Jacob Schor ND, FABNO
Boosting Vaccine Benefits Is Desirable
Several recent studies provide new information on vaccine adjuvants that might prove useful in lowering morbidity associated with Covid-19 and that also may translate into a broader understanding of how to boost immunity in general and specifically in cancer immunotherapy.
Exercise Increases Vaccine Effectiveness
These ruminations result from the study by Hallam et al. published in May 2022.1 These researchers examined the effect that exercise begun immediately after vaccine administration had on its effectiveness. Obviously increasing our ability to control viral infections, particularly Covid-19, is of interest, and, at the same time, these findings may better inform our naturopathic approaches to other illnesses.
Let’s consider Hallam’s study. They describe a series of experiments, including three human clinical trials, that used exercise as a ‘behavioral adjuvant’ post vaccination to increase antibody responses. They tried this with three separate vaccines (2009 influenza H1N1, seasonal influenza, and Covid-19 Pfizer). They also performed similar trials with mice for much the same purpose.
The human trials were small with about two dozen participants in each (H1N1 n=20, Flu n=28, Covid-19 n=36). In each trial the participants were split into two groups. Those in the experimental group were made to exercise for prescribed periods (45 or 90 minutes) starting shortly after receiving their vaccinations using a cycle ergometer. The participants in the covid vaccine trial walked outside instead, fast enough to keep their heart rate at 120-140 bpm. When recruiting these participants, the researchers had selected relatively fit individuals who were capable of this kind of extended exercise.
In the seasonal flu vaccine experiment, the time spent exercising was varied by age: younger subjects (age 18–33), not in the control group, exercised for either 45 min or 90 min. Older subjects (age 62–87) were assigned to either the control group of no exercise, or to 45 minutes.
90-minutes of Exercise Makes a Difference
In all the trials IgG antibody levels increased after vaccination, but they increased significantly more in participants who exercised for 90 minutes compared to the control groups that abstained from exercise. Exercise was not associated with any increase in side effects after the Covid-19 vaccine. These results suggest people can increase their antibody response to influenza or Covid-19 vaccines by performing a single but lengthy session of light-to-moderate-intensity exercise post-immunization. Given that the effectiveness of vaccines and their subsequent boosters appears to be waning, having a no-cost, no-side-effect way to increase benefit is worth our attention.
It should be mentioned that in the trial using seasonal influenza vaccine that 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. For the time being, get patients to go for a long walk after receiving any vaccination—a long walk as the data suggests; while 90 minutes is helpful, 45 minutes is not.
Behavioral Adjuvants: A New Concept
This study adds a new term to our glossary: Behavioral Adjuvant. Most vaccine adjuvants are chemical, so it is appropriate to distinguish exercise and other non-chemical interventions as “behavioral adjuvants.” The use of adjuvant chemicals to enhance vaccine effectiveness has been standard practice for nearly a century. The idea that changing behaviors might also increase vaccine effectiveness is a new idea. Yet really isn’t changing behavior to improve immunity and protect health what naturopathy has always been about?
Historical Adjuvants Have Been Chemical
That an ‘adjuvant’ of any sort can amplify vaccine effectiveness was serendipitously discovered back in 1925 by Gaston Ramon, a French veterinarian. Ramon noticed that the yield of tetanus and diphtheria anti-sera from horses was higher in animals that had developed an abscess at the injection site. He went on to show that co-administration of his newly invented diphtheria toxoid together with other compounds such as tapioca, lecithin, agar, starch oil, saponin or breadcrumbs increased horse’s antitoxin responses to diphtheria.
A year later, in 1926, Glenny et al. reported that aluminum salts also increased immune response. These salts were added into human vaccines in the 1930s and the practice has continued to the present. Aluminum salts were initially incorporated into diphtheria, pertussis and tetanus vaccines and are now also added to hepatitis A and B, Haemophilus influenzae type b, pneumococcus and human papilloma virus vaccines. The addition of these chemical adjuvants is considered essential for these vaccines to be effective in achieving long-lasting disease immunity. 2-4
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 greater the immune reaction they trigger, the more the patient reacts to the vaccine. This current study using exercise as an adjuvant is intriguing as there were no indications in the data that exercise increased unwanted side effects as chemical adjuvants would.
The idea that vaccine effectiveness might be achieved by other than chemical means is both novel and important. Over the years the antigenic materials in vaccines have become increasingly subtle and more refined. Instead of living or dead disease organisms, vaccines now contain highly refined or synthesized materials that are less likely to provoke immune responses on their own. As a result, modern vaccines rely even more heavily on adjuvants. We should also note that producing adequate vaccine material in global quantities is a challenge for manufacturers, and adjuvants allow vaccination campaigns to ‘do more with less’, using lower doses of vaccine antigens and relying on adjuvants to compensate.
