key: cord-0283668-ohp80e25
authors: Marconato, M.; Abela, I. A.; Hauser, A.; Schwarzmueller, M.; Katzensteiner, R.; Braun, D. L.; Epp, S.; Audige, A.; Weber, J.; Rusert, P.; Schindler, E.; Pasin, C.; West, E.; Boeni, J.; Kufner, V.; Huber, M.; Zaheri, M.; Schmutz, S.; Frey, B. M.; Kouyos, R. D.; Gunthard, H. F.; Manz, M. G.; Trkola, A.
title: Contribution of endogenous and exogenous antibodies to clearance of SARS-CoV-2 during convalescent plasma therapy
date: 2021-12-11
journal: nan
DOI: 10.1101/2021.12.09.21267513
sha: b0b86bc01674196884195147ceb028d87d21cbb1
doc_id: 283668
cord_uid: ohp80e25

Abstract Neutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The ability of antibody-based therapies, including convalescent plasma, to affect established disease remains to be elucidated. Only few monoclonal therapies and only when used at a very early stage of infection have shown efficacy. Here, we conducted a proof-of-principle study of convalescent plasma therapy in a phase I trial in 30 COVID-19 patients including immunocompromised individuals hospitalized early after onset of symptoms. A comprehensive longitudinal monitoring of the virologic, serologic, and disease status of recipients in conjunction with detailed post-hoc seroprofiling of transfused convalescent plasma, allowed deciphering of parameters on which plasma therapy efficacy depends. Plasma therapy was safe and had a significant effect on viral clearance depending on neutralizing and spike SARS-CoV-2 antibody levels in the supplied convalescent plasma. Endogenous immunity had strong effects on virus control. Lack of endogenous neutralizing activity at baseline was associated with a higher risk of systemic viremia. The onset of endogenous neutralization had a noticeable effect on viral clearance but, importantly, even after adjusting for their endogenous neutralization status recipients benefitted from therapy with high neutralizing antibody containing plasma. In summary, our data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia in the early stages of infection and provide directions for improved efficacy evaluation of current and future SARS-CoV-2 therapies beyond antibody-based interventions. Incorporating an assessment of the endogenous immune response and its dynamic interplay with viral production is critical for determining therapeutic effects.

Neutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines.

The ability of antibody-based therapies, including convalescent plasma, to affect established disease 26 remains to be elucidated. Only few monoclonal therapies and only when used at a very early stage of 27 infection have shown efficacy. Here, we conducted a proof-of-principle study of convalescent plasma perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint

Proof-of-principle study design

To investigate the potential of convalescent plasma therapy, we conducted a non-randomized, open-110 label, phase I clinical trial (NCT04869072) that included a comprehensive SARS-CoV-2 antibody 111 profiling of donor plasma alongside a longitudinal monitoring of laboratory and clinical parameters 112 ( Fig.1 A, Table S1 -S4). The aim of this proof-of-principle study was to ascertain safety of plasma therapy 113 (primary outcome) and by extensive monitoring of parameters, to determine which effect transfused 114 SARS-CoV-2 plasma antibodies have on the virological and disease status (secondary outcomes) ( Table   115 S4). Ranked as a first-in-human study by Swiss authorities, the safety focus was a requirement and 116 excluded the formation of a no-treatment group. We accordingly tailored the study to allow a within- 

The study protocol did not specify a threshold for SARS-CoV-2 serum antibodies in donor plasma for 122 several reasons. At the time of study initiation, April 2020, the role of protective, neutralizing 123 antibodies had not been ascertained and validated serology and neutralization tests were not yet 124 available. Setting arbitrary thresholds for SARS-CoV-2 reactivity without knowing relevant protective 125 levels was thus considered as problematic, as if wrongly set, this may limit the potential to retrieve 126 information on the therapeutic effect of SARS-CoV-2 antibodies. The study design thus allowed for 127 inclusion of plasma donors without prior screening for SARS-CoV-2 antibody levels. This ascertained 6 During the trial period, mostly SARS-CoV-2 lineages derived from B. 

The key outcome measured across current SARS-CoV-2 convalescent plasma trials is mortality, 161 assessed 3-4 weeks post transfusion (23, 24, 42). In our trial, one patient (Pat 15, Table S5 ) suffering 162 from chronic lymphocytic leukemia died from bacterial, hospital acquired pneumonia by day 12. No 163 other deaths occurred by study completion, resulting in an overall mortality rate of 3.3% (Table S7) 164 within 72 days after study enrolment.

