key: cord-0830336-zh4afl54
authors: Kanji, J. N.; Bailey, A.; Fenton, J.; Ling, S. H.; Rivera, R.; Plitt, S.; Sligl, W. I.; Taylor, S. C.; Turnbull, L.; Tipples, G.; Charlton, C. L.
title: Detection of SARS-CoV-2 antibodies formed in response to the BNT162b2 and mRNA-1237 mRNA vaccine by commercial antibody tests
date: 2021-04-06
journal: nan
DOI: 10.1101/2021.03.30.21254604
sha: b42674e68207706a07024dd482f9f80e61cfdf3b
doc_id: 830336
cord_uid: zh4afl54

PURPOSE With rapid approval of SARS-CoV-2 vaccines, the ability of clinical laboratories to detect vaccine-induced antibodies with available high-throughput commercial assays is unknown. We aimed to determine if commercial serology assays can detect vaccine-induced antibodies (VIAs) and understand the vaccination response. METHODS This cohort study recruited healthcare workers and residents of long-term care facilities (receiving the BNT162b2 and mRNA-1273 products, respectively) who underwent serum collection pre-vaccination (BNT162b2 group), 2-weeks post vaccination (both groups), and pre-2nd dose (both groups). Sera were tested for the presence of SARS-CoV-2 IgG using four commercial assays (Abbott Architect SARS-CoV-2 IgG, Abbott Architect SARS-CoV-2 IgG II Quant, DiaSorin Liaison Trimeric S IgG, and GenScript cPASS) to detect VIAs. Secondary outcomes included description of post-vaccination antibody response and correlation with neutralising titers. RESULTS 225 participants (177 receiving BNT162b2 and 48 receiving mRNA-1273) were included (median age 41 years,; 66-78% female). Nucleocapsid IgG was found in 4.1% and 21.9% of the BNT162b2 (baseline) and mRNA-1273 (2-weeks post first dose). All anti-spike assays detected antibodies post-vaccination, with an average increase of 87.2% (range 73.8-94.3%; BNT162b2), and 25.2% (range 23.8-26.7%; mRNA-1273) between the first and last sampling time points (all p<0.05). Neutralising antibodies were detected at all post-vaccine timepoints for both vaccine arms, with increasing titers over time (all p<0.05). CONCLUSION Anti-spike vaccine-induced SARS-CoV-2 IgG are detectable by commercially available high-throughput assays and increases over time. Prior to second dose of vaccination, neutralising antibodies are detectable in 73-89% of individuals, suggesting the majority of individuals would have some degree of protection from subsequent infection.

To date, the principal utility of SARS-CoV-2 IgG high throughput serology assays has been 83 to conduct seroprevalence studies for large cohorts to aid public health decision-making [1, 84 2] . Until recently, all seroprevalence studies have examined detection of antibodies from 85 natural infection. While most vaccine candidates produced detectable antibody levels on 86 specific serological research assays in early phase trials [3] [4] [5] , it is unclear how currently 87 available high-throughput commercial assays will detect vaccine-induced antibody in the 88 clinical laboratory. In the case of varicella, detection of vaccine-induced antibody is variable 89 among commercial kits compared to detection of antibodies produced from natural infection, 90

which are more robust [6] . 91 92 SARS-CoV-2 neutralization antibodies have been shown to predict disease severity and 93 survival [7] . There is also evidence of their protective capacity in preventing infection in 94 animal models and humans [8] [9] [10] . These data corroborate evidence for neutralising antibody 95 (nAb) protection in numerous viral infections including yellow fever, encephalitis, dengue, 96 mumps, influenza and others [11] . To date, there is little data measuring the level of nAbs 97 pre/post-vaccination for SARS-CoV-2 nor how results compare with vaccine efficacy and 98 protection. 99 100 Currently approved SARS-CoV-2 vaccines in the United States and Canada (BNT162b2 and 101 mRNA-1273 products) consist of lipid nanoparticles formulated nucleoside-modified 102 messenger RNA (mRNA) [12, 13] . Both formulations induce T-cell activation and 103 production of antibodies in response to in vivo production of SARS-CoV-2 spike (S) protein 104 following translation of the synthetic mRNA in human cells [14] . Antibodies against the 105 receptor binding domain (RBD) found in the S1 region of the spike gene [3, 15] , anti-S1 106 protein IgG [14] , as well as neutralising antibody [14, 16] have been detected in response to 107 both vaccines. 108 109 We aimed to evaluate the ability of three commercial SARS-CoV-2 IgG assays and one 110 functional nAb test to detect and quantify antibodies in two separate patient populations 111 receiving their first doses of the BNT162b2 and mRNA-1273 SARS-CoV-2 mRNA vaccines. 112

