Three-Month Follow-Up of Heterologous vs. Homologous Third SARS-CoV-2 Vaccination in Kidney Transplant Recipients: Secondary Analysis of a Randomized Controlled Trial

Abstract

Response to SARS-CoV-2-vaccines in kidney-transplant recipients (KTR) is severely reduced. Heterologous3rd vaccination combining mRNA and vector vaccines did not increase seroconversion at 4 weeks after vaccination, but evolution of antibody levels beyond the first month remains unknown. We have recently completed a randomized-controlled trial on heterologous (Ad26COVS1) vs. homologous (BNT162b2 or mRNA-1273) 3rd vaccination in 201 KTR not developing SARS-CoV-2-spike-protein antibodies following two doses of mRNA vaccine (EurdraCT: 2021-002927-39). Here, we report seroconversion at the second follow-up at 3 months after the 3rd vaccination (prespecified secondary endpoint). In addition, higher cut-off levels associated with neutralizing capacity and protective immunity were applied (i.e., > 15, > 100, > 141, and > 264 BAU/ml). A total of 169 patients were available for the 3-month follow-up. Overall, seroconversion at 3 months was similar between both groups (45 vs. 50% for mRNA and the vector group, respectively; p = 0.539). However, when applying higher cut-off levels, a significantly larger number of individuals in the vector group reached antibody levels > 141 and > 264 BAU/ml at the 3-month follow-up (141 BAU/ml: 4 vs. 15%, p = 0.009 and 264 BAU/ml: 1 vs. 10%, p = 0.018 for mRNA vs. the vector vaccine group, respectively). In line, antibody levels in seroconverted patients further increased from month 1 to month 3 in the vector group while remaining unchanged in the mRNA group (median increase: mRNA = 1.35 U/ml and vector = 27.6 U/ml, p = 0.004). Despite a similar overall seroconversion rate at 3 months following 3rd vaccination in KTR, a heterologous 3rd booster vaccination with Ad26COVS1 resulted in significantly higher antibody levels in responders.

Immune Response to COVID-19 mRNA Vaccination in Previous Nonresponder Kidney Transplant Recipients After Short-term Withdrawal of Mycophenolic Acid 1 and 3 Months After an Additional Vaccine Dose

“…The increase in KTRs displaying neutralizing antibody activity against the Omicron variant from 6 of 45 (13%) at t1 to 10 of 45 (22%) at t2 in our study cohort was striking, although not significant. Notably, other studies have also observed delayed immune responses, with Heinzel et al 21 observing an increase in antispike IgG antibodies in 8% of 169 assessed KTRs from 1 to 3 mo after a third COVID-19 vaccination. In addition, Ronicke et al 22 reported increasing antispike S1 IgG levels in 26 of 148 seroconverted KTRs (18%) comparing antibody levels at 1 mo with levels at 2 and 4 mo after at least 1 COVID-19 vaccination and demonstrated that MPA intake led to delayed immune responses.…”

Comparable cellular and humoral immunity upon homologous and heterologous COVID-19 vaccination regimens in kidney transplant recipients

“…KTRs receiving immunosuppressive therapy are at higher risk for poor COVID-19-related outcomes and therefore in urgent need for establishing a vaccine-induced SARS-CoV-2-specific humoral and cellular immune response to prevent severe COVID-19 (15,(36)(37)(38). Immunosuppressive therapies could hinder (19,37) and the administration of different vaccine regimens could influence the development of vaccine-induced immune responses in KTRs. As a consequence, close vaccine-accompanying immune monitoring is highly recommended for KTRs to assess the vaccination effectiveness (38,39).…”

“…First, several immunosuppressed patients are found to have a decreased humoral vaccination response (14)(15)(16). Second, other arms of the adaptive immune response are not always considered, and the emerging data so far show an inconsistent picture (17)(18)(19). Due to the lower response to the vaccine, more severe courses of COVID-19 and increased mortality are currently found in immunosuppressed patients, even if the overall mortality has been significantly lower as compared to the infection with the delta variant (20)(21)(22).…”

Effectiveness, Immunogenicity and Harms of Additional SARS-CoV-2 Vaccine Doses in Kidney Transplant Recipients: A Systematic Review

“…We identified 2 RCTs, 8 non-randomiz studies comparing interventions and 27 prognostic studies without a control ar Twenty-six studies investigated a study population containing seropositive KTRs af their previous vaccination series . Eight studies included only seronegative KT [47][48][49][50][51][52] and three studies included only KTRs with low or no previous seroconvers [53][54][55].…”