Neither of the two common Covid-19 vaccines nor the influenza vaccines contain aluminum salts. The Moderna and Pfizer Covid-19 vaccines encapsulate messenger RNA into nanoparticles made from polyethylene glycol (PEG). These nanoparticles transport the RNA into the cells. PEG itself serves as the adjuvant arousing an immune reaction. PEG, or the reaction to it, may be why some people have allergic responses to these vaccines.
The idea that we might increase vaccine effectiveness with exercise instead of irritating chemicals intrigues this writer and begs the question as to what other ‘behavioral adjuvants’ might be employed to increase vaccine effectiveness.
A Good Night’s Sleep, Timing, and More
A paper published in early 2021 by Prather et al describes a study (n=83) that tracked sleep prior to flu vaccination and tracked antibody response. The authors report that sleeping poorly for two nights prior to a flu shot lowered antibody production. 5 So, we might also suggest getting a good night’s sleep for a night or two prior to getting vaccinated.
One way to achieve a good night’s sleep might be to take melatonin. Regardless of the impact on sleep, melatonin is already suggested in some papers as a possible Covid-19 vaccine adjuvant.6,7 An early animal study on using melatonin in this way reported a curious finding though: melatonin only appears to enhance effect if the vaccine also contains aluminum salts.8
It also seems that the time of day a vaccine is received may also alter effectiveness. In a study by Erber et al., (n=803) published in November 2022, morning vaccination was associated with the highest (9:00-10:00 AM) antibody response while early afternoon vaccination with the lowest (12:00-1:00 PM), and late afternoon vaccination with intermediate (2-3 PM) antibody levels. 9
An earlier paper from December 2021 (n= 2,784) also suggested that time of day makes a difference but somewhat muddles the 2022 findings. In this earlier study getting vaccinated late in the day, between 3:00 and 9:00 PM, resulted in the highest and longest lasting antibody production.10 Taken together this might suggest that patients should either schedule vaccinations for 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 with influenza and hepatitis B vaccines. Discovered in 1994, leptin is an adipokine, a protein that functions as a hormone.11 Currently it is believed that leptin resistance—that is when the body does not adequately respond to leptin—is the leading driver of fat gain in humans, especially in those who have previously lost weight by dieting.12
In that 2021 study, low leptin levels were associated with poor vaccine responses (n=76). Apparently, leptin is necessary for follicular helper cells to mature. Fasting, which reduces leptin levels, decreases flu vaccine effectiveness against infection.13 Thus, it is probably preferable to want leptin levels high following vaccination. As dieting and particularly fat loss, lowers leptin, we might want to convince people to discontinue weight loss diets for a few days before and after receiving a vaccination. Leptin drops as blood levels of fat drop, yet apparently eating carbohydrates raises blood leptin levels even more than eating fat. Both high fat and high carbohydrate diets thus might be helpful for a few days to raise leptin levels pre and post vaccination.14 Of course, convincing dieters of the value of doing so might be easier said than done.
Vitamin D?
Vitamin D in combination with exercise has been suggested to reduce morbidity from covid infections by reducing risk of those cytokine storms, so perhaps spending time outdoors in the sun might also be considered a behavioral adjuvant.15 It should be noted that our belief that vitamin D reduces risk of upper respiratory infections, including from Covid-19, was recently called into question by the clinical trial by Joliffe et al. published in September 2022.16
In their phase-3 open-label controlled trial, 2958 people were tested for vitamin D levels. People considered low in vitamin D, ~86% of those tested, (< 75 nmol/L) were given six months of vitamin D, either 800 IU/day (n=1328) or 3200 IU/day (n=1346). A control group were neither tested nor supplemented (n=3100). The researchers monitored the proportion of participants diagnosed with acute respiratory tract infection of any cause and the proportions of participants with confirmed Covid-19. A total of 4.6% of those in the control group who were neither tested nor supplemented with vitamin D had at least one acute respiratory infection during the six months of follow up (136/2949). In contrast 5.7% of those given low dose (800 IU/day) (87/1515) and 5.0% in the higher dose group (76/1525) experienced an infection. The results were no more promising for Covid-19 in which 2.6% of the control group, 3.6% in the low dose and 3.0% of the high dose group were infected during the trial.
