key: cord-0303121-f0m9s902 authors: Havervall, S.; Marking, U.; Greilert-Norin, N.; Gordon, M.; Ng, H.; Christ, W.; Blom, K.; Phillipson, M.; Nilsson, P.; Hober, S.; Klingstrom, J.; Mangsbo, S.; Aberg, M.; Thalin, C. title: Impact of SARS-CoV-2 infection on longitudinal vaccine immune responses date: 2021-10-19 journal: nan DOI: 10.1101/2021.10.16.21264948 sha: 39d512b8b91e3372e48dca0877b31f99d0753094 doc_id: 303121 cord_uid: f0m9s902 Background Recent serological investigations imply waning immune responses following SARS-CoV-2 vaccination, but prior infection may impact the breadth and duration of vaccine immune responses. Methods Using longitudinally collected blood samples from the COMMUNITY study, we determined binding (WHO BAU/ml) and neutralizing antibody titers against ten SARS-CoV-2 variants over seven months following BNT162b2 in healthcare workers with (n=111) and without (n=298) confirmed prior SARS-CoV-2 infection. A smaller group with (n=47) and without (n=61) confirmed prior SARS-CoV-2 infection receiving ChAdOx1 ncov-19 was followed for three months. Results Vaccination (BNT162b2 and ChAdOx1 ncov-19) following SARS-CoV-2 infection resulted in higher wild-type BAU/ml geometric mean titers (GMTs) at all sampling time points when compared to SARS-CoV-2 naive vaccinees (all p<0.001). GMTs were 1875 BAU/ml in convalescent and 981 BAU/ml in naive BNT162b2 vaccinees 6 weeks post vaccination. 29 weeks post vaccination, GMTs had decreased to 524 BAU/ml in convalescent and 148 BAU/ml in naive vaccinees. GMT differences between convalescents and naive following ChAdOx1 ncov-19 mirrored those after BNT162b2, but the titers were considerably lower. Finally, at all time points, neutralizing antibody titers against all ten tested SARS-CoV-2 variants were at least 2 respectively 3-fold higher in SARS-CoV-2 recovered as compared to naive vaccinees following BNT162b2 and ChAdOx1 ncov-19, respectively (all p<0.001). Conclusions These findings of substantially more robust serological responses to vaccine after natural infection imply that prior infection may be taken into consideration when planning booster doses and design of current and future SARS-CoV-2 vaccine programs. Clinical trials and post marketing effectiveness data have shown that currently used 69 COVID-19 vaccines protect strongly against hospitalization and death in most 70 settings 1-3 . However, real-world efficacy estimates are affected by population 71 demographics, characteristics of circulating SARS-CoV-2 variants, vaccine protocols 72 and time since vaccination. An increased risk of breakthrough infections is now 73 observed, partly explained by immune waning [4] [5] [6] [7] [8] Immunity) study 13, 24, 27, 28 we herein report binding and pseudo-neutralizing antibody 92 titers elicited over seven months following mRNA BNT162b2 (Comirnaty, Pfizer 93 BioNTech) and over three months following adenovirus-vectored ChAdOx1 nCoV-19 94 (Vaxzevria, AstraZeneca) vaccination in 517 healthcare workers (HCW) higher in previously SARS-CoV-2 infected vaccinees compared to SARS-CoV-2 172 naïve vaccinees (all p<0.001). Table 2 and Figure 2A . A decrease of spike IgG GMTs 173 by 2-fold between week 6 and 12, and by 6.6-fold between week 6 and 29 were 174 observed in SARS-CoV-2 naïve BNT162b2 vaccinees. This decrease was not as 175 explicit in vaccinees with SARS-CoV-2 infection prior to vaccination, as GMTs 176 decreased by 1.5-fold between week 6 and 12, and by 3.6-fold between week 6 and 177 It has been reported that a longer interval between BNT162b2 doses can result in 198 higher antibody titres 31 . In this cohort, BNT162b2 vaccinees were administered with 199 a 3-4 week dose interval in January to February 2021, and with a prolonged dose 200 interval of 6-8 weeks in April to July 2021. 201 202 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 October 19, 2021. ; https://doi.org/10.1101/2021.10.16.21264948 doi: medRxiv preprint 12 weeks post second dose, there were no significant differences in spike IgG GMTs 203 following BNT162b2 with the 3-4 week and the 6-8-week dose interval, regardless of 204 prior SARS-CoV-2 infection (all p>0.05). Table 2 GMTs against both the WT and Delta variant were, however, slightly but significantly 206 increased 12 weeks following second dose after the prolonged dose interval 207 (p=0.016 and p=0.017, respectively) in SARS-CoV-2 naïve vaccinees when adjusted 208 for sex and age. A similar trend was seen in SARS-CoV-2 recovered vaccinees, 209 although the differences were not significant (all p>0.05). Table 2 . 210 211 As data following BNT162b2 vaccination displayed an improved long-term immune 214 response in SARS-CoV-2 recovered individuals we also explored this in the context 215 of the ChAdOx1 nCoV-19 vaccine. Spike IgG GMTs in SARS-CoV-2 naïve vaccinees 216 were 4.5-fold lower following ChAdOx1 nCoV-19 as compared to those after 217 BNT162b2 (p<0.001). Similar to what was observed after BNT162b2 vaccination, 218 spike IgG GMTs were substantially increased in SARS-CoV-2 recovered ChAdOx1 219 nCoV-19 vaccinees compared to SARS-CoV-2 naïve vaccinees at all sampling time 220 points (all p<0.001). Table 2 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In light of the substantial increases in antibody titres observed in SARS-CoV-2 248 recovered vaccinees as compared to SARS-CoV-2 naïve vaccinees, we proceeded 249 to determine