Article Title: Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2
Authors: Parakkal Deepak, Wooseob Kim, Michael A Paley, Monica Yang, Alexander B Carvidi, Alia A El-Qunni, Alem Haile, Katherine Huang, Baylee Kinnett, Mariel J Leibeskind, Zhouming Liu, Lily E McMorrow, Diane Paez, Dana C Perantie, Rebecca E Schriefer, Shannon Sides, Mahima Thapa, Mate Gergely, Suha Abushamma, Micahel Kelbert, Lynne Mitchell, Billy Nix, Jonathan D Graf, Kimberly E Taylor, Salim Chahin, Matthew A Ciorba, Patricia A Katz, Mehrdad Matloubian, Jane A O’Halloran, Rachel M Presti, Gregory F Wu, Sean PJ Whelan, William J Buchser, Lianne S Gensler, Mary C Nakamura, Ali H Ellebedy, Alfred HJ Kim
Contributors: Kristen Young, Richard Howard, and Mithu Maheswaranathan on behalf of the lay summaries sub-group
Acknowledgments: Thank you Jean Liew, Monique C Gore-Massy and Laura Tomasella for your feedback.
Many types of vaccines have been developed to protect patients from becoming ill from COVID-19, which is caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The goal of vaccines is to prevent severe illness through creating antibodies specific to the vaccine, and to create long lasting immunity. By developing antibodies to the vaccine, your body will be able to fight off the virus (that causes COVID-19 disease) if exposed to the virus in the future.
Patients with chronic inflammatory diseases (CID) including inflammatory bowel diseases (IBD), rheumatoid arthritis (RA), psoriasis, systemic lupus erythematosus (SLE or lupus), and multiple sclerosis (MS) are often on medications that suppress the immune system, which can affect their ability to prevent severe illness from COVID-19. We also know that certain medications are associated with more severe COVID-19 infection: rituximab (Rituxan) or other B-cell depleting therapies (medications that reduce your B-cells), glucocorticoids (steroids, commonly prednisone), and sulfasalazine. Thus, it is recommended for all patients with CID to get the COVID-19 vaccine.
This US study evaluated patients with chronic inflammatory diseases (CID) and compared them to healthy patients without CID to compare their immune response to the mRNA-based vaccines (Pfizer and Moderna). This study looked at one part of the immune system, the humoral immune response to the vaccine.
Why is this important?
This is an important study, because the initial clinical trials did not include patients on immunosuppression (medications that suppress the immune system) and there is little data on how immunosuppression affects the vaccine response.
Antibody Responses to the Vaccine is NOT the same as Vaccine Efficacy:
- Please keep in mind, evaluating the reduction in the antibody response in this study does not translate to “efficacy” or how effective the vaccine is.
- The vaccine efficacy numbers that you see reported in the news, such as 95% efficacy for the Pfizer or Moderna vaccine, refer to how good the vaccine was at preventing a group of vaccinated people from getting COVID-19. This does not refer to any one person’s level of protection.
What was done?
133 patients with CID and 53 healthy controls had their blood drawn up to 2 weeks prior to their first dose of the vaccine and no later than 20 days after their second dose of the vaccine. The labs that were tested were the anti-S IgG (antibodies that recognize part of the spike protein on the SARS-CoV-2 virus, which were made by the body after receiving the vaccine) and the antibodies that are able to block the virus (neutralizing antibodies), which can be helpful in predicting protection of the antibodies. Both of these tests help assess how the (humoral) immune system has responded to the vaccine (the antibody response). Of note, the antibody response is not directly equivalent to the “amount you are protected.” This study assessed lab responses only: it did not assess outcomes such as whether participants were diagnosed with COVID-19 infection, had symptoms or were hospitalized.
What was found?
Patients with chronic inflammatory diseases were still able to make antibodies, but the amount of antibodies made was 3 times less (3x reduced) compared to controls (healthy adults).
The researchers compared the specific medications to see which immunosuppressive medications had the largest effect: in other words, which medications reduced the antibody response the most.
Patients on B-cell depleting therapies (such as rituximab or ocrelizumab) had a 36-fold reduction in the antibody response (anti-spike protein antibody titers and neutralization titers). Those on oral glucocorticoids (steroids such as prednisone) had a 10-fold reduction in the antibody response. The dose of the steroid did not affect the response (meaning even patients on low doses of steroids still had reduced antibodies).
There was a small reduction in the antibody response for patients on antimetabolites (including methotrexate and mycophenolate mofetil/CellCept, which were studied together as a group), JAK inhibitors (tofacitinib/upadacitinib) and TNF inhibitors (adalimumab/etanercept/infliximab).
So how much was the antibody dose reduced?
|Amount the Antibody Was Reduced||Percentage of Antibodies Compared to Healthy Controls|
|WORST (HIGHEST REDUCTION in ANTIBODY AMOUNT)||B-cell depleting treatment (Rituximab)||36x||2.7%|
|Antimetabolites (methotrexate, mycophenolate mofetil or CellCept, azathioprine or Imuran)||3x||33%|
|LEAST (LOWEST REDUCTION IN ANTIBODY AMOUNT)||TNF inhibitors||2.5x||40%|
For example, patients on steroids had a 10x reduction in the amount of antibodies. To try to illustrate this, imagine a patient without steroids develops 10 antibodies against the COVID-19 virus after 2 doses of the COVID-19 (mRNA) vaccine. On average, a patient on steroids (such as prednisone) will only develop 1 antibody. The reality is that we typically make millions of antibodies after vaccination. So, using numbers closer to reality, if someone not on steroids made 10 million antibodies, someone on steroids will more likely make 1 million instead.
What does this mean?
- Most patients on immunosuppression will still make detectable antibodies and neutralizing antibodies, though less than those seen in healthy adults (which appear to correlate with those who have protective responses)
- B-cell directed therapy (such as Rituximab) and steroids were the medications that most dramatically reduced the antibodies made in response after the 2 vaccines.
- JAK inhibitors and antimetabolites (methotrexate, mycophenolate and azathioprine) are also associated with decreases in antibodies after 2 mRNA-based vaccines
- The dose of steroids did not seem to matter in this study: whether high dose (20mg daily) or low dose (1 mg daily), some patients did not make antibodies.
- TNFi did not seem to lower antibody or neutralizing antibody response
- IL-12/23 inhibitors and vedolizumab had minimal impact on antibody titers.
- It’s important to remember that this study only looked at one part of the immune system (the humoral response), we also have the cellular (“T Cells”) response, which has been implicated as an important part of the response to COVID-19 infection. Future studies will look at the cellular immune system response.
- Patients on immunosuppressive medications should speak with their physicians about getting the vaccine and if they should hold or adjust their dose of their immunosuppressive medication beforehand.