key: cord-0307345-6xh6c3on authors: Thuluva, S.; Paradkar, V.; Gunneri, S.; Yerroju, V.; Mogulla, R.; Pothakamuri, S. V.; Turaga, K.; Kyasani, M.; Manoharan, S.; Adabala, S.; Javvadi, A. S.; Medigeshi, G. R.; Singh, J.; Shaman, H.; Binayke, A.; Aymaan, Z.; Awasthi, A.; Narang, M.; N, P.; Mahantshetti, N.; Garg, B. S.; Ravi, M. title: Safety, tolerability and immunogenicity of Biological Es CORBEVAX vaccine in children and adolescents: A Prospective, Randomised, Double-blind, Placebo controlled, Phase-2/3 Study. date: 2022-04-26 journal: nan DOI: 10.1101/2022.04.20.22274076 sha: 2554564768d2368ce36520d49d6613830201a0de doc_id: 307345 cord_uid: 6xh6c3on Background: After establishing safety and immunogenicity of Biological Es CORBEVAX vaccine in adult population (18-80 years) in Phase 1-3 studies, vaccine is further tested in children and adolescents in this study. Methods: This is a phase-2/3 prospective, randomised, double-blind, placebo controlled, study evaluating safety, reactogenicity, tolerability and immunogenicity of CORBEVAX vaccine in children and adolescents of either gender between 17 to 12 years of age in Phase-II and 17-5 years of age in Phase-III with placebo as a control. This study has two age sub groups; age subgroup-1 with subjects 17 to 12 years of age and age subgroup-2 with subjects 11 to 5 years of age. In both age sub groups eligible subjects (SARS-CoV-2 RT-PCR negative and seronegative at baseline) were randomized to receive either CORBEVAX vaccine or Placebo in 3: 1 ratio. Findings: The safety profile of CORBEVAX vaccine in both pediatric cohorts was comparable to the placebo control group. Majority of reported adverse events (AEs) were mild in nature. No severe or serious AEs, medically attended AEs (MAAEs) or AEs of special interest (AESI) were reported during the study period and all the reported AEs resolved without any sequelae. In both pediatric age groups, CORBEVAX vaccinated subjects showed significant improvement in humoral immune-responses in terms of anti-RBD-IgG concentrations, anti-RBD-IgG1 titers, neutralizing antibody (nAb)-titers against Ancestral Wuhan and Delta strains. Significantly high interferon gamma immune response (cellular) was elicited by CORBEVAX vaccinated subjects with minimal effect on IL-4 cytokine secretion. Interpretations: The safety profile of CORBEVAX vaccine in 17 to 5 years children and adolescents was found to be safe and tolerable. The adverse event profile was also found to be acceptable. Significant increase in anti-RBD IgG and nAb titers and IFN-gamma immune responses were observed post vaccination in both pediatric age sub groups. Both humoral and cellular immune responses were found to be non-inferior to the immune responses induced by CORBEVAX vaccine in adult population. This study shows that CORBEVAX vaccine is highly immunogenic and can be safely administered to pediatric population as young as 5 years old. ≥ 5 years of age. In both age sub groups eligible subjects (SARS-CoV-2 RT-PCR negative and seronegative at baseline) were randomized to receive either CORBEVAX™ vaccine or Placebo in 3: 1 ratio. The safety profile of CORBEVAX™ vaccine in both pediatric cohorts was comparable to the placebo control group. Majority of reported adverse events (AEs) were mild in nature. No severe or serious AEs, medically attended AEs (MAAEs) or AEs of special interest (AESI) were reported during the study period and all the reported AEs resolved without any sequelae. In both pediatric age groups, CORBEVAX™ vaccinated subjects showed significant improvement in humoral immune-responses in terms of anti-RBD-IgG concentrations, anti-RBD-IgG1 titers, neutralizing antibody (nAb)-titers against Ancestral Wuhan and Delta strains. Significantly high interferon gamma immune response (cellular) was elicited by CORBEVAX™ vaccinated subjects with minimal effect on IL-4 cytokine secretion. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Interpretations: The safety profile of CORBEVAX™ vaccine in <18 to ≥ 5 years' children and adolescents was found to be safe and tolerable. The adverse event profile was also found to be acceptable. Significant increase in anti-RBD IgG and nAb titers and IFN-gamma immune responses were observed post vaccination in both pediatric age sub groups. Both humoral and cellular immune responses were found to be non-inferior to the immune responses induced by CORBEVAX™ vaccine in adult population. This study shows that CORBEVAX™ vaccine is highly immunogenic and can be safely administered to pediatric population as young as 5 years old. The study was prospectively registered with clinical trial registry of India-CTRI/2021/10/037066 Covid-19, Vaccine, Receptor Binding Domain, SARS-Cov-2, Protein Subunit, Adverse Events, Neutralizing Antibodies All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2022. ; https://doi.org/10.1101/2022.04.20.22274076 doi: medRxiv preprint COVID-19 infection among children is generally asymptomatic or mild in nature compared to adults. However, severe COVID-19 associated cases of multi system inflammatory syndrome (MIS-C) and long-term sequelae, such as the long COVID, cardiovascular complications, neurological manifestations, dermatological manifestations, acute kidney failure etc. were reported in children. [1] [2] [3] [4] Importantly, SARS-CoV-2 can be efficiently transmitted from school-age children and adolescents to household members and can led to the hospitalization of adults with secondary cases of Covid-19. 