Optimization of interferon gamma ELISPOT assay to detect human cytomegalovirus specific T-cell responses in solid organ transplants

Background Attenuated immune responses to mRNA SARS-CoV-2 vaccines have been reported in solid organ transplant recipients. Most studies have assessed serological responses alone, and there is limited immunological data on vector-based vaccines in this population. This study compares the immunogenicity of BNT162b2 with ChAdOx1 in kidney transplant patients, assessing both serological and cellular responses. Methods 920 patients were screened for spike protein antibodies (anti-S) following 2 doses of either BNT162b2 (n=490) or ChAdOx1 (n=430). 106 patients underwent assessment with T-cell ELISpot assays. 65 health care workers were used as a control group. Results Anti-S was detected in 569 (61.8%) patients. Seroconversion rates in infection-naïve patients who received BNT162b2 were higher compared with ChAdOx1, at 269/410 (65.6%) and 156/358 (43.6%) respectively, p<0.0001. Anti-S concentrations were higher following BNT162b, 58(7.1-722) BAU/ml, compared with ChAdOx1, 7.1(7.1-39) BAU/ml, p<0.0001. Calcineurin inhibitor monotherapy, vaccination occurring >1st year post-transplant and receiving BNT162b2 was associated with seroconversion. Only 28/106 (26.4%) of patients had detectable T-cell responses. There was no difference in detection between infection-naïve patients who received BNT162b2, 7/40 (17.5%), versus ChAdOx1, 2/39 (5.1%), p=0.15. There was also no difference in patients with prior infection who received BNT162b2, 8/11 (72.7%), compared with ChAdOx1, 11/16 (68.8%), p=0.83. Conclusions. Enhanced humoral responses were seen with BNT162b2 compared with ChAdOx1 in kidney transplant patients. T-cell responses to both vaccines were markedly attenuated. Clinical efficacy data is still required but immunogenicity data suggests weakened responses to both vaccines in transplant patients, with ChAdOx1 less immunogenic compared with BNT162b2.

Download Full-text

Human Cytomegalovirus Differentially Controls B Cell and T Cell Responses through Effects on Plasmacytoid Dendritic Cells

The Journal of Immunology ◽

10.4049/jimmunol.179.11.7767 ◽

2007 ◽

Vol 179 (11) ◽

pp. 7767-7776 ◽

Cited By ~ 71

Author(s):

Stefania Varani ◽

Madeleine Cederarv ◽

Sari Feld ◽

Charlotte Tammik ◽

Giada Frascaroli ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

B Cell ◽

Human Cytomegalovirus ◽

T Cell Responses ◽

Plasmacytoid Dendritic Cells ◽

Cell Responses

Download Full-text

Human cytomegalovirus-specific CD4+ and CD8+ T cell responses in primary infection of the immunocompetent and the immunocompromised host

Clinical Immunology ◽

10.1016/j.clim.2009.02.002 ◽

2009 ◽

Vol 131 (3) ◽

pp. 395-403 ◽

Cited By ~ 20

Author(s):

Daniele Lilleri ◽

Paola Zelini ◽

Chiara Fornara ◽

Giuditta Comolli ◽

Maria Grazia Revello ◽

...

Keyword(s):

T Cell ◽

Human Cytomegalovirus ◽

Primary Infection ◽

T Cell Responses ◽

Immunocompromised Host ◽

Cd8 T Cell ◽

Cell Responses

Download Full-text

Identification of key peptide-specific CD4+T cell responses to human cytomegalovirus: implications for tracking antiviral populations

Clinical & Experimental Immunology ◽

10.1111/j.1365-2249.2006.03193.x ◽

2006 ◽

Vol 146 (2) ◽

pp. 203-210 ◽

Cited By ~ 7

Author(s):

G. C. Harcourt ◽

T. J. Scriba ◽

N. Semmo ◽

S. Bounds ◽

E. Taylor ◽

...

