Explore 2023 Research

Overview

This research focused on how well two COVID-19 vaccines, AstraZeneca and Pfizer, work in people who have autoimmune diseases such as rheumatoid arthritis. These people were taking different types of drugs that change the way their immune system works. The study was extensive and involved 240 patients from different centres. They looked at how the body’s defense system (the immune system) responded after these people got vaccinated. We measured the SARS-CoV-2 IgG titre, which is a way of seeing how many protective substances (antibodies) the body makes after getting the vaccine.

The patients were grouped based on the three type of medication they were taking which were conventional synthetic drugs (csDMARD), biological drugs (bDMARD), or a third group called targeted synthetic drugs (tsDMARD). The study compared the immune response in patients who kept taking their medication after getting vaccinated with those who temporarily stopped taking it, and also with a control group of people who did not have these immune diseases.

After the first dose of the vaccine, people with these immune diseases who continued taking their csDMARD and tsDMARD had lower rates of developing a protective immune response at 40.9 and 19.2% respectively. However, if they stopped these drugs right after getting the vaccine, their antibody response was better improving to 76.2 and 64.3% for csDMARD and tsDMARD respectively. Following the second vaccine dose the antibody response improved even further especially in the groups that paused therapy with the seroconversion rate being restored to 100% for all DMARD groups.  Specifically, stopping a drug called methotrexate which is a common drug used to treat rheumatoid arthritis for one to two weeks after getting vaccinated seemed to help, especially for people older than 60.

Six months after getting vaccinated, most people in the study still had protective antibodies. However, those who received the Pfizer vaccine tended to retain these antibodies for a longer time compared to the AstraZeneca vaccine. When people in the study got a third booster shot, their immune response was strong across all groups. However, those who continued with the tsDMARDs had slightly lower antibody levels compared to other groups.

In conclusion, this study suggests that for people with these immune diseases, temporarily stopping some of their medications right after getting the COVID-19 vaccine can help their bodies develop a better protective response. The Pfizer vaccine seemed to offer longer-lasting protection than the AstraZeneca vaccine.

In the extension phase, the study continued to look at how long people with immune diseases, who were on various immunosuppressive medications, kept their immunity after getting the AstraZeneca and Pfizer COVID-19 vaccines. We wanted to see how the immune response changed six months after getting the vaccines and after getting an additional mRNA booster shot.

The study included the same participants from the initial study and we checked to see how many of them still had protective antibodies six months after the first vaccinations. In the group that received the AstraZeneca vaccine, over 85% of people still had protective antibodies, regardless of whether they stopped or continued their medication, or if they were in the control group without an immune disease. The people who were administered the Pfizer vaccine had a slightly better response, with more than 91% of them still having protective antibodies.

After getting a booster shot, everyone in all groups developed a strong immune response, with 100% of them showing a good level of protective antibodies. However, we noticed was that people who were on a specific type of medication (tsDMARD) and continued it had lower levels of antibodies compared to the control group.

We also looked at how long the protective antibodies lasted. We found that this varied depending on which vaccine people received and what type of medication they were on. In general, the Pfizer vaccine gave longer-lasting protection than the AstraZeneca vaccine.

This part of the study shows that the type of medication people with immune diseases are taking can affect how long the vaccine protection lasts. However, a third booster shot was effective in restoring the protective antibody levels in all groups.

In summary we highlight that the effectiveness of the AstraZeneca and Pfizer vaccines improves when certain medications for immune diseases are paused shortly after vaccination. This is especially true for older people and for two types of these medications (csDMARDs and tsDMARDs). Six months after getting vaccinated, most people had a level of protection similar to those without immune diseases, except for those on tsDMARDs. The Pfizer vaccine provided longer-lasting immunity due to higher initial antibody levels after the second dose. Booster shots were effective for everyone, indicating they are a good way to maintain immunity in people with immune diseases on these medications and that getting a booster dose every year might be a good way to keep these patients protected. However, stopping the medication should be carefully considered to avoid worsening of the immune disease. More research is needed, especially about the long-term effects of repeated booster shots in these patients.

Research Accomplishments

Publications:

1. Tran, A.P., D. Tassone, J. Nossent, et al., Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b vaccines after temporary suspension of DMARD therapy in immune-mediated inflammatory disease (RESCUE). RMD Open, 2022. 8(1).
2. Tran, A.P., D.F. Tassone, N.S. Ding, et al., Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b vaccines after temporary suspension of DMARD therapy in immune-mediated inflammatory disease: an extension study (RESCUE 2). RMD Open, 2023. 9(1).

