key: cord-0712643-ywa4awlb
authors: Shrotri, M.; Fragaszy, E.; Geismar, C.; Nguyen, V.; Beale, S.; Braithwaite, I.; Byrne, T. E.; Fong, W. L. E.; Kovar, J.; Navaratnam, A. M. D.; Patel, P.; Rodger, A.; Hayward, A. C.; Aldridge, R. W.
title: Spike-antibody responses following first and second doses of ChAdOx1 and BNT162b2 vaccines by age, gender, and clinical factors - a prospective community cohort study (Virus Watch)
date: 2021-05-15
journal: nan
DOI: 10.1101/2021.05.12.21257102
sha: 59b1a6d21da5b60428db88bedc059e5029282214
doc_id: 712643
cord_uid: ywa4awlb

Background Vaccination constitutes the best long-term solution against Coronavirus Disease 2019 (COVID-19). Real-world immunogenicity data are sparse, particularly for ChAdOx1 and in populations with chronic conditions; and given the extended dosing interval in the UK, it is also important to understand antibody responses in SARS-CoV-2-naive individuals following a single dose. Methods Adults aged 18+ years from households enrolled in Virus Watch, a prospective community cohort study in England and Wales, provided capillary blood samples and self-reported vaccination status. Primary outcome variables were quantitative Spike total antibody levels (U/ml) and seropositivity to Spike (>=0.8 U/ml), as per the Roche Elecsys Anti-SARS-CoV-2 S assay. Samples seropositive for Nucleocapsid, and samples taken prior to vaccination, were excluded. Outcomes were analysed by days since vaccination, vaccine type (BNT162b2 and ChAdOx1), and a range of self-reported demographic and clinical factors. Results 8,517 vaccinated participants (median age 65 years [IQR: 58, 71]), contributed 13,232 samples (8,115 following ChAdOx1, 5,008 following BNT162b2). Seropositivity to Spike was 96.42% (95%CI 96, 96.79) at 28-34 days following a single dose, reaching 99.08% (97.8, 99.62) at 7-14 days after a second dose. Seropositivity rates, and Spike-antibody levels rose more quickly following the first dose of BNT162b2, however, were equivalent for both vaccines by 4 and 8 weeks, respectively. There was evidence of lower S-antibody levels with increasing age (p=0.0001). In partially vaccinated 65-79 year-olds, lower S-antibody levels were observed in men (25.9 vs 42.3 U/ml, p<0.0001), those with a chronic condition (33.0 vs 41.2 U/ml, p<0.0001), diabetes (22.32 vs 36.01 U/ml, p<0.0001), cardiovascular disease (32.1 vs 36.7 U/ml, p=0.0002), or history of cancer (30.1 vs 35.7 U/ml, p=0.0001), particularly those with haematological rather than solid organ cancer (7.48 vs 31.68 U/ml, p<0.0001), and those currently on immunosuppressive therapy (21.7 vs 35.6 U/ml, p<0.0001). Following a second dose, high S-antibody titres (>=250U/ml) were observed for nearly all individuals. Interpretation A single dose of either BNT162b2 or ChAdOx1 leads to high Spike seropositivity rates in SARS-CoV-2-naive individuals. However, observed disparities in antibody levels after the first dose by vaccine type, age, and comorbidities highlight the importance of ongoing non-pharmaceutical preventative measures such as social distancing, for partially vaccinated adults, particularly those who are older and more clinically vulnerable.