While decreasing mortality in COVID-19 is the ultimate goal, we sought to further include outcome 166 measures that allow a gradual assessment of disease progression and cure. To this end we 167 longitudinally assessed patient's health status by a seven-category ordinal scale for pulmonary 168 function as described (43, 44). The function score improved gradually, with 25/30 (83%) patients 169 reaching full pulmonary function by study completion (Fig. 1B, Table S8 ). Median duration of 170 hospitalization was 8 days (IQR: 6-13). Only two participants required intensive care over the trial 171 period and needed mechanical ventilation (Fig. 1B , Table S5 and S7) . Notably, we observed overall a 172 rapid improvement in respiratory rate, oxygen saturation and body temperature at day 9 since first 173 convalescent plasma unit, i.e. one week after the last plasma dose (Fig. S1A , Table S9 ). Laboratory 174 markers of inflammation progressively improved and were within the reference values at study 175 completion (day 72, 10 weeks post transfusion) for the majority of participants (Fig. S1B ). C-reactive 7 patients with COVID-19 and is associated with subsequent thromboembolic events and severe 179 outcomes (45-49). Notably, fibrinogen was elevated at baseline in all patients but was already 180 significantly decreased by day 4 (p= 0.0062, paired t-test), whereas D-Dimer levels were elevated only 181 in a fraction of participants (21/28, 75%) and remained at comparable levels throughout.

To monitor virological improvement, we measured SARS-CoV-2 viral load in blood and nasopharyngeal 183 swabs (NPS) (Fig. 1C-D) . Median log10 baseline viral load in NPS was 4.5 (IQR: 3.9-5.2), with 16 184 individuals presenting with measurable SARS-CoV-2 viremia in plasma. Viral load in both specimens 185 rapidly decreased in line with the normalization of clinical parameters (Fig. 1C-D) .

Antibody profiling of SARS-CoV-2 convalescent plasma 188 During the study, a total of 105 plasma donations were collected from convalescent male donors to 189 ascertain the availability of AB0 compatible plasma ( Fig. 2A , Table S10 ). Post-hoc analysis of the SARS- high-and low-titer plasma were found to be very comparable (Table 1) perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint measurement and adjusted for two recipient baseline parameters. We adjusted for viral load 215 (measured in NPS) because higher viral loads are likely to require longer to clear. We also considered 216 that viral clearance was mediated by both, the patient's endogenous immune response and the 217 supplied convalescent plasma. We also adjusted for comorbidities, as several trial participants had 218 underlying diseases that can lead to impaired immune function (Table S5 ). The parametric model 219 including viral load and comorbidity confirmed the effect of convalescent plasma content on viral 220 clearance (adjusted hazard ratio (HR) = 3 [95% confidence interval (CI) 1.1-8.1], p = 0.026, Fig. 3BC ).

Three individuals were incapable of mounting an antibody response to SARS-CoV-2. Excluding these 222 patients in a sensitivity analysis did not alter the result (adjusted hazard ratio (HR) = 2.71 [95% 223 confidence interval (CI) 1.0-7.7], p = 0.046, Fig. S4AB ). Four patients received in addition to 224 convalescent plasma also the antiviral remdesivir, which may equally impact on viral clearance.

Excluding remdesivir treated individuals from the hazard ratio analysis in a further sensitivity 226 verification, we observed an even higher impact of plasma neutralizing activity on viral clearance 227 (adjusted hazard ratio (HR) = 4.8 [95% confidence interval (CI) 1.6-14], p = 0.0056 Fig. S4CD ). Equally, 228 excluding both, remdesivir treated individuals and those incapable of mounting an antibody response 229 (n=6) does not alter the outcome of the analysis (Fig. S4EF ). Based on these analyses, we concluded 230 that high neutralizing activity in convalescent plasma promotes rapid viral clearance.

