Immunosuppression Adjustment for Improved COVID-19 Vaccine Response

(ADIVKT Trial)

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: University of California, Davis

Must be taking: Mycophenolate, Azathioprine

Disqualifiers: Pregnancy, Vaccine allergy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether reducing certain medications can improve vaccine responses in kidney transplant recipients. Kidney transplant recipients with a weak immune response to the COVID-19 vaccine might benefit from this study. Participants will either temporarily reduce their antimetabolite immunosuppressive medication (such as mycophenolate or azathioprine) or continue their usual treatment while receiving their third COVID-19 vaccine dose. The goal is to determine if this change enhances the immune response and to assess its safety. Individuals who had a kidney transplant more than six months ago, are on medications like mycophenolate or azathioprine, and have low COVID-19 antibodies might be suitable for this study. As a Phase 4 trial, this study involves an FDA-approved treatment and aims to understand its benefits for more patients.

Do I have to stop taking my current medications for this trial?

The trial involves adjusting your current immunosuppressive medications, specifically mycophenolate or azathioprine, to improve vaccine response. It doesn't specify stopping them completely, but there will be a reduction in dosage.

Will I have to stop taking my current medications?

The trial involves reducing immunosuppressive medications temporarily to see if it improves the vaccine response. If you are on mycophenolate or azathioprine, you may need to adjust your medication as part of the study.

What is the safety track record for the reduction in antimetabolite immunosuppression?

Research has shown that reducing certain immune-suppressing drugs can improve vaccine responses in transplant patients. One study found that pausing these drugs during COVID-19 vaccinations led to a better immune response in 91.5% of patients, compared to 57.7% who continued their medication. Only 2.1% of patients experienced mild side effects, such as slightly increased liver enzymes, indicating some liver stress but not serious.

These results suggest that this approach is generally safe. However, any changes to medication should always occur under a doctor's guidance. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about this trial because it explores adjusting immunosuppression to improve vaccine responses in immunocompromised patients. Most treatments for such individuals involve maintaining a standard level of immunosuppression to prevent organ rejection but may lead to reduced vaccine effectiveness. The unique approach here is the temporary reduction of antimetabolite immunosuppression around the time of a COVID-19 vaccine dose, which could enhance the immune response without compromising organ health. This strategy aims to strike a balance between protecting against severe COVID-19 and maintaining organ transplant stability, potentially offering a significant advancement in care for immunocompromised patients.

What evidence suggests that immunosuppression adjustment could improve COVID-19 vaccine response in kidney transplant recipients?

Research has shown that organ transplant patients often respond weakly to COVID-19 vaccines, especially when taking certain immune-suppressing medications. These medications, known as antimetabolites, can hinder the body's ability to produce sufficient antibodies, even after multiple vaccine doses. In this trial, one group of participants will temporarily reduce these medications to potentially enhance the body's vaccine response. Early evidence suggests this approach could help the immune system generate more antibodies against the virus, aiming to provide better protection without compromising safety. Another group will maintain the standard of care, with no changes to their immunosuppression regimen. ^{1 4 6 7 8}

Are You a Good Fit for This Trial?

This trial is for kidney transplant recipients who have had a low response to COVID-19 vaccines, measured by antibody tests. They must be on specific immunosuppressive drugs and at least 6 months post-transplant. Participants need to consent to the study.

Inclusion Criteria

Negative or low positive antibody titer on SARS-CoV-2 antibody assay

On a mycophenolate or azathioprine based immunosuppressive regimen

Participant is willing and able to give informed consent for participation in the study

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a third dose of SARS-CoV-2 mRNA vaccine with adjusted immunosuppression

4 weeks

Follow-up

Participants are monitored for safety and effectiveness after the third vaccine dose

8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Reduction in antimetabolite immunosuppression

Trial Overview The study is testing if reducing doses of certain immunosuppressant drugs can improve the body's immune response to an additional dose of a COVID-19 mRNA vaccine in those who've had weak responses previously.

How Is the Trial Designed?

