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.
Abstract
Background
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.
Methods
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.
Results
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).
Conclusion
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.
ity of Alberta and has received training in patient-oriented research through the University of Calgary’s PACER (Patient and Community Engagement Research) Program. He is the Patient, Family, and Donor Partnerships & Education Manager with the Canadian Donation and Transplantation Research Program. In this role, Manuel builds relationships patient partners with investigators and strengthens capacity among CDTRP patient partners.
Anders Billström 
Gareth Wiltshire
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Sherrie Logan 
born and raised in Edmonton, AB. With a degree in Music Performance (saxophone performance) and Education, Lindsey has taught for over a decade in the Edmonton Public School system. When she is not teaching, she is very involved in the music community, performing in the Edmonton Winds, conducting her own community ensemble (The Beer League Band) and on numerous musical boards across the province. For the past 5 years, Lindsey has had to take a break from teaching after having her amazing son, George. Maternity leave did not goes as expected as George was diagnosed with Dilated Cardiomyopathy at 5 months old and required 2 heart transplants before the age of 4. During this time, Lindsey has also began to dedicate her time building and expanding her charity: Big Gifts for Little Lives, where they raise money to fund Pediatric Heart Transplant research at the Stollery.
Dr. Caigan Du is a scientist at the Vancouver Coastal Health Research Institute and an assistant professor in the Department of Urologic Sciences at the University of British Columbia. He received a Ph.D. degree in Biochemistry in UK and postdoctoral training in Immunology in USA. He is interested in the pathogenesis of kidney ischemia-reperfusion injury and transplant rejection, and molecular control of urinary malignancies. He has been studying the impact of kidney donor-derived factors on renal allograft rejection, and the molecular pathways of kidney injury and regeneration in experimental models. He is also interested in developing medical solution including drugs made from natural compounds for all kinds of health problems, including immune disorders, organ preservation, kidney failure and urinary cancer. He is the PI of many grant supports from the Kidney Foundation of Canada and the Canadian Institutes of Health Research.
Heather Badenoch is a non-directed living liver donor and communications strategist. As the president of Village PR, she provides strategic communications direction and training to not-for-profit clients in community and health. An active transplant volunteer, Heather helps transplant candidates find living donors by running their public appeals, small and large, pro-bono. She also mentors potential living donors on the path to living donation. Heather is a volunteer with the UHN Centre for Living Organ Donation and the Canadian Donation and Transplant Research Program. She and her spouse adopt rescue dogs and volunteer together with Community Veterinary Outreach, a group providing free veterinary care to the pets of people who are homeless.
Sean Dicks is a clinical psychologist who has 20 years’ experience supporting both families of organ donors and transplant recipients. While it is rare for him to have contact with a donor family and recipient linked to the same organ donation-transplantation event, his contact with families who have lived experience with organ donation on the one hand, and patients who have received transplants on the other hand has provided opportunities to explore how their journeys become linked when they attempt to make sense of and find meaning in their respective crises.
Terri Hansen-Gardiner is a Cree speaking Metis woman from Northern Saskatchewan as well as a 10 year Breast Cancer Survivor. Her tireless spirit and dedication to her community is undeniable. Terri is a cancer survivor who travels around the province to provide assistance, information, and support to Indigenous patients who are trying to access and navigate the cancer care system.
Dr. Golnaz Karoubi is Assistant Scientist at the Toronto General HospitalResearch Institute and principal investigator in the Latner Thoracic Research Labs. She currently holds an Assistant Professor appointment in the department of Laboratory Medicine and Pathobiology and a cross-appointment in the department of Mechanical and Industrial Engineering at the University of Toronto. Dr. Karoubi received her PhD in Applied Science and Engineering at the University of Toronto and joined the Lung Regenerative Medicine Program in the Department of Clinical Research in Berne University, Switzerland for a post-doctoral research fellowship. She stayed on as a Group Leader in 2008 to direct the basic and transitional science as related to Cancer Stem Cell and Lung Regenerative Medicine in the Department of Biomedical Research at the University of Berne until 2012. In early 2012, she joined the team of Dr. Tom Waddell at the Toronto General Hospital Research Institute as a Senior Scientific Associate and was appointed to Assistant Scientist at the Toronto General Hospital Research Institute (University Health Network) in November 2019 and to Assistant Professor in the Department of Laboratory Medicine and Pathobiology in July 2020.