Considering that most convalescent plasma studies did not measure for neutralizing activity to assess 232 antibody activity in convalescent plasma and instead relied on more readily available serologic assays, Table S12 ). In each of these analyses, we stratified plasma 238 according to the median reactivity into a high-and low-reactivity treatment group and again controlling 239 for remdesivir treatment and immune suppression in sensitivity analyses. Most neutralizing SARS-CoV-240 2 antibodies target the RBD and the receptor-binding motif within the RBD, leaving only a 241 comparatively small fraction of neutralization to S1 trimer-specific, spike N-terminal domain, and spike 242 S2 antibodies (53-59). Accordingly, we initially focused on RBD responses but did not detect a 243 differential effect of plasma on viral clearance when stratifying based on the Elecsys S assay that 244 records binding to RBD (Fig. 4A, Fig. S6 ). This was in stark contrast to reactivities determined by the 245 ABCORA seroprofiling test, where high S1 IgG, IgA, and IgM levels and high RBD IgA levels were perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in This was also evident in our plasma donor cohort (Fig. S8 ). Based on the observed high association of 251 S1 reactivities with viral clearance we selected the composite S1 value comprising IgG, IgA, and IgM S1 252 activity (sum S1), as parameters to be included in further analysis (Fig. 4B ).

We further quantified the effect of plasma therapy on virus decay dynamics using censored regression 254 models. We found that half-lives of virus load in NPS in recipients of high neutralizing plasma were 255 shorter confirming the results from the hazard analysis ( 

Neutralization titers significantly increased in both recipients of high and low neutralization plasma by 285 day 9 since first convalescent plasma unit suggesting that by this time point the measured activity is 286 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint dominated by the endogenous neutralization response and transfused antibodies have a marginal 287 contribution ( Fig. 7A -C). Titers in low NT plasma recipients significantly decreased (p=0.047) by day 70, 288 whereas recipients of high NT plasma overall maintained endogenous activity (p=0.13) (Fig. 7A ).

Neutralization activity increased in immune competent individuals with and without endogenous 290 neutralization activity at baseline over the observation period (Fig.7B) . However, the increase in 291 neutralization activity was significantly higher for individuals that already had neutralizing activity at 292 baseline (p=0.038 at day 9) and these individuals maintained the gained activity longer (p=7.9x10^-3) 293 ( Fig. 7C) . response, is more plausibly explained by the rapid increase in neutralizing activity that we observed 303 between baseline and day 9 of the study (Fig. 6A, Fig. 7BC ). For patients that already have neutralizing 304 antibodies at baseline, viral clearance is already ongoing and their virus loads at baseline need to be 305 interpreted as declining. An increase in the endogenous neutralization response during the trial may 306 thus not change their clearance rate substantially above levels at baseline. In contrast, for patients that 307 mount an endogenous neutralization response only after trial entry, the measured viral clearance will 308 be more notably impacted by the endogenous neutralization activity irrespective of the donor plasma 309 they receive.

Evaluation of the effects of S1 antibody levels in both convalescent plasma and recipients at baseline 311 corroborated the effects of convalescent plasma on viral clearance but not recipients' S1 antibodies, 312 thereby reaffirming the effects of endogenous neutralizing antibodies on viral clearance (Fig. 7E, Fig. 313 S13).

In the present study we demonstrate the capacity of convalescent plasma therapy to induce rapid viral perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint response is not yet fully developed. Several trials with therapeutic SARS-CoV-2 antibody and 322 convalescent plasma that showed efficacy, support this, suggesting that antiviral antibodies may be of 323 most benefit when administered early in the course of infection (11, 12, 17, 42, 43, 60). While reducing 324 mortality is the primary goal of any treatment, the fact that antibody-based therapeutics can be 325 clinically impactful at early disease stages necessitates the measurement of additional outcomes.

Although net effects of plasma treatment on mortality reduction could not be formally verified in the 327 absence of a control group, the low mortality we observed in the trial is nonetheless noteworthy. The 328 average mortality rates for hospitalized COVID-19 cases in the same time period in Switzerland of 9-329 13% were clearly higher (38, 39) allowing to exclude harmful effects of plasma treatment with respect 330 to mortality in our study. Owing to its comparatively small size and specific design, the proof-of- 

The results we present here provide key insights that may explain the apparent disparity of results of 357 All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint

The fact that the convalescent plasma in our study was provided during the build-up phase of the 358 endogenous immunity may have been crucial in deciphering the effect of antibody therapy. Immune 

Antibody treatments need to be carefully evaluated for the absence of disease-exacerbating effects. 