Group I: Immunosuppression reduction Experimental Treatment 1 Intervention

Reduction of immunosuppression before and after administration of a third dose of SARS-CoV-2 mRNA vaccine

Group II: Standard of care Active Control 1 Intervention

No change to immunosuppression before or after receipt of a third dose of SARS-Co-2 mRNA vaccine

Who Is Running the Clinical Trial?

University of California, Davis

Lead Sponsor

Trials

958

Recruited

4,816,000+

CareDx

Industry Sponsor

Trials

26

Recruited

15,500+

Published Research Related to This Trial

In a study of 34 patients receiving anti-CD20 antibody treatment for renal immune disease, 92% developed a cellular response to SARS-CoV-2 vaccines, but only 32.4% showed a humoral response, highlighting the challenges of vaccination in this population.

The study found that humoral immunity was linked to B-cell counts and the timing of vaccination after treatment, suggesting that delaying anti-CD20 therapy to allow for B-cell recovery could enhance vaccine effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to SARS-CoV-2 vaccines in patients receiving B-cell modulating antibodies for renal autoimmune disease. Arnold, F., Huzly, D., Tanriver, Y., et al.[2022]

Patients with psoriasis on methotrexate showed significantly lower seroconversion rates and neutralizing antibody responses to the COVID-19 vaccine BNT162b2 compared to healthy controls, indicating impaired humoral immunity.

In contrast, patients receiving targeted biological therapies maintained neutralizing activity similar to controls, and all groups exhibited preserved cellular immune responses, suggesting that cellular immunity may still be effective despite impaired antibody responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study. Mahil, SK., Bechman, K., Raharja, A., et al.[2023]

Patients on B-cell depletion therapies (BCDT) showed a reduced ability to produce antibodies after mRNA COVID-19 vaccination, with infused BCDT (like ocrelizumab and rituximab) resulting in lower seroconversion rates compared to ofatumumab.

In contrast, patients treated with natalizumab and those not on disease-modifying therapies (DMT) had a normal humoral response, suggesting that certain DMTs may be more favorable during the COVID-19 pandemic.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Seroconversion after COVID-19 vaccination for multiple sclerosis patients on high efficacy disease modifying medications. Levit, E., Longbrake, EE., Stoll, SS.[2022]

Patients with inflammatory bowel disease (IBD) on immune-modifying therapies showed a strong and sustained spike-specific T cell response after COVID-19 vaccination, comparable to healthy individuals, lasting up to 6 months.

Despite reduced antibody responses, these T cell responses were effective against the Omicron variant and exhibited a favorable Th1/IL-10 cytokine profile, suggesting potential ongoing protection against COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable vaccine-induced SARS-CoV-2-specific T cell response profile in patients undergoing immune-modifying therapies. Qui, M., Le Bert, N., Chan, WPW., et al.[2022]

In a study of 121 individuals with psoriasis, those receiving methotrexate or targeted biologics showed robust humoral immunity (neutralizing antibodies) after the second dose of the COVID-19 vaccine BNT162b2, similar to healthy controls.

However, a lower percentage of patients on methotrexate (62%) and targeted biologics (74%) had detectable T-cell responses compared to 100% of healthy controls, indicating potential limitations in cellular immunity among those on immunosuppressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Humoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: a longitudinal cohort study. Mahil, SK., Bechman, K., Raharja, A., et al.[2023]

In a study of 353 multiple sclerosis patients, those not on disease-modifying therapies (DMTs) and those on certain DMTs like interferons and natalizumab showed strong antibody responses to COVID-19 vaccination, with 100% positivity in some groups.

Conversely, patients on anti-CD20 therapies had significantly lower antibody responses (only 37.6% positive), indicating that certain DMTs can impair the immune response to COVID-19 vaccines, highlighting the need for further research on booster vaccinations and immune monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential antibody response to COVID-19 vaccines across immunomodulatory therapies for multiple sclerosis. Satyanarayan, S., Safi, N., Sorets, T., et al.[2022]

In a study of 1,668 patients with multiple sclerosis (MS) treated with disease-modifying therapies (DMTs), COVID-19 vaccination was found to be safe, with all reported adverse events classified as mild, primarily pain at the injection site.

