Superior cellular and humoral immunity toward SARS-CoV-2 reference and alpha and beta VOC strains in COVID-19 convalescent as compared to the prime boost BNT162b2-vaccinated dialysis patients
Authors: Arturo Blazquez-Navarro, Lema Safi, Toni L. Meister, Constantin J. Thieme, Sviatlana Kaliszczyk, Krystallenia Paniskaki, Mara Stockhausen, Jan Hörstrup, Okan Cinkilic, Linus Flitsch-Kiefner, Corinna Marheinecke, Eike Steinmann, Felix S. Seibert, Ulrik Stervbo, Timm H. Westhoff, Stephanie Pfaender, Toralf Roch, Nina Babel
Journal: Kidney International (2021)

Patients undergoing maintenance dialysis (DP) have a high risk of fatal coronavirus disease 2019 (COVID-19).1ERA-EDTA Council, ERACODA Working GroupChronic kidney disease is a key risk factor for severe COVID-19: a call to action by the ERA-EDTA.Nephrol Dial Transplant. 2021; 36: 87-94Crossref PubMed Google Scholar Recent epidemiological data raise apprehension with respect to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) for DP.2Kumar V. Iyengar K. Garg R. Vaishya R. Elucidating reasons of COVID-19 re-infection and its management strategies.Diabetes Metab Syndr. 2021; 15: 1001-1006Crossref PubMed Scopus (28) Google Scholar,3Geers D. Immunol S. Geers D. et al.SARS-CoV-2 variants of concern partially escape humoral but not T-cell responses in COVID-19 convalescent donors and vaccinees.Sci Immunol. 2021; 6eab1750Crossref Scopus (379) Google Scholar Therefore, ensuring cellular and humoral immunity directed to SARS-CoV-2 including VOC isolates is essential for this population. There are no data on vaccine-induced nor on natural SARS-CoV-2 infection–induced long-term immunity and its responsiveness to VOC isolates in DP. Here, we assessed cellular and humoral immunity to SARS-CoV-2 reference strain and alpha as well as beta VOC in 18 patients convalescing from mild or moderate COVID-19, which were compared to 22 age- and sex-matched DP after prime boost BNT162b2 vaccination (Supplementary Table S1). The great majority of infections occurred in November 2020 in Germany; therefore, contact of the convalescent subcohort with VOCs is unlikely. Appearance of the alpha and beta variants in Great Britain und South Africa, respectively, was first reported in December 2020. Our data demonstrate a significantly higher number of humoral responders to VOCs and titers of neutralizing antibodies to both SARS-CoV-2 and VOCs in convalescent compared with vaccinated DPs (Figure 1a and b). Accordingly, cellular immune response also demonstrated significantly higher levels and functionality of T cells directed to the Spike (S)-protein of SARS-CoV-2 and VOCs in convalescent compared with vaccinated DPs. Frequencies of S-protein–reactive CD4+ T cells (Figure 1c) including effector molecule-producing T cells (Supplementary Figure S1) as mono- or polyfunctional cells were significantly higher in convalescent DPs. Furthermore, frequencies of S-protein–reactive CXCR5+ follicular T helper cells and effector memory T cells—phenotypes associated with T-cell functionality—were also significantly higher in convalescent patients (Figure 1f and g). For the employed gating strategy, see Supplementary Figure S2; representative dot plots of cytokine expression are shown in Supplementary Figure S3. The data obtained from DPs (who were convalescent for >5 months), compared with data from vaccinated DPs, suggest superiority of adaptive immunity directed to SARS-CoV-2 and VOCs. This is remarkable, due to the longer time since infection compared with time from vaccination. The data on humoral immunity are in contrast to most available data in healthy cohorts.4Röltgen K, Nielsen SCA, Arunachalam PS, et al. mRNA vaccination compared to infection elicits an IgG-predominant response with greater SARS-CoV-2 specificity and similar decrease in variant spike recognition [preprint]. medRxiv. https://doi.org/10.1101/2021.04.05.21254952. Accessed June 30, 2021.Google Scholar, 5Supasa P. Zhou D. Dejnirattisai W. et al.Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera.Cell. 2021; 184: 2201-2211Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 6Edara VV, Norwood C, Floyd K, et al. Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant [preprint]. bioRxiv. https://doi.org/10.1101/2021.02.20.432046. Accessed June 30, 2021.Google Scholar, 7Khoury D.S. Cromer D. Reynaldi A. et al.Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.Nat Med. 2021; 27: 1205-1211Crossref PubMed Scopus (2477) Google Scholar, 8Mulligan M.J. Lyke K.E. Kitchin N. et al.Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults.Nature. 