The ongoing Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic and the morbidity and mortality resulting from the associated clinical syndrome, Coronavirus disease-2019 (COVID-19), has had a devastating impact on many nations with over 158,651,638 confirmed cases and 3,299,764 deaths reported globally as of 11 May 2021 1 . Early in the pandemic, global vaccine developers joined the race to find a definitive, long-term solution, pivoting both established and experimental vaccine platforms towards SARS-CoV-2, with many candidates having now completed clinical testing and achieved licensure 2 . Pfizer/BioNTech's BNT162b2 messenger RNA vaccine, and Oxford/AstraZeneca's ChAdOx1 nCoV-19 non-replicating adenovirus-vectored vaccine were licensed in the UK in December 2020 3, 4 . Both vaccines are based on the Spike protein of SARS-CoV-2, which contains the receptor binding domain -the target for neutralising antibodies that can prevent the virus binding to the ACE2 receptor on the human cell surface 5 . The formulation of these vaccines allows antibodies against the Nucleocapsid protein, an abundant and highly immunogenic viral antigen 6 , to remain discriminatory for natural infection.

Vaccination has been offered in accordance with the UK's Joint Committee on Vaccination and Immunisation's prioritisation framework 7 , with 35,587,348 people having received their first vaccine dose as of 11 May 2021 8 .

Trial and observational data have demonstrated efficacy of both vaccines against infection and clinical severity 9-12 , with increasing evidence for impact on transmission 11, [13] [14] [15] . While there are abundant trial data on immunogenicity, evidence is generally limited to younger, healthier trial populations, as well as to manufacturer-recommended dosing regimens. In the UK, the recommended dosing interval was extended from 3-4 weeks, to 8-12 weeks in order to maximise first-dose coverage across the population 16 ; thus there is a pressing need to understand features of the humoral immune response between 4-12 weeks in a real-world setting, particularly for BNT162b2. Furthermore, it is critical to understand immunogenicity amongst older people, those with metabolic risk factors, and those from ethnic minority backgrounds, as these groups are at highest risk of COVID-19 morbidity and mortality [17] [18] [19] [20] ; as well as those on immunosuppressive therapies, which are likely to attenuate vaccine responses 21 . The existing observational data are limited by reporting on specific populations such as healthcare workers 22,23 or long-term care residents 24 ; by focusing solely on BNT162b2 22,25,26 or shorter dosing intervals 25 ; by lack of detailed information on underlying health conditions 27 ; and often relatively small sample sizes.

We analysed serological data from a large prospective community cohort, Virus Watch 28 , obtained using a widely available, validated commercial assay. We determined seropositivity rates for Spike, and Spike-antibody levels in order to investigate vaccine responses in individuals without prior infection from the general population of England and Wales.

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The analysis was conducted as part of a prospective community cohort study based in England and Wales, which commenced recruitment in May 2020. Invitations to participate in monthly antibody testing were sent to previously enrolled eligible households over February-March 2021. Consenting participants provided monthly capillary blood samples and weekly self-reported vaccination data in addition to demographic and clinical data collected at enrolment into the study.

Blood samples were self-collected by participants using an at-home capillary blood sample collection kit, manufactured by the company Thriva [https://thriva.co/]. Completed kits were returned by participants using prepaid envelopes and priority postage boxes to UKAS-accredited laboratories, for serological testing using Roche's Elecsys Anti-SARS-CoV-2 assays targeting total immunoglobulin (Ig) to the Nucleocapsid (N) protein or to the receptor binding domain in the S1 subunit of the Spike protein (S) (Roche Diagnostics, Basel, Switzerland).

At the manufacturer-recommended cut-offs (≥0.1 cut-off index [COI] for N and ≥ 0.8 units per millilitre [U/ml] for S), the N assay has a sensitivity of 97·2%-99.5% and specificity of 99.8% 29-31 , while the S assay has a sensitivity of 97.9%-98.8% and a specificity of 100% [32] [33] [34] , with high agreement between the assays for samples from previously infected individuals 32 .

Within the Virus Watch cohort, eligible households were defined as having at least one adult aged 18 years and over, a valid England or Wales postcode, a complete postal address registered at enrollment, complete gender and ethnicity information for all household members, and not enrolled in the study sub-cohort undergoing longitudinal point-of-care antibody testing as part of index case investigations 28 .

Individuals that were 18 years and over within eligible households could consent to participate through provision of valid, electronic consent. Individuals were included in this analysis if they had provided at least one sample following one or more doses of vaccination. Evidence of natural infection was defined as seropositivity for the Nucleocapsid protein. Individuals meeting this criterion were excluded from the analysis. Samples with void results from either assay were also excluded from the analysis.

Individuals reporting vaccination prior to national licensure dates (8 December 2020 for BNT162b2 and 30 December 2020 for ChAdOx1) were assumed to either be clinical trial participants or to have reported an erroneous date and were excluded from the analysis.

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Self-reported vaccination status was collected through the weekly Virus Watch questionnaire. The item was introduced on 11 January 2021 and asked about any prior vaccination for the first two surveys. Subsequently, participants were asked to provide a weekly update only.

Time since vaccination was defined according to whether a sample was recorded as being i) on the same date as, or subsequent to, the first vaccine dose, and prior to the date of the second dose (considered a first dose sample), or ii) on the same date as, or subsequent to, the second dose -considered a second dose sample. Days since vaccination were then grouped into the following intervals: 0-6, 7-13, 14-20, 21-27, 28-34, 35-41, 42-55, 56-69, and 70-83 days for first dose; and 0-6, 7-13, ≥ 14 days for second dose samples. Binary variables were created to indicate results that were ≥ 28 days following the first vaccine dose, and ≥ 14 days following the second vaccine dose.

The main outcome variables were seropositivity to Spike, and level of Spike antibodies (U/ml), as per Roche's Elecsys Anti-S total immunoglobulin assay. The assay measuring range was 0.4 250 U/mL, with cut-off for positivity at ≥ 0.8 U/ml.

Self-reported demographic data, including age, sex, and ethnicity, as well as binary health status variables, including current immunosuppressive therapy, cancer diagnosis (previous or current), and current chronic diseases, were collected at enrollment. Where appropriate, individual conditions were grouped into broader categories such as respiratory, neurological, or cardiovascular conditions. Self-reported 'no chronic condition' status excluded obesity, which was assigned by the research team as BMI ≥ 30, calculated using self-reported height and weight data, or from a visual analogue scale for body size if biometric data were unavailable.

Age was grouped into 18-34, 35-49, 50-64, 65-79, ≥ 80 years categories. Ethnicity data were collapsed into White, South Asian, Other Asian, and Mixed categories. Sex was limited to Male and Female with other categories suppressed due to small numbers. Vaccine types other than BNT162b2 and ChAdOx1 were not examined separately due to small numbers.

We calculated proportions of seropositive individuals (as per ≥ 0.8 U/ml cut-off) for each time interval and the 95% confidence interval around each proportion. We calculated the median and interquartile range of S-antibody levels for each group from all available values, including those below the cut-off for binary positivity.

The distribution of S-antibody levels was tested for normality using the Kolmogorov-Smirnov test. Bonferroniadjusted p-values for the difference between median S-antibody levels between different groups were derived using . CC-BY-NC-ND 4.0 International license It 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 preprint this version posted May 15, 2021. ; https://doi.org/10.1101/2021.05.12.21257102 doi: medRxiv preprint 6 non-parametric tests: the Mann-Whitney U (Wilcoxon Rank Sum) test for two groups, or the Kruskal-Wallis test for >2 groups. We compared S-antibody levels between BNT162b2 and ChAdOx1 vaccinees and between age groups, at ≥ 28 days after the first dose. We also compared S-antibody levels by sex, ethnicity, and chronic condition, obesity, or immunosuppressive therapy status at ≥ 28 days after the first dose; to minimise confounding by age this analysis was restricted to 65-79 year-olds for most conditions as it was the largest age group; however for HIV the 35-49 years age group was used as it contained most individuals with HIV. We did not compare S-antibody levels after the second dose due to small numbers and limitations of the dynamic range of the assay. 

