Understanding the impact of prior infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the response to vaccination is a priority for responding to the coronavirus disease 2019 (COVID-19) pandemic. In particular, it is necessary to understand how prior infection plus vaccination can modulate immune responses against variants of concern. To address this, we sampled 20 individuals with and 25 individuals without confirmed previous SARS-CoV-2 infection from a large cohort of healthcare workers followed serologically since April 2020. All 45 individuals had received two doses of the Pfizer-BioNTech BTN162b2 vaccine with a delayed booster at 10 weeks. Absolute and neutralizing antibody titers against wild-type SARS-CoV-2 and variants were measured using enzyme immunoassays and pseudotype neutralization assays. We observed antibody reactivity against lineage A, B.1.351 and P.1 variants with increasing antigenic exposure, either through vaccination or natural infection. This improvement was further confirmed in neutralization assays using fixed dilutions of serum samples. The impact of antigenic exposure was more evident in enzyme immunoassays measuring SARS-CoV-2 spike protein-specific IgG antibody concentrations. Our data show that multiple exposures to SARS-CoV-2 spike protein in the context of a delayed booster expand the neutralizing breadth of the antibody response to neutralization-resistant SARS-CoV-2 variants. This suggests that additional vaccine boosts may be beneficial in improving immune responses against future SARS-CoV-2 variants of concern.

Biologists have long tried to describe and name the different phenotypes that make up the shell polymorphism of the land snail Cepaea nemoralis . Traditionally, the view is that the ground colour of the shell is one of a few major colour classes, either yellow, pink or brown, but in practise it is frequently difficult to distinguish the colours, and define different shades of the same colour. To understand whether colour variation is in reality continuous, and to investigate how the variation may be perceived by an avian predator, we applied psychophysical models of colour vision to shell reflectance measures. We found that both achromatic and chromatic variation are indiscrete in Cepaea nemoralis , being continuously distributed over many perceptual units. Nonetheless, clustering analysis based on the density of the distribution did reveal three groups, roughly corresponding to human-perceived yellow, pink and brown shells. We also found large-scale geographic variation in the frequency of these groups across Europe, and some covariance between shell colour and banding patterns. Although further studies are necessary, the observation of continuous variation in colour is intriguing because the traditional theory is that the underlying supergene that determines colour has evolved to prevent phenotypes from “dissolving” into continuous trait distributions. The findings thus have significance for understanding the Cepaea polymorphism, and the nature of the selection that acts upon it, as well as more generally highlighting the need to measure colour objectively in other systems.

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6Running head: Redefining a snail colour polymorphism 7 2 Biologists have long tried to describe and name the different phenotypes that make 8 up the exuberant colour polymorphism of the land snail Cepaea nemoralis. 9 Traditionally, the view is that the ground colour is one of a few major colour classes, 10 either yellow, pink or brown, but in practise it is frequently difficult to distinguish the 11 colours, and consistently define different shades of the same colour. To understand 12 whether colour variation is continuous, and to investigate how the variation may be 13 perceived by an avian predator, we applied psychophysical models of colour vision 14 to shell reflectance measures. The main finding is that both achromatic and 15 chromatic variation are indiscrete, being continuously distributed over many 16 perceptual units, with the major axis of chromatic variation representing differences 17 in saturation, or purity of colour. Nonetheless, clustering analysis based on the 18 density of the distribution revealed three groups, roughly corresponding to human-19 perceived yellow, pink and brown shells. There is also large-scale geographic 20 variation between these morphs across Europe, and some covariance between shell 21 colour and banding patterns. Although further studies are necessary to understand 22 the evolutionary origins and impact of natural selective upon this variation, the 23 observation of continuous variation in colour is intriguing, given that the underlying 24 supergene that determines colour should prevent phenotypes from "dissolving" into 25 continuous trait distributions. 26 27 3 Throughout the past century, the study of animal colour has been critical in making 28 progress in understanding the principles of biology, especially with respect to 29 genetics and evolution (McKinnon and Pierotti 2010; McLean and Stuart-Fox 2014; 30 Cuthill et al. 2017; San-Jose and Roulin 2017). For instance, early studies on the 31 inheritance of colour traits were important in establishing an understanding of basic 32 Mendelian genetics (Wheldale 1907; Staples-Browne 1908). Subsequently, studies 33 of the distribution and predation of colour morphs have and continue to shape our 34 understanding of how natural and sexual selection operate in wild populations 35 (Hugall and Stuart-Fox 2012; Dale et al. 2015; Delhey et al. 2017). Most recently, 36 candidate gene and latterly genomic approaches have been used to identify the 37 underlying genes that determine the colour differences (references in Hoekstra 2006; 38 McLean and Stuart-Fox 2014; San-Jose and Roulin 2017).39For practical reasons, many of these prior studies have taken advantage of 40 traits that exhibit relatively simple, discrete variation and straightforward inheritance 41 patterns, but this risks missing the extraordinary variation of life forms and colour 42 traits. It is also likely that in nature discrete variation is the exception rather than the 43 ruleand this is becoming more evident as researchers increasingly use 44 instrument...

are joint senior author. *The members of the COVIDsortium investigators and COVIDsortium immune correlates network can be found at the end of the Acknowledgements.

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Objectives COVID-19 vaccine responses in rare autoimmune rheumatic diseases (RAIRD) remain poorly understood, in particular there is little known about whether people develop effective T cell responses. We conducted an observational study to evaluate the short-term humoral and cell-mediated T cell response after the second SARS-CoV-2 vaccination in RAIRD patients compared with healthy controls (HC). Methods Blood samples were collected after the second dose and anti-spike, anti-nucleocapsid antibody levels and SARS-CoV-2 specific T cell responses were measured and compared with HC. Activation induced marker and deep phenotyping assays were used to identify differences in T cells between high and low/no antibody groups, followed by multi-dimensional clustering. Results 50 patients with RAIRD were included (31 with AAV, 4 with other systemic vasculitis, 9 with SLE and 6 with myositis). Median anti-spike levels were significantly lower in RAIRD compared with HC (p< 0.0001). 15 (33%) patients had undetectable and 26 (57%) had lower levels than the lowest HC. Rituximab in the last 12 months (p= 0.003) was associated with reduced immunogenicity compared with a longer pre-vaccination period. There was a significant difference in B cell percentages (p= 0.03) and spike-specific CD4+ T cells (p= 0.02) between no/low antibody vs. high antibody groups. Patients in the no/low antibody group had a higher percentage of terminally differentiated (exhausted) T cells. Conclusions Following two doses, most RAIRD patients have lower antibody levels than the lowest HC and lower anti-spike T cells. RAIRD patients with low/no antibodies have diminished numbers and poor quality of memory T cells which lack proliferative and functional capacities.