It was hypothesized that assays targeting non-spike proteins (e.g., nucleocapsid (N) protein) 113 would screen positive only in individuals who previously recovered from natural SARS-114

CoV-2 infection. It was further postulated that there could be a difference between the IgG 115 binding antibody total immune response versus the nAb response to vaccination. 116 117

Participant sample collection 119 Serum samples were collected prospectively from two separate patient groups undergoing 120 COVID-19 vaccination. The first group consisted of healthcare workers (HCWs) who 121 received the BNT162b2 vaccine series while the second group consisted of residents of long-122 term care facilities who received the mRNA-1273 vaccine series. Herein the groups will be 123 referred to as the BNT162b2 and the mRNA-1273 groups, respectively. 124 125 Serum samples in the BNT162b2 group were planned to be drawn at the following 126 approximate time points: (i) at baseline (defined as (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Samples were stored at -20 o C and underwent one freeze-thaw cycle prior to testing. Sera 153 were tested for SARS-CoV-2 IgG using three high-throughput commercial assays: Abbott 154

Architect SARS-CoV-2 IgG (IgG targeting the N-protein; qualitative result only) [18] , 155

Abbott Architect SARS-CoV-2 IgG II Quant (IgG targeting the RBD-region of the S-protein; 156 quantitative result) [18] , and DiaSorin Liaison (trimeric S-protein assay targeting the S1/S2 157 regions of the S-protein; quantitative result) [19] . In addition, we evaluated the presence of 158 SARS-CoV-2 nAbs using the GenScript cPass Neutralisation antibody detection kit (Table  159 S1) [20, 21] . All testing was done according to product inserts and qualitative and 160 quantitative values (where available) were recorded for each assay. Only the assay by 161

GenScript has a claim to detect nAbs. 162

Baseline demographics of all participants were extracted from the provincial electronic 165 medical record (EMR) ( Table S1 ). Continuous variables were compared using Mann-166 Whitney tests while categorical variables were compared using Chi-square or Fisher's exact 167 tests. All statistical analysis and graphing were done using Stata version 16.1 (Table S1) IgG directed towards the SARS-CoV-2 N-protein was found in 3.6-5.4% and 18.9-21.9% of 186 the BNT162b2 and mRNA-1273 groups, respectively ( Fig. 1) . Over the course of the blood 187 sampling times in each group, the positivity rate for anti-N IgG detection did not change 188 significantly from the baseline to pre-2 nd dose sample (p=0.86; BNT162b2 group) and from 189 the 2-week and pre-2 nd dose samples (p=0.76; mRNA-1273 group) in either group. 190

In the BNT162b2 group, all four participants who were COVID-19 recovered prior to their 191 first dose had a detectable anti-N IgG (Table S2) (Table S3 ) with no detectable anti-N IgG in 44.4% (4/9) participants just 195 prior to receiving their 2 nd vaccine dose. 196