Dr. Haykal graduated from the University of Ottawa Faculty of Medicine in2007 as class valedictorian and silver medalist, and subsequently completed her residency training in Plastic and Reconstructive Surgery at the University of Toronto in 2016. During her residency, she completed a four-year Doctorate of Philosophy (PhD) in tissue engineering, regenerative medicine and immunology with a focus on tracheal reconstruction. She obtained numerous grants and awards including a CIHR Vanier Scholarship. Dr. Haykal then pursued fellowship training in microsurgical reconstruction at the Albany Medical Centre in New York. Dr. Haykal joined the University Health Network and the Toronto General Hospital in 2018. Her clinical focus is on complex oncological reconstruction and microsurgical reconstruction of the breast, head and neck and extremity. She started a lymphedema program in 2019 where she offers microsurgical techniques for the treatment of lymphedema.
Dr. Ahmed is a Professor in the Cumming School of Medicine at the University of Calgary. The recipient of the 2022 Hypertension Canada Senior Investigator Award, she is a nephrologist and clinician-scientist with a focus on sex and gender differences in human cardiovascular/kidney physiology and clinical outcomes. Dr. Ahmed is the Vice Chair (Research) for the Department of Medicine, Lead of the Libin Institute Women’s Cardiovascular Health Research Initiative at the University of Calgary and Lead of the Alberta Strategy for Patient Oriented Research Capacity Development Platform. Dr. Ahmed is an Advisory Board member for the Canadian Institutes of Health Research Institute of Gender and Health, a member of the Canadian Medical Association Journal Governing Council and the President-Elect for the Organization for the Study of Sex Differences.
r. Christopher Nguan is an Associate Professor at the University of British Columbia in the Department of Urological Sciences, Surgical Head of Kidney Transplantation at Vancouver General Hospital and the Director of the Surgical Technologies Experimental Laboratory & Advanced Robotics (STELLAR) facility at Vancouver General Hospital.
r Caroline Lamarche is a clinician scientist and transplant nephrologist at Maisonneuve-Rosemont Hospital. She is an assistant clinical professor at the Université de Montréal. After her nephrology training at the Université de Montréal (2015), she completed a Master degree on the use of adoptive immunotherapy to treat/prevent BK nephropathy in kidney transplant recipients. She then pursued a post-doctoral fellowship with Dr. Megan Levings at the University of British Columbia on the use of chimeric antigen receptor (CAR) regulatory T cells (Tregs) to induce transplant tolerance. Her lab is working on the development of adoptive immunotherapy in nephrology and understanding Treg dysfunction.
Dr. Tandon is an Associate Professor of Medicine, Co-Director of the Cirrhosis Care Clinic, Transplant Hepatologist and lead of the Cirrhosis Care Alberta quality improvement program. She obtained her training at the University of Alberta, the Hospital Clinic in Barcelona and Yale University. Her clinical practice and research are focused on cirrhosis with research interests including cirrhosis related complications, malnutrition, frailty, exercise therapy, palliative care, integrative health approaches such as meditation and knowledge translation. It is her career goal to provide wholistic, interdisciplinary, evidence based, patient-centered care through education, empowerment, engagement and team-work.
Emily is a PhD student at the University of Alberta, where she completed her Master of Science (MSc) degree in medicine. With a passion for patient-oriented research and a commitment to improving health outcomes, Emily’s doctoral project focuses on EMPOWER, a 12-week online mind-body wellness program designed for adults living with chronic health conditions.
Dr Basil S. Nasir, M.B.B.Ch
Dr. Victor Ferreira is an Assistant Scientist in the Ajmera Transplant Centre at the University Health Network (UHN) and the Toronto General Hospital Research Institute (TGHRI). He is also an Assistant Professor at the University of Toronto in the Department of Laboratory Medicine and Pathobiology (LMP). He completed his PhD in Medical Sciences – Infection and Immunity Specialization at McMaster University in 2014 and post-doctoral training at UHN. His research program is focused on three pillars: I) using systems vaccinology to reveal insights into vaccine responses in immunocompromised individuals like transplant recipients; II) characterizing the impact of chronic viral infection on host immune responses; and III) developing novel methods for eliminating latent viruses in human organs. His work has been cited >2,500 times and is published in journals including the New England Journal of Medicine, Nature Immunology, the Lancet Infectious Diseases, Clinical Infectious Diseases, the American Journal of Transplantation and Journal of Infectious Diseases.