ARTICLE https://doi.org/10.1038/s41467-022-29911-3 OPEN Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients Pere Millat-Martinez1,2,62, Arvind Gharbharan3,62, Andrea Alemany1,4,5,62, Casper Rokx 3, Corine Geurtsvankessel 6, Grigorios Papageourgiou7, Nan van Geloven 8, Carlijn Jordans3, Geert Groeneveld9, Francis Swaneveld10, Ellen van der Schoot11, Marc Corbacho-Monné1,5,12, Dan Ouchi 1,13, 1234567890():,; Francini Piccolo Ferreira 14, Pierre Malchair15, Sebastian Videla 1,16,17, Vanesa García García15, Anna Ruiz-Comellas 18,19,20, Anna Ramírez-Morros 18, Joana Rodriguez Codina21, Rosa Amado Simon21, Joan-Ramon Grifols4,22, Julian Blanco 23, Ignacio Blanco 4,24, Jordi Ara4,25, Quique Bassat 2,26,27,28,29, Bonaventura Clotet1,4,20,23, Bàrbara Baro 2, Andrea Troxel30, Jaap Jan Zwaginga31,32,63, Oriol Mitjà1,4,20,33,63, Bart J. A. Rijnders 3,63 ✉, CoV-Early study group* & COnV-ert study group* Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind rando- mized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of recruitment target was achieved. A Bayesian-adaptive individual patient data meta- analysis was implemented. Outpatients aged ≥50 years and symptomatic for ≤7days were included. The intervention consisted of 200–300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667–1.311); OR for hospitalization or death was 0.919 (CI 0.592–1.416). CP effect on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658, 95%CI 0.394–1.085). CP did not decrease the time to full symptom resolution. Trial registration: Clinicaltrials.gov NCT04621123 and NCT04589949. Registration: NCT04621123 and NCT04589949 on https://www.clinicaltrials.gov A full list of author affiliations appears at the end of the paper. NATURE COMMUNICATIONS | (2022)13:2583 | https://doi.org/10.1038/s41467-022-29911-3 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-29911-3 T he unprecedented pace and amount of research on the Board of the Hospital Germans Trias I Pujol (reference PI 20- pathogenesis of severe acute respiratory syndrome cor- 313) and the CoV-Early study received approval from the Insti- onavirus 2 (SARS-CoV-2) led to the availability of tutional Review Board of the Erasmus Medical Center Rotterdam mortality-reducing therapies within a year after the start of the (reference MEC-2020-0682). Briefly, the COnV-ert study ran- coronavirus disease 2019 (COVID-19) pandemic1–3. For non- domized outpatients at 4 sites in Catalunya (Spain) aged ≥50 hospitalized COVID-19 patients, only anti-SARS-CoV-2 mono- years with ≤7 days of symptoms to one unit (200–300 mL) of CP clonal antibodies have emerged as a treatment that reduces or sterile 0.9% saline solution, both covered with opaque tubular hospital admission but only when given in the first week of ill- bags for blinding investigators and patients. The COnV-ert study ness. However, they are typically unavailable to middle and low- joined the consortium when 65 of 474 planned patients were income countries4–7. enrolled. CoV-Early enrolled outpatients at 10 sites aged ≥50 Convalescent plasma (CP) from COVID-19 recovered patients years with ≤7 days of symptoms and at least one additional risk contains polyclonal anti-SARS-CoV-2 antibodies, can be collected factor for severe COVID-19 to receive either one unit (300 mL) of in large quantities at relatively low costs and was used as a CP or non-convalescent plasma (donated before 01/2020) masked therapeutic strategy in previous viral outbreaks8,9. So far, ran- to investigators and patients. It had randomized 150 of the 690 domized trials were unable to generate convincing evidence in planned patients when they joined the consortium. Details about support of CP for hospitalized patients with COVID-1910–18. the allocation concealment, blinding and selection of CP donors However, because an autologous SARS-CoV-2 antibody response in both trials can be found in Supplementary Table 2 and the typically precedes hospital admission, CP is more likely to be study protocols. beneficial when it is administered very early after symptom The COnV-ert study selected the CP after being screened for onset19. Indeed, the only evidence from a randomized trial in high anti-SARS-CoV-2 IgG titers with ELISA (EUROIMMUN favor of CP for COVID-19 comes from a small study in which ratio ≥6), according to guidelines, and supplied by the regional elderly outpatients received CP in the first 72 h after symptom blood bank (Banc de Sang i Teixits de Catalunya—BST); and the onset20. In a more recent trial, CP did not reduce the risk of CoV-Early study selected the convalescent plasma based on a disease progression of COVID-19 in patients with early disease plaque reduction neutralization test (PRNT) 50 titer of 1:160 or (≤7 days). However, in this trial, patients were recruited at higher. The two trials used a different assay to measure the titer of emergency rooms and were, therefore, more likely to manifest SARS-CoV-2 neutralizing antibodies. Therefore, a panel of 15 severe symptoms21. This approach resulted in a trial profile of plasma samples was provided for comparison by the Support-E patients with moderate or late-stage disease, opposed to what was consortium, aimed at harmonizing CP evaluation in Europe23. intended in the design. Hence, whether early treatment with CP These results confirmed the linearity of both assays and allowed improves the outcome of outpatients with COVID-19 remains an conversion of all neutralizing antibody titers into international important question. units (IU/mL). The median neutralizing antibody titer in the As soon as effective vaccines against COVID-19 became plasma units was 1:386 (IQR 1:233–1:707) IU/mL, which is twice available in high-income countries, they were prioritized for the median titer we previously observed in Dutch CP donors19. individuals at higher risk for a poorer COVID-19 outcome. More details are described in the online Supplementary Data Because studies on CP for outpatients with COVID-19 focus on (page 13), in Supplementary Tables 1, 2 and in the individual these high-risk populations as well, a high vaccination uptake will study