Of the KTRs showing BA

Of the KTRs showing BA.5 neutralization at day 30, 0/4 and 2/4 showed BQ.1.1 and XBB.1 neutralization, respectively. CD4+ TCR expansion was comparable between KTRs and HCs, yet KTR CD8+ TCR depth was 7.6-fold lower (= .001). Global unfavorable response was seen in 7% KTRs, associated with high-dose MMF (= .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263) Keywords: SARS-CoV-2, kidney transplant, vaccination, immunogenicity, antibody, clinical trial Graphical abstract PRIMA-1 Open in a separate window 1.?Introduction Kidney transplant recipients (KTRs) demonstrate poorer humoral1 and cellular immunogenicity2 PRIMA-1 , 3 following primary mRNA SARS-CoV-2 vaccination and endure higher rates of vaccine breakthrough.4 Neutralizing antibody (nAb) is the best available correlate of protection against SARS-CoV-2 infection,5 approximated by the clinically accessible anti-receptor binding domain name (anti-RBD) antibody biomarker.6 High levels of nAb, however, are required for KTRs to neutralize Omicron Rabbit Polyclonal to NPHP4 subvariants.7 , 8 Associations with anti-RBD response in KTRs are well defined, including the negative impact of immunosuppressive regimens containing MMF.9, 10, 11 Anti-RBD level has also emerged as PRIMA-1 a powerful predictor of response to additional vaccine doses,12, 13, 14 with the potential to identify subgroups at higher risk for COVID-19 breakthrough15, 16, 17 and the need for immunoprophylactic interventions. The determinants and clinical impact of T cell responses induced by SARS-CoV-2 vaccines are less well delineated, in part owing to use of varying assays and metrics across studies. Additionally, discordance between antibody and T cell response has been reported in 0% to 50% of transplant recipients.18, 19, 20, 21 These patterns of humoral and/or cellular anti-SARS-CoV-2 immune responses and their underlying mechanistic drivers remain incompletely characterized. It is therefore uncertain whether immunoprotection against COVID-19 is usually achieved among KTRs following full (ie, 3-dose) vaccination, particularly among vulnerable KTRs who do not develop high-level anti-RBD. Given these knowledge gaps, we enrolled a homogenous KTR cohort with poor anti-RBD response following 2-dose mRNA vaccination in a clinical trial to determine the effects of third vaccination on (1) anti-RBD and variant neutralization, (2) SARS-CoV-2Cspecific T cell expansion using 2 complementary assays, and (3) global patterns of immune responses as compared with healthy controls (HCs). Clinical and immunological associations with vaccine breakthroughs were recorded. 2.?Methods 2.1. Participants and design 2.1.1. Study background and design The COVID-19 Protection After Transplant (CPAT) trials were funded by the National Institutes of Health to investigate the safety and immunogenicity of SARS-CoV-2 vaccination strategies in solid organ transplant recipients. The single-arm, open-label trial described herein began PRIMA-1 August 10, 2021 to test immune responses to additional (third) homologous mRNA vaccination in KTRs who failed to respond to 2 prior mRNA vaccinations. Failure to respond was defined as unfavorable (<0.8 U/mL, anti-RBDNEG) or low-titer (0.8 to 50 U/mL, anti-RBDLO) around the Roche Elecsys anti-SARS-CoV-2 S assay; this threshold was chosen given the minimal probability of neutralizing PRIMA-1 ancestral SARS-CoV-222 , 23 (Supplement). Participants included adult, kidney-only recipients on stable calcineurin inhibitor-based immunosuppression, without major graft dysfunction or organ rejection within 6 months; full criteria are listed at ClinicalTrials.gov (NCT04969263), and the study flow diagram is presented in Supplementary Physique?S1. The primary immunogenicity outcome was day 30 anti-RBD, stratified by day 0 serostatus (anti-RBDNEG/anti-RBDLO), given anticipated differential responses.14 , 24 Secondary outcomes included SARS-CoV-2 variant neutralization and cellular responses. Safety outcomes included reactogenicity and alloimmune events. Serial monitoring for SARS-CoV-2 contamination occurred via polymerase chain reaction testing of nasal swabs and anti-nucleocapsid antibody testing at days 30, 90, 180, and 365; symptom screening occurred at each visit, and continuous for-cause testing was performed via clinical teams. This trial was approved by the Johns Hopkins University IRB (IRB00288774); participants provided written informed consent. 2.1.2. Healthy control (HC) cohort In a.