The study indicated that pain at the injection site was more common after the first dose, particularly among younger individuals (ages 30-40) and those with lower disability levels (EDSS ≤2), but no specific DMTs were linked to increased side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of Side Effects Following Vaccination Against COVID-19 Among Individuals With Multiple Sclerosis Treated With DMTs in Poland. Czarnowska, A., Tarasiuk, J., Zajkowska, O., et al.[2022]

In a study of 323 COVID-19 inpatients, elevated levels of inflammatory biomarkers like IL-6 and procalcitonin were linked to patients requiring higher levels of respiratory support, indicating a correlation between inflammation and disease severity.

The study found that patients on Non-Invasive Ventilation or High Flow Oxygen had the most variable clinical outcomes, with sRAGE levels predicting treatment failure and worse 60-day mortality, highlighting the importance of monitoring inflammatory responses for better patient management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trajectories of host-response biomarkers and inflammatory subphenotypes in COVID-19 patients across the spectrum of respiratory support. Lu, M., Drohan, C., Bain, W., et al.[2023]

In a study of 27 lung transplant recipients infected with SARS-CoV-2, a treatment strategy involving the reduction of antimetabolites and temporary escalation of corticosteroids was implemented, showing no incidence of de novo donor specific-antibodies (dnDSA) in the months following infection.

This approach appears to be a safe and effective way to manage immunosuppression in lung transplant recipients during SARS-CoV-2 infection, suggesting that it does not negatively impact anti-HLA dynamics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of SARS-CoV-2 infection on anti-HLA antibodies and de novo donor specific antibodies incidence in lung transplant recipients. Zajacova, A., Dvorackova, E., Casas-Mendez, LF., et al.[2023]

In a study of 29 kidney transplant recipients, a temporary 5-week hold on mycophenolate (MPA) immunosuppression before a fourth SARS-CoV-2 vaccine dose led to a 76% seroconversion rate, indicating a significant improvement in humoral immune response.

The study found that while most patients treated with calcineurin inhibitors responded positively to the vaccine, those on belatacept showed much lower response rates, suggesting that the type of immunosuppressive therapy may influence vaccine efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients. Schrezenmeier, E., Rincon-Arevalo, H., Jens, A., et al.[2022]

In a study involving 1971 hospitalized patients with COVID-19 pneumonia, the addition of abatacept, cenicriviroc, or infliximab to standard care did not significantly improve the time to recovery compared to placebo.

However, abatacept and infliximab were associated with lower all-cause 28-day mortality rates compared to placebo, suggesting a potential benefit in reducing death rates without increasing safety risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. O'Halloran, JA., Ko, ER., Anstrom, KJ., et al.[2023]

Citations

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Efficacy and safety of COVID-19 vaccination in solid organ ... The nonrandomized evidence evaluating COVID-19 vaccination strategies patient-important outcomes, including COVID-19 infection, mortality, hospitalization, ICU ...

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Efficacy of covid-19 vaccines in immunocompromised ... Seroconversion rates after covid-19 vaccination were significantly lower in immunocompromised patients, especially organ transplant recipients.

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Temporary antimetabolite treatment hold boosts SARS ... Transplant recipients exhibit an impaired protective immunity after SARS-CoV-2 vaccination, potentially caused by mycophenolate (MPA) immunosuppression.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165247824000609

Effect of antimetabolite regimen on cellular and humoral ... Our results showed that immunocompromised transplanted patients displayed a weak cellular and humoral memory to SARS-CoV-2 mRNA vaccination.

8. mdpi.com mdpi.com/2076-393X/10/11/1827

Determinants of Antibody Response to SARS-CoV-2 ... Immunosuppression suspension during the two vaccinations yielded a higher response rate (91.5% vs. 57.7%). Only eight patients (2.1%) experienced transaminase ...