Preprint Not Peer Reviewed

1 Levels of SARS-CoV-2 lineage P.
1 neutralization by antibodies
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2 elicited after natural infection and vaccination
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4 Authors: William M. Souza, PhD1†; Mariene R. Amorim, MSc2†, Renata Sesti-Costa, PhD 3,4†,
5 Lais D. Coimbra, MSc3, Daniel A. Toledo-Teixeira, MSc2, Pierina L. Parise, BSc 2, Priscilla P.
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6 Barbosa, MSc2, Karina Bispo-dos-Santos, BSc2, Luciana S. Mofatto, PhD2, Camila L. Simeoni2,
7 Natalia S. Brunetti, BSc5, Ingra M. Claro, BSc6,7, Adriana S. S. Duarte, PhD4, Thais M. Coletti,
8 BSc6, Audrey B. Zangirolami, Msc4, Carolina Costa-Lima, MSc4, Arilson Bernardo S. P. Gomes,
9 MSc5, Lucas I. Buscaratti, BSc8, Flavia C. Sales, BSc6,7, Vitor A. Costa, BSc4, Lucas A.M. Franco,
10 PhD6, Darlan S. Candido, MSc9, Oliver G. Pybus DPhil 9, Jaqueline G. de Jesus, PhD6, Camila A.
11 M. Silva, BSc6, Mariana S. Ramundo, PhD6, Giulia M. Ferreira, BSc6,10, Mariana C. Pinho, BSc6,
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12 Leandro M. Souza6, Esmenia C. Rocha6, Pamela S. Andrade6,11, Myuki A.E. Crispim, PhD12,
13 Grazielle C. Maktura, PhD8, Erika R. Manuli, BSc6,7, Magnun N.N. Santos, PhD13, Cecilia C.
14 Camilo, BSc14, Rodrigo N. Angerami, MD, PhD15,16, Maria L. Moretti, MD, PhD15, Fernando R.
15 Spilki, PhD17, Clarice W. Arns, PhD18, Marcelo Addas-Carvalho, MD, PhD 4, Bruno D. Benites,
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16 MD, PhD4, Marcelo A.S. Mori, PhD19,20,21, Nelson Gaburo, PhD22, Christopher Dye, DPhil 9,
17 Chieh-Hsi Wu, PhD23, Henrique Marques-Souza, PhD8, Rafael E. Marques, PhD3, Alessandro S.
18 Farias, PhD5,20,21, Michael S. Diamond, PhD24, Nuno R. Faria, DPhil 6,9,25†*, Ester C. Sabino, MD,
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21 1
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PhD6,7†*, Fabiana Granja, PhD2,26†*, Jose Luiz Proenca-Modena, PhD2,20†*
Virology Research Centre, Ribeirão Preto Medical School, University of São Paulo, Ribeirão
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22 Preto, SP, Brazil.
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23 Laboratory of Emerging Viruses, Department of Genetics, Microbiology and Immunology,
24 Institute of Biology, University of Campinas, Campinas, SP, Brazil.
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25 National Biosciences Laboratory, Brazilian Centre for Research in Energy and Materials
26 (CNPEM), Campinas, SP, Brazil.
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27 Hematology and Transfusion Medicine Centre, University of Campinas, Campinas, SP, Brazil.
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28 Autoimmune Research Laboratory, Department of Genetics, Microbiology and Immunology,
29 Institute of Biology, University of Campinas, Campinas, SP, Brazil.
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30 Tropical Medicine Institute, Medical School, University of São Paulo, São Paulo, SP, Brazil.
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31 Department of Infectious and Parasitic Disease, Medical School, University of São Paulo, São
32 Paulo, SP, Brazil.
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33 Brazilian Laboratory on Silencing Technologies, Department of Biochemistry and Tissue
34 Biology, Institute of Biology, University of Campinas, Campinas, SP, Brazil.
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35 Department of Zoology, University of Oxford, UK.
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36 Laboratory of Virology, Institute of Biomedical Sciences, Federal University of Uberlândia,
37 Uberlândia, MG, Brazil.
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38 School of Public Health, University of São Paulo, São Paulo, SP, Brazil.
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39 Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas, Manaus, AM, Brazil.
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40 Department of Clinical Pathology, School of Medical Sciences, University of Campinas,
41 Campinas, SP, Brazil.
This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=3793486
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42 CDL Laboratório Santos e Vidal Ltda., Manaus, AM, Brazil.
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43 Department of Internal Medicine, School of Medical Sciences, University of Campinas,
44 Campinas, SP, Brazil
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45 Campinas Department of Public Health Surveillance, Campinas, SP, Brazil.
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46 One Health Laboratory, Feevale University, Novo Hamburgo, RS, Brazil.
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47 Animal Virology Laboratory, Department of Genetics, Microbiology and Immunology, Institute
48 of Biology, University of Campinas, Campinas, SP, Brazil.
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49 Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, Institute of
50 Biology, University of Campinas, Campinas, SP, Brazil.
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51 Experimental Medicine Research Cluster, University of Campinas, Campinas, SP, Brazil.
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52 Obesity and Comorbidities Research Center (OCRC), University of Campinas, Campinas, SP,
53 Brazil
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54 DB Diagnósticos do Brasil, São Paulo, SP, Brazil
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55 Mathematical Sciences, University of Southampton, Southampton, UK.
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University School of Medicine, St. Louis, USA.