2020; 586: 589-593Crossref PubMed Scopus (1064) Google Scholar Thus, mRNA vaccines have been repeatedly found to elicit stronger humoral neutralizing responses against the reference strain and VOCs.4Röltgen K, Nielsen SCA, Arunachalam PS, et al. mRNA vaccination compared to infection elicits an IgG-predominant response with greater SARS-CoV-2 specificity and similar decrease in variant spike recognition [preprint]. medRxiv. https://doi.org/10.1101/2021.04.05.21254952. Accessed June 30, 2021.Google Scholar, 5Supasa P. Zhou D. Dejnirattisai W. et al.Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera.Cell. 2021; 184: 2201-2211Abstract Full Text Full Text PDF PubMed Scopus (340) Google Scholar, 6Edara VV, Norwood C, Floyd K, et al. Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant [preprint]. bioRxiv. https://doi.org/10.1101/2021.02.20.432046. Accessed June 30, 2021.Google Scholar, 7Khoury D.S. Cromer D. Reynaldi A. et al.Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.Nat Med. 2021; 27: 1205-1211Crossref PubMed Scopus (2477) Google Scholar, 8Mulligan M.J. Lyke K.E. Kitchin N. et al.Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults.Nature. 2020; 586: 589-593Crossref PubMed Scopus (1064) Google Scholar The results are even more striking when considering that a drop of >50% in neutralizing antibody titers has been observed after the third month after infection.6Edara VV, Norwood C, Floyd K, et al. Reduced binding and neutralization of infection- and vaccine-induced antibodies to the B.1.351 (South African) SARS-CoV-2 variant [preprint]. bioRxiv. https://doi.org/10.1101/2021.02.20.432046. Accessed June 30, 2021.Google Scholar We are not aware of any study directly comparing cellular immunity in the general population, although robust T-cell responses in convalescent and mRNA-vaccinated immunocompetent patients have already been reported.9Anft M. Blazquez-Navarro A. Paniskaki K. et al.SARS-CoV-2–reactive cellular and humoral immunity in hemodialysis population.Kidney Int. 2021; 99: 1489-1490Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar,10Westhoff TH, Seibert FS, Anft M, et al. Correspondence on 'SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response' [e-pub ahead of print]. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2021-220756. Accessed July 18, 2021.Google Scholar The reason for a significantly stronger humoral and cellular immune response found in DP after natural COVID-19 infection is unknown. We hypothesize that the high inflammation level observed in DPs during COVID-19 contributes to a stronger antigenic challenge and lymphocyte recruitment, generating superior cellular and humoral immunity as compared to prime boost vaccination in DPs. Although further studies are required, our preliminary data might have important implications for vaccination recommendation in patients who are convalescing. We thank Thorsten Wolff, Jessica Schulz, and Christian Mache from the Robert-Koch Institute (Fachbereich 17) and Martin Beer from the Friedrich Loeffler Institute for providing SARS-CoV-2 VOC alpha and beta isolates. Download .pdf (.82 MB) Help with pdf files Supplementary File (PDF) SARS-CoV-2–reactive cellular and humoral immunity in hemodialysis populationKidney InternationalVol. 99Issue 6PreviewThe outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients receiving hemodialysis (HD) is significantly worse compared with the general population.1–3 Whether the SARS-CoV-2–specific immunity in patients with coronavirus disease 2019 (COVID-19) receiving dialysis is impaired as a possible cause for the inferior outcome is not known so far. Full-Text PDF Improved cellular and humoral immunity upon a second BNT162b2 and mRNA-1273 boost in prime-boost vaccination no/low responders with end-stage renal diseaseKidney InternationalVol. 100Issue 6PreviewPatients with end-stage renal disease (ESRD) develop inefficient immune responses upon vaccination and have a high risk of developing severe coronavirus disease 2019 (COVID-19). The globally expanding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC), B.1.6.17.2/Delta, evades immune responses and might constitute a particular threat to these patients.1–3 Full-Text PDF Waning humoral response 6 months after SARS-CoV-2 vaccination with the mRNA-BNT162b2 vaccine in hemodialysis patients: time for a boostKidney InternationalVol. 100Issue 6PreviewWe and others have found a high short-term seroconversion rate between 71% and 98% in hemodialysis patients following a complete 2-dose vaccination course with the mRNA-BNT162b2 vaccine (Pfizer–BioNTech).1,2 After natural infection, 76% of hemodialysis patients remained seropositive after a median time period of 124 days after infection.3 However, to our knowledge, there are no serial data available on the maintenance of the vaccine-induced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) humoral response in hemodialysis patients. Full-Text PDF