This study has been approved by the Hampstead NHS Health Research Authority Ethics Committee. Ethics approval number -20/HRA/2320.

The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

The corresponding author had full access to all data in the study and had final responsibility for the decision to submit for publication. Results 8,517 participants without evidence of prior infection (N-antibody negative), with a median age of 65 (IQR 58, 71), of whom 57% were female and 97% were of a White ethnicity, contributed 13,232 samples following at least one dose of a COVID-19 vaccine (Table 1) . 70.4% (n=5,997) of individuals reported at least one chronic condition, with 10% (n=881) reporting ever having received a cancer diagnosis and 0.9% (n=74) reporting prior or current haematological malignancy. 4.0% (n=342) were classified as obese, and 6.8% (n=579) reported currently taking some form of immunosuppressive therapy. The majority of included samples (11, 645, 88 Demographic and clinical characteristics were broadly similar across the two main vaccine types, though BNT162b2 vaccinees were slightly older and more likely to report a chronic condition or immunosuppressive therapy, and also to have longer median intervals between first or second dose date and sample dates (dose 1: 48 vs 35 days; dose 2: 12 vs 6) ( Table 2 ). The majority of second dose samples were from BNT162b2 vaccinees (997/1,409, 70.8%).

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The proportion of seropositive individuals rose more quickly following the first dose of BNT162b2 than ChAdOx1; these were 89.27% (83. 52 

S-antibody levels increase over time after the first vaccine dose for both main vaccine types, however levels were higher at earlier time points following BNT162b2 than ChAdOx1 (Table 3, Figure 2 ). There also appeared to be a . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 15, 2021. ; https://doi.org/10.1101/2021.05.12.21257102 doi: medRxiv preprint very slight but consistent decline in S-antibody levels for BNT162b2 vaccinees from 35-41 days onwards, and conversely a slight but sustained increase in titres in ChAdOx1 vaccinees over the same period.

There was evidence to suggest a significant difference in S-antibody levels by age group at ≥ 28 days after a single dose (p=0.0001), with lower S-antibody levels seen in older age groups (18- Figure 3 ).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. clinical groups after the first dose, particularly amongst those with diagnoses or therapies affecting the immune system. Importantly, S-antibody levels are significantly lower in individuals with common comorbidities such as diabetes and cardiovascular disease; interestingly however, this is not the case for obesity.

A study of a larger healthcare worker cohort found that seroconversion rates were 99.5% (2706/2720) and 97.1%

(864/890) at >14 days after a single dose of BNT162b2 and ChAdOx1, respectively 23 . The slightly lower seroconversion rates observed in our cohort could be attributed to the older average age and higher prevalence of comorbidities, and thus a reduced healthy-worker bias. Conversely, seroconversion rates appear substantially higher in our cohort than those reported by the REACT2 study 35 which found 84.1% (82.2, 85.9) seroconversion ≥ 21 days after a dose of BNT162b2; though this may be attributable to differences in assay sensitivities.

A large observational study including 38,262 SARS-CoV-2-naive individuals (from a community cohort enrolled in the UK's national COVID-19 Infection Survey), modelled the probability of seroconversion to Spike following a single dose vaccination 27 . Similar to our findings, they reported lower probabilities of seroconversion, as well as slower rate of increase of S-antibody titres, following ChAdOx1 compared with BNT162b2; also in line with our findings, differences between the two vaccines attenuated at later time points following the first dose. For BNT1612b2, the authors reported a gradual decline in anti-S levels from 35 days post-first dose, whereas titres remained stable for ChAdOx1. We also observed a very slight decline over this time period for BNT162b2, but noted a slight and sustained increase in titres for ChAdOx1 over the same time period. It is not possible to compare the magnitude of these effects across the studies due to lack of standardisation across the different assays; nor is it yet clear whether these trends are of clinical significance.