197

The antibody positivity rate for all three S-protein based commercial assays (RBD IgG, 199 Trimeric S IgG, and GenScript nAb) increased on average by 87.2% (range 73.8-94.3%) 200 between baseline and the 2-week samples in the BNT162b2 group, reaching levels of >88% 201 positivity (p<0.0001 for each assay) just prior to the second vaccine dose (Fig. 1) . Similarly, 202 large positivity increases between 23.8 and 26.7% were observed between the 2-week post-203 first dose and pre-2 nd dose time points in the mRNA-1273 group with overall increases of 204 >50% and >70% positivity at the two time points respectively, p<0.05 for all comparisons 205 (Table 2 ). For both time points and with both vaccines the number of participants who were 206 positive for nAbs was significantly lower than those who were positive for IgG binding 207 antibodies by a factor of 10% to 20% (Fig. 1) . 208 209 Quantifiable titers of antibodies detected by each assay were detectable at all time points and 210 increased significantly over time in both vaccine groups (Table 2 and Fig. 2 ). In the 211 BNT162b2 group, titers increased by 1.8, 1.2, and 1.8-fold for the RBD IgG, Trimeric S IgG, 212

and GenScript nAb assays respectively, from the 2-week blood sampling to the samples 213 drawn just prior to the participants' 2 nd dose (with a median number of 11 days between 214 blood draws). Higher-fold titer increases (3.5, 4.1, and 4.5-fold respectively) were seen in the 215 mRNA-1273 participants between blood sampling at similar time points (p=0.06 for RBD 216 IgG and p<0.05 for Trimeric S IgG and nAb assays) (median seven days between blood 217 draws) ( Table 2 Quantitative titres in the mRNA-1273 group were found to be significantly higher among 222 participants who were COVID-19 recovered compared to those with no history of laboratory-223 confirmed COVID-19 infection (Table S4; In this study, we demonstrate that vaccine-induced antibodies stimulated by FDA approved 239 SARS-CoV-2 mRNA vaccines (BNT162b2 and mRNA-1273) can be detected by commercial 240 high-throughput assays currently used in clinical laboratories. As predicted, detectable 241 antibody was restricted to assays identifying IgG directed against the viral S-protein, and not 242 against the nucleocapsid protein. Anti-spike vaccine-induced antibodies were detectable as 243 early as ten days following the first dose of an mRNA vaccine. Titres increased significantly 244 over the three-week period from baseline sampling to pre-second dose sampling. Vaccine-245 induced nAbs targeting the SARS-CoV-2 spike protein were successfully detected, using a 246 surrogate virus neutralization test (sVNT) kit without the use of cell lines and viral culture 247 required for plaque reduction neutralization assays (PRNT) supporting protective immunity 248 [7, 8, 10, 22] . However, there were significantly less participants with detectable nAbs post-249 vaccination as those with a binding antibody IgG response. 1273 group which did not measure levels from baseline but only from two weeks post 262 vaccination. Given the lack of an international standard, antibody titres can only be directly 263 compared between successive samples measured on the same assay run [25] . However, when 264 samples from participants in the same vaccine group on the same assay were compared, wide 265

IQRs of titre values were observed (Table 2; Fig. S1 ). The observed variation is likely 266 multifactorial, and dependant on history of previous SARS-CoV-2 infection, use of 267 immunosuppressive medications, advanced age, and frailty [26] . There is limited data to 268 conclude whether the differing titres in participants in the same group (classified qualitatively 269 as positive), assay, and time-point of sampling, translates to clinical differences in response to 270 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted April 6, 2021. ; https://doi.org /10.1101 /10. /2021 infection. For other vaccines, such as hepatitis B and varicella, an initial antibody response 271 following first vaccine dose generally translates into protection from subsequent infection 272 [27, 28] . However, protection is derived from both humoral and cell-mediated responses, of 273 which only humoral is detected by the commercial high throughput EIAs [27, 28] . 274

For other viral infections including SARS-CoV-2, there is significant evidence that nAbs are 276 correlated to protection and immunity [7, 11] . Animal challenge studies have provided 277 conclusive evidence for nAb protection to SARS-CoV-2 [22] . nAbs have also been 278 successfully tested in humans to treat the disease [29] . When comparing the prevalence of 279 neutralising and IgG antibodies from SARS-CoV-2 infected and recovered individuals, the 280 prevalence of nAbs was comparable to IgG binding antibodies and to gold standard PRNT 281