Keyword(s):

T Cell ◽

Human Cytomegalovirus ◽

T Cell Responses ◽

Cd4 T Cell ◽

Cell Responses

Download Full-text

Cell-Mediated Immune Responses After Influenza Vaccination of Solid Organ Transplant Recipients: Secondary Outcomes Analyses of a Randomized Controlled Trial

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz471 ◽

2019 ◽

Vol 221 (1) ◽

pp. 53-62 ◽

Cited By ~ 3

Author(s):

Arnaud G L’huillier ◽

Victor H Ferreira ◽

Cedric Hirzel ◽

Yoichiro Natori ◽

Jaclyn Slomovic ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Influenza A ◽

Organ Transplant ◽

T Cell Responses ◽

Cd8 T Cell ◽

Solid Organ Transplant ◽

Solid Organ ◽

Cell Responses ◽

Influenza A H1n1

Abstract Background Despite annual immunization, solid organ transplant (SOT) patients remain at increased risk for severe influenza infection because of suboptimal vaccine immunogenicity. We aimed to compare the CD4+ and CD8+ T-cell responses of the high-dose (HD) and the standard-dose (SD) trivalent inactivated vaccine. Methods We collected peripheral blood mononuclear cells pre- and postimmunization from 60 patients enrolled in a randomized trial of HD versus SD vaccine (30 HD; 30 SD) during the 2016–2017 influenza season. Results The HD vaccine elicited significantly greater monofunctional and polyfunctional CD4+ and CD8+ T-cell responses against influenza A/H1N1, A/H3N2, and B. For example, median vaccine-elicited influenza-specific polyfunctional CD4+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza A/H1N1 (1193 vs 0 per 106 CD4+ T cells; P = .003), A/H3N2 (1154 vs 51; P = .008), and B (1102 vs 0; P = .001). Likewise, vaccine-elicited influenza-specific polyfunctional CD8+ T cells were higher in recipients of the HD than SD vaccine after stimulation with influenza B (367 vs 0; P = .002). Conclusions Our study provides novel evidence that HD vaccine elicits greater cellular responses compared with the SD vaccine in SOT recipients, which provides support to preferentially consider use of HD vaccination in the SOT setting.

Download Full-text

DNA Immunization Using Highly Conserved Murine Cytomegalovirus Genes Encoding Homologs of Human Cytomegalovirus UL54 (DNA Polymerase) and UL105 (Helicase) Elicits Strong CD8 T-Cell Responses and Is Protective against Systemic Challenge

Journal of Virology ◽

10.1128/jvi.00633-07 ◽

2007 ◽

Vol 81 (14) ◽

pp. 7766-7775 ◽

Cited By ~ 21

Author(s):

Christopher S. Morello ◽

Laura A. Kelley ◽

Michael W. Munks ◽

Ann B. Hill ◽

Deborah H. Spector

Keyword(s):

T Cells ◽

T Cell ◽

Dna Polymerase ◽

Human Cytomegalovirus ◽

Cd8 T Cells ◽

T Cell Responses ◽

Cd8 T Cell ◽

Murine Cytomegalovirus ◽

Dna Immunization ◽

Cell Responses

ABSTRACT Human cytomegalovirus (HCMV) establishes a lifelong infection with the potential for reinfection or viral transmission even in the presence of strong and diverse CD8 T-lymphocyte responses. This suggests that the CMVs skew the host T-cell response in order to favor viral persistence. In this study, we hypothesized that the essential, nonstructural proteins that are highly conserved among the CMVs may represent a novel class of T-cell targets for vaccine-mediated protection due to their requirements for expression and sequence stability, but that the observed subdominance of these antigens in the CMV-infected host results from the virus limiting the T-cell responses to otherwise-protective specificities. We found that DNA immunization of mice with the murine CMV (MCMV) homologs of HCMV DNA polymerase (M54) or helicase (M105) was protective against virus replication in the spleen following systemic challenge, with the protection level elicited by the M54 DNA being comparable to that of DNA expressing the immunodominant IE1 (pp89). Intracellular gamma interferon staining of CD8 T cells from mice immunized with either the M54 or M105 DNAs showed strong primary responses that recalled rapidly after viral challenge. M54- and M105-specific CD8 T cells were detected after the primary MCMV infection, but their levels were not consistently above the background level. The conserved, essential proteins of the CMVs thus represent a novel class of CD8 T-cell targets that may contribute to a successful HCMV vaccine strategy.

Download Full-text