protocols. reduce the number of COVID-19 patients eligible for these stu- dies. More importantly, the risk for a severe outcome will be small when patients become infected despite vaccination. Therefore, we Study patients and recruitment. Between November 2020 and anticipated that vaccination would slow down recruitment, July 2021, the CoV-Early and COnV-ert study teams contacted reduce the number of events in the recruited patients and result approximately 4450 outpatients with a positive SARS-CoV-2 PCR in individual studies being underpowered. In light of the uncer- or an antigen test. The majority of exclusions occurred for one of tainty for achieving recruitment goals, real-time pooling of the following reasons: few remaining or clearly improving individual patient data from ongoing clinical trials was proposed symptoms, no comorbidities, >7 days of symptoms, unable to as a tool for providing timely data to respond to the public health come to study site or declined to participate. The online sup- crisis22. With this in mind, we initiated the COntinuous Mon- plement provides more information about the recruitment pro- itoring of Pooled International trials of convaLEscent plasma for cedures of each trial. COVID-19 patients at home Consortium (COMPILEhome), which The rapid uptake of COVID-19 vaccination in Europe, which provided a platform to pool individual patient data continuously significantly affected recruitment rate in both studies (Supple- and in real-time from randomized clinical trials (RCTs) on CP for mentary Fig. 2) and the authorization of specific anti-SARS-CoV- outpatients with COVID-1922. This COMPILEhome consortium 2 monoclonal antibodies for high-risk outpatients resulted in prospectively pooled and monitored the data from 2 double-blind early trial termination (COnV-ert on 8th of June and CoV-Early RCTs, the CoV-Early (NCT04589949) and the COnV-ert on 13th of July 2021) following recommendations of their (NCT04621123) studies, to assess the effectiveness of high-titer DSMBs. By that time, 797 participants had been enrolled and 782 CP for COVID-19 outpatients. of them had received the allocated intervention and could be pooled for the analysis (Fig. 1). Results Patients included in the analysis had a median age of 58 years Trials profile. The search for trials resulted in 35 identified stu- (IQR 53–64), a median of 5 days (IQR 4–6) from symptom onset, dies, thirty-one of which did not meet the selection criteria of the and a median of 1 comorbidity (IQR 0-2). According to the consortium (Supplementary Fig. 1). Of the four remaining stu- baseline assessment, 688 patients (93%) had a negative result for dies, one study team opted to abstain from pooling data while serum IgG anti-SARS-CoV-2 S-protein, and 21 had completed another never responded to repeated emails and calls, resulting in their COVID-19 vaccination. 14 participants had received one of two trials included in the pooled analysis: The COnV-ert study 2 doses of a mRNA vaccine at the time of inclusion. Baseline (NCT04621123) and the CoV-Early study (NCT04589949). The characteristics were comparable between both study arms COnV-ert study received approval from the Institutional Review (Table 1). 2 NATURE COMMUNICATIONS | (2022)13:2583 | https://doi.org/10.1038/s41467-022-29911-3 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-29911-3 ARTICLE Fig. 1 CONSORT flow diagram. Figure shows the CONSORT flow diagram of the COMPILEhome patients. 833 patients were screened at a study site and 782 were included for analysis. Table 1 Baseline characteristics. Characteristic Total CPa Control (n = 782) (n = 390) (n = 392) Male sex—no. (%) 522 (66.8%) 267 (68.5%) 255 (65.1%) Age—median (IQR) 58 (53–64) 58 (53–64) 58 (54–65) 50–60 y 428 222 206 61–70 y 217 103 114 >70 y 82 36 46 O2 saturation—median (IQR)b 97 (96–98) 97 (96–98) 97 (96–98) Severe immunodeficiency—no. (%) 13 (1.7%) 5 (1.3%) 8 (2.1%) Number of comorbidities—median (IQR)c 1 (0–2) 1 (0–2) 1 (0–2) 0 225 111 114 1 349 171 178 2–3 192 100 92 >3 15 7 8 Days since first symptoms—median (IQR) 5 (4–6) 5 (4–6) 5 (4–6) Positive antibody status at baseline—no. (%) 53 (7.0%) 28 (7.7%) 24 (6.4%) aConvalescent plasma. bBaseline oxygen saturation without supplementary oxygen. cObesity, cardiac disease, lung disease, neurological disease, diabetes, chronic renal failure, cancer and/or liver disease. See the Supplementary Appendix for additional details of the comorbidities. Primary endpoints. Table 2 and Fig. 2 show the distribution of death occurred in 34 of 390 (8.7%) patients treated with CP and patients across the five categories of the disease severity scale. The in 40 of 392 (10.2%) patients in the control arm with an OR of overall estimated OR for patients treated with CP was 0.936 0.919 (posterior mean, 95% credible interval 0.592–1.416) and a (posterior mean, 95% credible interval 0.667–1.311) with a 64.9% 64.3% posterior probability of benefit. Although being included in posterior probability of benefit (OR <1). Hospital admission or the COnV-ert trial was associated with a poorer overall outcome, NATURE COMMUNICATIONS | (2022)13:2583 | https://doi.org/10.1038/s41467-022-29911-3 | www.nature.com/naturecommunications 3 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-29911-3 Table 2 Distribution of the outcome of the patients in the 28 days after inclusion across the 5-points disease severity scale. Worst disease severity score Total CPa Control (n = 782) (n = 390) (n = 392) Recovered before day 8 after transfusion—no. (%)b 143 (18.3%) 74 (19.0%) 69 (17.6%) Continued symptoms after day 7—no. (%)c 565 (72.3%) 282 (72.3%) 283 (72.2%) Admitted to hospital but no invasive ventilation needed—no. (%) 65 (8.3%) 31 (7.9%) 34 (8.7%) Admitted to hospital and invasive ventilation needed—no. (%) 6 (0.8%) 2 (0.5%) 4 (1.0%) Death—no. (%) 3 (0.4%) 1 (0.3%) 2 (0.5%) aConvalescent plasma. bRecovered with no symptoms related to COVID-19 within 7 days after inclusion. cContinued symptoms attributable to COVID-19. CP 74 282 31 3 Control 69 283 34 6 Number of Patients Recovered before day 8 after transfusion Admitted to hospital and