if SARS-CoV-2 variants contributed differently. Pseudo-neutralizing 250 antibody titres were assessed against ten SARS-CoV-2 variants, including all 251 variants of concern (VOC) (B.1.1.7 (Alpha), B.135.1 (Beta), P.1 (Gamma) and 252 B.1.617.2 (Delta)). Notably, neutralizing antibody titers against all ten tested SARS-253 CoV-2 variants were at least 2 respectively 3-fold higher in SARS-CoV-2 recovered 254 as compared to naïve vaccinees following BNT162b2 and ChAdOx1 nCoV-19, 255 respectively (all p<0.001). Figure 3 A-C and Table S1 . Using a large cohort with longitudinally collected blood samples following SARS-260 COV-2 vaccination, we show that vaccination following SARS-COV-2 infection 261 resulted in remarkably and sustained higher antibody titres with an increased 262 neutralizing potency and breadth against SARS-CoV-2 variants as compared to 263 vaccination in SARS-COV-2 naïve individuals. Furthermore, we reveal a significant 264 decline in BAU/ml and pseudo-neutralizing antibody titres over the first months 265 following both ChAdOx1 nCoV-19 and BNT162b2 vaccination. Direct comparisons 266 showed substantially lower titres following immunization with ChAdOx1 nCoV-19 267 compared to BNT162b2. These findings are important for decisions on booster doses 268 and design of current and future SARS-CoV-2 vaccine programs, as these should be 269 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. CoV-2, binding and pseudo-neutralizing antibody titres correlate inversely with risk of 300 infection 14,34 . Extensive efforts are therefore now invested into establishing the levels 301 at which vaccine-generated antibodies protect against infection, aiming to facilitate 302 rapid licensure of new vaccine platforms, support recommendations for vaccine 303 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 October 19, 2021. ; https://doi.org/10.1101/2021.10.16.21264948 doi: medRxiv preprint boosters and inform public health decisions. One such effort recently presented an 304 80% vaccine efficacy against symptomatic SARS-COV-2 infection at 264 BAU/ml, 305 declining to 60% vaccine efficacy at 54 BAU/ml 35 . These estimates were derived 306 from a cohort vaccinated with the ChAdOx1 nCoV-19 vaccine, but similar levels are 307 shown for mRNA vaccines 36 . Although these correlates require validation in further 308 cohorts, our findings show that antibody titres have declined below these thresholds 309 in a portion of study participants within 3-7 months from the second vaccine dose. (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 October 19, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. CoV-2 infection. A) Binding antibody titers against SARS-CoV-2 wild type over 7 520 months following the second BNT162b2 dose and 3 months following the second 521 ChAdOx1 nCoV-19 dose in SARS-CoV-2 recovered and naïve vaccinees, B) 522 pseudo-neutralizing antibodies against the wild type over 7 months following the 523 second BNT162b2 dose and 3 months following the second ChAdOx1 nCoV-19 dose 524 in SARS-CoV-2 recovered and naïve vaccinees, and C) pseudo-neutralizing 525 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 October 19, 2021. ; https://doi.org/10.1101/2021.10.16.21264948 doi: medRxiv preprint mean titers and bars represent 95 % CI. Solid lines represent SARS-CoV-2 529 recovered vaccinees and dotted lines represent SARS-CoV-2 naïve vaccinees. WT; 530 wild type, BAU; binding antibody units, AU; arbitrary units. 531 532 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 October 19, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 (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 October 19, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Safety and Efficacy of the BNT162b2 mRNA 363 Covid-19 Vaccine Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised 366 controlled trials in Brazil, South Africa, and the UK Safety and Efficacy of the BNT162b2 368 mRNA Covid-19 Vaccine through 6 Months Waning immunity of the BNT162b2 370 vaccine: A nationwide study from Israel Neutralizing antibody levels are highly 396 predictive of immune protection from symptomatic SARS-CoV-2 infection Covid-19 Breakthrough Vaccinated Health Care Workers WHO International Standard for anti-401 SARS-CoV-2 immunoglobulin From vaccines to memory and back mRNA vaccination boosts cross-variant 410 neutralizing antibodies elicited by SARS-CoV-2 infection mRNA vaccine-elicited antibodies to SARS-412 CoV-2 and circulating variants Impact of circulating SARS-CoV-2 variants 414 on mRNA vaccine-induced immunity Antibody responses to the BNT162b2 416 mRNA vaccine in individuals previously infected with SARS-CoV-2 Antibody responses after a single 419 dose of ChAdOx1 nCoV-19 vaccine in healthcare workers previously infected with SARS-420 Thrombotic Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination Myocarditis after Covid-19 Vaccination in a Large 425 SARS-CoV-2 exposure, symptoms and 427 seroprevalence in healthcare workers in Sweden Symptoms and Functional Impairment 429 Assessed 8 Months After Mild COVID-19 Among Health Care Workers Systematic evaluation of SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay Expansion of SARS-CoV-2-Specific Antibody Change in Antibodies to SARS-SARS-CoV-2 naïve SARS-CoV-2 recovered B.1.617.3 (India), P.1 (Gamma), and P.2 (Zeta) variants. 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