key: cord-0895161-c55fvww7 authors: Ciccone, E. J.; Zhu, D. R.; Ajeen, R.; Shook-Sa, B. E.; Boyce, R. M.; COVID HCW Study Team,; Aiello, A. E. title: SARS-CoV-2 seropositivity after infection and antibody response to mRNA-based vaccination date: 2021-02-19 journal: medRxiv : the preprint server for health sciences DOI: 10.1101/2021.02.09.21251319 sha: ba7e824a2e0f6b0014b61aec48fb387c82271e93 doc_id: 895161 cord_uid: c55fvww7 The effect of SARS-CoV-2 seropositivity on the immune response to mRNA-based SARS-CoV-2 vaccines has not been well-described. Here we report longitudinal SARS-CoV-2-specific antibody responses pre- and post-vaccination among a cohort of healthcare personnel, with and without prior infection, from a large academic medical center. Our results provide preliminary evidence that prior SARS-CoV-2 infection may prime the response to the first mRNA-based SARS-CoV-2 vaccine dose. These findings could have significant impact on the allocation of mRNA-based vaccines and support the need for future research into the effect of prior infection on magnitude and durability of vaccination response. The impact of prior SARS-CoV-2 infection on antibody response to mRNA-based vaccines has not been well-characterized. Early reports suggest that it may prime the immune response to the first vaccine dose, but these reports did not include longitudinal antibody levels before vaccination. [1] [2] [3] This information is important as the timing of natural infection in relation to vaccination may impact response. The Centers for Disease Control and Prevention (CDC) recently suggested that individuals with documented immunity might defer vaccination for 90 days to expedite access for those without immunity, but data supporting these guidelines are limited. 4 Here, we examined longitudinal SARS-CoV-2 antibody responses among healthcare personnel (HCP) with and without prior infection to examine the impact of natural infection on vaccination response. We conducted a longitudinal study of HCP at a large medical center that began enrolling in July 2020. 5 Participants provided blood samples every two weeks for the first 12 weeks and monthly thereafter. mRNA-based SARS-CoV-2 vaccinations (Pfizer-BioNTech [BNT162b2] and Moderna [mRNA-1273]) became available to HCP on December 16, 2020. For all pre-and postvaccination samples, we measured total immunoglobulin antibodies specific to the receptor binding domain of the SARS-CoV-2 spike protein by ELISA with a positive to negative ratio (P/N) cut-off of 2.57 to ensure 99.5% specificity per CDC guidelines. 6, 7 Exact Wilcoxon rank sum tests were used to compare median P/N between seropositive and seronegative participants and change in P/N for those with paired pre-and post-vaccination measurements. As of February 2, 2021, the study enrolled 213 HCP with 194 (91%) providing at least one blood sample. One individual was excluded due to co-enrollment in a SARS-CoV-2 treatment trial. Table 1 presents the cohort demographics. Five participants (3%) had antibodies to SARS-CoV-2 at their baseline study visit (prevalent seropositive; Figure 1A ). Notably, one demonstrated persistent seropositivity for six months, while another remained seropositive for over three months before reverting to seronegative one month prior to vaccination. Five participants (3%) became seropositive during the study (incident seropositive; Figure 1A ); four (80%) reported COVID-19 symptoms at seroconversion. Most participants (96%, 187/193) received at least one dose of a SARS-CoV-2 mRNA-based vaccine. Antibody measurements after at least one vaccine dose were available for 60% (6/10) of seropositive and 44% (81/183) of seronegative participants. Those who were seropositive at any point developed a two-fold higher antibody response to their first vaccine dose (V1) compared to those who were seronegative (median P/N 13.8 vs. 7.0; p=0.008; Figure 1B) . Additionally, the post-V1 antibody levels in seropositive participants were similar to those of seronegative participants after the second vaccine dose (13.8 vs. 13.2; p=0.768). The magnitude of the increase in antibody levels from pre-vaccination to post-V1 was greater for seropositive than seronegative participants (change in P/N 8.6 vs. 5.4, p=0.14). Our findings provide preliminary evidence that prior SARS-CoV-2 infection may prime the primary vaccination response, corroborating recent non-peer-reviewed findings. 1-3 Specifically, we observed that the response to one vaccine dose among seropositive individuals was of similar magnitude to that of seronegative individuals to two vaccine doses. Additionally, our results suggest that the magnitude of the increase in antibody levels in response to the first dose of vaccine might be larger for seropositive than seronegative individuals. Future research on the durability of response to the first dose of SARS-CoV-2 vaccine among previously infected All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 19, 2021. ; https://doi.org/10.1101/2021.02.09.21251319 doi: medRxiv preprint individuals, and the impact of time between infection and vaccination, will help guide the allocation of the limited supply of mRNA-based vaccines. As 27 million Americans have been infected with SARS-CoV-2 to date, the potential ability for some individuals to forgo a second vaccination may have substantial impact on vaccination distribution strategies. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. We thank the participants for their willingness to contribute to advancing our understanding of the SARS-CoV-2 epidemic and its impact on healthcare personnel, especially during the early and uncertain months of the pandemic. We also appreciate the hard work of the graduate student assistants from the University of North Carolina Gillings School of Global Public Health (Elle Law, BS, Elyse Miller, BA, and Paul Zivich, MPH) and the phlebomists who contributed to the sample collection, protocols, and day-to-day implementation of the study (these individuals received compensation for their work on the study). We acknowledge Premkumar Lakshmanane, PhD who spearheaded development of the ELISA assay and produced and supplied the necessary antigens for the study through funding from the National Cancer Institute [1U54CA260543]. Finally, we thank Subhashini Sellers, MD, MSc and Meghan Rebuli, PhD (University of North Carolina School of Medicine) and Bailey Fosdick, PhD (Colorado State University Department of Statistics) for their support of this study and its analysis. These contributors did not receive any contribution for their role in the study. The authors report no conflicts of interest. This project was supported by funds from the following sources: The funding organizations/sponsors were not involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 19, 2021. ; https://doi.org/10.1101/2021.02.09.21251319 doi: medRxiv preprint Table 1 . Demographics, serostatus, and vaccinations for the entire cohort and the sub-sample with paired pre-and post-vaccination antibody measurements. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 19, 2021. ; https://doi.org/10.1101/2021.02.09.21251319 doi: medRxiv preprint Figure 1 . Antibody levels of healthcare personnel over time (A) and in response to vaccination (B). Panel A demonstrates the change in antibody levels over time in SARS-CoV-2 seronegative and seropositive individuals, including those who were seropositive at the time of enrollment (prevalent seropositive) and those who became seropositive over the study period (incident seropositive). The dotted grey line represents a P/N ratio of 2.57, which is the ELISA cut-off associated with 99.5% specificity (SARS-CoV-2 Ig-positive above the line, Ig-negative below). The x-axis represents the number of days to vaccination, and values occurring after day 0 represent the antibody response post-vaccine dose 1. Panel B shows box plots with the median and interquartile range of P/N ratios for pre-vaccination, post-vaccine dose 1, and postvaccine dose 2 by serostatus. The upper whisker extends to the largest value no further than 1.5 * IQR from the hinge. The lower whisker extends to the smallest value at most 1.5 * IQR of the hinge. Data beyond the end of the whiskers are outliers. Seronegative (n(-)) individuals are shown as circles and seropositive (n(+)) individuals as triangles with grey and light blue lines connecting participants over time. For the pre-vaccine time point, the most recent antibody level prior to vaccination (for those who were vaccinated) or most recent antibody level overall (for those who were not vaccinated) is shown. The black numbers next to the triangles in the Post Dose 1 plot indicate the number of days between vaccination and blood sample collection for seropositive individuals (median 9, range 6-20). For seronegative participants, the median time between the first vaccine dose and sample collection was 16 days (range 1 to 34 days). All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 19, 2021. ; https://doi.org/10.1101/2021.02.09.21251319 doi: medRxiv preprint All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted February 19, 2021. ; https://doi.org/10.1101/2021.02.09.21251319 doi: medRxiv preprint Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine. medRxiv Single dose vaccination in healthcare workers previously infected with SARS-CoV-2. medRxiv Antibody responses boosted in seropositive healthcare workers after single dose of SARS-CoV-2 mRNA vaccine. medRxiv Interim Clinical Considerations for Use of mRNA COVID-19 Vaccines SARS-CoV-2 infection in healthcare personnel and their household contacts at a tertiary academic medical center: Protocol for a longitudinal cohort study (preprint). JMIR Preprints Interim Guidelines for COVID-19 Antibody Testing The receptor binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients