Neutralization of SARS-CoV-2 variants by three-dose mRNA vaccinated kidney transplant recipient sera

In a recent study researchers determined three-dose messenger ribonucleic acid (mRNA) vaccinated kidney transplant recipients’ (KTRs) neutralizing responses against severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) variants, breakthrough coronavirus disease 2019 (COVID-19) infection rate, and transplant rejection rate.

The study, published on the medRxiv* preprint server, concluded that after three doses of mRNA vaccine in KTRs, antibody responses against wild type (WT) and other variants of SARS-CoV-2 markedly increased, with an exception against the Omicron variant.

Background

The majority of COVID-19-associated deaths in the United States (US) have been attributed to the SARS-CoV-2 Delta (B.1.617.2) and Omicron (B.1.1.529) variants. The vaccine-induced antiviral responses against WT SARS-CoV-2 are lower in KTRs than the nontransplant patients, and hence they have an increased risk for COVID-19-associated mortality.

Even after vaccination, the neutralizing antibodies in the immunocompetent sera are less sensitized against the SARS-CoV-2 Omicron and Delta variants. However, sufficient data regarding vaccinated KTRs’ neutralizing responses against SARS-CoV-2 variants like Omicron and Delta are limited.

About the study

In the present prospective multi-center cohort study, anti-SARS-CoV-2 antibody responses of COVID-19 mRNA-vaccinated KTRs towards WT and other SARS-CoV-2 variants, the occurrence of severe adverse events, breakthrough rate, and transplant rejection rate was evaluated.

The study included 51 two-dose mRNA-1273 or BNT162b2-vaccinated KTRs who were 18 years or older, more than three months after transplantation with stable graft function and without a history of rejection in preceding months. All participants were enrolled for the study after submitting written informed consent. The study was conducted as per the Declaration of Helsinki and Istanbul guidelines. The subjects received a third BNT162b2 or mRNA-1273 vaccine dose during the study period.

Antibodies against the receptor-binding domain (RBD) and spike (S) protein of the SARS-CoV-2 WT, Alpha, Beta, Gamma, Delta, and Omicron variants were measured using a Luminex-based multiplex assay and by enzyme-linked immunosorbent assay (ELISA). Antibody neutralizing activity against the SARS-CoV-2 Omicron, WT, and Delta variants was assessed using a surrogate virus neutralization test (SVNT).

Further, subjects were monitored for any occurrences of severe, life-threatening, or disabling adverse events. Donor-derived cell-free DNA and donor-specific antibodies (DSA), serum creatinine, and proteinuria were determined using KTRs’ blood and urine samples collected before and one month after the third mRNA vaccination. Transplant rejection was monitored using these blood and urine samples. Pre-pandemic sera samples from 15 KTRs and five healthy controls were used for comparison.

Results

According to the results, the median age of the study population was 63 years, females constituted 43% of the population, and 94% of participants received the BNT162b2 vaccine. The participants received the third dose at a median of 187 days after the second dose. Blood and urine samples were collected at a median of five and 29 days before and after the third dose vaccination, respectively.

The Luminex-based multiplex assay indicated that anti-SARS-CoV-2 spike antibodies against the WT, Alpha, Beta, Gamma, and Delta variants after the third dose of mRNA vaccine developed in 67%, 51%, 53%, 39%, and 25% of KTRs, respectively. Similarly, after the third vaccine dose, anti-RBD antibody levels against the SARS-CoV-2 Omicron, Delta, and WT variants in KTRs showed an increase based on the results of the ELISA test. However, anti-RBD antibody levels against Omicron were lower than the WT SARS-CoV-2.

Based on the SVNT, before the third vaccine dose, none of the KTRs had neutralizing response against the SARS-CoV-2 Omicron variant. After the third dose vaccination, KTRs’ neutralizing activity against WT, Delta, and Omicron variants were 61%, 59%, and 12%, respectively. At a median of 89 days, three patients developed breakthrough COVID-19 infection.

Further, none of the KTRs had any episodes of allograft rejection, de novo DSA, or allograft injury before and after three doses of mRNA vaccination.

Conclusions

The present study is among the first studies that characterized humoral responses in three-dose mRNA vaccinated KTRs against the SARS-CoV-2 variants, including Omicron. The study demonstrated that three-dose mRNA-vaccinated KTRs had a boost in antiviral antibody responses against SARS-CoV-2 WT and other variants. Only a few subjects showed an increase in the neutralizing activity against the SARS-CoV-2 Omicron variant after the third vaccine dose.

Overall, the neutralization of Omicron remained low in KTRs even after three doses of mRNA vaccination. In addition, both before and after vaccination, there was no evidence of severe adverse events, de novo DSA development, allograft injury, and transplant rejection.

Future studies exploring Omicron-associated cellular responses and effects of low neutralization ability in association with risk and severity of SARS-CoV-2 infection in KTRs are required.

The present study highlights the requirement of higher vaccine doses and homologous or heterologous booster doses in KTRs to enhance anti-SARS-CoV-2 immune responses, especially during the current surge of the SARS-CoV-2 Omicron variant throughout the world.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.