Abstract/Poster

1. European Crohn’s and Colitis Organisation 2022. Antibody response to the COVID-19 ChAdOx1nCov-19 and BMT162b2 vaccines in the immunosuppressed (RESCUE)
2. Australian Rheumatology Association Annual Meeting 2023. Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b2 vaccines after temporary suspension of DMARD therapy in immune mediated inflammatory disease – an extension study (RESCUE 2)

Study Overview 

Vasculitis refers to a group of diseases characterized by their ability to cause inflammation to develop in and around blood vessels. While there are many forms of vasculitis (such as Kawasaki Disease, Takayasu’s arteritis or Giant Cell arteritis), all share the potential to cause adverse remodelling of the inflamed blood vessels. In severe cases, this remodelling can lead to narrowing of the lumen, restricting blood flow to the downstream tissue. This process can lead to tissue-ischemia, which is the leading cause of morbidity and mortality for vasculitis patients. The aim of this study was to investigate the pathophysiology of adverse blood vessel remodelling and identify new treatment strategies to prevent this life-threatening pathology developing in vasculitis patients.

Study Methodology

Adverse remodelling is caused by the excessive accumulation of fibroblasts within the intimal layer of inflamed vessels. In this study, we investigated how such intimal fibroblasts develop during Kawasaki Disease (KD), a paediatric vasculitis typically involving the coronary arteries. To follow the origin of intimal fibroblasts, we performed lineage tracing studies in a murine model of KD, induced by the injection of Candida albicans water soluble complex (CAWS). We also used conditional genetic deletion strategies to identify intrinsic regulators of intimal fibroblast formation and analysed patient samples to study this population in human disease.

Major Project Findings 

A summary of the major findings is given below. For a full description of these results, refer to the attached manuscript or https://www.biorxiv.org/content/10.1101/2023.12.15.571811v1 where  the paper has  been uploaded onto Biorxiv.

1. By using an array of lineage tracing systems in the CAWS mouse model of Kawasaki Disease, we have shown that the intimal thickening that emerges during vasculitis is caused by the migration and proliferation of smooth muscle cells (SMCs) into and within the intimal of inflamed vessels.
2. By using immunofluorescent microscopy, we have shown that migration of SMCs into the inflamed intima coincides with their activation of the mechanistic target of rapamycin (mTOR) signalling pathway.
3. By use Cre-LoxP genetic systems to selectively delete the mTORC1 subunit RAPTOR in SMCs, we have shown that genetically deleting mTOR signalling in SMCs completely abrogated their ability to migrate into the intima during vasculitis.
4. By using both genetic and pharmacological (i.e. rapamycin) strategies to inhibit mTOR, we have shown that stopping mTOR signalling reduces SMC proliferation and the severity of adverse blood vessel remodelling during vasculitis.
5. By analysing arterial sections (obtained during autopsy or biopsy) from patients with active Kawasaki Disease, Takayasu’s arteritis or Giant Cell arteritis, we have shown that the mTOR signalling pathway is activated by the intimal fibroblasts that drive intimal hyperplasia in human disease.
6. Pending – We are in the midst of completing RNA-sequencing of SMCs to describe the molecular basis for SMCs activation and how mTOR signalling controls this event (this analysis is underway).

Summary of the study findings and their clinical significance 

In total, our findings from this study reveal that the mTOR signalling pathway is an intrinsic, essential and druggable pathway which is activated in the intimal vascular fibroblasts that drive adverse blood vessel remodelling in vasculitis. We believe that these findings provide compelling rationale for using mTOR inhibitors as a novel therapeutic strategy in systemic vasculitis. Indeed, this study has prompted at Clinicians at the Royal Melbourne Hospital (RMH) to treat one Takayasu’s arteritis patient with mTOR inhibitors to control their progressive stenotic disease (Ian Wicks, Personal Communication). This illustrates the clinical potential for this approach. We hope that these results will lead to the further clinical application and/or clinical trials of mTOR inhibitors to treat vasculitis patients in the near future.

Project Publications 

The major findings from this study have formed the basis for the below manuscript, which is currently under External Peer Review at EMBO Reports. This manuscript is available on Bioxriv (see below link) and has been provided as an attachment with this report.

• mTOR signaling controls the formation of smooth muscle cell-derived intimal fibroblasts during vasculitis. T. Stock*, Sarah Parsons, Jacinta. A. Hansen, Damian. B. D’Silva, Graham Starkey, Aly Fayed, Xin Yi Lim, Rohit D’Costa, Claire. L. Gordon & Ian. P. Wicks*. Under Peer Review at EMBO Reports.
• The above manuscript is available online at: https://www.biorxiv.org/content/10.1101/2023.12.15.571811v1.

Presentations 

• I have given an Oral presentation of this study at the 2023 ARA Victorian/Tasmanian ASM. NB – I was awarded the best Basic Science Presentation.

I have been invited to give an Oral Presentation of this study at the 2024 International Kawasaki Disease Symposium (iKDS) in Montreal Canada