Vaccination: better early than late

During a recent lecture about immunotherapy, one statement really caught my attention:

“Immunotherapy works better in the morning and the same goes for vaccination.”

This finding could be important to boost individual vaccination response, especially in this age of declining vaccination uptake and thus decreased herd immunity. Moreover, maybe there were other ways to boost individual vaccine response (beside having an excellent vaccine). In the post, I try to answer the following questions.

1. Is there a diurnal effect in the immune response to vaccination?

2. Are there other environmental factors that might influence vaccine response?

1. Is there a diurnal effect in the immune response to vaccination?

There are good reasons to belief our immune system works according to a biological clock and thus favors vaccination at certain times during the day.

- A set of “clock” genes is present in most immune cells, which results in a circadian fluctuation of gene expression and by consequence a variation in the immune response throughout the day (2). This has been shown in both human mononuclear cells and in CD4+ T-cells (1)

- Experimental evidence in mice has shown that the outcome of infections varies according to the time of the day. For instance, when clock genes of mice were in their rest phase, the bacterial load of Salmonella typhimurium was much higher than if these genes were active (2).

- In vivo studies also have shown that vaccine response varies on the time of the day. However, the best time couldn’t be established.

- As mentioned before, early administration of immune checkpoint inhibitors has been linked to increased progression-free and/or overall survival (3).

- In humans, however, a recent systematic review of 23 studies couldn’t provide conclusive evidence of a better immune outcome when vaccination occurred during certain times of the day (2). Moreover, most included studies had some major drawbacks:

• Almost all studies were observational and contained intrinsic biases, going from moderate to critical. For instance, often the participant could choose the time of vaccination (2). This will almost cause a bias as people who can only come in the evening most certainly have a different lifestyle than those who can come early morning. Also, shift work was often not taken into consideration (2)

• Most studies assessed immune response by the induced antibody titer. However, the latter correlates only moderately with vaccine protection (1,2).

• Even among the ‘positive’ studies, there wasn’t an agreement in the optimal timing for vaccination (2).

Recently, 2 very large, observational trials have been published (from the same group) that demonstrated that morning vaccination might be beneficial. Both trials looked at breakthrough infection as outcome (instead of antibody response as most trials).

a) Hazan et al (2022).

This retrospective cohort study included 1,515,754 people who received Covid vaccination (almost all BNT162b2) in Israel between December 2020 and April 2022 (4). They found a sinusoidal relationship in vaccine effectiveness throughout the day: people who were vaccinated in the morning and early afternoon had less breakthrough infections than people vaccinated after 4 pm.

Astonishingly, the number needed to treat depending on which dose the patient received varied between 18.7 and 54.5 (4). In other words, if all 1,515,745 participants were vaccinated early in the day 27,812 to 81,055 breakthrough infections could have been avoided. If you know that in the study period a total 278,488 positive Covid-19 test were detected, this seems a bit to good to be through in my opinion.

Strengths:

- Large data set with a homogenous population as for immunization to Covid-19 and type of vaccine (4).

- Outcome reflects real-world vaccine protection (which was a first) (5)

- Long clinical follow-up of minimal 16 months (4).

Limitations:

- High likelihood that unmeasured confounders influenced the result of this study (5). The previous discussed systematic review assessed the risk for bias due to confounding as serious, which also led to a serious risk for overall bias (1).

- Observational study and thus no random assignment to a specific vaccination time (4).

b) Danino et al (2024).

This was another retrospective, observational study spanning two decades that looked at the rate of breakthrough infections in function of the time of varicella vaccination (6). Children less than 6 years old had less risk of varicella when they received their first varicella vaccine in the late morning to early afternoon compared to the evening.

Strengths:

- The same strengths apply as for the previous study.

- More uniform circadian rhythm in the study population, considering the fact that the average age was 1.2 years.

Limitations:

- As with the previous study, there is a high likelihood of bias due to confounders. The authors did a Cox multivariate regression to correct for sex, immunodeficiency, ethnicity and obesity and still found the same significant impact of the time of day on vaccine efficacy. However, parents who went for vaccination after 4 pm most likely have a different lifestyle/social background than parents who can go in the morning.

My view:

It seems biological plausible that there is an effect of chronovaccination, the circadian timing of vaccination (2). However, in my opinion, the data in humans are so far only indicating an effect and I would wait for randomized controlled trials before making any definitive conclusions. Furthermore, the most important thing remains that people get the vaccine. Introducing new hurdles by only allowing morning vaccination might decrease the population vaccination uptake (which is already under threat in lots of places). Nevertheless, I probably would preferentially vaccinate elderly and immunocompromised patients in the morning.

2. Are there other environmental factors that might influence vaccine response?

In the literature, other factors are suggested to increase vaccine efficacy:

• A systematic review suggested that chronic insomnia might reduce vaccine efficacy (7). No meta-analysis was possible due to lot of heterogeneity among studies.

• A randomized controlled trial found that 15 minutes of moderate exercise prior to vaccination induced a larger response in the half-dose group (8). However, if people were vaccinated with the full-dose vaccine, exercising before vaccination didn’t make any difference.

• A systematic review found that chronic aerobic exercise increased influenza antibodies, although in pneumococcal vaccination, the same intervention didn’t make any difference (9). No clear effect of vaccine efficacy was seen after acute exercise.

My view:

It makes sense that a healthy lifestyle renders vaccines more efficacious although the impact seems rather limited. Besides, all these studies are very prone to bias. In my view, the clinical relevance of these findings is very limited

References:

 1. Wyse CA, Rudderham LM, Nordon EA, et al. Circadian Variation in the Response to Vaccination: A Systematic Review and Evidence Appraisal. J Biol Rhythms. 2024 Jun;39(3):219-236.

 2. Otasowie CO, Tanner R, Ray DW, et al. Chronovaccination: Harnessing circadian rhythms to optimize immunisation strategies. Front Immunol. 2022 Oct 7;13:977525.

 3. Karaboué A, Innominato PF, Wreglesworth NI, et al. Why does circadian timing of administration matter for immune checkpoint inhibitors' efficacy? Br J Cancer. 2024 Sep;131(5):783-796.

 4. Hazan G, Duek OA, Alapi H, et al. Biological rhythms in COVID-19 vaccine effectiveness in an observational cohort study of 1.5 million patients. J Clin Invest. 2023 Jun 1;133(11):e167339.

 5. Rasmussen-Torvik LJ. Time of day for COVID vaccine administration linked to clinical effectiveness. J Clin Invest. 2023 Jun 1;133(11):e168233.

 6. Danino D, Kalron Y, Haspel JA, et al. Diurnal rhythms in varicella vaccine effectiveness. JCI Insight. 2024 Sep 3;9(20):e184452.

 7. Rayatdoost E, Rahmanian M, Sanie MS, et al. Sufficient Sleep, Time of Vaccination, and Vaccine Efficacy: A Systematic Review of the Current Evidence and a Proposal for COVID-19 Vaccination. Yale J Biol Med. 2022 Jun 30;95(2):221-235.

 8. Edwards KM, Pung MA, Tomfohr LM, et al. Acute exercise enhancement of pneumococcal vaccination response: a randomised controlled trial of weaker and stronger immune response. Vaccine. 2012 Oct 5;30(45):6389-95.

 9. Dinas PC, Koutedakis Y, Ioannou LG, et al. Effects of Exercise and Physical Activity Levels on Vaccination Efficacy: A Systematic Review and Meta-Analysis. Vaccines (Basel). 2022 May 12;10(5):769.