The coronavirus disease 2019 (COVID-19) pandemic has infected nearly 400 million people globally and accounts for over five million deaths. Although vaccination has helped control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the emergence of resistant strains has resulted in a surge in the number of infections and deaths. The recent Omicron variant is resistant to humoral immunity and is highly infectious even in fully vaccinated individuals. The risk is exaggerated for solid organ transplant recipients (SOTR) as they are on immunosuppressant therapy.
According to recent reports, two-dose of RNA-based vaccines confer limited immunity in SOTRs, while the increased number of antibody titers against the viral receptor-binding domain (RBD) and other subdomains of the spike protein was found after a booster dose.
Study: Prior SARS-CoV2 infection in vaccinated solid organ transplant recipients induces potent neutralization responses against variants, including Omicron. Image Credit: David Tadevosian/Shutterstock
A recent study posted to the medRxiv* preprint server explored COVID-19 vaccine-induced immunity in SOTRs. The present study entailed assessments of both infected and uninfected SOTRs against the D614G-CoV2 baseline virus and eight other variants.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
About the study
The study was carried out in a cohort of Heart transplant recipients (HTRs), Kidney transplant recipients (KTR), or recipients of both transplants (HKTRs) who had received either a single dose of COVID-19 vaccine (J&J) or two doses of COVID-19 vaccine (Pfizer or Moderna). Overall, 51 participants were recruited for the study, out of which 16 reported a prior COVID-19 infection, while 14 were recruited after their third dose, of which 11 were newly third-dose vaccinated SOTRs.
Blood samples were collected within a five-month window after the second and third Pfizer and Moderna vaccine doses. The samples were analyzed for CoV-2 neutralization and antibody binding activity against the receptor-binding domain (RBD) of the CoV-2 Spike protein—the prime target for the virus-neutralizing antibodies.
Expression and purification of CoV-2 RBD and Nucleocapsid (NC) proteins were carried out, RBD and NC Plasma Antibody were detected using the Enzyme-Linked Immunosorbent Assay (ELISA). Thereafter, CoV-2 pseudovirus (psV) preparation was done, followed by ACE2-HeLa cell-based neutralization assay.
Findings
On screening patients after either a single dose of vaccine by J&J or two doses of vaccine by Pfizer or Moderna, it was found that the anti-RBD IgG, IgA, and IgM were present in only 27% of SOTRs, of which 50% had a history of prior SARS-CoV-2 infection. The antibody titers were significantly higher for all anti-RBD isotypes in the infected-vaccinated group compared to uninfected-vaccinated SOTRs.
Anti-RBD-IgM was detected in 39% SOTRs, anti- RBD-IgG in 61% SOTRs, whereas anti-RBD-IgA was present in 51% SOTRs. Further research revealed the presence of RBD antibodies and low or undetectable CoV-2 NC-specific antibodies in uninfected SOTRs compared to previously infected and vaccinated participants who possessed relatively high titers of CoV-2 NC and RBD-specific antibodies.
Strong correlations between CoV-2 neutralization plasma IC50 and RBD antibody titers against both, Omicron and D614G were found. Very strong neutralization titers were seen in seven out of eight CoV-2 infected-vaccinated SOTRs. Only two out of 43 uninfected-vaccinated SOTRs showed similar neutralization titers against D614G.
Meanwhile, six out of the eight SOTRs who had received two doses of COVID-19 vaccination and had a history of prior infection showed strong neutralization of Omicron compared to only two out of 43 uninfected-vaccinated SOTRs. On screening uninfected SOTRs who had received COVID-19 vaccine doses, it was found that only 17% reached the minimal protective titer against D614G, which was lower (9%) against the Omicron variant.
A similar trend was found in the infected-vaccinated cohort for both the COV-2 variants. Infected SOTRs who received booster COVID-19 vaccine doses showed improved immunity compared to the two-dose cohorts – with 15% reaching the minimal protective titer against Omicron and 35% achieving protection against D614G.
Three uninfected and five infected two-dose vaccinated SOTRs were selected to compare the plasma neutralization resistance by multiple variants—where potent neutralization was seen against D614G. Comparable neutralization was seen against D614G, Alpha, Gamma, Lambda, and Delta variants in all the eight plasmas where the neutralization was above the minimal protective titer. Nearly a 10-fold drop in the neutralization potency was recorded in most of the plasmas collected against the Omicron variant. In contrast, only a minor decline was observed against the Beta variant in these plasmas.
Comparing the post-second and post-third dose of Pfizer or Moderna vaccination with respect to plasma neutralization potencies and RBD antibody titers in 14 SOTRs, it was found that only four infected SOTRs could evade alterations in plasma neutralization potencies and RBD antibody titers against the D614G virus. On the other hand, ten uninfected SOTRs had undetectable post-second dose RBD antibodies, out of which only two showed significant increases in their antibody titers post-third dose. At the same time, eight remained below the detectable threshold for RBD antibody titers.
On investigating factors such as age, gender, ethnicity, time since transplantation, and type of transplanted organ (with one dose of J&J or two doses of mRNA vaccine), it was found that, compared to the Whites, the African American cohort had significantly lower RBD antibody titers. However, no such difference was noted between Hispanic and White SOTRs.
Additionally, 43 uninfected SOTRs vaccinated between 0.2-22 years after transplantation were screened for RBD antibody titers. SOTRs who were vaccinated within 18 months since transplantation had significantly lower antibody titers than those who were vaccinated later. The results suggested that SOTRs who received COVID-19 vaccinations 1.5 years post-transplantation have stronger immune systems than those vaccinated before.
All 29 KTRs and 12 HTRs were on immunosuppressant drugs. Comparing vaccine-induced RBD antibodies between the two cohorts (with and without prednisolone) showed that prednisolone negatively impacted the RBD antibody responses to vaccines in uninfected SOTRs.
Immunosuppressive drugs induce nephrotoxicity; it has been reported that an elevated level of serum creatinine (SCr) is a risk factor for a negative response towards COVID-19 vaccination. A significantly negative correlation was detected between vaccine-induced RBD-IgA versus Scr and RBD-IgG versus SCr levels. On the contrary, the vaccine type, gender, type of transplanted organ, and age showed no influence on CoV-2 RBD antibody response.
The findings can aid in managing factors that affect vaccine-induced antibody responses in SOTRs and devising efficient vaccination strategies in this cohort in the future.
*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.
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