Their results call into question the common practice of testing and supplementing vitamin D for those with suboptimal levels to prevent URIs. Mind you, these numbers were not significantly different from each other so all we should say was that there was no better outcome, but the trends do kind of suggest that doing nothing was better than intervening by testing and supplementing.17
Other Adjuvants
Laser light targeting the injection site pre-vaccination has also been proposed as a nonchemical adjuvant with some evidence in support of the idea.18,19 We might not consider this as behavioral though as much as external. I don’t imagine we will see laser treatments being made available at vaccine locations.
There are 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.20 Multiple veterinary animal studies have been published using saponins derived from ginseng stem and leaves to enhance vaccine effectiveness in various animal models of disease prevention.21 These aren’t the only Chinese traditional 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.22 As these are internalized, they are not ‘behavioral’ but they certainly might be considered as adjunctive adjuvants (if such a term isn’t too redundant).
Adjuvants and Oncology
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 auto-vaccination. 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.23 As such, 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 clear interest.
Although this current study under discussion is about common vaccinations, we might optimistically 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 most abundant. This would probably be during early treatment with chemotherapy and radiation or post-surgical resection.
Current data already presents 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.24 Earlier reviews have established benefits in a range of cancers.25 Helping patients to increase physical activity is now considered the best way to support cancer patients.26
It seems in fact that there is a strong correspondence between those things that act as vaccine adjuvants and things that naturopathic physicians already suggest to their oncology patients. I’ve mentioned in past articles how some colleagues suggest to patients that they get vaccinated against various diseases to enhance antibody production, admitting that we don’t know if it is exposure to the disease antigens or the chemical adjuvants that was most helpful.
As one ruminates on these thoughts, one has to wonder whether this concept of auto-vaccination might better inform our timing of various interventions. During our years in practice, it was common for cancer patients to often delay starting naturopathic interventions until their standard medical treatments were completed. Often the visit would begin with their saying, “Now that I’ve finished chemo and radiation, I want to know what else I might do.” If we are to think about our naturopathic interventions as enhancing an antibody response to cancer cells then we want to start earlier, possibly even before the medical interventions start or as soon as possible afterwards. That is when the dying cancer cells will increase antigenic exposure and when the patient’s immune systems will be the least damaged by treatment. Thus, our lesson from this study may be in the earlier the better. For exercise, we might translate this into long sessions of moderate intensity exercise as soon after chemo and radiation as possible. Melatonin starting as soon as possible prior to treatment and so on.
1. 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 May;102:1-10.
2. Vogel F., Hem S.L. Vaccines. Saunders Elsevier; Philadelphia, PA, USA: 2004. Immunologic adjuvants; pp. 69–79.
3. Christensen D. Vaccine adjuvants: Why and how. Hum Vaccin Immunother. 2016 Oct 2;12(10):2709-2711.
4. Di Pasquale A, Preiss S, Tavares Da Silva F, Garçon N. Vaccine Adjuvants: from 1920 to 2015 and Beyond. Vaccines (Basel). 2015 Apr 16;3(2):320-43.
5. Prather AA, Pressman SD, Miller GE, Cohen S. Temporal Links Between Self-Reported Sleep and Antibody Responses to the Influenza Vaccine. Int J Behav Med. 2021 Feb;28(1):151-158.
6. Haskologlu IC, Erdag E, Sayiner S, Abacioglu N, Sehirli AO. Melatonin and REGN-CoV2 combination as a vaccine adjuvant for Omicron variant of SARS-CoV-2. Mol Biol Rep. 2022 May;49(5):4061-4068.
7. Kow CS, Ramachandram DS, Hasan SS. Melatonin: Revisited Role as Vaccine Adjuvant During Outbreaks of COVID-19 Caused by the Delta Variant. J Neuroimmune Pharmacol. 2021 Nov 30:1–2.
8. Regodón S, Martín-Palomino P, Fernández-Montesinos R, Herrera JL, Carrascosa-Salmoral MP, Píriz S, Vadillo S, et al. The use of melatonin as a vaccine agent. Vaccine. 2005 Nov 16;23(46-47):5321-7.
9. Erber AC, Wagner A, Karachaliou M, Jeleff M, Kalafatis P, Kogevinas M, et al. The Association of Time of Day of ChAdOx1 nCoV-19 Vaccine Administration With SARS-CoV-2 Anti-Spike IgG Antibody Levels: An Exploratory Observational Study. J Biol Rhythms. 2022 Nov 11:7487304221132355.
