Reference
Hallam J, Jones T, Alley J, Kohut ML. Exercise after influenza or COVID-19 vaccination increases serum antibody without an increase in side effects. Brain Behav Immun. 2022;102:1-10.
Design
Pooled analysis of 3 separate controlled, interventional trials.
This article describes a series of clinical trials, including 3 human trials, that used exercise as a “behavioral adjuvant” after vaccinations to increase antibody response against 3 separate vaccines (the 2009 pandemic influenza H1N1, seasonal influenza, and SARS-CoV2). The article also describes similar trials conducted using mice for the same purpose.
Study Objective
To evaluate the effects of exercise on antibody response to vaccinations (2009 pandemic influenza H1N1, seasonal influenza, and Covid-19). A rodent study was also done to assess interferon alpha (INF-α) involvement.
Key Takeaway
Antibody levels are higher in those who exercise for 90 minutes after receiving a vaccine compared to those who don’t.
Participants
Trial 1: Investigators enrolled 20 participants in the trial of the H1N1 vaccine, of which 16 were included in the analysis.
Trial 2: In the seasonal influenza vaccine trial, 28 were enrolled, and 26 of these were included in the analysis.
Trial 3: In the Covid-19 vaccine (Pfizer-BioNTech) trial, investigators enrolled 36 and eliminated 8 after determining based on initial antibody levels that they had already been infected. Total participants for analysis was 70. All study participants had exercised regularly before recruitment.
The mice were also subjected to varying degrees of exercise, and researchers monitored their levels of antibody and IFNα.
Study Intervention
Each trial was randomized to an interventional group and a control group. Participants in the experimental arm of each trial exercised for prescribed periods starting within 30 minutes of receiving the vaccinations. Each trial had a control group that did not exercise. In the H1N1 vaccine trial, the active participants exercised for 90 minutes. In the seasonal flu vaccine trial, the time spent exercising varied by age: Younger subjects (aged 18–33 years) not in the control group exercised for either 45 minutes or 90 minutes. Older subjects (aged 62–87 years) were assigned to either the control group of no exercise or to 45 minutes of exercise.
In the Covid-19 trial, the participants were told to either exercise for 90 minutes or to go about their daily routine while avoiding exercise on the day of their first vaccination. In the other 2 trials, participants exercised indoors using cycle ergometers. In the Covid-19 experiment, exercise took place outdoors to limit infection risk. The participants followed a walking/jogging route, going fast enough to maintain a heart rate of 120 to 140 beats per minute.
Outcome Measures
Blood samples were collected just prior to vaccination and then 2 weeks and 4 weeks postimmunization to measure antibody levels. The Covid-19 trial included the second (booster) dose at week 3.
Key Findings
In all the human trials, immunoglobulin G (IgG) antibody levels increased after vaccination but increased significantly more so in the 90-minute exercise groups vs the control groups that abstained from exercising. Exercise was not associated with any increase in side effects after the Covid-19 vaccination. These findings suggest that adults who exercise regularly may increase antibody response to influenza or Covid-19 vaccines by performing a single but lengthy session of light- to moderate-intensity exercise postimmunization.
Only the trial using seasonal influenza vaccine compared 45- vs 90-minute exercise sessions. In those who exercised for only 45 minutes, antibody levels did not differ significantly from those in the group that did not exercise.
IFNα, according to results from mice, may contribute to the exercise-related effects of higher antibody titers over time.
Transparency
The study states, “The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.”
Practice Implications
The first implication of this report is that the effectiveness of vaccinations can increase without increasing side effects. Put simply, patients should go on a long walk at a decent clip after receiving their vaccination. How long? The data suggest that while 90 minutes was helpful, 45 minutes had no effect.
The authors dubbed exercise a “behavioral adjuvant” with the potential to increase the effectiveness of antigen stimulation of vaccination. This contrasts with most vaccine adjuvants, which are chemical. Adding adjuvant chemicals to enhance vaccine effectiveness has been standard practice for nearly a century.
That an “adjuvant” could amplify vaccine effectiveness was serendipitously discovered in 1925 by Gaston Ramon, a French veterinarian who observed that the yield of tetanus and diphtheria antisera from horses was higher from animals that had developed an abscess at the injection site. He went on to show that coadministration of his newly invented diphtheria toxoid together with other compounds such as tapioca, lecithin, agar, starch oil, saponin, or breadcrumbs increased antitoxin responses to diphtheria. A year later, in 1926, Glenny et al reported that aluminum salts also increased immune responses. Such salts were first used in human vaccines in the 1930s, and the practice continues until the present. Aluminum salts were initially used in diphtheria, pertussis, and tetanus vaccines and are now also found added to vaccines against hepatitis A and B, Haemophilus influenzae type b, pneumococcus, and human papillomavirus. The addition of these chemical adjuvants is considered essential for these vaccines to be effective at achieving long-lasting disease immunity.1,2,3
Aluminum salts remain the most common adjuvant, followed by various water and oil emulsions, often using squalene as the oil. The problem with adjuvants is that the better they work (that is, the more of an immune reaction they generate), the more the patient experiences a reaction to the vaccine. This current study using exercise as an adjuvant is intriguing as there were no indications in the data that the exercise increased unwanted side effects.
The idea that vaccine effectiveness might be increased by nonchemical means is both novel and increasingly important. Over the years the antigenic materials employed in vaccines have become increasingly subtle and more refined. Instead of containing living or dead disease organisms, vaccines now contain highly refined or synthesized materials that are less likely to provoke immune responses. As a result, modern vaccines rely heavily on adjuvants.
