Age-dependent immune response to the
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Biontech/Pfizer BNT162b2 COVID-19
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vaccination
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Lisa Müller#
+1
, Marcel Andrée#
+1
, Wiebke Moskorz
1
, Ingo Drexler
1
, Lara Walotka
1
,
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Ramona Grothmann
1
, Johannes Ptok
1
, Jonas Hillebrandt
1
, Anastasia Ritchie
1
, Denise
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Rabl
1
, Philipp Niklas Ostermann
1
, Rebekka Robitzsch, Sandra Hauka
1
, Andreas
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Walker
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, Christopher Menne
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, Ralf Grutza
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, Jörg Timm
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, Ortwin Adams*
+1
and Heiner
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Schaal*
+1
9
# shared first authors
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* shared senior authors
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+
Corresponding authors
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Institute of Virology, University Hospital Düsseldorf, Heinrich Heine University
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Düsseldorf, Düsseldorf, Germany
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15
Abstract
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Background:
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The SARS-CoV-2 pandemic has led to the development of various vaccines. Real-life
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data on immune responses elicited in the most vulnerable group of vaccinees over 80
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years old is still underrepresented despite the prioritization of the elderly in vaccination
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campaigns.
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Methods:
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We conducted a cohort study with two age groups, young vaccinees below the age of
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60 and elderly vaccinees over the age of 80, to compare their antibody responses to
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the first and second dose of the BNT162b2 COVID-19 vaccination.
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Results:
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. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprintthis version posted March 5, 2021. ; https://doi.org/10.1101/2021.03.03.21251066doi: medRxiv preprint
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
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While the majority of participants in both groups produced specific IgG antibody titers
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against SARS-CoV-2 spike protein, titers were significantly lower in elderly
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participants. Although the increment of antibody levels after the second immunization
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was higher in elderly participants, the absolute mean titer of this group remained lower
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than the <60 group. After the second vaccination, 31.3 % of the elderly had no
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detectable neutralizing antibodies in contrast to the younger group, in which only 2.2%
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had no detectable neutralizing antibodies.
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Conclusion:
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Our data suggests that lower frequencies of neutralizing antibodies after BNT162b2
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vaccination in the elderly population may require earlier revaccination to ensure strong
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immunity and protection against infection.
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Introduction
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In December 2019, authorities in China’s Wuhan province reported a lung disease of
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unknown cause. Back in January 2020, the sequence of a novel coronavirus was
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published and identified as the causative agent of this disease [1]. In March of the
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same year, the World Health Organization (WHO) declared the spread of this virus a
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public health emergency of international concern. With limited drug treatment options
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available, research on prophylactic immunization, especially for high-risk groups,
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became a priority [2].
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The zoonotic beta-coronavirus SARS-CoV-2 is closely related to severe acute
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respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome
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coronavirus (MERS-CoV), which caused outbreaks in 2002/2003 and 2012
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respectively [3]. SARS-CoV-2 and its associated disease COVID-19, however, show
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distinct characteristics [4] including a highly variable severity of clinical symptoms, from
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asymptomatic infection to severe COVID-19 with lung manifestation and acute
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respiratory distress syndrome. Viral replication usually begins and continues in the
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upper respiratory tract for up to 14 days after the onset of symptoms, which contributes
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to the rapid spread of the virus. While the clinical course of COVID-19 is usually quite
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mild and often presents with flu-like symptoms, up to 14% of patients show a severe
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course of infection [5]. The elderly population is primarily at risk for severe disease, as
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. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprintthis version posted March 5, 2021. ; https://doi.org/10.1101/2021.03.03.21251066doi: medRxiv preprint
2
adults over 65 years of age account for approximately 80% of hospitalizations [6, 7]
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and higher death rates have been reproducibly reported in this population [8, 9].
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Additionally, prolonged disease from hospitalization, delayed viral clearance, and/or a
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higher fatality rate is also reported to be age-related [9]. Comorbidities such as
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cardiovascular disease, diabetes, and obesity are discussed as the primary cause of
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a more severe COVID-19 course, however, these comorbidities alone do not explain
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why age is such a strong risk factor.
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Aging is accompanied by changes in the immune system, particularly affecting
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adaptive immunity’s three fundamental pillars, i.e. B cells, CD4+ T cells, and CD8+ T
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cells [10]. Although hallmarks of immunosenescence depend on multifaceted factors
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and vary greatly between individuals, they are generally considered to be related to i)
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the decreased ability to respond to new antigens associated with a reduced peripheral
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plasmablast response; (ii) decreased capacity of memory T cells and (iii) a low level of
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persistent chronic inflammation [11-14]. This leads to declining immune efficiency and
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fidelity, resulting in increased susceptibility to infectious diseases and decreased
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response to vaccinations. Additionally, it contributes to increased susceptibility to age-
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related pathological conditions including cardiovascular diseases or autoreactive
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diseases such as rheumatoid arthritis [12, 15].