25
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Departments of Medicine, Molecular Microbiology, Pathology and Immunology, Washington
MRC Centre for Global Infectious Disease Analysis, J-IDEA, Imperial College London, London,
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59 UK.
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60 Biodiversity Research Centre, Federal University of Roraima, Boa Vista, RR, Brazil.
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62 *Correspondence to: jlmodena@unicamp.br, fabiana.granja@ufrr.br, sabinoec@usp.br and
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63 n.faria@imperial.ac.uk
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64 These authors contributed equally to this work.
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73 Abstract
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74
75 Background: A new SARS-CoV-2 lineage, named P.1 (20J/501Y.V3), has recently been detected
76 in Brazil. Mutations accrued by the P.1 lineage include amino acid changes in the receptor-binding
77 domain of the spike protein that also are reported in variants of concern in the United Kingdom
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78 (B.1.1.7) and South Africa (B.1.325).
79 Methods: We isolated two P.1-containing specimens from nasopharyngeal and bronchoalveolar
80 lavage samples of patients of Manaus, Brazil. We measured neutralization of the P.1 virus after
81 incubation with the plasma of 19 COVID-19 convalescent blood donors and recipients of the
82 chemically-inactivated CoronaVac vaccine and compared these results to neutralization of a
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83 SARS-CoV-2 B-lineage previously circulating in Brazil.
84 Findings: The immune plasma of COVID-19 convalescent blood donors had 6-fold less
85 neutralizing capacity against the P.1 than against the B-lineage. Moreover, five months after
86 booster immunization with CoronaVac, plasma from vaccinated individuals failed to efficiently
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87 neutralize P.1 lineage isolates.
88 Interpretation: These data indicate that the P.1 lineage may escape from neutralizing antibodies
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generated in response to polyclonal stimulation against previously circulating variants of SARS-
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92 Funding: São Paulo Research Foundation, MCTI/FINEP, Medical Research Council, National
93 Council for Scientific and Technological Development, National Institutes of Health.
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96 Introduction
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97 Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a betacoronavirus
98 (Coronaviridae family) that was first reported in Wuhan, China, in December of 2019 (1). As of
99 14 February 2021, SARS-CoV-2 has caused over 108 million cases and 2.38 million deaths
100 globally (2). More than 500,000 SARS-CoV-2 genome sequences have been classified in over 869
101 lineages (3). The appearance and spread of some spike protein mutations has resulted in more
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102 transmissible SARS-CoV-2 variants, such as D614G(4). The receptor-binding domain (RBD) is
103 the primary target of neutralizing antibodies in the SARS-CoV-2 response; however, it is a highly
104 variable region and circulating SARS-CoV-2 may be under antibody-mediated selective pressure
105 (5, 6). Consequently, the emergence of SARS-CoV-2 variants with mutations in the RBD has
106 raised concerns for compromising neutralizing antibody responses and the efficacy of vaccination
107 programs (7, 8).
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109 In late 2020, the B.1.1.7 and the B.1.325 lineages were detected in the United Kingdom and South
110 Africa, respectively (9, 10). As of 16 February 2021, the B.1.1.7 and the B.1.325 lineages have
111 been identified in 82 and 40 countries (11). Both these lineages have an enhanced transmissibility
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112 compared to previously circulating SARS-CoV-2 lineages, and carry unique constellations of
113 spike protein mutations. SARS-CoV-2 pseudoviruses carrying the same mutations described in
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these lineages were efficiently neutralized by immune sera of individuals that received BNT162b2
vaccine, suggesting that these lineages might be inhibited by vaccine-mediated humoral immunity
(8, 12-16). Recently, a new SARS-CoV-2 lineage P.1 was discovered in Manaus City, Amazonas
state, Brazil in early January 2020 (17). P.1 has a signature set of 17 unique amino acid changes,
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118 including a trio of mutations (E484K, K417T, and N501Y) in the RBD that also are present in the
119 B.1.325 lineage (17, 18). Here, we investigated whether the full set of mutations found in the spike
120 protein gene of the P.1 lineage can escape from neutralizing antibodies (NAb) generated by
121 COVID-19-convalescent patients or individuals previously immunized with the inactivated
122 CoronaVac vaccine(19, 20).
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124 Methods
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126 Ethics statement
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127 All procedures followed the ethical standards of the responsible committee on human
128 experimentation and approved by the ethics committees from the University of Campinas, Brazil
129 (Approval number CONEP 4.021.484 for plasma collection of blood donors, CAEE
130 32078620.4.0000.5404 and 30227920.9.0000.5404 for the sampling of vaccinated and viral
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131 genome sequencing, respectively). All patient data were anonymized before study inclusion.
132 Informed consent was obtained from all subjects for being included in the study.
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134 SARS-CoV-2 lineage P.1 samples
135 We used residual nasopharyngeal, oropharyngeal or bronchoalveolar lavage specimens of 20
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136 patients from Manaus City, Brazil. These samples were positive for SARS-CoV-2 by real-time
137 quantitative polymerase chain reaction (RT-qPCR), and were obtained from a private medical
138 diagnostics laboratory and Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas,
139 Brazil. All samples used in this study were previously classified as P.1 by virus genome sequencing
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140 (17). Patient information used in this study was collected from electronic health records, including
141 age, sex, collection data, sample type, symptoms (if reported) and reverse transcription polymerase
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142 chain reaction (RT-qPCR) cycle threshold (CT) values (Table S1).
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144 Virus isolation
145 Nasopharyngeal, oropharyngeal or bronchoalveolar lavage samples were inoculated into Vero
146 cells (CCL-81) for virus isolation based on previous described methods (21). Briefly, Vero cells
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147 were plated in a T225 flask at a concentration of 5x105 cells/mL with Dulbecco’s Modified Eagle
148 Medium (DMEM) containing 10% fetal bovine serum (FBS) and 1% of 10,000 units of penicillin
149 and 10 mg of streptomycin/mL solution (Sigma-Aldrich, USA). Samples were thawed on ice,
150 diluted 1:10 in DMEM medium, and centrifuged at 12.000 x g for 5 min at 4ºC. Then, samples
151 were filtered using 0.22 μm syringe filters, and incubated on ice for 1 h with a solution of 10,000
152 units of penicillin and 10 mg of streptomycin/mL and amphotericin B 250 μg/mL (1:1) (Sigma-
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153 Aldrich, USA) in a final dilution of 1:10. After incubation at 37°C for 1 h (adsorption), the
154 inoculum was removed from the culture and replaced with fresh culture medium. Cells were
155 incubated at 37°C and observed for cytopathic effects (CPE) daily up to 72 h. Subsequently, the
156 cultural supernatant was collected daily and virus replication was confirmed through RT-qPCR.
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157 Viral RNA was extracted from the supernatant cells using the Quick-RNA viral kit (Zymo
158 Research, USA) following the manufacturer-recommended procedures. RT-qPCR protocol was
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used to confirm the isolation through the increase of Ct-value (22). All experiments related to
culture cells and viral replication were performed in the biosafety level 3 laboratory (BSL-3) of
Emerging Viruses Laboratory (LEVE) of the University of Campinas, Brazil.
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163 Immunofluorescence (IF) assay
164 Infection by isolates was confirmed by an immunofluorescence assay. Cells were prepared onto
165 silanised glass slides, fixed and stained as previously described (23). Briefly, after fixation with
166 4% paraformaldehyde (PFA), cells were washed with PBST (Phosphate Buffered Saline with
167 Tween® 20) 0.1 M pH 7,4. Subsequently, cells were incubated per 10 min with glycine 0,1M and
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168 treated with a 1% BSA (bovine serum albumin) solution (Sigma) for 30 min. Cells then were