5 Moreover, home confinement, isolation during the infection and reduced physical activity had greater impact on their lifestyle, psychological and social wellbeing. 6 were approved by Chinese authorities for the age group of 3-17 years. 10, 11 An adjuvanted inactivated vaccine (Covaxin) and a novel DNA vaccine, ZycovD were approved by the Indian regulators in the 12-17 years age group, but not yet received WHO EUL for this All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. CORBEVAX™ is a protein sub unit vaccine containing receptor binding domain (RBD) of spike protein of SARS-CoV-2, adjuvanted with CpG1018 and Al3+. Safety and immunogenicity of CORBEVAX™ is well established in our previous Phase 1-3 clinical trials in adult population. 13 In Adults, vaccine exhibited excellent safety and minimal reactogenicity with no observed safety concerns. Neutralizing antibody titers in CORBEVAX™ vaccinated subjects indicated high vaccine effectiveness in preventing symptomatic infection and severe disease; >90% vaccine effectiveness against Wuhan variant and >80% vaccine effectiveness against the Delta variant based on neutralizing antibodies correlates of protection. 13 In the study, we further report safety and immunogenicity of CORBEVAX™ in a prospective, randomised, double-blind, placebo controlled, phase-2/3 study conducted in children and adolescents. This is an ongoing prospective, randomized, double-blind, placebo controlled, seamless phase-2/3 study to demonstrate safety, reactogenicity & immunogenicity of BE's CORBEVAX™ vaccine in children and adolescents. Study was conducted at 23 sites across India in accordance with the principles defined in the Declaration of Helsinki, International Conference on Harmonization guidelines (Good Clinical Practices), and the local regulatory guidelines. The Investigational Review Board or Ethics Committee at All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Participants were healthy children (SARS-CoV-2 RT-PCR and anti-SARS-CoV-2 antibody negative) between <18 to ≥ 5 years of age. The enrolment was done in an age descending approach with two age subgroups viz. age subgroup-1 with subjects <18 to ≥ 12 years of age and age subgroup-2 with subjects <12 to ≥ 5 years of age. Study subjects were randomized to receive either test vaccine (CORBEVAX™) or placebo in a 3:1 ratio in both age subgroups. A total of 1910 subjects were screened to enroll 624 (n=312 in age sub groups 1 and n=312 in age sub group 2) subjects into the study. All enrolled subjects received either two doses of CORBEVAX™ vaccine or placebo through intramuscular route on Day0 and Day28(+4). From age sub group-1, 134 subjects were enrolled into phase-2 part of the study (100 participants were randomized to receive CORBEVAX™ vaccine and 34 subjects received placebo). Safety data from phase-2 study participants was reviewed by Data Safety Monitoring Board (DSMB) at day-7 post first dose of vaccination. Based on the favorable recommendations by DSMB on safety profile of the CORBEVAX™ vaccine in adolescents, study was progressed to phase-3 and recruited remaining 178 subjects in age sub group-1 (134 subjects, under test vaccine arm and 44 subjects under placebo arm) and n=312 subjects were recruited in age sub group-2, 5-11 years old children (234 subjects, under test vaccine arm and 78 subjects under placebo arm). During the conduct of this study, there were no major protocol deviations reported at any of the study sites. Few subjects reported for their visits out of window period but All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. these deviations were not found to be significant and all deviations were communicated to ethics committees of the respective study sites. The total duration of the study (interim analysis) was 56 days for each subject from the 1 st dose of vaccination and are followed up further for 3 months and 6 months after the second dose. A booster dose will be given at 6 months post 2 nd dose visit and subjects will be followed up for 28 days' post booster dose. A time window of +4 days is allowed from Day 28 to Day 56 and a time window of 14 days will be allowed for 3 months and 6 months follow up respectively to ensure participant compliance. After all screening-related activities were completed and prior to the first dose of study vaccine, participants in the study were stratified and randomized to either test or placebo groups in 3:1 ratio according to a random generated codes using the interactive web response system (IWRS) platform. Participants and investigators were blinded to group allocation. Except independent statistician and personnel responsible for conducting packaging/ labelling/blinding of the investigational product, all the personnel involved in the study remained blinded to the study vaccine. The test and placebo were labelled and packed identical to each other. Biological E's CORBEVAX™ vaccine is a recombinant sub unit vaccine consists of RBD protein as an antigen, CpG 1018 and Aluminium hydroxide as adjuvants formulated in Tris buffer. 