo significant effect on/association with vaccine response
Table S5.
Prebiotic Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Long-chain inulin 50% and oligofructose 50% mixture (brand: Orafti Synergy 1) | 8g/day | 4 weeks before vaccination and continuing for 4 weeks after | 4g/day maltodextrin | 45-63 years; mean age 55 (54.98) n=43 |
TIV | Significant improvement in antibody response to H3N2 strain and significant increase in vaccine specific IgG1a | Lomax et al54 |
| Combination with FOS (9%) 71% maltodextrin 20% sucrose | 8 oz liquid multivitamin and mineral plus beta-carotene, taurine, carnitine, omega- 3 fatty acids, medium chain triglycerides and fermentable oligosaccharides (prebiotics) daily | 183 days with vaccination on day 15 ± 2 | 8 oz of an isonitrogenous/isoenergetic standard liquid nutritional formula (brand unspecified) 77% maltodextrin 23% sucrose daily | 65+ years; mean age 82-84 n=66 |
TIV | Significant improvement in antibody response to H3N2 but not other strainsa | Langkamp-Henken et al30 |
| Combination with FOS (9%) 71% maltodextrin | 240 mL liquid multivitamin and mineral plus beta-carotene, taurine, carnitine, omega- 3 fatty acids, medium chain triglycerides and fermentable oligosaccharides (prebiotics) daily | 4 weeks prior to, and 6 weeks after, vaccination | 240mL of an isonitrogenous/isoenergetic standard liquid nutritional formula (brand: EnsurePlus, Abbott Laboratories) 0% FOS 77% maltodextrin daily | 65+ years; mean age 81-85 n=92 |
TIV | Significant improvement in antibody response to H1N1 but not other strainsa | Langkamp-Henken et al31 |
| Raftilose 70% and raftiline 30% mixture (brand: Prebio 1) | 6g/day In addition to a nutritional supplement providing 15 g protein and 50% of vitamin daily reference values. | 28 weeks, with vaccination at week 2 | 6g/day maltodextrin In addition to a nutritional supplement providing 15 g protein and 50% of vitamin daily reference values. | 70+ years; mean age 75.73 n=43 |
TIV and Pneumococcal | No significant difference in antibody response between groupsb | Bunout et al57 |
| Mekabu fucoidan (brand: Riken Mekabu Fucoidan); and Indigestible dextrin (brand: Fibersol-2) | 300 mg/day mekabu fucoidan plus 300 mg/day dextrin | 4 weeks prior to vaccination | 600mg/day indigestible dextrin | 60+ years; mean age 87 years n=70 |
TIV | aSignificant improvement in antibody response to B strain. Nonsignificant improvement in antibody response to other strainsa | Negishi et al58 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
bNo significant effect on/association with vaccine response
Table S6.
Synbiotic Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Fermented milk (containing Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus) + Bifido growth factor (BGF) and Galacto-oligosaccharides (GOS), as part of a multi- nutrient formula (enteral feeding) | Enteral formula with lactic acid bacteria (dose unspecified), plus 4 g GOS and 0.4 g BGF daily | 10 weeks, with vaccination given at week 4 | Similar enteral formula without lactic acid bacteria, GOS and BGF | Mean age 77.8 (intervention), 84.5 (control); fed by enteral tube feeding n=23 | TIV | Significant improvement in antibody response to H3N2. In addition, antibodies to H1N1 and H3N2 were maintained longer in the intervention groupa | Akatsu et al59 |
| Fermented milk products (Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus) + Bifido growth stimulator (BGS) and Galacto-oligosaccharides (GOS), as part of a multi- nutrient formula (enteral feeding) | Enteral formula with lactic acid bacteria (dose unspecified), plus 0.4g/100kcal GOS and 1.65ug/100kcal BGS daily | 14 weeks, with vaccination given at week 4. | Similar enteral formula without lactic acid bacteria, GOS and BGS | 60+ years; mean age 80; fed by enteral tube feeding n=24 | TIV | No significant improvement in antibody response. Intervention group had significantly lower B strain antibodiesb However, intervention group A/H1N1 antibodies were maintained for longer than control. | Nagafuchi et al60 |
| Lactobacillus paracasei (NCC 2461) + fructooligo-saccharides (FOS) as part of a multi-nutrient formula | Nutritional formula that included 120 IU vitamin E, 3.8 mcg vitamin B12, 400 mcg folic acid, 10 bn CFU Lactobacil-lus paracasei (NCC 2461), 6 g fructo-oligosaccharide prebiotics and 480 kcal energy (25% protein, 23% fat, 51% carbohydrate) daily | 12 months, with vaccination after 4 months | No nutritional supplementation | 70+ years; participants had “low socioeconomic status” n=60 | TIV and pneumococcal | No significant improvement in antibody responseb Increased innate immunity (NK activity) and lower rates of infection. | Bunout et al29 |
| Bifidobacterium longum bv. infantis CCUG 52486 + gluco-oligosaccharide (Gl-OS) | Bifidobacterium 10 billion CFU/day, Gl-OS 8g/day | 8 weeks, with vaccination after 4 weeks | 9g/day maltodextrin | 60-85 years n=112 |
TIV | No significant improvement in antibody responseb | Przemska-Kosicka et al61 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup;
bNo significant effect on/association with vaccine response
Table S7.