169 incubated overnight at 4°C with SARS-CoV-2 spike S1 antibody (HC2001) (GenScript, Cat No.
170 A02038) or nucleocapsid antibody (MAb 40143 R001) in a dilution of 1:100 in BSA 1%. The
171 slides were washed and incubated for 2h with secondary antibodies (Anti-Human IgG Alexa 488
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172 Thermo Fisher Scientific - Cat No. A11013 and Anti-Rabbit IgG Alexa 594 Thermo Fisher
173 Scientific - Cat No. A21207) diluted 1:500 in 1% BSA. Cells then were washed and stained with
174 DAPI (Santa Cruz Biotechnology, SC3598) and Phalloidin 647 (Thermo Fisher Scientific - Cat
175 No. A22287). Microscopy images were acquired with a Zeiss LSM880 with Airyscan on an Axio
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176 Observer 7 inverted microscope (Carl Zeiss AG, Germany) with a C Plan Apochromat 63x/1.4 Oil
177 DIC objective, 4x optical zoom. Prior to image analysis, raw.czi files were automatically processed
178 into deconvoluted automatically Airyscan images using Zen Black 2·3 software. DAPI were
179 acquired conventional confocal image using 405 nm laser line for excitation and pinhole set to 1
180 AU.
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182 Plasma specimens of COVID-19-convalescent blood-donors
183 Plasma samples from 19 COVID-19-convalescent blood-donors were collected using the
184 Amicus™ automated blood cell separator (Fresenius Kabi AG, Germany) at the Hematology and
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185 Hemotherapy Centre in the University of Campinas, Brazil. Clinical data for blood-donors were
186 collected from electronic health records, including age, sex, diagnosis methods, symptom duration,
187 time between symptoms and collection, and if there was a required hospitalization during the
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188 SARS-CoV-2 infection (Table S2). IgM and IgG antibodies against proteins of SARS-CoV-2 in
189 plasma of COVID-19 convalescent blood-donors were measured by Abbott SARS-CoV-2
190 chemiluminescence microparticle immunoassay (CMIA) using the Architect instrument according
191 to the manufacturer instructions (24).
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193 Plasma specimens of CoronaVac vaccinated individuals
194 Plasma samples from 8 participants in the Sinovac phase 3 trial (Clinical Trial Identification
195 Number: NCT04456595) were collected by venipuncture procedure at Clinical Hospital of the
196 University of Campinas, Brazil. The clinical trial was conducted in Brazil following the
197 Declaration of Helsinki and Good Clinical Practice Guidelines and with approval by the competent
198 regulatory authority (Brazilian Health Regulatory Agency, Brazil). Full information for individual
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199 was collected, such as age, sex, first and date of the second dose (Table S3). IgM and IgG
200 antibodies against SARS-CoV-2 in vaccinated individuals were also quantified by Abbott SARS-
201 CoV-2 CMIA, and the antibody levels were expressed using the relative binding signals compared
202 with the cut-off value of each assay (S/CO)(24).
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204 SARS-CoV-2 virus neutralization tests
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SARS-CoV-2 virus neutralization tests were performed as previously described elsewhere (21). In
brief, two-fold dilutions starting at dilution range of 1:20 to 1:2,560 of heat-inactivated sera (30
min 56°C) were incubated with 103 PFU/mL of SARS-CoV-2 lineage P.1 (isolates P.1/12 and
P.1/30) or lineage B (isolate SARS.CoV2/SP02.2020 with GenBank Accession Number:
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209 MT126808) recovered from a sample collected on the 28 February 2020 in Brazil(21). Plasma
210 dilutions were mixed 1:1 with isolates of SARS-CoV-2 lineage B (isolates
211 SARS.CoV2/SP02.2020) and P.1 (isolates P.1/12 and P.1/30) for 1 h at 37°C before addition to
212 Vero cell monolayers (104 cells per well) and incubation at 37°C with 5% CO2 for one additional
213 hour. After virus removal, cells were incubated for 72 h with DMEM 10% FBS. The plasma virus
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214 neutralization titer (VNT50) was defined as the sample dilution's reciprocal value that showed a
215 50% protection of CPE, similar to a TCID50 analysis. A sample set of plasma from 19 COVID-19-
216 convalescent blood donors and 8 vaccinated individuals in the Sinovac phase 3 trial were tested
217 for neutralizing capacity against isolates of SARS-CoV-2 lineage P.1 and B. Each plasma sample
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218 was tested in duplicate using two independent assays. Supplementary Tables 4 and 5 show the
219 neutralization titers.
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221 Statistical analysis
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222 We investigated whether convalescent individuals have reduced plasma virus neutralization titers
223 against isolates of SARS-CoV-2 lineage P.1 compared to those against lineage B viruses. To this
224 end, we first calculated the paired differences in the neutralization titers between lineages P.1/12
225 and B, and those between P.1/30 and B. Subsequently we dichotomized the paired differences into
226 “greater than 0” and “less or equal to 0” to produce count tables. The count table is the same for
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227 both paired differences, so we only need to conduct one hypothesis test. For the hypothesis test,
228 we assumed that each sample was an independent draw from a much larger population, and every
229 sample had the same probability of p of having a paired difference > 0. Consequently, we used a
230 binomial distribution to model the count of “difference > 0”. As an indication of statistical support,
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231 we calculated the p-value, which is the probability of observing at least as many “differences > 0”
232 out of the total sample size, given that there is no difference in proportions/probabilities between
233 “differences > 0” and “differences <= 0”. We repeated the above procedure for the vaccinated
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234 samples. A Bonferroni multiple test correction was applied. We used R version 3.6.2 for the
235 calculations above and Pearson’s correlation between the two paired differences in the
236 convalescent samples. All scripts are available on Dryad (available upon acceptance of the
237 publication).
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239 Results and Discussion
240 We isolated the P.1 lineage viruses in Vero cells (CCL-81) from 2 of 20 nasopharyngeal and
241 oropharyngeal samples using a previously published protocol (21). The isolates were named P.1/12
242 and P.1/30. All samples used in this study were confirmed as belonging to the P.1 lineage by
243 genome sequencing using the MinION sequencing platform (Oxford Nanopore Technologies,
244 ONT, UK) (17). The clinical information of the patients is described in Table S1. Cytopathic effect
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245 in Vero cell monolayer was observed 3 days post-inoculation (dpi) and cell culture supernatant
246 was harvested on 4 dpi (Fig. S1 A-B). The titers of the P.1/12 and P.1/30 were 2.5x105 and 1.2x105
247 plaque-forming units (PFU)/mL. The presence of SARS-CoV-2 RNA was confirmed using the
248 real-time quantitative polymerase chain reaction (RT-qPCR) targeting the envelope gene (Fig. S1
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249 C-D). An immunofluorescence assay performed with infected Vero cells and commercially-
250 purchased monoclonal antibodies against SARS-CoV-2 spike S1 and nucleocapsid proteins
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(GenScript, Cat No. A02038 and MAb 40143 R001) revealed robust binding to the nucleocapsid
protein, but reduced binding to the spike protein of P.1 isolates (Fig. 1), suggesting that SARS-
CoV-2 lineage P.1 might escape from recognition by antibodies formed against other previously
circulating lineages.
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256 To evaluate the capacity of P.1 isolates to be neutralized by antibodies generated against other,
257 previously-circulating SARS-CoV-2 viruses, we collected plasma from 19 COVID-19-
258 convalescent blood-donors infected that had inferred confirmed by laboratory methods between
259 May and August 2020, months before the first recorded infections associated with the P.1 lineage.
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260 The convalescent COVID-19 plasma was collected from blood donors with absence of symptoms
261 for at least 28 days according to blood donation criteria and national legislation (25). The COVID-
262 19-convalescent blood-donors had a median age of 34 years (interquartile range = 31 to 43),
263 male:female ratio of 1·11, an average of 65 days (interquartile range = 45 to 69) after the onset of
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264 symptoms, and had high levels of SARS-CoV-2-specific IgM or IgG antibodies (Table S2). We
265 also included plasma from a negative control, a person who was not previously infected with
266 SARS-CoV-2 and who had undetectable levels of anti-SARS-CoV-2 IgM and IgG antibodies. We
267 then tested the plasma of these COVID-19-convalescent blood-donors for neutralization of the P.1