13 The recombinant RBD protein is produced in Pichia Pastoris culture as secretory protein and purified via multiple chromatography and ultrafiltration/normal-All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2022. ; https://doi.org/10.1101/2022.04.20.22274076 doi: medRxiv preprint filtration steps. A 0.5mL of CORBEVAX™ or placebo (Adjuvant formulated in Trisbuffer) was administered via an intramuscular (IM) injection into the deltoid muscle in a 2-dose schedule (Day 0 & Day 28). Prophylactic medication is not prescribed either before or after vaccination. Participants were evaluated with SARS-CoV-2 real-time RT-PCR and sero-status was assessed using Anti-SARS CoV-2 Human S1/S2 IgG ELISA using Diasorin kits. Participants who were negative for both SARS CoV-2 infection and Anti-SARS CoV-2 human S1/S2 IgG antibodies were enrolled into the study. The primary outcome of the phase-2 and secondary outcome of phase-3 part of the study was to assess the safety, tolerability and reactogenicity of CORBEVAX™ vaccine in children and adolescents in comparison to placebo group in terms of occurrence of any solicited and unsolicited AEs for 28 days' post vaccination. The primary outcome of phase-3 part of the study was demonstration of immunogenic non-inferiority of BE's CORBEVAX™ vaccine against adult population in terms of geometric mean neutralizing titers and their geometric mean fold rise from baseline, at day 42 (14 days after 2nd dose). Exploratory outcomes include measuring, SARS-COV-2 virus neutralizing antibodies against variant strains (Beta and Delta), anti-RBD IgG subclass (IgG1 and IgG4) titer assessment, cellular immune response assessment at baseline and at Day 42 in a randomly selected subset of study population. Other exploratory outcomes were to assess occurrence and severity of SAEs and medically attended AEs (MAAEs) and persistence of immune responses at 3 and 6 months' post 2 nd dose of vaccination. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Occurrence and severity of all adverse reactions were collected for the safety assessments, which includes solicited and unsolicited, non-serious and serious adverse events (AEs), medically attended AEs (MAAEs) and adverse events of special interest (AESI) reported in the study from the time of first dose of the vaccine. All participants were observed for at least 60 mins post vaccination to assess reactogenicity. Solicited local and general AEs were recorded for 7 consecutive days (Day 0-6), captured through subject diary after each vaccine dose. Unsolicited AEs, if any were collected until day 42. SAEs, MAAEs and AESI were collected throughout the study period. Relatedness of study vaccine was assessed for all reported AEs and adverse reactions were scored by severity (mild, moderate, severe and life threatening). Details on assessment of reported AEs was provided as supplementary information. Sera samples were collected from all the subjects in the immunogenicity cohort at Day-0 (pre-vaccination) and at Day-42 (14 days after second vaccine dose) time points. Following measurements were conducted to assess humoral immune response 1. Overall humoral immune response generated by vaccination was tested by measuring the anti-RBD IgG concentration via ELISA method conducted at Dang's Lab, India. Subject sera samples collected prior to vaccination (Day-0) and fourteen days after two doses of vaccination (Day-42). The antibody concentrations were reported in ELISA Units/mL for each subject and Geometric Mean Concentrations were calculated for both age sub group cohorts at day0 and day42. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. There are two pediatric subgroups stratified by age viz <18 to ≥ 12 years, <12 to ≥ 5 years in this study. Sample size was sufficiently powered at subgroup level to allow for separate comparisons of geometric mean titers at day 42 for each of the two pediatric subgroups against the adult immunogenicity data. Immunogenic non-inferiority of BE's CORBEVAX™ vaccine in pediatric population was demonstrated against adult population in terms of geometric mean neutralizing titers and their geometric mean fold rise from baseline, at day 42. Data of adult cohort was used from another phase-2/3 study 13 (BECT-069) which was conducted prior to the start of the pediatric study and formed the basis for non-inferiority