[30]. However, we found a significantly lower fraction of participants elicited protective 282 nAbs compared to those with IgG antibodies. A potential explanation is RBD IgG and 283 trimeric S IgG assays measure total binding antibodies, but are unable to differentiate 284 between nAbs and non-nAbs that also bind to the S-protein [31] . Several studies comparing 285 surrogate nAb assays to traditional methods (PRNT) have found them to be effective proxies 286 for detection and quantification of immunodominant nAbs seen in SARS-CoV-2 infection, 287 specifically RBD-targeting nAbs [21, 31] [32] . Encouragingly, at the final study blood draw 288 (pre-second vaccination dose), nAbs were detectable in 73-89% of samples tested from both 289 vaccine groups. Although the prevalence of nAbs remained significantly lower than total 290 binding IgG's, the data support that the majority of individuals would have at least some 291 protection from subsequent infection prior to the second dose, particularly as detection of 292 nAbs has been previously correlated with vaccine efficacy [33, 34] . However, these data 293 underline a cautionary note in that up to 27% of vaccinated individuals did not have 294 All rights reserved. No reuse allowed without permission.

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protective nAbs prior to the second dose and should remain vigilant in exercising protective 295 public health measures to limit viral spread. 296

In a post-COVID-19-vaccination era, it may not be necessary to differentiate between 298 vaccine induced antibody responses and natural infection. Although we found, at baseline, a 299 number of COVID-19 recovered participants had detectable anti-N IgG (which would 300 confirm previous infection), 30% were undetectable by the pre-second dose blood draw 301 (Table S2 and Table S3 ). This may be due to a number of factors including, the severity of 302 the initial SARS-CoV-2 infection [35] , the specific anti-N IgG assay used [36] , the natural 303 decline of N antibodies overtime [37], or possible immune modulation from the vaccine, 304

where the abundance of antibodies produced switched from anti-N following natural 305 infection to anti-S antibodies following vaccination. 306

To effectively compare antibody titres (across vaccine groups and assays), a quantitative 308 reference standard and a robust correlation with nAbs is needed for commercial assays to 309 accurately assess the effectiveness of vaccine responses. It will be important for clinical 310 laboratories to identify that vaccine induced antibodies can be detected for each vaccine, and 311 work with public health partners to understand the best use for serological testing. Current 312 guidelines [38, 39] do not recommend clinical serology testing pre or post-vaccination, 313 however these recommendations may change over time with more study. A further 314 understanding of the population-based efficacy and longevity is required to structure 315 recommendations for individualized post-vaccine serology testing in clinical decision 316 making. 317 318 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted April 6, 2021. ; https://doi.org /10.1101 /10. /2021 Although sample sizes were low, we observed in the mRNA-1273 group that vaccine-319 induced antibody responses titres of all three quantitative assays were significantly higher at 320 all time points in participants who recovered from confirmed COVID-19 infection (Table  321 S4). Similar findings have been reported from several other research groups where post-322 vaccination titres were 10-20 times higher in COVID-19 recovered individuals [40, 41] . 323 Furthermore, the responses prior to the second dose of vaccine in COVID-19 recovered 324 participants also exceeded the titres of those from the SARS-CoV-2 naïve participants by fold. This has led to early recommendations by some governments to consider providing 326 only a one-dose primary series in COVID-19 recovered individuals [42] . 327

For the four participants on immune suppressive treatment who were not previously SARS-329

CoV-2 infected, a marked difference between nAb and IgG response to vaccination was 330 observed. Although the participants in this group all produced measurable IgG's two weeks 331 after receiving the first vaccine dose, only two gave measurable nAb levels and the remaining 332 two were just above the detection limit. These data underline the importance of assuring 333 immune protection to SARS-CoV-2 in this highly susceptible subpopulation of 334 immunocompromised individuals. 335