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268 isolates (i.e., P.1/12 and P.1/30) and a Brazilian B lineage reference isolate
269 (SARS.CoV2/SP02.2020) using a 50% virus neutralization test (VNT50), an assay based on the
270 detection of CPE(26) (Fig. S2). The geometric mean virus neutralization titer (GMT, 50%
271 inhibition) of the convalescent plasma against the P.1 lineage isolates was statistically reduced
272 compared to the B lineage isolate (p-values ≤ 0.0001) (Fig. 2A). Convalescent plasma had GMTs
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273 of 40 and 35 for P.1/12 (interquartile range =20-70) and P.1/30 isolate (interquartile range =<20-
274 52.50) respectively, compared to a GMT of 240 (interquartile range =120-480) for the B lineage
275 isolate, indicating neutralization antibodies capacity was reduced by 6-fold for P.1 lineage isolates
276 in comparison with the B lineage isolate (Fig. 2A and Table S3). In addition, we find that, in the
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277 convalescent samples, higher paired differences in virus neutralization titers between P.1/12 and
278 B lineage correspond to higher paired differences between P.1/30 and B1 (Pearson’s correlation =
279 0·999), indicating consistency between the results for both isolates of P.1. Collectively, these data
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280 suggest that P.1 lineage is able to escape from NAb responses generated by prior SARS-CoV-2
281 infection, and thus, reinfection may be plausible with antigenically distinct variants with mutations
282 in spike protein. Interestingly, reinfection with P.1 lineage has been detected in Manaus (27),
283 where high seroprevalence rates have been previously observed (18, 28).
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285 To date, CoronaVac vaccine was approved for emergency use in Brazil, China, Colombia,
286 Indonesia, Mexico and Turkey. In Brazil, the Brazilian Health Regulatory Agency (ANVISA)
287 authorized 10.1 million doses for emergency use on 17 January 2021 (29). To investigate whether
288 the P.1 lineage also might escape neutralization by antibodies induced by the CoronaVac vaccine,
289 we collected a set of plasma from eight participants in the previously reported Sinovac phase 3
290 trial in Brazil in August, 2020(30). All CoronaVac vaccinated individuals in this study received
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291 the vaccine and not placebo. CoronaVac immunized individuals had an average age of 35 years
292 (interquartile range = 34 to 39), male:female ratio of 1·0, and were 153 to 159 days after the
293 CoronaVac booster immunization at the time of donation. The vaccinated individuals had antibody
294 titers between 0·03 to 0·87 relative binding signals compared with the cut-off value of each assay
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295 (S/CO) S/CO for IgM and 0·06 to 0·38 S/CO for IgG antibodies, both based on chemiluminescent
296 microparticle immunoassay (CMIA) methods(24) (Table S4). Subsequently, each plasma was
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evaluated for neutralization activity against both P.1 and B isolates. The 50% neutralization GMT
of the all plasma samples from CoronaVac-vaccinated individuals (n=8) against both P.1 isolates
was below the limit of detection (value <20), whereas the GMT was 25 (interquartile range = <20-
30) for the B lineage isolate (Fig. 2B and Table S5). However, no statistical support was found for
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301 these differences because the sample size is small and the neutralization against both B and P.1
302 viruses was quite low and near the limit of detection of our assay. Notwithstanding this point, these
303 results suggest that P.1 virus might escape from neutralizing antibodies induced by an inactivated
304 SARS-CoV-2 vaccine (i.e., CoronaVac).
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306 Neutralization assays with pseudoviruses of SARS-CoV-2 containing key RBD mutations (i.e.,
307 E484K + N501Y + D614G) that are present in lineages B.1.1.7 and B.1.325 suggested that both
308 lineages are efficiently inhibited by antibodies elicited by the BNT162b2 vaccine and present after
309 natural infection (12, 13). However, the neutralization potency of plasma of individuals immunized
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310 with the BNT162b2 vaccine was reduced against the pseudoviruses with three mutations in RBD
311 (E484K + N501Y + D614G) (8, 13). Another study showed that pseudoviruses harboring the same
312 mutations as the Brazilian P.1 variant also escaped from anti-RBD monoclonal antibodies and sera
313 or plasma from convalescent or BNT162b2 vaccinated individuals (16, 31). Unexpectedly, plasma
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314 from individuals who received two CoronaVac doses had a low level of neutralizing antibodies
315 against the B lineage, with many samples failing to show inhibitory activity against the P.1 strains
316 at the limit of detection (1:20) of the VNT50 assay (26).
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318 A reduction of neutralization activity of more than four-fold based on hemagglutination-inhibition
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319 titers is typically used to update human influenza virus vaccines strains(32). Here, we described a
320 loss of neutralization capacity of at least 6-fold in plasma from COVID-19 convalescent patients
321 against isolates of P.1 (P.1/12 and P.1/30), a B-lineage isolate recovered from a virus previously
322 circulating in Brazil in late February 2020(21). A recent study shows that sera of individuals
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323 infected with common cold coronavirus HCoV-229E in the 1980s and 1990s had a neutralization
324 antibody capacity reduced at least 4-fold against contemporary HCoV-229E strains, an observation
325 that is comparable to the differences we observed in neutralizing activity against the B and P.1
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326 SARS-CoV-2 strains(7). As SARS-CoV-2 antibody levels may gradually start decreasing up to
327 five months post-infection (33), monitoring neutralization activity of vaccinated individuals is
328 necessary, and boosting with updated versions may be required to halt transmission of new
329 variants.
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331 Lower neutralization capacity of SARS-CoV-2 antibodies and partial immunity against new
332 variants suggests that reinfection might could occur in convalescent or even vaccinated
333 individuals. Nonetheless, the protection of CoronaVac against severe COVID-19 cases (34) may
334 indicate that neutralizing antibodies are not the only contributing factor, and that memory T or B
335 cell responses may reduce disease severity. Further clinical and epidemiological studies are needed
336 to clarify how previous exposure through natural infection and through different vaccines may
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337 protect from new infections with existing and newly emerging variants of concern.
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339 In conclusion, our data suggest that the SARS-CoV-2 lineage P.1 can escape from neutralization
340 antibodies elicited during infection or immunization with previously circulating viral variants.
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341 Continued and enhanced genetic surveillance of SARS-CoV-2 variants worldwide, paired with
342 plasma neutralizing antibody assays, may help guide updates of immunization programs.
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Acknowledgments er
We thank Prof. Wendy Barclay for helpful discussions. We thank all blood donors, vaccinated
individuals and SARS-CoV-2 patients who provided clinical species for this study. We thank
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347 Thermo Fisher Scientific, which kindly provided an EVOS inverted microscope for the BSL3
348 facility at LEVE; UNICAMP-Task-Force against COVID-19 that facilitated this study; Elzira E.
349 Saviani for technical support; and all individuals involved in the diagnosis and generation of
350 SARS-CoV-2 sequences as part of the CADDE-Genomic-Network. Finally; the MCTI and all
351 members of the Corona-ômica network for support.
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353 Funding
354 This study was supported by grants from São Paulo Research Foundation (FAPESP)
355 (#2016/00194-8, #2020/04558-0), FAEPEX-UNICAMP (#2266/20). This study was also
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356 supported by MCTI through the Rede Corona-ômica BR MCTI/FINEP and FINEP grant
357 01.20.0003.00 to REM affiliated to RedeVírus/MCTI (FINEP = 01.20.0029.000462/20, CNPq =
358 404096/2020-4). This project was supported by the Medical Research Council and FAPESP -
359 CADDE partnership award (MR/S0195/1 and FAPESP 2018/14389-0) (http://caddecentre.org/).
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360 WMS is supported by FAPESP #2017/13981-0, 2019/24251-9 and CNPq #408338/2018-0. NRF
361 is supported by a Wellcome Trust and Royal Society Sir Henry Dale Fellowship (204311/Z/16/Z).
362 BDB is supported by Grant from the National Council for Scientific and Technological
363 Development (CNPq, #401977/2020). K.B.S., CLS., P.L.P were supported by FAPESP