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In December 2020, the first vaccines for COVID-19 were approved worldwide and the
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first vaccinations were carried out [16-19]. While the German Standing Committee on
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Vaccination (STIKO) recommends immunization against SARS-CoV-2, access to the
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vaccine in Germany and many other countries worldwide at the beginning of 2021 is
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offered in a prioritization procedure due to limited availability. First, groups of people
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who are at particularly high risk for severe courses of COVID-19 disease or who are
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professionally in close contact with such vulnerable people were vaccinated. These
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two prioritized groups include senior residents of nursing homes aged ≥ 80 years, and
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their caregivers typically aged ≤ 65 years. A recent, thorough study using mathematical
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modeling to investigate vaccine prioritization strategies supports the preferential
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vaccination of the elderly [20]. This study describes a scenario where cumulative
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incidence rates were minimized when vaccination of the population aged 20-49 years
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was prioritized, while mortality was decreased when the population aged 60 years or
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older was prioritized. This model took age-structure, age-related efficacy, and
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infection-fatality rates into account. They conclude that prioritizing the population aged
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. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprintthis version posted March 5, 2021. ; https://doi.org/10.1101/2021.03.03.21251066doi: medRxiv preprint
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> 60 years, thus directly protecting the vulnerable population, would decrease mortality
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rates, a strategy that is currently employed by various nations but without the support
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of recent and thorough data [20].
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The current vaccination strategy for the Biontech/Pfizer Comirnaty (BNT162b2) is a
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two-step "prime and boost" procedure in which the first vaccination is followed by a
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second vaccination with the same dose at least 21 days later [18]. Initial experience
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shows high effectiveness of the vaccines in preventing clinical symptoms after the first
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dose [21].
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Immediately after the start of the official vaccination campaign in Germany at the end
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of December 2020, we started a daily practice study in a retirement home. To
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accommodate two clearly distinct populations in this study, we compared the induction
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of immune responses between young and elderly vaccinees (< 60 years of age and >
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80 years of age respectively) who received their first and second vaccines on the same
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day. For this purpose, the IgG titers against SARS-CoV-2 spike S1 as well as
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neutralization titers were determined after both the first and second vaccination. Self-
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reported side effects were scored according to the sum of symptoms post-vaccination.
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Methods
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Study population
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Characteristics of the study population are summarized in Table 1. The ethics
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committee of the Medical Faculty at the Heinrich-Heine University Düsseldorf,
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Germany (study no. 2021-1287), approved the study. Informed consent was obtained
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from all volunteers (N = 179) before sampling. All blood samples were collected on
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January 15
th
, 2021 (first collection, 17—19 days after first immunization) and February
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5
th
, 2021 (second collection, 17 days after second immunization) and stored at 4 °C.
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Medical questionnaires including the following categories were scored according to the
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sum of symptoms post-vaccination: i) elevated temperature and fever, ii) chills, iii) pain
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at the injection site, iv) head/limb pain, v) fatigue/tiredness, vi) nausea/dizziness, vii)
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other complaints (unscored).
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. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprintthis version posted March 5, 2021. ; https://doi.org/10.1101/2021.03.03.21251066doi: medRxiv preprint
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Commercially available Anti-SARS-CoV-2 tests systems
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Samples were tested for Anti-SARS-CoV-2 antibodies using two commercially
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available test systems: Euroimmun Anti-SARS-CoV-2-QuantiVac-ELISA measuring
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IgG levels against SARS-CoV-2 spike S1 subunit and Abbott Architect SARS-CoV-2
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IgG recognizing SARS-CoV-2 nucleocapsid (N) antibodies.
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Euroimmun ELISA was performed on the Euroimmun Analyzer I-2P according to the
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manufacturer's instructions. Results < 25.6 BAU/ml were considered as negative, ≥
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25.6 BAU/ml ≤ 35.2 BAU/ml as indeterminate, and > 35.2 BAU/ml as positive (BAU =
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Binding Antibody Units). The upper detection limit for undiluted samples was > 384
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BAU/ml, the lower detection limit was < 3.2 BAU/ml. For samples over the detection
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limit, 1:10 or 1:100 dilutions were performed in IgG sample buffer according to the
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manufacturer’s instruction. The SARS-CoV-2 IgG chemiluminescent microparticle
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immunoassay (CMIA) from Abbott was performed on an ARCHITECT i2000 SR. The
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relation of chemiluminescent RLU and the calibrator is given as the calculated index
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(S/C). An index (S/C) <1.4 as was considered negative, ≥1.4 was considered positive.
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In-house SARS-CoV-2 neutralization test
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A neutralization test with the infectious SARS-CoV-2 isolate (EPI_ISL_425126) was
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performed in a BSL-3 facility to determine the SARS-CoV-2 neutralization capacity of
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the serum samples after the first and second vaccination. A serial dilution endpoint
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neutralization test for SARS-CoV-2 was performed as previously described [22]. Serial
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dilutions of heat-inactivated (56°C, 30 minutes) serum samples were pre-incubated in
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cell-free plates with 100 TCID50 units of SARS-CoV-2 for 1 hour at 37° C. After pre-
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incubation, 100µl of cell suspension containing 7×10
4
/ml Vero cells (ATTC-CCL-81)
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were added. Plates were incubated at 37°C, 5% CO2 for 4 days before microscopic
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inspection for virus-induced cytopathic effect (CPE). The neutralization titer was
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determined as the highest serum dilution without CPE. Tests were performed in
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duplicate for each sample. Positive, negative, virus only, and cell growth controls were
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run during each assay.
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. CC-BY-NC-ND 4.0 International licenseIt is made available under a
is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)
The copyright holder for this preprintthis version posted March 5, 2021. ; https://doi.org/10.1101/2021.03.03.21251066doi: medRxiv preprint
