key: cord-0835910-z0uh5mcu
authors: Thomson, T.; Prendecki, M.; Gleeson, S.; Martin, P.; Spensley, K.; Seneschall, C.; Gan, J.; Clarke, C. L.; Lewis, S.; Pickard, G.; Thomas, D. C.; McAdoo, S. P.; Lightstone, L.; Cox, A.; Kelleher, P.; Willicombe, M.
title: Comparative immunogenicity of heterologous versus homologous 3rd SARS-CoV-2 vaccine doses in kidney transplant recipients
date: 2022-01-26
journal: nan
DOI: 10.1101/2022.01.25.22269778
sha: a4af4ca5855043562d3440d19c652c114b76f7cd
doc_id: 835910
cord_uid: z0uh5mcu

Background Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. Emerging evidence suggests at least equivalent immunogenicity of heterologous compared with homologous vaccine regimens in the general population. In this study, we report on immune responses to 3rd dose BNT162b2 vaccines in transplant recipients either primed with ChAdOx1 or BNT162b2. Methods 700 kidney transplant recipients were prospectively screened for serological responses (median time of 33 (21-52) days) following 3 primary doses of a SARS-CoV2 vaccine. All vaccine doses were received post-transplant, and all 3rd doses were BNT162b2. All participants had serological testing performed post-2nd vaccination at a median time of 34 (IQR 26-46) days following the 2nd inoculation, and at least once prior to their 1st dose of vaccine. Results 366/700 (52.3%) participants were primed with BNT162b2, whilst 334/700 (47.7) had received ChAdOx1. Overall, 139/700 (19.9%) participants had evidence of prior infection. Of 561 infection-naive participants, 263 (46.9%) had no detectable anti-S following 2-doses of vaccine (V2). 134 (23.9%) participants remained seronegative post 3rd vaccine (V3); 54/291 (18.6%) and 79/270 (29.3%) of participants receiving BNT162b2 and ChAdOx1 respectively, p=0.0029. Median anti-S concentrations were significantly higher post-V3 in patients who had received BNT162b2 compared with ChAdOx1, at 612 (27-234) versus 122 (7.1-1111) BAU/ml respectively, p<0.0001. Cellular responses were investigated in 30 infection-naive participants at a median time of 35 (24-46) days post-V3. Eighteen of 30 (60.0%) participants had undetectable T-cell responses. There were neither qualitative or quantitative differences in T-cell responses between those patients who received BNT162b2 or ChAdOx1 as their first 2-doses, with 10/16 (62.5%) and 8/14 (57.1%) respectively having undetectable T-cell responses, p=0.77. Conclusion A significant proportion of transplant recipients remain seronegative following 3 doses of SARS-CoV-2 vaccines, with anti-S concentrations lower in patients receiving heterologous versus homologous vaccinations.

Weakened immunogenicity to SARS-CoV-2 vaccines has now been extensively demonstrated in recipients of solid organ transplants (1, 2) . To circumvent the potential attenuation in clinical efficacy, many countries have sanctioned additional vaccine doses to transplant and other immunosuppressed populations. Countries leading this strategy are almost exclusively utilising mRNA-based vaccines, either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna). Unlike many other developed countries, the UK rolled out BNT162b and ChAdOx1 nCoV-19 replication-deficient adenoviral vector vaccines in equal measure as primary vaccines, with third primary doses, consisting of solely mRNA-based vaccines, approved in September 2021.

Emerging data have since provided evidence on at least equivalent immunogenicity of heterologous compared with homologous vaccine regimens in both transplant recipients and the general population (3) (4) (5) (6) (7) . In this study, we report on immune responses to 3 rd dose BNT162b2 vaccines in transplant recipients either primed with ChAdOx1 or BNT162b as their first two doses.

Seven-hundred kidney transplant recipients were prospectively screened for serological responses following 3 primary doses of a SARS-CoV2 vaccine. All 3 rd doses received were BNT162b2, whilst the first 2 doses were either BNT162b2 or ChAdOx1. All vaccine doses were received posttransplant. All participants had serological testing performed post-2 nd vaccination at a median time of 34 (IQR 26-46) days following the 2 nd inoculation, and at least once prior to their 1 st dose of vaccine.

Of 700 participants included, 366/700 (52.3%) had received BNT162b2 as the first 2 doses, whilst 334/700 (47.7) had received ChAdOx1 (Supplemental Information Figure S1) Information Table S1 ).

Median anti-S concentrations were significantly higher post-V3 in patients who had received BNT162b2 compared with ChAdOx1, at 612 (27-234) versus 122 (7.1-1111) BAU/ml respectively, p<0.0001 (Figure 1a) . Anti-S concentrations had significantly increased post-V2 compared with V3 in both recipients of BNT162b2, 45 (7.1-510) to 612 (27-234) BAU/ml respectively, p<0.0001, and ChAdOx1, 7.1 (7.1-24) to 122 (7.1-1111) respectively, p<0.0001 (Figure 1b) . There was also a trend towards an inverse correlation between increasing age and T-cell response, r=-0.35, p=0.05.