364 fellowships (#2020/02159-0, 2020/02448-2 and 2017/26908-0). MRA, PPB were supported by
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365 CAPES fellowships, while DATT, LSM were supported by CNPq fellowships (#141844/2019-1,
366 #382206/2020-7). M.S.D. was supported by a grant from the NIH (U01 grant AI151810).
367
368 Contributors
Pr
369 Conception: WMS, MRA, RSC, ECS, FG, NRF, JLPM; Acquisition: WMS, MRA, RSC, LDC,
370 DATT, PLP, PPB, KBS, LSM, CLS, NSB, IMC, ASSD, TMC, ABZ, CCL, ABSP, LIB, FCS,
371 VAC, LMF, DSC, JGJ, CAMS, MSR, GMF, MCP, LMS, ECR, PSA, MAEC, GCM, ERM,
ed
372 MNNS, CCC, RNA, NG, MLM, HMS, FG, JLPM; Analysis: WMS, MRA, RSC, DATT, LSM,
373 CW, ECS, FG, JLPM; Interpretation: WMS, MRA, RSC, LDC, DATT, LMS, NRF, ECS, FG,
374 OGP, CD, JLPM; Drafting: WMS, RSC, JLPM; Revising: WMS, RSC, MRA, RNA, MLM, RRS,
375 OGP, CD, MAC, BDB, MASM, HMS, REM, ASF, ECS, FG, NRF, JLPM. All authors have read
376 and approved the final version of the manuscript. Funding: WMS, FRS, MASM, REM, ASF, NRF,
iew
377 ECS, NRD, JLPM.
378
379 Declaration of interests M.S.D. is a consultant for Inbios, Vir Biotechnology, NGM
380 Biopharmaceuticals, and Carnival Corporation, and on the Scientific Advisory Boards of Moderna
381 and Immunome. The Diamond laboratory has received funding support in sponsored research
382 agreements from Moderna, Vir Biotechnology, and Emergent BioSolutions.
ev
383
384 Data sharing
385 All metadata will be available after publication in a research data repository at the University of
386 Campinas (http://www.sbu.unicamp.br/sbu/repositorio-de-dados-de-pesquisa-da-unicamp/).
r
387 References
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410 Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2
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417 [cited 2021].
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421 13. Xie X, Liu Y, Liu J, Zhang X, Zou J, Fontes-Garfias CR, et al. Neutralization of SARS-
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427 15. Wibmer CK, Ayres F, Hermanus T, Madzivhandila M, Kgagudi P, Lambson BE, et al.
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430 16. Diamond M. CR, Xie, X. Case J., VanBlargan, et al.,. SARS-CoV-2 variants show
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431 resistance to neutralization by many monoclonal and serum-derived polyclonal antibodies.
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445 Oswaldo Cruz. 2020;115.
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446 22. Corman VM, Landt O, Kaiser M, Molenkamp R, Meijer A, Chu DK, et al. Detection of
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448 23. Davanzo GG, Codo AC, Brunetti NS, Boldrini V, Knittel TL, Monterio LB, et al. SARS-
449 CoV-2 Uses CD4 to Infect T Helper Lymphocytes. medRxiv. 2020:2020.09.25.20200329.
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450 24. Zhao J, Yuan Q, Wang H, Liu W, Liao X, Su Y, et al. Antibody Responses to SARS-CoV-
451 2 in Patients With Novel Coronavirus Disease 2019. Clin Infect Dis. 2020;71(16):2027-34.
452 25. Ribeiro LC, Benites BD, Ulaf RG, Nunes TA, Costa-Lima C, Addas-Carvalho M, et al.
453 Rapid clinical recovery of a SARS-CoV-2 infected common variable immunodeficiency patient
454 following the infusion of COVID-19 convalescent plasma. Allergy Asthma Clin Immunol.
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455 2021;17(1):14.
456 26. Rijkers G, Murk JL, Wintermans B, van Looy B, van den Berge M, Veenemans J, et al.
457 Differences in Antibody Kinetics and Functionality Between Severe and Mild Severe Acute
458 Respiratory Syndrome Coronavirus 2 Infections. J Infect Dis. 2020;222(8):1265-9.
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459 27. Naveca F CC, Nascimento V, Souza V, Corado A, Nascimento F. et al., SARS-CoV-2
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460 reinfection by the new Variant of Concern (VOC) P.1 in Amazonas, Brazil. Virological.org. [cited
461 2021].
462 28. Buss LF, Prete CA, Abrahim CMM, Mendrone A, Salomon T, de Almeida-Neto C, et al.
463 Three-quarters attack rate of SARS-CoV-2 in the Brazilian Amazon during a largely unmitigated
464 epidemic. Science. 2021;371(6526):288-92.
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465 29. Brasil MdSd. Plano
466 Nacional de Operacionalização da Vacinação contra a COVID-19. In: Sanitária AnNdVn, editor.
467 Agência Nacional de Vigilância Sanitária2021.
468 30. Palacios R, Patiño EG, de Oliveira Piorelli R, Conde MTRP, Batista AP, Zeng G, et al.
469 Double-Blind, Randomized, Placebo-Controlled Phase III Clinical Trial to Evaluate the Efficacy
470 and Safety of treating Healthcare Professionals with the Adsorbed COVID-19 (Inactivated)
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471 Vaccine Manufactured by Sinovac - PROFISCOV: A structured summary of a study protocol for
472 a randomised controlled trial. Trials. 2020;21(1):853.
473 31. Hoffmann M, Arora P, Groß R, Seidel A, Hörnich B, Hahn A, et al. SARS-CoV-2 variants
474 B.1.351 and B.1.1.248: Escape from therapeutic antibodies and antibodies induced by infection
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475 and vaccination. bioRxiv. 2021:2021.02.11.430787.
476 32. Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus AD, et
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33.
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al. Mapping the antigenic and genetic evolution of influenza virus. Science. 2004;305(5682):371-
6.
Röltgen K, Powell AE, Wirz OF, Stevens BA, Hogan CA, Najeeb J, et al. Defining the
features and duration of antibody responses to SARS-CoV-2 infection associated with disease
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481 severity and outcome. Sci Immunol. 2020;5(54).
482 34. LC R, BD B, RG U, TA N, C C-L, M A-C, et al. Rapid clinical recovery of a SARS-CoV-
483 2 infected common variable immunodeficiency patient following the infusion of COVID-19
484 convalescent plasma. Allergy, asthma, and clinical immunology : official journal of the Canadian
485 Society of Allergy and Clinical Immunology. 2021;17(1).
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486
487
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488 Figures legend
ed
489
490 Figure 1. SARS-CoV-2 lineage P.1 is poorly recognized by a commercial SARS-CoV-2 anti-
491 spike (S1) antibodies. Cells were inoculated with isolates B and P.1 (P.12) of SARS-CoV-2,
492 cultured in glass slides, fixed with 4% PFA and stained with anti-N in red (A, B), anti-S in green
iew
493 (C, D), images were merged using ImageJ (E, F) and phalloidin for actin filaments (G, H). Nuclei
494 were labelled with DAPI in blue. Slides were analyzed by confocal microscopy. Images showed
495 were representative of P.1/12 isolate.
496
497
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498 Figure 2. P.1 SARS-CoV-2 isolates are neutralized less efficiently by plasma from COVID-
499 19-convalescent blood-donors and CoronaVac vaccine recipients. (A) Plasma of COVID-19-
500 convalescent blood-donors (n=19) were analysed by VNT50 against two isolates of P.1 lineage
501 (isolate P.1/12 and isolate P.1/30) and compared to an isolate of the B lineage (isolates
r
502 SARS.CoV2/SP02.2020). (B) Plasma of CoronaVac vaccine recipients (n=8) were tested by
503 VNT50 against two isolates of P.1 lineage (isolate P.1/12 and isolate P.1/30) and compared to a B.
504
505
506
er
lineage isolate (isolates SARS.CoV2/SP02.2020). Dashed lines indicate the cut-off of VNT50 assay
for samples with low or absent virus neutralization capacity. The median and interquartile are
indicate with black dots and lines, respectively. Each data point is the average of a duplicate assay
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507 in two independent assays. ND = number of samples with VNT50 titre <20. LOD, limit of
508 detection.
509
510
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511
512
513
514
515
Figure 1.
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516
517
518 Figure 2.
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520
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521 Supplementary material
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522
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523
524
525 Supplementary Figure 1. SARS-CoV-2 lineage P.1 (P.1/12 and P.1/30) isolated from
tn
526 nasopharyngeal and bronchoalveolar lavage samples of COVID-19 patients from Manaus,
527 Amazonas, Brazil. Isolation of P.1 lineage of SARS-CoV-2 was performed in Vero cells in a
528 Biosafety Level 3 Facility of the Emerging Viruses Laboratory (LEVE) at the University of
529 Campinas, and a typical cytopathic effect was observed after 72hpi in inoculated cells (A) in
530 comparison with uninfected cells (B). The isolation was also confirmed by RT-qPCR for the
rin
531 envelope gene after RNA extraction of the cell supernatant, where is possible to observe an
532 increase in viral load (C) and a decrease in the CT value (D) after the sustained passages in Vero
533 cells. Images were obtained in an EVOS inverted microscope kindly provided by Thermo Fisher
534 Scientific. Images showed were representative of P.1/12 isolate.
ep
535
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536
537
538 Supplementary Figure 2. Representative image of virus neutralization test of plasma from
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539 COVID-19-convalescent blood-donors and CoronaVac vaccine recipients against isolates of

