Spotlight paper in Clinical Infectious Diseases: Victor H Ferreira
The CDTRP would like to congratulate Victor Ferreira, Scientific Associate at UHN’s Ajmera Transplant Centre, for his recent publication entitled: “Omicron BA.4/5 neutralization and T-cell responses in organ transplant recipients after Booster mRNA vaccine: a Multicenter Cohort Study” in Clinical Infectious Diseases!
This new publication is derived from the CDTRP supported initiative – an observational study evaluating COVID-19 vaccine immunogenicity in solid organ and hematopoietic stem cell transplant recipients; The PREVenT-COVID Study.
The study involved analyzing a cohort of 220 solid organ transplant recipients for factors that affect immune protection against the Omicron BA.4/5 lineage of COVID-19. The findings revealed that compared to a three-dose COVID-19 vaccination series, receiving a fourth dose significantly increased the levels of neutralizing antibodies specific to Omicron BA.4/5. Additionally, those who had previously contracted COVID-19 prior to their fourth dose, had markedly higher levels of Omicron BA.4/5 specific neutralizing antibodies. This paper also highlights that the number of polyfunctional T cells, which are highly effective at fighting viruses such as COVID-19, were significantly increased after receiving a fourth dose vaccine. Moreover, older age, immunosuppressant medication, vaccine type, and prior COVID-19 infection were all factors that reduced immunity against Omicron BA.4/5.
Overall, these findings suggest that fourth dose vaccination and fourth dose vaccination in combination with previous COVID-19 infection, significantly increased solid organ transplant recipients’ immune protection against Omicron BA.4/5 COVID-19 infection.
To learn more about the PREVenT-COVID Study, please visit our website.
We asked Victor a few questions about the study that you can read below.
What are the main outcomes of the study?
Our study shows that a booster (fourth dose) of mRNA vaccine significantly increases neutralizing antibody responses in solid organ transplant (SOT) recipients against Omicron BA.4 and BA.5. These are highly contagious subvariants that are still circulating in many parts of the world. Booster vaccination also increased the number of CD4+ polyfunctional T-cells, a highly activated antigen-specific T-cell population. Together, these results suggest that highly immunized SOT recipients may be at lower risk for developing severe COVID-19. Importantly, we identified older age, lung transplantation, use of the immunosuppressive medications mycophenolate and prednisone, and vaccine type, as risk factors that independently predicted absence of neutralizing antibody response. In contrast, having COVID-19 prior to receiving a fourth dose was associated with greater BA.4/5 neutralization.
How do you think this research will advance knowledge in the field?
This data supports efforts to encourage transplant recipients to receive booster/4th doses of mRNA vaccines to bolster protection against circulating Omicron viruses. However, nearly half of the participants in our study did not generate neutralizing antibody responses to BA.4 and BA.5, even after four doses of COVID-19 vaccine. This suggests that a substantial proportion of transplant recipients – particularly those who are older, lung transplant recipients, and receiving treatment with certain classes of immunosuppressive drugs – remain disproportionately at risk for vaccine failure, and severe COVID-19. Our data support the expansion and implementation of mitigation strategies to protect these vulnerable individuals, including novel, non-replicative vaccine platforms, preventive monoclonal antibodies, and temporary reduction in immunosuppression.
How has the CDTRP supported the project?
CDTRP played an instrumental role in spearheading this collaborative initiative, seamlessly integrating the efforts of leading researchers from 10 renowned transplant centers spanning 4 provinces in Canada. Acting as a central hub of communication, CDTRP not only facilitated seamless coordination between researchers, but also offered national project management and cutting-edge knowledge mobilization efforts, playing a pivotal role in this study.
What are the next steps and how could the CDTRP support the future directions of this work?
Recently, bivalent vaccines targeting the ancestral strain of SARS-CoV-2 and Omicron subvariants (BA.1 or BA.4/5) were made available. We plan to investigate whether receipt of these new formulations provide additional protection to SOT recipients. We will also continue to evaluate how immunization and infection shape immune responses to novel, circulating strains that arise in the future. The CDTRP can support these directions by encouraging transplant recipients to keep up with immunization recommendations through campaigns, and to push for funding to support research into improving vaccine responses, and toward discovering new therapeutics for vulnerable transplant recipients.
In solid organ transplant (SOT) recipients, the primary vaccination series against COVID-19 is three doses followed by boosters. We determined whether a fourth dose booster induced Omicron BA.4/5 neutralizing antibodies and T-cells in a large multicenter cohort study.
Serum was collected 4-6 weeks post third and fourth dose of mRNA vaccine in 222 SOT recipients. Neutralizing antibodies (nAb) were measured using a pseudovirus neutralization assay targeting the Omicron BA.4/5 spike protein. A subset underwent T-cell testing.
Median age of the cohort was 63 years (IQR 50-68) with 61.7% men. BA.4/5 nAb detection increased from 26.6%(59/222) post third dose to 53.6%(119/222) post fourth dose (p<0.0001). In patients with breakthrough infection prior to fourth dose (n=27), nAb were detected in 77.8% and median nAb titers were significantly higher compared to those with four vaccine doses alone (p<0.0001). Factors associated with a low BA.4/5 neutralization response after fourth dose were older age (OR 0.96, 95%CI 0.94-0.99), mycophenolate use (OR 0.39, 95%CI 0.20-0.77) and prednisone use (OR 0.34, 95%CI 0.18-0.63), and vaccine type (OR 0.72, 95%CI 0.51-0.99) while breakthrough infection prior to fourth dose (OR 3.6, 95%CI 1.3-9.9) was associated with a greater nAb response. Polyfunctional BA.4/5-specific CD4+ T-cells significantly increased after four doses and were identified in 76.9% of patients at a median frequency of 213 per 106 cells (IQR 98-650).
In summary, a booster significantly increases BA.4/5-specific neutralization and polyfunctional CD4+ T-cell responses, suggesting protection from severe disease even with new Omicron variants. However, SOT recipients that are older, on mycophenolate and prednisone need further preventative strategies.
About Dr. Victor H Ferreira
Dr. Victor H Ferreira is a Scientific Associate working in the lab of Drs. Deepali Kumar and Atul Humar at UHN’s Ajmera Transplant Centre. His work investigating vaccine responses and viral immunology has been published in leading scientific journals including the NEJM, Nature Immunology, Clinical Infectious Disease and Lancet Infectious Disease. He resides with his partner in Toronto and hopes to start his own independent research program in the near future.