Both trial and observational data relating to single-dose BNT162b2 [36] [37] [38] [39] and ChAdOx1 27,40 indicate lower antibody titres in older adults compared to younger adults, which is also reflected in our findings. While evidence directly linking S-antibody titres with efficacy in older age groups is lacking, available data do suggest lower VE against infection in older populations 11, 41 ; however VE against clinical outcomes appears similar across age groups 9,42 , which may be because the baseline risk of these outcomes is much higher in older people. Taken together, these . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 15, 2021. ; https://doi.org/10.1101/2021.05.12.21257102 doi: medRxiv preprint findings suggest that immune correlates of protection are likely to vary by the specific clinical outcome studied and age disparities may be more apparent for some than others.

Notably, those with haematological malignancy and those on immunosuppressive medications, especially following organ transplantation, showed markedly lower seroconversion rates after the first vaccine dose. This is in line with findings from studies focusing on patients with cancer 43 , and specifically those with haematological malignancy 44 , as well as immunosuppression 45, 46 , particularly following organ transplantation [47] [48] [49] . Taken together, these findings highlight the need to further investigate vaccine immunogenicity and efficacy in these groups. Early data hinting at the correlation of S-antibody levels with protection against infection 50 suggest that the impact of expediting the second dose of vaccination in these groups should be explored.

Our findings provide immunological insights to support real-world data on vaccine effectiveness (VE infections 42 . Several studies also report reduced PCR Cycle threshold values, indicative of viral load and potential infectivity 51,52 , from as early as 12 days following a single dose 11, 13, 15 . Across most reports, protective effects first appear between 2-4 weeks after a single dose depending on the outcome studied, and VE appears to increase over time; these trends mirror the immunogenicity data on seroconversion rates and S-antibody titres reported here and elsewhere 27 . There is also emerging evidence from other studies to suggest lower VE in those with diabetes and cardiovascular conditions 41 . However, counter to observed immunological trends, there is as yet little observational evidence demonstrating significant differences in single-dose VE between BNT162b2 and ChAdOx1 at 2-8 weeks.

Differences may be masked by the uncertainty in the available VE estimates, or it may be that, beyond a certain threshold that both vaccines achieve early on, S-antibody levels do not exactly correlate with protection.

Accumulating evidence suggests the importance of T-cell responses in protection against COVID-19 50,53,54 , and it may be that, at earlier time points when S-antibody levels following ChAdOx1 are lower than BNT162b2, VE is driven by T-cell immunity. Furthermore, in those with immunosuppression or haematological malignancy, it is possible that helper T-cell impairment contributes to attenuated antibody responses. As has been noted with immune responses to infection 55 , it is possible that the overall balance and co-ordination between humoral and cellular arms of the adaptive immune response may be the best predictor of protection 56 , rather than the level of any one immune component alone. In future work, it will be important to link data from deeper immunophenotyping with the risk of vaccine breakthroughs and failures, and their clinical severity and viral load, in order to better understand immunity against these outcomes.

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The strengths of this study include the large community cohort, which spans many ages and ethnic groups, and includes large numbers of individuals with common chronic conditions as well as capturing those with rarer diagnoses. To the best of our knowledge, these data constitute some of the earliest real-world evidence on immunogenicity in many of these clinical groups and also for ChAdOx1. We employed a highly sensitive, widely used validated commercial assay that gives quantitative readouts on a linear scale, allowing these data to be easily understood, replicated, and informative for clinical practitioners. Limitations include the use of self-reported vaccination status, which may have introduced error into the assignment of vaccination date and type, or the omission of a recent second dose for some individuals; and collection of clinical data at enrolment only, which may have led to misclassification due to more recent diagnoses. Additionally, the cancer categories encompassed both prior and current diagnoses. Due to the available platform and dilution capabilities, the dynamic range of the anti-S assay was limited to 0.4U/ml -250U/ml, which precluded differentiation of S-antibody levels between groups following the second dose. With regards to immunosuppressive therapies such as steroids, attenuation of vaccine responses is likely to be dose-dependent, however we were not able to ascertain dosage or duration of therapy; and we were also unable to distinguish specific drugs most likely to affect humoral responses such as Methotrexate or Rituximab 21,44,46,57 .