540 P.1 (P.1/12) and B lineages.
541
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542 Table S1. Information of samples positive for SARS-CoV-2 lineage P.1 used in the viral
ed
543 isolation.
544
ID Sample Sex Age Collection date Symptoms CT-value 1 Viral isolation
type
iew
2 NPS or BAL male 37 23/12/20 unreported 28.78 no2
12 NPS or BAL male 30 17/12/20 unreported 20.33 yes
ev
13 NPS or BAL female 26 17/12/20 unreported 20.39 no2
r
28 NPS or BAL female 73 21/12/20 unreported 21.44 yes
30
31
34
NPS or BAL
NPS or BAL
NPS or BAL
male
female
female
28
27
45
21/12/20
21/12/20
22/12/20
er
unreported
unreported
unreported
29.38
22.41
22.11
yes
no2
no2
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2298 NPS and OR female 26 04/01/21 symptomatic 19.1 yes
2299 NPS and OR male 86 04/01/21 symptomatic 14.5 no2
2300 NPS and OR female 80 04/01/21 symptomatic 19.6 no2
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2304 NPS and OR male 28 04/01/21 unreported 28.6 no2

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2309 NPS and OR female 52 05/01/21 unreported 15.1 no2
2325 NPS and OR female 86 07/01/21 symptomatic 20.9 no2
2327 NPS and OR female 39 08/01/21 unreported 15.7 no2