Neither the Covid-19 vaccine nor the influenza vaccines contain aluminum salts. The Moderna and Pfizer Covid-19 vaccines encapsulate messenger RNA (mRNA) in nanoparticles made from polyethylene glycol (PEG). These nanoparticles are needed to transport the mRNA into the cells. PEG also acts as an adjuvant arousing the immune reaction. PEG is thought to be 1 reason some people have allergic responses to these vaccines.4
The idea that we can increase vaccine effectiveness with exercise raises the question of whether there are other behavioral adjuvants we might employ to increase vaccine effectiveness.
The idea that vaccine effectiveness might be increased by nonchemical means is both novel and increasingly important.
A paper published in early 2021 by Prather et al describes a study (N=83) that tracked sleep prior to flu vaccination and followed antibody responses. The authors report that sleeping poorly for 2 nights prior to a flu shot lowered antibody production.5 So, we might also validly suggest getting a good night’s sleep for a night or 2 before vaccination.
One way to achieve a good night’s sleep might be to take melatonin. Regardless of the impact on sleep, melatonin has already been suggested in some papers as a possible Coivd-19 vaccine adjuvant.6,7 An early animal study on using melatonin in this way reported a curious finding: Melatonin appeared to enhance the effect of the vaccine only if the vaccine also contained aluminum salts.8
It also seems that the time of day when patients receive a vaccine may also alter effectiveness. In a study by Erber et al (N=803), published in November 2022, morning vaccination (9:00–10:00 a.m.) was associated with the highest antibody response, while early afternoon vaccination (12:00–1:00 p.m.) was associated with the lowest antibody levels and late-afternoon vaccination (2:00–3:00 p.m.) with intermediate levels.9
An earlier paper published in December 2021 (N= 2,784) also suggests that time of day makes a difference but somewhat contradicts the 2022 findings. In this earlier study, getting vaccinated late in the day, between 3:00 and 9:00 p.m., was associated with the highest and longest-lasting antibody production.10 Taken together, this suggests that patients should schedule vaccinations either first thing in the morning or last thing in the evening.
A 2021 paper identified leptin, the metabolic-regulating hormone, as having an important role in vaccine effectiveness for influenza and hepatitis B vaccines. Discovered in 1994, leptin is an adipokine, a protein that functions as a hormone.11 It is now believed that leptin resistance (when the body does not adequately respond to this hormone) is the leading driver of fat gain in humans, especially those who have lost weight from dieting.12
In the 2021 study, low leptin levels were associated with poor vaccine responses (N=76). Current theories suggest that leptin is necessary for follicular helper cells to mature. Fasting, which reduces leptin levels, is associated with lower effectiveness of flu vaccine against infection.13 This means that theoretically, it’s preferable to have leptin levels high following vaccination to derive the greatest benefit. As dieting and particularly fat loss lower leptin, we might want to try to convince people on a weight-loss diet to discontinue for a few days before and after receiving a vaccination. Leptin drops as blood levels of fat drop, yet eating carbohydrates raises blood leptin levels even more than eating fat. Both high-fat and high-carbohydrate diets might be appropriate for a few days to raise leptin levels pre- and postvaccination.14
Vitamin D has also been proposed as a vaccine adjuvant, so perhaps spending time outdoors in the sun might also be considered a behavioral adjuvant.15
Laser light targeting the injection site prevaccination has also been proposed as a nonchemical adjuvant with some evidence supporting the idea.16,17 While not a behavioral adjuvant, it is another nontoxic, low-risk possibility to improve vaccine efficacy.
There are several botanical medicines that we categorize as immune stimulatory that act to increase responsiveness to vaccination and so might also be considered adjuvants. Ginseng comes to mind immediately. So does astragalus.18 Multiple veterinary animal studies have been published using saponins derived from ginseng stems and leaves to enhance vaccine effectiveness in various animal models of disease prevention.19
These aren’t the only traditional Chinese medicines shown to work. “Many studies have found that natural polysaccharides derived from Traditional Chinese Medicine (TCM) possess good immune promoting effects and simultaneously improve humoral, cellular and mucosal immunity,” write Wan X et al.20 As these are internalized, they are not “behavioral,” but they certainly might be considered as adjuvants.
The idea that there are multiple ways to enhance the immune protection derived from a vaccination by using either chemical, behavioral, or botanical adjuvants is of great interest to our colleagues whose practices focus on oncology. There is a long-standing belief that spontaneous or durable remissions in cancer occur through a process referred to as autovaccination. In such a scenario, some fragment of cancer cells in the patient’s body serves as the antigen to trigger a vaccine-like reaction in which the patient’s immune system learns to identify cancer cells. This has been observed particularly with radiotherapy and what is called the abscopal effect in which tumors outside of the treatment field shrink post therapy.21 Anything that increases the likelihood of the body’s immune system learning to recognize and respond to antigenic material derived from tumor cells is of interest. Although this current study under discussion is about common vaccinations, we might translate this information about exercise into an oncology setting. Exercise might be most appropriate for cancer patients when the presence of antigenic materials derived from their cancer are more abundant.
Current data already present a strong argument in favor of exercise for cancer patients. It is common to promote exercise to increase survival in cancer patients. A recent review on using exercise with ovarian cancer patients suggests that it not only improves survival but also quality of life and general symptoms without increasing adverse effects.22 Earlier reviews have established benefits in a range of cancers.”23 Helping patients to increase physical activity is now considered the best way to support cancer patients.24 Exercise may be the one intervention that is nearly always indicated.
