The impact of circadian rhythms on the immune response to influenza vaccination in middle-aged and older adults (IMPROVE): a randomised controlled trial

Abstract

Background Vaccination is important in influenza prevention but the immune response wanes with age. The circadian nature of the immune system suggests that adjusting the time of vaccination may provide an opportunity to improve immunogenicity. Our previous cluster trial in Birmingham suggested differences between morning and afternoon vaccination for some strains in the influenza vaccine in older adults. Whether this effect is also seen in a younger age group with less likelihood of compromised immunity is unknown. We therefore conducted an individual-based randomized controlled trial in Guangzhou to test the hypothesis that influenza vaccination in the morning induces a stronger immune response in older adults than afternoon vaccination. We included adults in middle age to determine if the effect was also seen in younger age groups. Results Of the 418 participants randomised, 389 (93.1%, 191 middle-aged adults aged 50–60 years and 198 older adults aged 65–75 years) were followed up. Overall, there was no significant difference between the antibody titers (geometric mean /95% CI) after morning vs afternoon vaccination (A/H1N1: 39.9 (32.4, 49.1) vs. 33.0 (26.7, 40.7), p = 0.178; A/H3N2: 92.2 (82.8, 102.7) vs. 82.0 (73.8, 91.2), p = 0.091; B: 15.8 (13.9, 17.9) vs. 14.4 (12.8, 16.3), p = 0.092), respectively. However, in pre-specified subgroup analyses, post-vaccination titers for morning versus afternoon vaccination in the 65–75 years subgroup were (A/H1N1): 49.5 (36.7, 66.6) vs. 32.9 (24.7, 43.9), p = 0.050; (A/H3N2): 93.5 (80.6, 108.5) vs. 73.1 (62.9, 84.9), p = 0.021; (B): 16.6 (13.8, 20.1) vs. 14.4 (12.3, 17.0), p = 0.095, respectively. Among females, antibody titers for morning versus afternoon vaccination were (A/H1N1): 46.9 (35.6, 61.8) vs. 31.1 (23.8, 40.7), p = 0.030; (A/H3N2): 96.0 (83.5, 110.3) vs. 84.7 (74.4, 96.5), p = 0.176; (B): 14.8 (12.7, 17.3) vs. 13.0 (11.3, 14.9), p = 0.061, respectively. In the 50–60 years old subgroup and males, there were no significant differences between morning and afternoon vaccination. Conclusions Morning vaccination may enhance the immunogenicity to influenza vaccine in adults aged over 65 and women. An intervention to modify vaccination programs to vaccinate older individuals in the morning is simple, cost free and feasible in most health systems.

The Impact of Vaccination Time on the Antibody Response to an Inactivated Vaccine against SARS‐CoV‐2 (IMPROVE‐2): A Randomized Controlled Trial

“…[27] Our previous study found that morning vaccination may enhance the immunogenicity to influenza vaccine in adults aged over 65 instead of those aged 50-60. [8] In the present study, we observed higher neutralizing antibody titers in the younger adults after the second dose of inactivated SARS-CoV-2 vaccine but no significant interaction between age and vaccination time for the antibody response. This is consistent with a recent report studying a retrospective cohort of health care workers immunized with mRNA or Adenovirus SARS-CoV-2 vaccine, which showed no significant interactive effect between age and vaccination time.…”

“…[14,15] It was found that children vaccinated attenuated vaccine against poliomyelitis in the morning had better antibody responses compared to those vaccinated in the evening. [9] Recent studies showed that morning vaccination of seasonal influenza [8] or Bacille Calmette-Guerin [16] elicited a stronger trained immunity and adaptive immune response when compared to afternoon vaccination. However, the effect of vaccination time may vary in different vaccines.…”

“…The circadian rhythm regulates many aspects of immune system, including vaccination. [ 5,6 ] A previous cluster trial from Birmingham [ 7 ] and our recent randomized controlled trial [ 8 ] reported differences in immune response between morning and afternoon influenza vaccination. Other studies revealed that morning vaccination of poliomyelitis [ 9 ] and Hepatitis A [ 10 ] in the morning had better antibody responses compared to those vaccinated in the evening.…”

Circadian Effects on Vascular Immunopathologies

“…73 Other data have implicated humoral immune responses to be highly time-ofday dependent in both the preclinical and the clinical setting, thus linking circadian oscillations in B cells to vaccination efficacy. 74,75 Hematopoietic Stem and Progenitor Cells Hematopoietic stem and progenitor cells (HSPCs) are also known to be subject to circadian regulatory patterns. HSPCs in the bone marrow generate various lineages of blood cells and many of their functions, such as proliferation, differentiation, or trafficking, exhibit timedependent fluctuations that require tight coordination to ensure daily blood cell replenishment in both mice and humans.…”

Biological Rhythms in Covid-19 Vaccine Effectiveness

“…Some theorize that the circadian rhythms in humans should translate, directly or indirectly, into preferable times of day to vaccinate patients 1,2,[19][20][21] . However, clinical studies differ on whether rhythms exist in vaccine responses, including those against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus infectious disease-19 (COVID-19) [22][23][24][25][26][27][28][29][30][31] . While important, prior studies had limited sample sizes and focused on markers of immunogenicity like antibody titers rather than clinical outcomes.…”