We observed no negative impact of plasma treatment in our study. None of the measured antibody 376 parameters was associated with slowing of viral clearance. The overall mortality rate in the 30 treated 377 participants was low (3.3%) and well below the 9-13% average mortality among hospitalized perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint comparatively small, the absence of transfusion-related adverse events, supports that low volume 394 application together with restriction to male plasma donation should be generally considered to limit 395 adverse events by convalescent plasma therapy.

We consider several factors to be crucial as to why our study showed an effect of convalescent plasma 397 therapy that was not observed in other studies. First, the recipients were at an early stage of infection 398 and received the plasma therapy before the peak of endogenous antibody activity, allowing the 399 passively administered antibodies to exert their effect. Second, the convalescent plasma was not perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

Therefore, no placebo arm was allowed and tolerability was addressed as a primary objective. We (Table S4 ) an extended evaluation of clinical parameters was conducted based on routine 496 diagnostic analyses from chemistry, hematology, immunology, microbiology and virology (Table S3) . perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint 50% effective titer concentrations (EC50) using a four-parameter logistic curve (y=Bottom+(Top-524 Bottom)/(1+10^((logEC50-X)*HillSlope) as described . perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint Statistical analyses were performed in R (Version 4.0.5). Figures were made using the ggplot2 package 559 (79). All reported statistical analyses are of explorative, descriptive nature. We therefore opted not to 560 adjust for multiple testing.

Completion of plasma therapy (day 2, after third dose) was defined as End of Treatment (EOT). To 562 assess benefits of treatment, laboratory and respiratory outcomes were compared between baseline 563 and follow-up visits using a paired t-test. Plasma recipients with missing values either at baseline or 564 after therapy were not considered in this analysis.

Analyzing the difference of clinical, laboratory and immunologic parameters between different groups 566 among recipients (e.g. between recipients receiving plasma with high or low neutralization titers) was 567 done by unpaired t-test. Differences in times to viral clearance according to given subgroups were 568 assessed either by a Kaplan-Meier analysis or by interval-censored survival parametric survival models.

In the Kaplan-Meier analyses time to viral clearance was defined as the first negative PCR test (no Ct 570 or Ct ≥ 45) that was not followed by any positive test.

Our parametric survival model assumed a Gamma-distributed time to clearance and used the last 572 positive and first negative SARS-CoV-2 RT-PCR tests in NPS to define the interval in which the virus was 573 cleared. The difference in time to viral clearance between the two groups was modelled assuming 574 proportional hazard. We adjusted these analyses for two potential confounders: baseline viral load 575 and the presence of any comorbidity. Finally, we determined the impact of the donor plasma on virus 576 decay using censored regression.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint

General 580

Funding: This study was funded via an "Innovation-Pool" project by the University Hospital 581

Zurich and via the "Swiss Red Cross "Glückskette" Corona Funding". perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint 9 (7-11.8) 9 (6-11) 9 (7-12) 0.48 9 (5-11.5) 11 (7.5-11.5) 0.68

Number of days since admission to hospital, median (IQR)

Disease severity score, No. (%) 1 0 (0%) 0 (0%) 0 (0%) 1 0 (0%) 0 (0%) 1 2 14 (47%) 6 (46%) 8 (47%) 1 5 (33%) 9 (60%) 0.27 3 10 (33%) 4 (31%) 6 (35%) 1 6 (40%) 4 (27%) 0.7 4 5 (17%) 2 (15%) 3 (18%) 1 3 (20%) 2 (13%) 1 5 0 (0%) 0 (0%) 0 (0%) 1 0 (0%) 0 (0%) 1 6 1 (3%) 1 (8%) 0 (0%) 0.43 1 (7%) 0 (0%) 1 7 0 (0%) 0 (0%) 0 (0%) 1 0 (0%) 0 (0%) perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

Low and high binding activity for each binding antibody parameter is stratified by the respective 917 median binding reactivity.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint 923 level of binding defined by the ABCORA test sum of S1 SOC values. Low and high sum of S1 binding is 924 stratified by the median binding reactivity. Significance was assessed using a two-sided t-test.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted December 11, 2021. ; https://doi.org/10.1101/2021.12.09.21267513 doi: medRxiv preprint 

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