invasive ventilation or Death Continued symptoms after day 7 Admitted to hospital but no invasive ventilation needed Fig. 2 Distribution for COVID-19 severity at 28 days. CP Convalescent plasma. Figure shows the distribution of the outcome of the patients in the 28 days after inclusion across the 5-point disease severity scale: 1 = recovered before day 8 after transfusion, 2 = continued symptoms after day 7, 3 = hospital admission, 4 = invasive ventilation, 5 = death. Moving from lighter to darker shading represents increasing scores on the severity scale. The darker shade includes point 4 and 5 of the scale (invasive ventilation or death). the effect of CP was similar in both trials. This increased risk for observed when patients with IgG anti-SARS-CoV-2 antibodies patients in COnV-ert was independent of age, sex, and the detected at baseline were excluded (OR 0.880, 95% CI number of comorbidities. The results of all covariates included in 0.590–1.310 for the binary outcome, OR 0.892, 95% CI the primary analysis can be found in the online supplement 0.643–1.236 for ordinal outcome, Supplementary Figs. 7, 8). (Supplementary Figs. 5, 6). Safety. The intervention was well-tolerated. 89 serious adverse Secondary endpoints. No differences between CP and control events (SAE) were reported, 4 were considered related to the patients regarding time to complete resolution of COVID-19 plasma transfusion (3 in the control arm). Three patients could symptoms was seen (log-rank p = 0.66, Fig. 3). The effect size of leave the hospital <24 h after transfusion while the fourth was CP on the binary outcome of hospital admission or death was hospitalized for 5 days 1 week after the CP transfusion and larger in patients with ≤5 days of symptoms (OR 0.658, 95% CI diagnosed with thrombophlebitis at the infusion site and a pul- 0.394-1.085) compared to those with >5 days (OR 1.427, 95% CI monary embolism (Table 3). 0.789–2.580) and comparable results were observed for the ordinal outcome (OR 0.720, 95% CI 0.486–1.064 in the early Discussion treated group, Supplementary Figs. 7, 8). In this analysis of 782 patients with COVID-19 randomized to Finally, the ORs for patients who received CP with neutralizing high-titer CP or placebo within 7 days of disease onset, treatment antibody titers above or below the median titer were nearly with CP did not prevent COVID-19 progression, hospitalization, identical (Supplementary Fig. 9). Also, no notable difference was or other clinical outcomes. Our results agree with those by Korley 4 NATURE COMMUNICATIONS | (2022)13:2583 | https://doi.org/10.1038/s41467-022-29911-3 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-29911-3 ARTICLE Treatment arm + Control + CP 1.00 Probability of full symptom resolution 0.75 + + 0.50 Log−rank 0.25 p = 0.66 0.00 0 14 28 Days since randomization Number at risk Treatment arm Control 392 211 114 CP 390 217 121 0 14 28 Days since randomization Fig. 3 Time to full symptom resolution up to day 28 (end of follow-up). CP Convalescent plasma. Log-rank test p = 0.66. The dotted error bars represent the 95% CI. Table 3 Serious adverse eventsa. SAE category Total CPb Control (Prolongation of) hospital admission—no.c 80 37 43 Death—no. 3 1 2 Serious transfusion related adverse event—no.d 4 1 3 Life threatening transfusion reaction—no.e 2 0 2 Other AE 2 1 1 aSerious adverse events (SAE) were registered in all patients that signed the informed consent form (n = 797) regardless of being transfused or not. bConvalescent plasma. cWhen a patient is hospitalized more than once, each admission is counted separately. dAny transfusion reaction associated with a plasma transfusion that was considered as a SAE. e2 patients with anaphylaxis very soon after discharge that required urgent therapy by paramedics. et al. in patients of the same age and symptom duration but with patients were SARS-CoV-2 antibody negative at the time of probably more severe symptoms as they were recruited at inclusion confirms that they were recruited in the early stage of emergency rooms in the USA21. These findings differ from those the disease. Pooling of the data from both studies was pre- of a smaller trial that used CP within 72 h of symptom onset in planned and initiated before any interim analyses were performed much older patients (≥75 years)20. We explored signs of efficacy and when both studies were early in their recruitment. Both in various subgroups most likely to benefit from CP. The only teams remained fully blinded as the (interim) analyses were done subgroup in our study that we found that could potentially benefit by an unblinded statistical team that shared the results with the from CP was the subgroup with ≤5 days from the onset of DSMB on a regular basis. The COMPILEhome study used the symptoms (OR 0.70, CI 0.47–1.03). The potential effect of CP same primary endpoint as the CoV-Early trial, and therefore we when administered early after disease onset has been suggested by did not perform a separate sample size calculation. As our other authors24, and could explain the results reported by Libster assumptions about the outcome across the ordinal scale were et al. study20. However, in our study this was a secondary end- somewhat different than anticipated in the original sample size point and the confidence interval was wide, so confirmation in calculation (fewer hospitalizations and deaths in particular), we other studies is needed. Regarding the safety parameters of this repeated the calculation of the effect size that our study was strategy, our study shows no major concerns, with only four SAEs powered for post-hoc. This showed that our study still had 80% related to the plasma infusion; these findings are in line with power to detect an odds ratio of 0.65 for the primary endpoint, those described in previous studies25. very close to the original power calculation. We, therefore, con- Our study has several strengths. It is the largest of its kind, sider our results methodologically sound. studying the effect of CP for high-risk outpatients with COVID- Several limitations should be mentioned. Although we only 19 