key: cord-0915219-kfesocpm
authors: Barnoud, Coline; Wang, Chen; Scheiermann, Christoph
title: Timing vaccination against SARS-CoV-2
date: 2021-09-01
journal: Cell Res
DOI: 10.1038/s41422-021-00559-w
sha: 4c956adeba11dcda515ea2afde8dfc72efd86555
doc_id: 915219
cord_uid: kfesocpm

nan

autoimmune diseases, 2,5 during which they strongly modulate the response to inflammation. Such observations have led to the development of chronotherapies targeting the immune system, where time of day is used to enhance the treatment efficacy. In the context of vaccination, temporal oscillations in antibody production in response to the timed administration of specific antigens have been observed in both mice 6,7 and humans. 8, 9 A study by Zhang and colleagues in Cell Research, 10 has now investigated the immunological response to an inactivated SARS-CoV-2 vaccine administered to a cohort of healthcare workers either in the morning or in the afternoon. The authors found that volunteers who got vaccinated in the morning exhibited a significantly stronger immune response (Fig. 1) . A total of 63 volunteer healthcare workers (aged 24-28) were administered the inactivated SARS-CoV-2 vaccine (BBIBP-CorV, Sinopharm) at two times of day. The first cohort received the two vaccine doses on day 0 and day 28 in the morning between 9 am and 11 am, while the second cohort received both doses in the afternoon between 3 pm and 5 pm. The efficacy of morning or afternoon vaccine administration was evaluated by taking regular blood samples from the participants. Strikingly, the serological response to the vaccine was different between morning-vaccinated and afternoon-vaccinated cohorts with two-fold higher levels of volunteer healthcare workers (aged 24-28) separated into two groups who received the vaccine at two different times of the day (morning 9-11 am or afternoon 3-5 pm). Participants who received the vaccine in the morning experienced a stronger immune response with higher neutralizing antibody levels, stronger B and T fh cell response, and higher percentages of monocytes and DCs as well as spike-specific and RBDspecific memory B cells. T fh , T follicular helper cells; DCs, dendritic cells; RBD, receptor binding domain.

neutralizing antibodies in the morning-vaccinated cohort-an effect already observed after the first dose but with a more striking effect after two doses. Moreover, cellular responses to vaccination exhibited a time-of-day difference with stronger B cell and follicular T helper cell (T fh ) responses, as well as higher frequencies of monocytes and dendritic cells (DCs) in the morning cohort. In addition, the authors observed differences in memory B cells, indicating that vaccination in the morning could trigger a stronger long-term immunity than that in the afternoon. Thus, a simple change in time alters the vaccination response.

Findings uncovered by Zhang and colleagues will be key to the optimization of SARS-CoV-2 vaccination strategies. Similar higher morning effectiveness for an influenza vaccine 9 indicate that this concept should also be applicable to other vaccines. However, it is currently not known whether these observed time-of-day dependent changes in the vaccination response provide a real benefit, i.e., a better protection against the virus. Following differently time-treated patient cohorts over time will be essential to assess this. A second important remaining question is whether the occurrence and strength of adverse effects associated with different vaccines are also dependent on the time of the day. Nevertheless, these data provide fundamental evidence for circadian rhythms in vaccination responses in humans, which is surprising, given that these take weeks to develop. Understanding the precise mechanisms on how these rhythms are initially generated and how they are maintained over such a long time frame will be critical for the design of better treatments targeting this important regulatory aspect of any immune response.

Proc. Natl. Acad. Sci. USA

Research in the lab is funded by the European Research Council (ERC CoG 101001233-CIRCADYN), the Swiss National Science Foundation (SNF, 310030_182417/1) as well as the Novartis Foundation for medical-biological Research (20A019). C.W. is the recipient of a fellowship of the Chinese Scholarship Council (CSC).

The authors declare no competing interests.

Correspondence and requests for materials should be addressed to C.S.Reprints and permission information is available at http://www.nature.com/ reprints