T-cell responses were assessed in 6 participants post-V3 with prior infection, and 5/6 (83.3%) were ELISpot positive. The median SFU/10 6 PBMC in infection exposed participants was 255 (108-372), . 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.

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which was significantly higher than in the infection naïve group, 28 (4-97) SFU/10 6 PBMC, p=0.0097.

In this study, we have shown that serological responses to a homologous 3-dose vaccine regimen (BNT162b2 x3) remained superior to a heterologous regimen (ChAdOx1x2/BNT162b x1) in patients without evidence of prior infection, with no differences seen in the measured cellular response between the two groups.

Importantly, a significant number of infection naïve patients, 23.9%, remained seronegative following 3 vaccine doses. Consequently, this population has been offered a 4 th or booster vaccine dose in the UK, which was actioned as part of the national response to the Omicron variant. However, to devise ongoing vaccine strategies to optimise the protection of this specific population, there are several aspects to consider. Whilst data suggest incremental increases in seropositivity, and hence anti-S concentrations in transplant recipients, with each consecutive vaccine dose, it is unlikely that patients who remain seronegative after 3-doses will mount a meaningful antibody response after 4-doses (2). This has recently been demonstrated in a 4-dose study of homologous mRNA vaccines, which (3, 4, 7) . Given the relatively small number of patients included in our cellular response analysis, and limitation of assessment of a single functional measure, our conclusions are restricted, but herein we report comparative cellular . 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.

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responses. Therefore, strategies involving multiple doses of heterologous vaccines may still have a role in the mechanism of defence against SARS-CoV-2 infection in transplant recipients.

Whilst immunogenicity data may provide useful data to guide clinical efficacy, real world data on the protection afforded to transplant recipients by vaccination, and the comparative impact of the different vaccines, will be key to the strategic planning to protect transplant recipients. Although data show a reduction in vaccine efficacy across the different platforms in transplant recipients, there are no data to suggest clinical outcomes significantly differ between mRNA-based vaccines and ChAdOx1 after two doses in the era where the Delta variant predominated (10) .

Importantly, whilst the transplant community continues to navigate its way through the pandemic, adaptation of approaches to protect transplant recipients will be necessary, and likely to be reliant on a variety of different methods. Such approaches need to be tailored to the individual patients, specific variants, and infection rates. For patients who have inadequate immune responses to 3-doses of vaccine, alternative immune protection could be better offered from passive immunity, however if repeated vaccine dosing is a strategy undertaken for non-responders, further assessment of the merits of heterologous vaccination regimens may be justified.

The study included 700 kidney transplant recipients, under the care of the Imperial College Renal and Transplant Centre, London. The study 'The effect of COVID-19 on Renal and Immunosuppressed patients', sponsored by Imperial College London, was approved by the Health Research Authority, Research Ethics Committee (Reference: 20/WA/0123).

Serum was tested for antibodies to nucleocapsid protein (anti-NP) using the Abbott Architect SARS-CoV-2 IgG 2 step chemiluminescent immunoassay (CMIA) according to manufacturer's instructions. This is a non-quantitative assay and samples were interpreted as positive or negative with a threshold index value of 1.4. Spike protein antibodies (anti-S IgG) were detected using the Abbott Architect SARS-CoV-2 IgG Quant II CMIA. Anti-S antibody titres are quantitative with a threshold value for positivity of 7.1 BAU/ml, to a maximum value of 5680 BAU/ml.

. 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. structural peptide pools; S1 protein, S2 protein, and positive PHA (phytohemagglutinin) and negative controls. Cells were incubated and interferon-γ secreting T cells were detected. Spot forming units (SFU) were detected using an automated plate reader (Autoimmun Diagnostika). Infection-naïve, unvaccinated participants were used to identify a threshold for a positive response using mean +3 standard deviation SFU/10 6 PBMC, as previously described. This resulted in a cut-off for positivity of 40 SFU/10 6 PBMC.

Statistical analysis was conducted using Prism 9.3.1 (GraphPad Software Inc., San Diego, California).

Unless otherwise stated, all data are reported as median with interquartile range (IQR). Where appropriate, Mann-Whitney U and Kruskal-Wallis tests were used to assess the difference between 2 or >2 groups, with Dunn's post-hoc test to compare individual groups. Multivariable analysis was carried out using multiple logistic regression using variables which were found to be significant on univariable analysis. 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 January 26, 2022. .

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 January 26, 2022. 

Immunological responses to SARS-CoV-2 vaccines in kidney transplant recipients

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Immunogenicity and ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. The Lancet

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Effectiveness of two-dose vaccination with mRNA COVID-19 vaccines against COVID-19-associated hospitalizations among immunocompromised adults-Nine States

Realworld Effectiveness of the Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S Vaccines Against SARS-CoV-2 in Solid Organ and Islet Transplant Recipients