The principal limitation in our findings is that they only demonstrate the production of 337 vaccine-induced antibodies in response to mRNA COVID-19 vaccines and their 338 quantification. Correlations of specific titre levels to protection or vaccine efficacy cannot be 339 made as the study is not designed or powered for this purpose. As the BNT162b2 and 340 mRNA-1273 vaccines are different products, it is difficult to comment on the difference in 341 median titres seen for the same time points on the same assay (which was observed in general 342 to be lower in the mRNA-1273 group, despite a higher proportion of COVID-19 recovered 343 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted April 6, 2021. ; https://doi.org /10.1101 /10. /2021 individuals). This may reflect differing median ages of the two groups or alternatively be 344 reflective of responses to varying vaccine products which is an artifact that could be corrected 345 with an international standard for COVID-19 serology. 346

Conclusions 348

We have shown that currently available commercial assays for detection of anti-spike IgG 349 binding antibodies were successfully able to detect vaccine induced antibodies in the vast 350 majority of vaccinated participants. In general, anti-spike IgG binding antibody titers 351 increased overtime, while anti-nucleocapsid antibodies declined. There was a marked 352 difference in the proportion of participants eliciting protective nAbs for both vaccines and at 353 all time points after the first dose underlining the difference between a general binding IgG 354 and a functional neutralising response correlating to protection. Just prior to the second dose 355 of vaccination, most samples had detectable neutralising antibodies. However, a significant 356 subpopulation did not produce nAbs which underlines the importance of the continued 357 practice of SARS-CoV-2 infection preventive measures after the first vaccine dose at least for 358 those individuals with no detectable levels of nAbs. 359 All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted April 6, 2021. ; https://doi.org /10.1101 /10. /2021 This work did not receive any specific grant from funding agencies in the public, commercial, 377 or not-for-profit sectors, however testing kits were provided in-kind by all manufactures. 378 379

The datasets used and/or analysed during the current study are available from the 381 corresponding author on reasonable request. 382 383 All rights reserved. No reuse allowed without permission.

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Authors methodology, validation, analysis, data curation, project 385 administration, Ashley Bailey -validation, investigation, data curation, writing -review and editing 387 Jayne Fenton -investigation, data curation, writing -review and editing 388

Sean H Ling -investigation, data curation, project administration, writing -review and 389 editing 390

Rafael Rivera -data curation, formal analysis, writing -review and editing 391

Sabrina Plitt -data curation, formal analysis, project administration, writing -review and 392 All authors attest they meet the ICMJE criteria for authorship. 407

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The copyright holder for this preprint this version posted April 6, 2021. ; b Between both groups, five participants were considered immunosuppressed. In the BNT162b2 group, four participants were using biologics (adalimumab, daratumumab/bortezomib, dupilumab, infliximab) for ankylosing spondylitis (n=1), relapsed/refractory multiple myeloma (n=1), atopic dermatitis (n=1), and inflammatory bowel disease (n=1). One participant in the mRNA-1273 group used methotrexate for rheumatoid arthritis. Dupilumab is considered to have a low potential for immunosuppression.

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The copyright holder for this preprint this version posted April 6, 2021. ; https://doi.org /10.1101 /10. /2021 c All p-values comparing baseline to pre-2 nd dose (BNT162b2) vaccine were <0.0001, except for nucleocapsid IgG (p=1.0). d 2-weeks versus pre-2 nd dose comparison (mRNA-1273): p=NS (Nucleocapsid IgG); p<0.01 (RBD IgG); p<0.05 (Trimeric S IgG and nAb assays).

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The copyright holder for this preprint this version posted April 6, 2021. ; https://doi.org /10.1101/2021.03.30.21254604 doi: medRxiv preprint e Figure 2 . Quantitative testing results from time of first vaccine dose for each vaccine group using the nAb assay (panels a and b); Trimeric S IgG assay (panel c); and RBD IgG assay (panels d and e). Panel (b) presents panel (a) results with y-axis limited to maximum titer of 6000 ng/mL. Panel (e) presents panel (d) results with a shortened y-axis (max titer 5000 AU/mL). All rights reserved. No reuse allowed without permission.

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According to product insert, titers <13 AU/mL (negative) and