early after initiation of symptoms. The fact that 93% of all included patients aged ≥50, and most of them also had NATURE COMMUNICATIONS | (2022)13:2583 | https://doi.org/10.1038/s41467-022-29911-3 | www.nature.com/naturecommunications 5 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-29911-3 comorbidities, the hospital admission and death rates were rela- The full COMPILEhome protocol is available as an online supplement. The study tively low at 9.5%. Therefore, the study was not powered to was designed as a Bayesian-adaptive individual patient data meta-analysis of ongoing clinical trials. Prior to the start of pooling, the study teams agreed upon a exclude a small overall treatment effect on these endpoints. minimal set of data required to analyze the primary and secondary endpoints was However, administering CP to infectious and symptomatic out- agreed upon by the study teams. Each trial provided updated data every 6 weeks. patients is complex and labor-intensive. Hence, we think that The pooled data were monitored by 2 unblinded statisticians and a data and safety CP’s clinical role is significantly diminished if unable to establish monitoring board (DSMB) every 6 weeks using a pre-established stopping something greater than “a small effect” because it ceases to be guideline for efficacy. At each interim analysis, a posterior distribution of the treatment effect was estimated. practical. The contribution of the individual comorbidities to COVID-19 risk in our study should be interpreted cautiously Study patients and selection criteria. Although the exact inclusion and exclusion because, owing to the lack of consensus regarding the relative criteria could vary across the trials, all the subjects had to fulfill the following relevance of each of them, we summed them in a non-weighted criteria; (1) Participant of a trial that joined the COMPILEhome consortium, (2) fashion. As vaccination uptake progressed in patients aged 50 or Confirmed COVID-19 diagnosis by a diagnostic PCR or antigen test of <7 days, (3) older and monoclonal antibody-based therapy with proven Neither hospitalized nor at the emergency room department of a hospital before or at the time of randomization, (4) Symptomatic with illness onset ≤7 days at the effectiveness in high-risk outpatients became available, the time of screening for the study defined by a physician with a complete clinical recruitment dropped dramatically as of June 2021. This resulted history, and (5) Age 50 or older. Trials had to be approved by the institutional in the recommendation by the individual and COMPILEhome review boards, and competent authorities of the countries involved, and all patients DSMBs that further enrollment was unlikely to change the results, gave written informed consent. and both studies were discontinued. Regarding the advent of the SARS-CoV-2 variants that may be less susceptible to antibodies Intervention. To qualify for COMPILEhome, participants randomly assigned to the experimental group had to receive an infusion of ABO-compatible CP with high induced by the original SARS-CoV-2 virus or the alpha variant, it antibody titers as determined via a semiquantitative antibody test against the spike is reassuring that >95% of the patients in both countries were protein or a virus neutralization assay. Only trials in which the participants were included at a time when the delta variant was still rare (<5%) masked for the intervention were included. (Supplementary Figs. 3, 4). The last limitation of our study (and all studies on CP for COVID-19 so far) is the lack of a proper Outcomes. Two primary efficacy outcome variables were selected. The first pri- phase 2 dose-finding study. In a recent study, we administered mary endpoint incorporated the speed of recovery as well as the risk of hospital admission, ICU admission or death in a 5-point ordinal scale. It was defined as the 600 mL of CP to 25 SARS-CoV-2 antibody-negative B-cell highest score on a 5-point ordinal disease severity scale within the 28 days after depleted patients diagnosed with COVID-1926. While all ser- randomization. A patient scored 1 if he/she recovered quickly (i.e., fully recovered oconverted immediately after transfusion, the median virus within seven days after transfusion), 2 when continued symptoms attributable to neutralization titer only rose to 1:40. This is 4 times lower than COVID-19 were present on day seven, 3 when admission to a hospital was required at any point within 28 days, 4 when invasive ventilation was required at any point the median titer in immunocompetent convalescent COVID-19 within 28 days, and 5 when the patient had died at any point within 28 days. This patients and up to 100 times lower than titers observed after means that the best outcome (ordinal scale score of 1) is given when a patient is treatment with monoclonal antibodies7,19. Therefore, we postu- fully recovered before day 8 and was never hospitalized nor died in the 28 days late that the range of neutralizing antibody titers present in the after transfusion, while a patient who recovered after day 7 but was never hospi- 200–300 mL of plasma we used may well have been too low. That talized nor died in the 28 days scored a 2 on the scale. The second primary endpoint was the occurrence of hospitalization or death within 28 days. Secondary underdosing may partially explain our findings is also suggested endpoints were time to full symptom resolution (assessed by the blinded study by a study in which human CP with a neutralizing antibody titer team during a telephone contact on day 7, day 14, and day 28) and the safety of CP of 1:320 did not prevent disease in hamsters while a titer of 1:2560 in outpatients with COVID-19. Pre-planned subgroup analyses assessed the effi- did27. Hence, we recommend that any future study on CP for cacy of the 2 primary outcomes in the following subgroups: (1) days since disease onset (1–5 or >5 days), (2) level of neutralizing antibody anti-SARS-CoV-2 titers in COVID-19 should use donors at the upper extreme end of transfused plasma, and (3) Negative serum anti-SARS-CoV-2 IgG status (Trimeric antibody titers (e.g., >1:2560 IU). Although, this was virtually Spike antibody test, Liaison, Diasorin, Saluggia, Italy). impossible in 2020, this should no longer be difficult now as plasma donors recently vaccinated or boosted with a mRNA Statistical analysis. The first primary endpoint was analyzed with a Bayesian SARS-CoV-2 vaccine can be selected. proportional odds model with normally distributed priors. The model included a Last but not least, a recent preprint publication by Sullivan main treatment effect shared among the trials (using a skeptical (i.e., conservative) standard deviation of 0.4), main trial effects (using standard deviation 0.5 for the et al. described the results of the CSSC04 study in which 1181 prior distribution), and trial by treatment interactions (using a standard deviation outpatients received one unit of convalescent or control plasma. of 0.14 for the prior distribution). The following covariates were included with a In this trial, CP lowered the risk of hospital admission or death standard deviation of 0.5 for the prior distribution of their effects: age, sex, number from 6.3 to 2.9%, p = 0.00428. Therefore, the limited impact on of comorbidities (0–9), oxygen saturation at baseline (in %), immunocompromised state (Y/N) and duration of time (in days) since COVID-19 symptom onset hospital admission or death in our study should be interpreted in (Supplementary Table 1). The second primary endpoint was analyzed with a the context of this trial. Bayesian logistic model with a similar specification. In conclusion, treatment of COVID-19 with CP in the first The use of the Bayesian framework and stopping rules enables continuous 7 days after symptom onset did not improve the outcome. Proper monitoring of the accrued data, and allowed for real-time decisions without dose-finding studies should be conducted, preferentially in penalties for multiple data looks associated with the classic frequentist approach. The results of each interim analysis were reported to the unblinded DSMB. The patients with ≤5 days of symptoms before future phase 3 studies process and pre- specified thresholds for efficacy are described in detail in the on CP are initiated. protocol. The full statistical analysis plan is available as an online supplement. The number of studies and patients included in COMPILEhome was not restricted and there was no pre-determined minimum or maximum sample size. Methods The monitoring was planned to continue until the DSMB determined that there was sufficient evidence to recommend stopping the study. This situation could be Overview of study design and research partners. Beginning in November 2020, achieved when the predefined stopping thresholds signaled efficacy or when the we systematically searched for RCTs recruiting outpatients that compared treat- included studies had finished enrollment or any future recruitment was very ment with CP with a blinded or unblinded control arm in the European (https:// unlikely to change the conclusion. www.clinicaltrialsregister.eu/) and American (www.clinicaltrials.gov) trial register. Search terms were convalescent plasma, COVID-19, phase 2 or phase 3, adult, and recruiting or not recruiting. Studies were selected if they were RCTs on outpatients, Ethical approval. The study was reviewed and approved by the institutional review if their inclusion criteria were confined to patients who had symptoms less than boards of the Erasmus University Medical Center. The study was done according to 7 days, and if they had a planned sample size of at least 100 participants of age 50 the Helsinki Declaration of the World Medical Association. Written informed or older. Investigators of qualifying trials were contacted and informed about consent was obtained from every patient or legal representative. The COMPILE- COMPILEhome and invited to collaborate in the study. home DSMB consisted of the chair (an infectious diseases physician), the 6 NATURE COMMUNICATIONS | (2022)13:2583 | https://doi.org/10.1038/s41467-022-29911-3 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-29911-3 ARTICLE unblinded statisticians from the individual studies and another infectious diseases 18. Bégin, P. et al. Convalescent plasma for hospitalized patients with COVID-19: specialist. They reviewed the pooled dataset on a regular basis as described in the an open-label, randomized controlled trial. Nat. Med. 27(Nov), 2012–2024 COMPILEhome study protocol and recommended the study team regarding the (2021). further conduct of the study. Findings are reported according to the CONSORT 19. Gharbharan, A. et al. Effects of potent neutralizing antibodies from (Consolidated Standards of Reporting Trials) statement. For the COnV-ert study, convalescent plasma in patients hospitalized for severe SARS-CoV-2 infection. the protocol was approved by the Ethics Committee at Hospital Germans Trias i Nat. Commun. 12, 3189 (2021). Pujol (number PI 20-313) and the institutional review boards of participating 20. Libster, R. et al. Early high-titer plasma therapy to prevent severe Covid-19 in centers. For the CoV-Early study, the protocol was approved by the medical ethical older adults. N. Engl. J. Med. 384, 610–618 (2021). review board of the Erasmus Medical Center (METC-2020-0682). 21. Korley, F. K. et al. Early convalescent plasma for high-risk outpatients with Covid-19. N. Engl. J. Med. 385(Nov), 1951–1960 (2021). Reporting summary. Further information on research design is available in the Nature 22. Petkova, E., Antman, E. M. & Troxel, A. B. Pooling data from individual Research Reporting Summary linked to this article. clinical trials in the COVID-19 era. Jama 324, 543–545 (2020). 23. Nguyen D. et al. SARS-CoV-2 neutralising antibody testing in Europe: towards harmonisation of neutralising antibody titres for better use of convalescent plasma and comparability of trial data. Euro Surveill. 26 (2021). Data availability 24. Arnold Egloff S. A. et al. Convalescent plasma associates with reduced The source data and generated data are available in the Supplementary Data files. mortality and improved clinical trajectory in patients hospitalized with COVID-19. J. .Clin. Investig. 