Our data indicate very high rates of seroconversion to Spike following a single dose of either vaccine, with nearcomplete seroconversion following a second dose, in individuals with no evidence of prior infection. Despite earlier responses with BNT162b2 compared to ChAdOx1, both vaccines demonstrate equivalent seropositivity rates and Santibody levels from 4 and 8 weeks following a single dose, respectively, with no differences in seropositivity seen after a second dose. Disparities in seropositivity rates between demographic and clinical groups also do not persist after the second dose. High seroconversion rates after the first dose lend support to the UK policy to prioritise firstdose coverage across the population, however our data also suggest attenuated immune responses in some clinical groups, which warrant further investigation. Studying longer-term dynamics of the humoral and cellular immune responses, and the correlates of protection against disease, asymptomatic infection, and onward transmission, including for emerging variants of concern, remain key questions for informing global COVID-19 control policies. 

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We aim to share aggregate data from this project on our website and via a "Findings so far" section on our websitehttps://ucl-virus-watch.net/. We will also be sharing individual record level data on a research data sharing service such as the Office of National Statistics Secure Research Service. In sharing the data we will work within the principles set out in the UKRI Guidance on best practice in the management of research data. Access to use of the data whilst research is being conducted will be managed by the Chief Investigators (ACH and RWA) in accordance with the principles set out in the UKRI guidance on best practice in the management of research data. We will put analysis code on publicly available repositories to enable their reuse.

Oliveira . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 15, 2021. ; https://doi.org/10.1101/2021.05.12.21257102 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 15, 2021 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Clin. Exp. Immunol. 202, 149-161 (2020) .

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It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint 

.

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint .

It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint Tables   Table 1. Demographic and clinical characteristics of individuals and samples included in the analysis. . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 15, 2021 . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 15, 2021 . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 15, 2021. ;  https://doi.org/10.1101/2021.05.12.21257102 doi: medRxiv preprint Table 2 . Key demographic and clinical features of individuals vaccinated with BNT162b2 and ChAdOx1, and the samples from these individuals. 

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The copyright holder for this preprint this version posted May 15, 2021. ; https://doi.org/10.1101/2021.05.12.21257102 doi: medRxiv preprint Table 4 . Numbers and proportions of samples positive for S-antibodies (≥0.8 U/ml), and average Santibody levels, at 28+ days since the first or 14+ days since the second dose of vaccination, by demographic and clinical characteristics (all ages). 

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. CC-BY-NC-ND 4.0 International license It 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 preprint this version posted May 15, 2021 . CC-BY-NC-ND 4.0 International license It 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 preprint this version posted May 15, 2021. ; https://doi.org/10.1101/2021.05.12.21257102 doi: medRxiv preprint Table 5 . Differences in S-antibody levels (U/ml) between demographic and clinical groups, following a single vaccine dose, with vaccine type and clinical categories restricted to the 65-79 years age group. . CC-BY-NC-ND 4.0 International license It 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)

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Early T cell and binding antibody responses are associated with COVID-19 RNA vaccine efficacy onset

Correlates of protection against SARS-CoV-2 in rhesus macaques

CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 775 (57%) 2,884 (58%) 3,064 (57%) 4,712 (58%) Median age, years (IQR) 68 (61, 73) 68 (62, 73) 64 (57, 70) 65 (58, 70) White ethnicity

 (35, 59) . CC-BY-NC-ND 4.0 International license It 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) . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 15, 2021 . CC-BY-NC-ND 4.0 International license It 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) . CC-BY-NC-ND 4.0 International license It is made available under a 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 May 15, 2021 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 preprint this version posted May 15, 2021. ; https://doi.org/10.1101/2021.05.12.21257102 doi: medRxiv preprint