DHEA Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| DHEA | 50 mg BID DHEAS (oral) 100mg total daily dosage | 4 days, starting 2 days prior to vaccination | 50 mg corn starch BID Total daily dose 100mg | Males 65+ years n=66 |
Tetanus booster | No significant change in vaccine responsea | Araneo et al63 |
| DHEA | 50 mg BID DHEA (oral) 100mg total daily dosage | 4 days, starting 2 days prior to vaccination | Not specified | 61-89 years n=71 |
TIV | No significant change in vaccine responsea Possible negative effect on vaccine response in individuals without baseline protective antibody titers. | Danenberg et al64 |
| DHEA | 7.5 mg subcutaneous DHEAS | Single dose concurrent to vaccination | Vaccination only | 73-90 years n=78 Control group consisted of adults <40 years |
TIV | Significantly improved serological protection for H3N2 in those with low pre-vaccination titers and lower DHEAS levels, but not other strainsb | Degelau et al65 |
aNo significant effect on/association with vaccine response
bSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
Table S8.
Physical Resilience, Activity & Exercise Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Frailty phenotype | n/a | n/a | n/a | 72-95 years; mean age 84.5 n=71 |
TIV | Non-frail phenotype associated with improved antibody responsea | Yao et al72 |
| Frailty phenotype | n/a | n/a | n/a | 50+ years+, mean age 62.3 n=106 |
TIV | No significant improvement in vaccine response for non-frail phenotypeb Frail phenotype associated with improved antibody response in 50-64 year group only. | Moehling et al73 |
| Frailty phenotype | n/a | n/a | n/a | 65-83 years; mean age 71.5 n=168 |
TIV | Non-frail phenotype not associated with improved antibody response (but there were differences in PBMCs)b | Moehling et al74 |
| Physical activity levels (as component of frailty phenotype) | n/a | n/a | n/a | 70-93 years n=76 |
TIV | Participants in the normal (compared to low) physical activity subgroup had significantly better vaccine response to H3N2 and B strainsa | Bauer et al75 |
| Physical activity levels | n/a | n/a | n/a | 62+ years n=56 |
TIV | High activity levels (regular, vigorous exercise at least 20 mins. 3 times per week) associated with improved antibody response and PBMCsa | Kohut et al76 |
| Physical activity levels | n/a | n/a | n/a | 67-91 years; mean age 81 n=30 |
TIV | Highest level of physical activity associated with improved antibody response (H3N2 strain only)a | Schuler et al77 |
| Physical activity levels | n/a | Vaccination at month 0 and month 20 with activity levels monitored for 2 weeks post vaccination | n/a | Females 65+ years n=56 |
TIV | Higher rates of walking associated with higher influenza B antibodies and H1N1 HAI titersa | Wong et al78 |
| Fitness levels | n/a | n/a | n/a | Males 65-85 years n=61 |
TIV | Both moderate and intense fitness levels (VO2 max) associated with significantly improved antibody response at both 6 weeks and 6 monthsa | de Araújo et al79 |
| Fitness levels | n/a | n/a | n/a | 60-76 years n=26 ‘ |