comparison. Noninferiority (NI) was assessed separately for each subgroup using the confidence interval for the GMT ratio method. For sample size estimation the true GMT ratio was assumed to be 0.8 with a standard deviation of log transformed data to be 1.2. The lower limit of NI margin is set at 0.5. The non-inferiority will be inferred if the lower limit of two sided 95% CI of GMT ratio is ≥ 0.5 limit set. The sample size of 210 evaluable subjects (SAS 9.4) in each age group will give around 87% power at 5% two-sided level of significance to test the GMT ratio between each age group with adult sample data. Including 10% dropout allocation, the required sample size will then be 234 in each of the two age All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. groups. Accordingly, the overall sample size in this phase-2/3 study would then be 468 eligible children. The overall sample size would be 624 subjects. Immunogenicity was compared using a two-sample t-test on the means of logtransformed titers at the 5% significance level in order to allow for pairwise comparisons. For each comparison, the ratio of the GMTs along with their corresponding 95% CI was presented. For the purposes of analysis, recruited subjects were further identified as total vaccinated cohort (TVC) for safety assessment and the according to protocol (ATP) cohort for immunogenicity assessment. All the demographic and primary safety analyses have been based on TVC population, defined as subjects who entered into the study and have received at least one single intramuscular dose of study vaccination or placebo. ATP population is defined as population, who have blood samples available for immunogenicity analysis at all protocol specified time points from CORBEVAX™ vaccinated cohorts. All data were summarized descriptively and data listings were based on all subjects enrolled in the study. By default, descriptive statistics for quantitative measurements included the number of subjects (n), mean, standard deviation (SD), minimum, median (IQR) and maximum. Safety data were summarized by System Organ Class and Preferred Term. Serious adverse events, related adverse events, adverse events leading to death or withdrawal, solicited adverse events, MAAEs and AESI were summarized separately. In addition, adverse events were also summarized by severity. All analyses were conducted using SAS® Version 9.4 or higher. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. BIRAC-a division of the Department of Biotechnology, Govt of India provided partial funding for the execution of trials. CEPI provided support for nAb titer testing in terms of reagents. Funding sources were not involved in the study conduct, data analysis/interpretation or writing the manuscript. In total, 1910 subjects were screened and 312 eligible subjects were enrolled into <18 to ≥ 12-year group and another 312 subjects were enrolled into <12 to ≥ 5-year group. Overall, 11 subjects dropped out from the study, 4 from age sub group-1 and 7 from age sub group-2 due to lost to follow up and migration from study area (Fig 1) . All the 624 subjects received two doses (0.5 ml) of either Biological E's CORBEVAX™ vaccine (468 subjects) or Placebo (156 subjects) and were part of safety analyses. Demographics of total vaccinated group were presented in table 1. All 624 enrolled subjects were followed up until day 56 post first dose of vaccination for any solicited local and systemic adverse reactions. 234 subjects in each age sub group were vaccinated with CORBEVAX™ and 78 subjects in each age sub group were vaccinated with placebo. In <18 to (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All the reported adverse events were mild to moderate in their intensity. There were no serious AEs/grade-3 AEs/deaths/AESIs reported during the study period and all the reported AEs resolved without any sequelae. Severity and causality of reported AEs were presented in table 4. Most of the AEs were related to vaccination. The safety profile of CORBEVAX™ arm in <18 to ≥ 5 years' children and adolescents was found to be safe. The adverse event profile was also found to be acceptable. Anti-RBD IgG data is available at day0 and day42 in 229 subjects each in 12 to <18 Years' and 5 to <12 Years' age-cohorts who received CORBEVAX™ vaccine. The corresponding data for the adult population tested as part of earlier clinical trial, BECT-069-Phase-2/3 study 13 , is also provided for comparison. The data is summarized in table 5 and shown in figure 2 . Seroconversion was observed in 91% and 96% of 12 to <18 Years' and 5 to <12 years' age-cohorts respectively, whereas seroconversion noted in 94% of subjects in adult population vaccinated with CORBEVAX™. The Th1 vs Th2 skew in the humoral immune response was assessed by measuring the anti-RBD titers for two IgG subclasses i.e. IgG1 and IgG4. The Geometric Mean Ratio of IgG1 to IgG4 titers post-vaccination was 40 and 45 fold in the 12 to <18 Years' and 5 