We observed no significant differences between PI donors who received one or two doses at V3 and V4. vaccine with sixteen weeks between doses. While administering Kaempferitrin a second dose to previously infected individuals did not significantly improve humoral responses, these responses significantly increased in naive individuals after a 16-week spaced second dose, achieving comparable levels as in previously infected individuals. Comparing these responses to those elicited in individuals receiving a short (4-week) dose interval showed that a 16-week interval induced more robust responses among naive vaccinees. These findings suggest Kaempferitrin that a longer interval between vaccine doses does not compromise efficacy and may allow greater flexibility in vaccine administration. Keywords: Coronavirus, COVID-19, SARS-CoV-2, Spike glycoproteins, delayed mRNA vaccine regimen, variants of concern, variants of interest, humoral responses, neutralization, ADCC Graphical abstract Open in a separate windows Tauzin et?al. characterize longitudinal humoral responses induced with an extended BNT162b2 vaccine interval between doses. They show that delaying the second dose in naive individuals elicits higher humoral responses than in those receiving a four-week interval. Vaccinated convalescent individuals present higher responses that dont improve after a boost. Introduction Since the end of 2019, the etiological agent of the coronavirus disease 2019 (COVID-19), the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread worldwide, causing the current pandemic (Dong et?al., 2020; World Health Business, 2021). In the last months, several vaccines against SARS-CoV-2, including the Pfizer/BioNtech BNT162b2 mRNA vaccine, have been approved in many countries. This vaccine targets the highly immunogenic trimeric Spike (S) glycoprotein that facilitates BRIP1 SARS-CoV-2 entry into host cells via its receptor-binding domain (RBD), which interacts with angiotensin-converting enzyme 2 (ACE-2) (Hoffmann et?al., 2020; Walls et?al., 2020) and has shown an Kaempferitrin important vaccine efficacy (Polack et?al., 2020; Skowronski and De Serres, 2021). The approved BNT162b2 mRNA vaccine regimen comprises two doses administered 3 to 4 4?weeks apart (WHO, 2021). However, at the beginning of the vaccination campaign (Winter/Spring 2021), vaccine scarcity prompted some public health agencies to extend the interval between doses in order to maximize the number of immunized individuals. This strategy was supported by results indicating that a single dose affords 90% protection starting 2?weeks post vaccination, concomitant with the detection of some vaccine-elicited immune responses (Baden et?al., 2021; Pilishvili et?al., 2021; Polack et?al., 2020; Skowronski and De Serres, 2021; Tauzin et?al., 2021). The rapid emergence of several variants of concern (VOCs) and variants of interest (VOIs), which are more transmissible and in some cases more virulent (Allen et?al., 2021; Brown et?al., 2021; Davies et?al., 2021; Fisman and Tuite, 2021; Pearson et?al., 2021), remains a major public health preoccupation as the vaccine campaign advances worldwide. For example, the mutation D614G in the S glycoprotein, which appeared very early in Kaempferitrin the pandemic, is now present in almost all circulating strains (Isabel et?al., 2020). The B.1.1.7 (Alpha) variant emerged in late 2020 in the United Kingdom and, due to its increased affinity for the ACE2 receptor, which leads to increased transmissibility (Davies et?al., 2021), it became in just a few months a predominant strain worldwide (Davies et?al., 2021; Prvost et?al., 2021; Rambaut et?al., 2020). The B.1.351 (Beta) and P.1 (Gamma) variants that first emerged in South Africa and Brazil, respectively, have largely spread and are now circulating in many countries (ECDC, 2021; Tang et?al., 2021). The B.1.526 (Iota) variant first identified in New York in early 2021 is on an upward trajectory in the United States (Annavajhala et?al., 2021). More recently, the B.1.617.2 (Delta) variant, which emerged in India and has high transmissibility, is now the dominant strain in several countries (Allen et?al., 2021; Dagpunar, 2021). Although several studies have shown that mRNA vaccines protect against severe disease caused by these variants, it has also been shown that some of them present resistance to some vaccine-elicited immune responses, notably against neutralizing antibodies (Annavajhala et?al., 2021; Goel et?al., 2021a; Planas et?al., 2021a; Puranik et?al., 2021; Wall et?al., 2021; Wang et?al., 2021a)..