10. Wang W, Balfe P, Eyre DW, Lumley SF, O’Donnell D, Warren F, et al. Time of Day of Vaccination Affects SARS-CoV-2 Antibody Responses in an Observational Study of Health Care Workers. J Biol Rhythms. 2022 Feb;37(1):124-129.
11. Mendoza-Herrera K, Florio AA, Moore M, Marrero A, Tamez M, Bhupathiraju SN, Mattei J. The Leptin System and Diet: A Mini Review of the Current Evidence. Front Endocrinol (Lausanne). 2021 Nov 24;12:749050.
12. Park HK, Ahima RS. Physiology of leptin: energy homeostasis, neuroendocrine function and metabolism. Metabolism. 2015 Jan;64(1):24-34.
13. Deng J, Chen Q, Chen Z, Liang K, Gao X, Wang X, et al. The metabolic hormone leptin promotes the function of TFH cells and supports vaccine responses. Nat Commun. 2021 May 24;12(1):3073.
14. Romon M, Lebel P, Velly C, Marecaux N, Fruchart JC, Dallongeville J. Leptin response to carbohydrate or fat meal and association with subsequent satiety and energy intake. Am J Physiol. 1999 Nov;277(5):E855-61.
15. Bizuti MR, Starck É, da Silva Fagundes KK, Puhle JG, Lima LM, de Oliveira NR, wt al. Influence of exercise and vitamin D on the immune system against Covid-19: an integrative review of current literature. Mol Cell Biochem. 2022 Jun;477(6):1725-1737.
16. Jolliffe DA, Holt H, Greenig M, et al. Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT). BMJ. 2022 Sep 7;378:e071230.
17. Jolliffe DA, Holt H, Greenig M, et al. Effect of a test-and-treat approach to vitamin D supplementation on risk of all cause acute respiratory tract infection and covid-19: phase 3 randomised controlled trial (CORONAVIT). BMJ. 2022 Sep 7;378:e071230.
18. Maki Y, Kushibiki T, Sano T, Ogawa T, Komai E, Takahashi Set al. 1270 nm near-infrared light as a novel vaccine adjuvant acts on mitochondrial photoreception in intradermal vaccines. Front Immunol. 2022 Nov 10;13:1028733.
19. Kashiwagi S. Laser adjuvant for vaccination. FASEB J. 2020 Mar;34(3):3485-3500.
20. Lin G, Da F, Wan X, et al. Immune-enhancing effects of Astragalus polysaccharides and Ganoderma lucidum polysaccharides on Vibrio harveyi flgJ DNA vaccine in grouper. J Fish Dis. 2022 Nov 9.
21. Su F, Xu L, Xue Y, Xu W, Li J, Yu B, et al. Immune Enhancement of Nanoparticle-Encapsulated Ginseng Stem-Leaf Saponins on Porcine Epidemic Diarrhea Virus Vaccine in Mice. Vaccines (Basel). 2022 Oct 27;10(11):1810.
22. Wan X, Yin Y, Zhou C, Hou L, Cui Q, et al. Polysaccharides derived from Chinese medicinal herbs: A promising choice of vaccine adjuvants. Carbohydr Polym. 2022 Jan 15;276:118739.
23. Goto T. Radiation as an In Situ Auto-Vaccination: Current Perspectives and Challenges. Vaccines (Basel). 2019 Aug 26;7(3):100.
24. Sicardo Jiménez S, Vinolo-Gil MJ, Carmona-Barrientos I, et al. The Influence of Therapeutic Exercise on Survival and the Quality of Life in Survivorship of Women with Ovarian Cancer. Int J Environ Res Public Health. 2022 Dec 3;19(23):16196.
25. Stout NL, Baima J, Swisher AK, Winters-Stone KM, Welsh J. A Systematic Review of Exercise Systematic Reviews in the Cancer Literature (2005-2017). PM R. 2017 Sep;9(9S2):S347-S384.
26. Torregrosa C, Chorin F, Beltran EEM, Neuzillet C, Cardot-Ruffino V. Physical Activity as the Best Supportive Care in Cancer: The Clinician’s and the Researcher’s Perspectives. Cancers (Basel). 2022 Nov 2;14(21):5402
Published July 15, 2023
About the Author
Jacob Schor, ND, now retired, had a general practice with a focus on naturopathic oncology in Denver, Colorado. He served as Abstract & Commentary Editor for the Natural Medicine Journal for several years (https://www.naturalmedicinejournal.com/) and posts blog articles on natural therapies, nutrition, and cancer (https://drjacobschor.wordpress.com/). He is a board member of CoAND and past president of OncANP, and someone who is happier outdoors than inside.