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. trials showed that post-vaccination nAb GMT's of 100 IU/mL and 60 IU/mL are indicative of vaccine efficacy of >90% and >80% respectively. The observed nAb GMT's in both age groups that received CORBEVAX™ are much higher than these thresholds which is indicative of >90% vaccine effectiveness The nAb Geometric Mean titers were calculated for both the age-groups and the ratio of each cohort GMT to adult GMT was calculated. Then the variance of each cohort was calculated from the log transformed data and then the combined variance of the two comparator populations was determined. The lower bound of the 95% confidence interval of the ratio of the two GMT's was then determined by subtracting the variance multiplied by the correction factor from the ratio of the two GMT's. The non-inferiority calculation was summarized in table 8. For both the pediatric age cohorts, the lower bound of the ratio of the GMT with adult cohort was >0.5 which as the threshold for demonstration of non-inferiority. The Geometric Mean Fold Rise (GMFR) in nAb titer from baseline to Day-42 time-point are 22 and 26 respectively for 12 to <18 and 5 to <12 cohorts respectively. These pediatric GMFR's are higher than the adult cohort GMFR of 20. Cellular immune response involved direct measurement of cytokines secreted by stimulation of whole blood samples with SARS-COV-2 peptides using TrueCulture All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Table 9 summarizes the average concentrations of Interferon-gamma and Interleukin-4 In this trial, safety and immunogenicity of a sub-unit protein vaccine for Covid-19, CORBEVAX™ was studied in children (5-11 years) and Adolescents (12-17 years). Results indicated that CORBEVAX™ is safe and well tolerated with no vaccine related serious adverse events, MAAEs or AESI when administered to healthy children and adolescents. Consistent humoral immune response post-CORBEVAX™ vaccination was observed in both the pediatric age cohorts in terms of anti-RBD IgG concentrations, All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2022. following the second dose of BNT162b2 in adolescents. [16] [17] [18] [19] [20] [21] Similar AESI were observed in adolescents receiving another mRNA (Moderna) vaccine. 22 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 26, 2022. ; https://doi.org/10.1101/2022.04.20.22274076 doi: medRxiv preprint CORBEVAX™ was found to be safe without any observed severe, serious adverse events, AESI and MAAEs in both children and adolescents post second dose. Moreover, CORBEVAX™ uses a traditional recombinant protein-based technology (which is also used for the production of vaccines like Hepatitis B) that has a proven safety record in children making the vaccine more reliable, cost effective and safe to be administered. In addition, this platform enables the production of vaccine at large scales making it widely accessible to inoculate the global population. Limitations of the current study includes: Long-term safety in pediatric population was not established yet as interim results are available only until day 56. Safety profile of the CORBEVAX™ vaccine will be established up to 6 months after second dose of the vaccination. Immunogenicity of the candidate vaccine was studied but the efficacy of the vaccine against Covid-19 infection was not studied. Also, there is a need for evaluating antibody persistence in longer follow-up period and neutralizing potential against new Omicron variant was not tested in the current study which will be addressed in the future studies. In conclusion, CORBEVAX™ vaccine is safe, well tolerated and elicited excellent antibody and cellular immune responses that can offer significant protection against symptomatic infection from SARS-CoV-2 virus in pediatric population aged 5-17 years. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Number of subjects discontinued due to AE 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 0 (0.0) 0 Percentages were calculated using column header count as denominator. N 1 : Subject Count, N: Sample Size, n: Event Count. General Note: All AE's were represented as: Subject count (Percentage of subjects) Event Count. 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The copyright holder for this preprint this version posted Evaluation of mRNA-1273 SARS-CoV-2 Vaccine in Adolescents Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial Safety and immunogenicity of an inactivated COVID-19 vaccine, BBIBP-CorV, in people younger than 18 years: a randomised, double-blind, controlled, phase 1/2 trial Selection of optimum formulation of RBD-based protein sub-unit covid19 vaccine (Corbevax) based on safety and immunogenicity in an open-label, randomized Phase-1 and 2 clinical studies Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection Myocarditis Occurring After Immunization With mRNA-Based COVID-19 Vaccines No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.