131 (2021). 25. Joyner, M. J. et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin. Proc. 95, 1888–1897 (2020). Code availability 26. Gharbharan A. et al. Effects of treatment of COVID-19 with convalescent The codes generated during the current study are available from the corresponding plasma in 25 B-cell depleted patients. Clin. Infect. Dis. 74, 1271–1274 (2022). author on reasonable request. 27. Haagmans, B. L. et al. SARS-CoV-2 neutralizing human antibodies protect against lower respiratory tract disease in a Hamster Model. J. Infect. Dis. 223, 2020–2028 (2021). Received: 23 November 2021; Accepted: 7 April 2022; 28. Sullivan D. J. et al. Randomized controlled trial of early outpatient COVID-19 treatment with high-titer convalescent plasma. medRxiv https://doi.org/10. 1101/2021.12.10.21267485 (2021). Acknowledgements References For the CoV-Early study group. The DSMB members for COMPILEhome (Jan Nouwen, 1. Horby, P. et al. Dexamethasone in hospitalized patients with Covid-19. N. Andrea Troxel, Grigorios Papageorgiou, David Boulware, Josep Puig). All GGD contact Engl. J. Med. 384, 693–704 (2021). tracers who informed potential study candidates. All infectiologists at Erasmus MC who 2. Brown, M. J., Alazawi, W. & Kanoni, S. Interleukin-6 receptor antagonists in worked even harder during COVID times to let the study team focus on the COVID critically Ill patients with Covid-19. N. Engl. J. Med. 385, 1147 (2021). trials (Adam Anas, Hannelore Bax, Mariana de Mendonça-Melo, Els van Nood, Jan 3. RECOVERY Collaborative Group. Tocilizumab in patients admitted to Nouwen, Karin Schurink, Lennert Slobbe, Dorine de Vries-Sluijs) and the ER physicians hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, and collegues from the department of internal medicine who referred patients and platform trial. Lancet 397 1637–1645 (2021). facilitated patient recruitment. The medical students who contacted the patients (Romée 4. Dougan, M. et al. Bamlanivimab plus etesevimab in mild or moderate Covid- Land, Eva Pruijt, Silje Taal, Liselotte Jeletich, Willem Sebrechts, Femke de Vries, Tia 19. N. Engl. J. Med. 385(Oct), 1382–1392 (2021). Rijlaarsdam). The many research assistants, research nurses and other participants who 5. Gottlieb, R. L. et al. Effect of bamlanivimab as monotherapy or in combination helped in facilitating the study (Maartje Wagemaker, Marita Tjauw Joe Kim—Amad- with etesevimab on viral load in patients with mild to moderate COVID-19: a moestar, Diane Struik, Denise Heida-Peters, Sabine Harinck, Marjo van der Poel, Greetje randomized clinical trial. Jama 325, 632–644 (2021). van Asselt, Danielle Orij—Westerhof, Marloes Romeijn, Marlies Bouterse, Pepita de 6. Weinreich, D. M. et al. REGN-COV2, a neutralizing antibody cocktail, in Vries, Dewi Dubbelaar, Cynthia Oud, Jo Anne den Ouden, Milly Haverkort). Stichting outpatients with Covid-19. N. Engl. J. Med. 384, 238–251 (2020). Hemato-Oncologie voor Volwassenen Nederland (HOVON) for building the eCRF and 7. Weinreich D. M. et al. REGEN-COV antibody cocktail clinical outcomes study providing real-time support with the eCRF on very short notice (Henk Hofwegen, in Covid-19 outpatients. medRxiv https://doi.org/10.1101/2021.05.19. Ronnie van der Holt, Mirjam Stomp, Marleen Luten, Monique Steijart). Professor Eva 21257469 (2021). Petkova at NYU Langone who co-designed the COMPILE concept. All the persons 8. Garraud, O. et al. Plasma therapy against infectious pathogens, as of yesterday, involved in the blinding and distribution of plasma products at the sites. Last but cer- today and tomorrow. Transfus. Clin. Biol. 23, 39–44 (2016). tainly not least, all patients that participated in the trial, the thousands of plasma donors 9. Mair-Jenkins, J. et al. The effectiveness of convalescent plasma and and the COVID test centers who informed patients across the Netherlands about the hyperimmune immunoglobulin for the treatment of severe acute respiratory study. This study was made possible by a research grant from ZONMW, the Netherlands infections of viral etiology: a systematic review and exploratory meta-analysis. (10430062010001). Sanquin Blood Supply provided convalescent plasma free of charge J. Infect. Dis. 211, 80–90 (2015). for study sites in the Netherlands. For the COnV-ert study group. The trial was sponsored 10. Estcourt, L. J. et al. Effect of convalescent plasma on organ support-free days by the Fight AIDS and Infectious Diseases Foundation with funding from the phar- in critically ill patients with COVID-19: a randomized clinical trial. Jama 326, maceutical company Grifols S.A. and the crowdfunding campaign YoMeCorono (www. 1690–1702 (2021). yomecorono.com). The study received support of the Hospital Universitari Germans 11. Simonovich, V. A. et al. A randomized trial of convalescent plasma in Covid- Trias i Pujol, and Banc de Sang i Teixits de Catalunya (BST). We thank all the plasma 19 severe pneumonia. N. Engl. J. Med. 384, 619–629 (2021). donors and the participants in this study and all the effort they made to attend the visits 12. Agarwal, A. et al. Convalescent plasma in the management of moderate covid- for follow-up. We thank Gerard Carot-Sans for providing medical writing support with 19 in adults in India: open label phase II multicentre randomised controlled manuscript preparation and Roser Escrig for her support in the study design and medical trial (PLACID Trial). Bmj 371, m3939 (2020). writing assistance with the study documentation. We also thank Laia Bertran, Mireia 13. Li, L. et al. Effect of convalescent plasma therapy on time to clinical Clua, Jordi Mitjà, Claudia Laporte, Sergi Gavilan, Miquel Àngel Rodríguez, Joan Mercado improvement in patients with severe and life-threatening COVID-19: a and Enric Nieto for the operational and financial management of the project. We thank randomized clinical trial. Jama 324, 460–470 (2020). the personnel from the Fight Aids and Infectious Diseases Foundation for their support 14. O’Donnell M. R. et al. A randomized double-blind controlled trial of in administration, human resources and supply chain management. We thank the convalescent plasma in adults with severe COVID-19. J. Clin. Investig. 