TIV Tetanus toxoid | High fitness (VO2 max) associated with significantly higher influenza H1N1 and B strain antibodies, and Th2-skewed IgG2 tetanus toxocoid at 6 weeks, plus a trend towards higher infleunza B strain antibodies at 6 months.a | Keylock et al80 |
| Regular moderate aerobic exercise | Building up to 45-60 mins cardiovascular exercise (60-70% maximal oxygen uptake) three times per week (supervised) | 4 months prior to vaccination and continuing for a total of 10 months | Flexibility exercise program | Sedentary adults; 69.9 mean age n=144 |
TIV | Significantly improved seroprotection in the cardiovascular exercise intervention group (30-100% depending on variant), compared to flexibility exercise groupa | Woods et al82 |
| Regular moderate aerobic exercise | Building up to 25-30 mins aerobic exercise (65-75% of heart rate reserve) three times per week (supervised) | 4 weeks post first vaccination and continued for 13 months, with a second vaccination at 10 months | Control participants instructed to continue current level of physical activity/inactivity | 64+ years;, mean age 70 (intervention), 73 (control) n=28 |
TIV | Significantly improved antibody response for H1N1 and H3N2 strainsa | Kohut et al83 |
| Regular moderate aerobic exercise | 45 mins. per/day (independent) + 2.5 hour/wk group sessions Moderate intensity (Borg’s Rating of Perceived Exertion) | 6 weeks before and 2 weeks after vaccination | Assigned to wait-list | 50+ years; mean age 59 n=149 |
TIV | No significant change in vaccine responseb | Hayney et al84 |
| Acute moderate aerobic exercise | 40 mins 55-65% max. heart rate | Immediately prior to vaccination | No exercise | 55-75 years; mean age 67 n=55 (32 women and 23 men) |
TIV | Significantly improved antibody response at 4 weeks to H1N1 strain only in women (even after covarying for baseline value differences)a No significant change in vaccine response in men. No significant change in seroprotection (40+ HI titre) in either group. | Ranadive et al67 |
| Acute brisk walking | 45 mins at least 55% max. heart rate | Immediately prior to vaccination | No exercise (site quietly for 45 mins prior to vaccination) | 50-64 years; mean age 57.5 n=60 |
Pneumococcal (full dose) TIV (half dose) | No significant change in TIV responseb Pneumococcal IgM strains (pn1, pn4, pn18c) were significantly lower in the intervention group compared to controls. | Long et al69 |
| Acute resistance training | 45 mins. 5 sets; 8 reps; 2 minutes rest in between sets Moderate intensity (60% one repetition max) | Immediately prior to vaccination | No exercise (30 min. seated rest) | 65+ years; mean age 73.4 n=46 |
TIV | No significant change in vaccine responseb Control participants higher rates of mild symptoms (48h post vaccination). | Bohn-Goldbaum et al68 |
| Acute resistance training | Upper and lower body resistance exercises (60% one repetition max) | Immediately prior to vaccination | No exercise | Mean age 73 n=46 |
TIV | No significant change in vaccine responseb Control participants higher rates of adverse events (48h post vaccination). | Edwards et al70 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
bNo significant effect on/association with vaccine response
Table S9.