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545
546 Legend: 1CT-value based on RT-qPCR for the envelope gene of SARS-CoV-2. 2The viral isolation attempts these
547 samples are in progress. NPS, nasopharyngeal. BAL, bronchoalveolar lavage. OR, oropharyngeal. The samples
548 described here were classified in SARS-CoV-2 lineage P.1 by genome sequencing17.
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18
Table S2. Information of COVID-19-convalescent blood-donors.
ed
ID age sex Diagnosis Symptoms Time between Hospitalization Plasma IgM IgG Group
durations symptoms and collection
(days) collection
(days)
iew
BD280 31 female RT-qPCR 14 52 no 21/05/20 0.88 2.82 moderate
BD504 48 male RT-qPCR 11 42 no 01/06/20 7.92 3.54 highest
BD000 33 female RT-qPCR 19 44 no 11/06/20 5.48 8.15 highest
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BD129 34 male serology 4 69 no 08/07/20 0.74 5.73 highest
r
BD145 58 male serology 10 102 no 10/07/20 1.88 5.47 highest
BD927
BD935
BD947
44
28
18
male
female
male
RT-qPCR
serology
serology
2
10
3
er
68
56
84
no
no
no
24/07/20
24/07/20
21/07/20
16.34 6.31 highest
13.27 7.04 moderate
3.64 7.14 moderate