131 independent DSMB for their time and dedication: Cinta Hierro (Catalan Institute of (2021). Oncology, Badalona, Spain), Natalia Tovar (Hospital Clinic,Barcelona, Spain), Binh Ngo 15. Avendaño-Solà C. et al. Convalescent plasma for COVID-19: a multicenter, (University of Southern California, Los Angeles, US), David Boulware (University of randomized clinical trial: medRxiv https://doi.org/10.1101/2020.08.26. Minnesota, Minneapolis, US), Robin Mogg (Bill and Melinda Gates Research Institute, 20182444 (2020). Seattle, US). ISGlobal receives support from the Spanish Ministry of Science and Inno- 16. Janiaud, P. et al. Association of convalescent plasma treatment with clinical vation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program outcomes in patients with COVID-19: a systematic review and meta-analysis. (CEX2018-000806-S), and support from the Generalitat de Catalunya through the Jama 325, 1185–1195 (2021). CERCA Program. CISM is supported by the Government of Mozambique and the 17. RECOVERY Collaborative Group. Convalescent plasma in patients admitted Spanish Agency for International Development (AECID). BB was supported by a Beatriu to hospital with COVID-19 (RECOVERY): a randomised controlled, open- de Pinós postdoctoral fellow granted by the Government of Catalonia’s Secretariat for label, platform trial. Lancet 397, 2049–2059(2021). Universities and Research, and by Marie Sklodowska-Curie Actions COFUND Program NATURE COMMUNICATIONS | (2022)13:2583 | https://doi.org/10.1038/s41467-022-29911-3 | www.nature.com/naturecommunications 7 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-29911-3 (BP3, 801370). EP was supported by a doctoral grant from National Agency for Research Additional information and Development of Chile (ANID): 72180406. OM was supported by the European Supplementary information The online version contains supplementary material Research Council (ERC) under the European Union’s Horizon 2020 research and available at https://doi.org/10.1038/s41467-022-29911-3. innovation program. ZONMW, the Netherlands, grant number 10430062010001. SUP- PORT‐E, grant number 101015756. YoMeCorono, www.yomecorono.com. The Fight Correspondence and requests for materials should be addressed to Bart J. A. Rijnders. AIDS and Infectious Diseases Foundation with funding from the pharmaceutical com- pany Grifols S.A. The funders had no role in the design or conduct of the study; Peer review information Nature Communications thanks Waldo H Belloso, Dean collection, management, analysis, or interpretation of the data; preparation, review, or Follmann and the other, anonymous, reviewer(s) for their contribution to the peer review approval of the manuscript; or decision to submit the manuscript for publication. of this work. Peer reviewer reports are available. Reprints and permission information is available at http://www.nature.com/reprints Author contributions Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in B.J.A.R. conducted the search for studies that could potentially enter the COMPILEhome published maps and institutional affiliations. consortium. B.J.A.R. and OM agreed on the terms for the COMPILEhome consortium. B.J.A.R., O.M., P.M.M., A.G., A.A., C.R., M.C.M., B.B., A.T., and J.J.Z. conceived and designed the COnV-ert and CoV-Early studies. The COMPILEhome protocol was Open Access This article is licensed under a Creative Commons written by B.J.A.R. and G.P. G.P. and NvG wrote the statistical analysis plan and did the Attribution 4.0 International License, which permits use, sharing, statistical analysis. 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Competing interests © The Author(s) 2022 The authors declare no competing interests. 1 Fight AIDS and Infectious Diseases Foundation, Badalona, Spain. 2ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. 3 Department of Internal Medicine, Section of Infectious Diseases and department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. 4Hospital Universitari Germans Trias i Pujol, Badalona, Spain. 5Facultat de Medicina- Universitat de Barcelona, Barcelona, Spain. 6Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands. 7Department of Biostatistics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. 8Department of Biomedical Data Sciences, Section of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands. 9Department of Infectious Diseases and Acute Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands. 10Unit of Transfusion Medicine, Sanquin Blood Supply, Amsterdam, The Netherlands. 11Department of Experimental Immunohematology, Sanquin Research, Amsterdam, The Netherlands. 12Hospital Universitari Parc Taulí I3PT, Sabadell, Spain. 13 Universitat Autònoma de Barcelona, Barcelona, Spain. 14Bioclever-CRO, Barcelona, Spain. 15Emergency Department, Bellvitge University Hospital, L’Hospitalet de LLobregat, Barcelona, Spain. 16Clinical Research Support Unit (HUB-IDIBELL: Bellvitge University Hospital & Bellvitge Biomedical Research Institute), Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain. 17Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and 33 Health Sciences, IDIBELL, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain. 18Unitat de Suport a la Recerca de la Catalunya Central, Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina, Sant Fruitós de Bages, Spain. 19Health Promotion in Rural Areas Research Group, Gerència Territorial de la Catalunya Central, Institut Català de la Salut, Sant Fruitós de Bages, Spain. 20Universitat de Vic—Universitat Central de Catalunya (UVIC-UCC), Vic, Spain. 21Salut Catalunya Central, Hospital de Berga, Berga, Spain. 22Blood Bank Department—Banc de Sang i Teixits (BST), Barcelona, Spain. 23 IrsiCaixa AIDS Research Institute, Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain. 24Metropolitana Nord Laboratory, Institut Català de la Salut, Badalona, Spain. 25Gerència Territorial Metropolitana Nord, Institut Català de la Salut, Barcelona, Spain. 26Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique. 27Pg. Lluís Companys 23, ICREA, Barcelona, Spain. 28Pediatrics Department, Hospital Sant Joan de Déu, Universitat de Barcelona, Esplugues, Spain. 29Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. 30Department of Population Health, NYU Grossman School of Medicine, New York, NY, USA. 31Department of Haematology, Leiden University Medical Centre, Leiden, The Netherlands. 32CCTR, Sanquin Blood Supply, Amsterdam, The Netherlands. 33 Lihir Medical Centre—InternationalSOS, Lihir Island, Papua New Guinea. 62These authors contributed equally: Pere Millat-Martinez, Arvind Gharbharan, Andrea Alemany. 63These authors jointly supervised this work: Jaap Jan Zwaginga, Oriol Mitjà, Bart J.A. Rijnders. *Lists of authors and their affiliations appear at the end of the paper. ✉email: b.rijnders@erasmusmc.nl CoV-Early study group Arvind Gharbharan34, Casper Rokx34, Carlijn Jordans34, Corine Geurtsvankessel34, Grigorios Papageourgiou34, Bart Rijnders34, Peter Katsikis34, Yvonne Müller34, Marion Koopmans34, Susanne Bogers34, Jelle Miedema34, Henk Russcher34, Cees Scherpenisse34, Rene van Engen34, Ayten Karisli34, Hannelore Götz35, Jelle Struik36, Lotte Rokx-Niemantsverdriet36, Nan van Geloven37, Geert Groeneveld37, Jaap Jan Zwaginga37, Lisa Zwaginga37, Josine Oud37, Romy Meier37, Erik van Zwet37, Simon Mooijaart37, Arjan Albersen37, Francis Swaneveld38, 8 NATURE COMMUNICATIONS | (2022)13:2583 | https://doi.org/10.1038/s41467-022-29911-3 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-022-29911-3 ARTICLE Ellen van der Schoot38, Hans Vrielink38, Leo van de Watering38, Boris Hogema38, Peter van Wijngaarden39, Ronald van Etten39, Adriaan van Gammeren39, Nanda Maas39, Betty van Ginneken39, Jan den Hollander40, Jose Verstijnen40, Juliette van den Berg – Rahman40, Faiz Karim41, Siepke Hiddema41, Kim van Elst41, Elena van Leeuwen-Segarceanu42, Annette Reitsma42, Karin Molenkamp42, Robert Soetekouw43, Caterina Band43, José de Droog43, Jolanda Lammers44, Lonneke Buitenhuis44, Douwe Postma45, David Koster45, Michaèl Lukens45, Thea Scholtens45, Maartje van den Boomgaard45, Machiel Vonk45, Linda Kampschreur46, Marit van Vonderen46, Loes Vrolijk46, Chantal Reusken47, Johan Reimerink47 & Heli Harvala48 34 Erasmus MC, Rotterdam, The Netherlands. 35GGD Rotterdam, Rotterdam, The Netherlands. 36Gezondheidscentrum Mathenesserlaan, Rotterdam, The Netherlands. 37Leids Universitair Medisch Centrum, Leiden, The Netherlands. 38Sanquin Blood Supply, Amsterdam, The Netherlands. 39Amphia Hospital, Breda, The Netherlands. 40Maasstad ziekenhuis, Rotterdam, The Netherlands. 41Groene hart hospital, Gouda, The Netherlands. 42St Antonius hospital, Nieuwegein, The Netherlands. 43Spaarne Gasthuis, Hoofddorp, The Netherlands. 44Isala Hospital, Zwolle, The Netherlands. 45Universitair medisch centrum Groningen, Groningen, The Netherlands. 46Medical Center Leeuwarden, Leeuwarden, The Netherlands. 47Centrum voor Infectieziektebestrijding, RIVM, Bilthoven, The Netherlands. 48NHS Blood and Transplant, London, UK. COnV-ert study group Andrea Alemany49, Marc Corbacho-Monné49, Dan Ouchi49, Bonaventura Clotet49, Oriol Mitjà49, Gèlia Costes49, Mar Capdevila-Jáuregui49, Pamela Torrano-Soler49, Alba San José49, Zahida Jiménez49, Ferran Ramírez-Viaplana49, Susana Ferrer49, Mireia Gallardo49, Maria Ubals49, Camila González-Beiras49, Martí Vall-Mayans49, Miquel Angel Rodriguez-Arias49, Clara Suñer49, Jordi Puig49, Aroa Nieto49, Ivan Galvan-Femenia49, Xavier Comas-Leon49, Pere Millat-Martínez50, Quique Bassat50, Bàrbara Baro50, Ignacio Blanco51, Jordi Ara51, Glòria Bonet Papell51, Maria Delgado Capel51, Beatriz Díez Sánchez51, Maria Pons Barber51, Cristian Gonzalez Ruiz51, Laura Navarrete Gonzalez51, David González García51, Ainhoa Vivero Larraza51, Victor Carceles Peiró51, Clàudia Roquer López51, Magí Ferrer51, Pierre Malchair52, Sebastian Videla52, Vanesa García García52, Carlota Gudiol52, Aurema Otero52, Jose Carlos Ruibal Suarez52, Alvaro Zarauza Pellejero52, Ferran Llopis Roca52, Orlando Rodriguez Cortez52, Pablo Casares Gonzalez52, Gemma Arcos Vila52, Begoña Flores Aguilera52, Graciela Rodríguez-Sevilla52, Macarena Dastis Arias52, Anna Ruiz-Comellas53, Anna Ramírez-Morros53, Judit Roca Font53, Katherine M. Carrasco Matos53, Glòria Saüch Valmaña53, Carla Vidal Obradors53, Joana Rodríguez Codina54, Rosa Amado Simon54, Silvia Tarres García54, Margarida Curriu Sabatès54, Raquel Nieto Rodríguez54, Joan-Ramon Grífols55, Anna Millan55, Enric Contreras55, Àgueda Ancochea55, Rosa Línio55, Miriam Fornos55, Natàlia Casamitjana55, Eva Alonso55, Núria Martinez55, Laura Analía Maglio55, Laura Comellas Fernandez55, Nadia Garcia55, Luis Hernández55, María Isabel González55, Anna Bravo55, Yolanda García55, Núria Prat56, Joaquim Verdaguer56, Thatiana Vértiz Guidotti56, Sergio Benavent56, Andrea Sofia Bianco56, Ney Nicanor Briones Zambrano56, Maria Viozquez Meya56, Anna Forcada57, Josep Vidal-Alaball57, Montserrat Giménez58, Alexa París58, Gema Fernández Rivas58, Cristina Casañ Lopez58, Águeda Hernández58, Antoni E. Bordoy58, Victoria González Soler58, Julian Blanco59, Edwars Pradenas59, Silvia Marfil59, Benjamin Trinité59, Francini Piccolo Ferreira60, Mireia Bonet60, Jordi Cantoni60 & Michael Marks61 49 Fight AIDS and Infectious Diseases Foundation, Badalona, Spain. 50Barcelona Institute for Global Health, ISGlobal, Barcelona, Spain. 51Hospital Universitari Germans Trias i Pujol (HUGTiP), Badalona, Spain. 52Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain. 53 CUAP Manresa, Manresa, Spain. 54Hospital Comarcal de Sant Bernabé, Berga, Spain. 55Blood Bank Department—Banc de Sang i Teixits (BST), Barcelona, Spain. 56Gerència Territorial Metropolitana Nord, Badalona, Spain. 57Gerència Territorial Catalunya Central, Sant Fruitós de Bages, Spain. 58 Metropolitana Nord Laboratory, Badalona, Spain. 59IrsiCaixa AIDS Research Institute, Badalona, Spain. 60Bioclever-CRO, Barcelona, Spain. 61 London School of Hygiene and Tropical Medicine, London, UK. NATURE COMMUNICATIONS | (2022)13:2583 | https://doi.org/10.1038/s41467-022-29911-3 | www.nature.com/naturecommunications 9