Morning Vaccination Compared with Afternoon/Evening Vaccination on Humoral Response to SARS-CoV-2 Adenovirus Vector-Based Vaccine in Hemodialysis Patients

Patients with kidney failure who are undergoing hemodialysis have impaired immunogenicity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Age, dialysis vintage, use of immunosuppressive drugs, serum albumin, lymphocyte count, vaccine type, and coronavirus disease 2019 (COVID-19) experience have been identified to be associated with humoral and cellular responses.¹ A recent review highlights that vaccination responses also exhibit circadian rhythmicity.² However, the benefits of vaccination in the morning compared with later in the day among hemodialysis patients remain unclear. Therefore, we aimed to determine whether morning vaccination with a COVID-19 vaccine was able to induce a higher antibody response than afternoon/evening vaccination among hemodialysis patients.

We conducted a prospective observational study in the hemodialysis unit of Taipei Tzu Chi Hospital, Taiwan. Prevalent hemodialysis patients aged 20 years or older with no history of SARS-CoV-2 infection were eligible for enrollment. Patients were excluded if they had been vaccinated, refused vaccination, had inadequate dialysis, or declined to participate. Patients currently using immunosuppressants were also excluded. All participants received a priming dose of ChAdOx1 nCoV-19, an adenovirus-vectored vaccine, on June 16 or 17, 2021, during the hemodialysis session. IgG antibodies to the receptor-binding domain of the S1 subunit of the spike protein of SARS-CoV-2 were measured using the AdviseDx SARS-CoV-2 IgG II assay (Abbot Laboratories) on day 28 and day 56 after vaccination. The cutoff value for positivity was set at ≥50 arbitrary units per ml (AU/ml) on the basis of manufacturer's recommendations. This study was approved by the Institutional Review Board of Taipei Tzu Chi Hospital (10-XD-117). Multivariable logistic regression analyses were used to evaluate the relationship between the time of the day of vaccination and antibody response. Covariates identified by prior studies as significantly associated with vaccine response or with a P value of <0.1 between responders and nonresponders were fitted.¹

A total of 201 participants were included, with a male-to-female distribution of 52% (n=104) to 48% (n=97), a mean age of 67 years, and a median dialysis vintage of 7.7 years. Among the participants, 70 were dialyzed in the morning (between 7:00 am and 12:00 pm), 69 in the afternoon (between 12:00 and 5:00 pm), and 62 in the evening (between 5:00 and 10:00 pm) (Figure 1A). Overall, 137 (68%) participants developed antibodies against the SARS-CoV-2 spike protein after a single dose of ChAdOx1 nCoV-19. The median antibody level was 184.6 AU/ml. In the multivariable model, morning vaccination independently associated with a humoral response at day 28 (Figure 1B). Participants who received morning vaccination were more likely to develop seroconversion compared with those who received afternoon/evening doses (odds ratio, 3.81; 95% confidence interval, 1.59 to 9.15; P = 0.003). Anti-spike antibody titers were measured in 198 participants at day 56. The median antibody level was 153.7 AU/ml. A significantly higher proportion of morning-vaccinated hemodialysis patients remained seropositive (odds ratio, 2.54; 95% confidence interval, 1.15 to 5.61; P = 0.02).

Figure 1.

Patient characteristics and serological response by the time of vaccination. (A) Baseline characteristics of participants according to the time of vaccination. (B) Antibody response at day 28 and day 56 after vaccination. The odds ratio for seroconversion of anti-spike IgG antibodies was assessed using a logistic regression model adjusted for age, diabetes, coronary artery disease, dialysis vintage, body mass index, serum albumin, and Ln (lymphocyte count). Ab, antibody; IQR, interquartile range.

Our findings corroborate the idea that morning vaccination may be more beneficial than afternoon/evening vaccination among hemodialysis patients. Long et al. investigated the influence of diurnal variations on humoral response after influenza vaccination in a cohort of 295 elderly patients.³ They found that participants with morning vaccination had higher antibody titers than those with afternoon vaccination. Similarly, in an experimental study of healthy volunteers, morning vaccination with antituberculosis agent bacillus Calmette-Guérin elicited stronger adaptive responses and trained immunity compared with evening vaccination.⁴ In the era of the SARS-CoV-2 pandemic, Zhang et al. evaluated the potential effect of vaccine delivery timing on immune responses in a prospective cohort of 63 health care workers.⁵ They reported that participants with morning vaccination experienced a better immune response, with a two-fold greater level of neutralizing antibodies compared with those with afternoon vaccination after administration of an inactivated SARS-CoV-2 vaccine. Furthermore, morning vaccination induced stronger B-cell and T-helper cell responses. Overall, these data indicate that immune response to vaccination is time-of-day–dependent, with morning vaccination giving rise to a stronger response.

Our study has several limitations. First, we did not investigate whether morning-vaccinated patients had a lower risk of severe COVID-19 infection. However, accumulating data have indicated a positive association between vaccine efficacy and anti-spike IgG concentrations.⁶ Second, we observed a comparable antibody response (seroconversion >90%) in morning-vaccinated and afternoon/evening-vaccinated participants after they completed a third dose of the mRNA vaccine. Indeed, mounting evidence suggested that a booster dose of the mRNA vaccine was effective in providing high levels of antibody in vulnerable populations not uniformly protected from the initial vaccination. Third, antibody titers may vary diurnally, independent of the time of vaccination. Fourth, a better survival had been demonstrated among morning-shift hemodialysis patients.⁷ Unidentified factors may explain for the difference of humoral response in association with morning versus afternoon/evening dialysis. Finally, baseline differences not detected by looking at demographics alone may contribute to the observed difference.

Our preliminary results showed that circadian rhythms might be harnessed to optimize vaccination strategies for hemodialysis patients. Future studies with larger sample size are required to validate our findings.

Disclosures

S.-C. Hung reports honoraria from AstraZeneca and Boehringer Ingelheim. The remaining author has nothing to disclose.

Funding

T.-Y. Lin: Ministry of Science and Technology, Taiwan (MOST 111-2314-B-303-009 and MOST 111-2314-B-303-032), and Taipei Tzu Chi Hospital (TCRD-TPE-109-RT-2, TCRD-TPE-108-15, TCRD-TPE-108-19, TCRD-TPE-111-03, TCRD-TPE-111-05, TCMF-EP 108-06, TCMF-CP 111-02, and TCAS-108-02).

Author Contributions

Conceptualization: Szu-Chun Hung.

Data curation: Ting-Yun Lin.

Formal analysis: Ting-Yun Lin.

Funding acquisition: Ting-Yun Lin.

Investigation: Szu-Chun Hung, Ting-Yun Lin.

Writing – original draft: Ting-Yun Lin.

Writing – review & editing: Szu-Chun Hung.