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BD966 29 female RT-qPCR 13 43 yes 24/07/20 22.16 8.1 highest
BD160 34 female RT-qPCR 9 73 no 30/07/20 9.23 6.07 moderate
BD891 57 male serology 17 10 no 04/08/20 1.39 5.5 moderate

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BD900 36 female serology 0 28 no 05/08/20 1.94 7.61 moderate

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BD466 43 female serology 16 68 no 13/08/20 3.06 8.36 highest
BD5063 25 female serology 34 69 yes 27/08/20 0.29 2.55 highest
BD510 41 male RT-qPCR 16 65 no 29/08/20 7.87 0.63 moderate

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Legend: NAs, neutralizing antibodies.

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Table S4. Information of plasma specimens from CoronaVac vaccinated participants.
ID age sex 1st dose 2nd dose Plasma collection IgM IgG
iew
PiCoV-1 59 years female 13/08/20 28/08/20 28/01/21 0.29 0.33
PiCoV-3 29 years male 14/08/20 28/08/20 02/02/21 0.06 0.38
PiCoV-4 38 years male 14/08/20 28/08/20 02/02/21 0.06 0.08
ev
PiCoV-5 34 years male 14/08/20 28/08/20 02/02/21 0.15 0.36
PiCoV-7 32 years male 14/08/20 28/08/20 03/02/21 0.87 0.31
r
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20
Table S4. VNT50 values of COVID-19-convalescent blood-donors against isolates of SARS-CoV-
ed
2 lineage B (isolate SARS.CoV2/SP02.2020) and lineage P.1 (isolates P.1/12 and P.1/30).
VNT50 titer
iew
Plasma ID P.1 (isolate 12) P.1 (isolate 30) B
BD280 <20 <20 20
BD504 60 30 120
BD000 90 35 480
BD864 110 35 240
ev
BD900 50 50 320
BD129 30 60 320
BD138 20 <20 480
r
BD145 47 95 800
BD927 50 60 480
BD935
BD947
20
40
er <20
55
240
200
pe
BD966 140 120 2560
BD160 27 40 120
BD891 20 30 60
BD900 <20 <20 100
BD880 80 <20 2560
ot
BD466 90 35 320
BD5063 30 20 120
tn
BD510 <20 <20 50

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Table S5. VNT50 values of plasma from 8 CoronaVac post-immunization individuals against
ed
isolates of SARS-CoV-2 lineage B (isolate SARS.CoV2/SP02.2020) and lineage P.1 (isolates
P.1/12 and P.1/30).
VNT50 titer
iew
Plasma ID P.1 (isolate 12) P.1 (isolate 30) B
PiCoV-1 <20 <20 60
PiCoV-2 <20 <20 20
PiCoV-3 <20 <20 <20
ev
PiCoV-4 <20 <20 <20
PiCoV-5 <20 <20 30
PiCoV-6 <20 <20 20
r
PiCoV-7 <20 <20 30
PiCoV-8 <20 <20 30
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1 Levels of SARS-CoV-2 lineage P.

University School of Medicine, St. Louis, USA.

400 Serology. Cell. 2020;183(4).

409 9. Tegally H, Wilkinson E, Giovanetti M, Iranzadeh A, Fonseca V, Giandhari J, et al.

539 COVID-19-convalescent blood-donors and CoronaVac vaccine recipients against isolates of

2304 NPS and OR male 28 04/01/21 unreported 28.6 no2

2305 NPS and OR male 28 04/01/21 symptomatic 17.2 no2

2309 NPS and OR female 52 05/01/21 unreported 15.1 no2

2325 NPS and OR female 86 07/01/21 symptomatic 20.9 no2

2327 NPS and OR female 39 08/01/21 unreported 15.7 no2

BD504 48 male RT-qPCR 11 42 no 01/06/20 7.92 3.54 highest

BD000 33 female RT-qPCR 19 44 no 11/06/20 5.48 8.15 highest

BD864 31 female RT-qPCR 22 66 no 26/06/20 2.11 4.66 highest

BD129 34 male serology 4 69 no 08/07/20 0.74 5.73 highest

BD138 32 female RT-qPCR 16 60 no 09/07/20 2.48 0.01 highest

13.27 7.04 moderate

3.64 7.14 moderate

BD160 34 female RT-qPCR 9 73 no 30/07/20 9.23 6.07 moderate

BD891 57 male serology 17 10 no 04/08/20 1.39 5.5 moderate

BD900 36 female serology 0 28 no 05/08/20 1.94 7.61 moderate

BD880 34 male RT-qPCR 13 45 no 10/08/20 45.86 5.62 highest

BD466 43 female serology 16 68 no 13/08/20 3.06 8.36 highest

BD5063 25 female serology 34 69 yes 27/08/20 0.29 2.55 highest

BD510 41 male RT-qPCR 16 65 no 29/08/20 7.87 0.63 moderate

Legend: NAs, neutralizing antibodies.

PiCoV-2 40 years female 14/08/20 28/08/20 28/01/21 0.26 0.06

PiCoV-3 29 years male 14/08/20 28/08/20 02/02/21 0.06 0.38

PiCoV-4 38 years male 14/08/20 28/08/20 02/02/21 0.06 0.08

PiCoV-6 36 years female 14/08/20 28/08/20 02/02/21 0.12 0.16

PiCoV-7 32 years male 14/08/20 28/08/20 03/02/21 0.87 0.31

BD510 <20 <20 50

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