Psychological Factors and Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Caregiver stress | n/a | n/a | Non-caregiver controls | Mean ages 73.12 (caregivers to Alzheimer’s disease patients) and 73.30 (controls) n=64 | TIV | Caregivers met criteria for vaccine response significantly less frequently than controlsa | Kiecolt-Glaser et al86 |
| Caregiver stress | n/a | n/a | Non-caregiver controls | Median age 73 (caregivers to Alzheimer’s disease patients) and 68 (controls) n=117 | TIV | Caregivers met criteria for vaccine response significantly less frequently than controlsa Scores of emotional distress and salivary cortisol were higher in caregivers than controls. | Vedhara et al87 |
| Caregiver stress | n/a | n/a | Non-caregivers | Mean age 73.43 (caregivers) and 75.03 (controls) n=44 |
TIV | No significant difference in vaccine responseb | Segerstrom et al88 |
| Caregiver stress | n/a | n/a | Former caregivers and non-caregivers | Mean age 68.09 (caregivers), 72.46 (former caregivers), 69.54 (controls) n=52 |
Pneumococcal | Caregivers had similar antibody response at 2 weeks and 1 month post-vaccination but reduced antibody response at 3 and 6 monthsa | Glaser et al89 |
| Bereavement Marital status Social support structures | n/a | n/a | n/a (all participants completed the questionnaires) | Mean age 75, n=184 (80 men, 104 women) |
TIV | Bereavement within last year associated with lower antibody response to A/Panama and B/Shangdonga Being married and having higher marital satisfaction associated with greater antibody response to A/Panama. Social support measures were not related to vaccine response. | Phillips et al90 |
| Social support structures | n/a | n/a | n/a (all participants completed the questionnaires) | Mean age 84; residents of long-term care facility n=37 | TIV | Higher levels of social support structures were significantly positively correlated with pre-vaccination titers, but negatively associated with some post-vaccination titers. Perceived stress was negatively associated with some pre-vaccination titersa | Moynihan et al91 |
| Positive mood | n/a | n/a | n/a (all participants received the same evaluation) | Mean age 72.87 n=138 |
TIV | Positive mood on day of vaccination and across 6-week observation period significantly positively associated with H1N1 seroprotection rate. But not for other strainsa | Ayling et al92 |
| Cognitive behavioural stress management | 1 hr per week for 8 weeks | Vaccine administered 2-3 weeks after final intervention session | No intervention. Both caregivers and non-caregivers were included in the control group and analyzed separately | Mean age 75 years (intervention) and 71 (control). n=70 |
TIV | Significant improvement in caregiver vaccine response with intervention, compared with caregiver controls. Intervention appeared to restore reduced seroresponse of caregivers to match that of non-caregiver controlsa | Vedhara et al85 |
| Tai Chi | Tai Chi group: 40 min 3 times per week for 16 weeks | Vaccine administered at the end of intervention | Health Education group: 16 general health presentations | Mean age 69.6 (intervention) and 70.2 (control) n=112 |
Varicella zoster | Tai Chi group had significantly improved measures of cell-mediated immunity compared to health education groupa | Irwin et al92 |
| Tai Chi/Qigong combination | 1 hr 3 times per week for 20 weeks | Vaccine administered during first week of intervention | Continue routine activities for 20 weeks | Mean age 80 (intervention) and 75 (control) n=50 |
TIV | Significant increase in antibody titers in intervention group at 3 and 20 weeks, but not at 6 weeksa | Yang et al94 |
| Meditation/Mindfulness | 45 mins. per/day (independent) + 2.5 hour/wk group sessions | 6 weeks before and 2 weeks after vaccination | Assigned to wait-list (control) or exercise intervention arm | Mean age 60 (intervention), 59 (control) No prior meditation experience n=149 |
TIV | No significant change in vaccine responseb | Hayney et al84 |
| Mood-enhancement | 15-minute video intended to induce positive mood | Vaccination immediately after watching video | Matched neutral control video | 65-85 years n=103 |
Influenza (quadrivalent) | Non-significant improvement in intervention groupb | Ayling et al95 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup
bNo significant effect on/association with vaccine response
Table S10.
Sleep Modulation of Vaccine Efficacy
| Dosage | Timing (before/after vaccination) |
Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Sleep Duration Observational | n/a | n/a Psychosocial measures taken two weeks before and four weeks after vaccination. | n/a | 65-85 years n=138 |
TIV | No association between self-reported sleep duration and antibody responsea | Ayling et al92 |
aNo significant effect on/association with vaccine response
Table S11.
Time of Day of Vaccine Administration Modulation of Vaccine Efficacy
| Dosage | Timing | Control | Population | Vaccine Type | Outcome | Citation | |
|---|---|---|---|---|---|---|---|
| Morning vs afternoon vaccine administration | n/a | Group 1AM (9-1 lam), Group 2 PM (3-5 pm) vaccination | n/a | 65+ years n=276 |
TIV | AM vaccination significantly improved antibody response to the H1N1 A & B strains only, compared to PM vaccinationa | Long et al105 |
| Morning vs afternoon vaccine administration | n/a | Group 1 AM (8-11 am), Group 2 PM (1-4pm) vaccination | n/a | 65+ years; mean age 73.1 n=89 (38 men) |
TIV | AM vaccination improved antibody response to the H1N1 A strain in males only, compared to PM vaccinationa | Phillips et al104 |
aSignificant effect on/association with vaccine response for at least one vaccine strain/subgroup