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

Trial Summary

What is the purpose of this trial?

Immunocompromised individuals, such as solid organ transplant (SOT) recipients are at high risk of COVID-19 associated complications and mortality. Retrospective studies so far have shown that a majority of SOT recipients did not develop appreciable anti-spike antibody response after a first, second, or even third dose of mRNA vaccine. Treatment with antimetabolites was associated with poor vaccine response. The goal of this study is 1) examine whether transient immunosuppression reduction improves the immune response to a third dose of SARS-CoV-2 mRNA vaccine in kidney transplant recipients and 2) to assess the safety of immunosuppression reduction before and after third dose SARS-CoV-2 mRNA vaccination.

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 data supports the idea that Immunosuppression Adjustment for Improved COVID-19 Vaccine Response is an effective treatment?

The available research shows that patients undergoing immune-modifying therapies, like those for inflammatory bowel disease, can still have a strong T cell response to COVID-19 vaccines, even if their antibody response is weaker. This suggests that adjusting immunosuppression can help maintain some level of protection against COVID-19. Specifically, patients on TNF inhibitor therapy had a sustained T cell response for up to 6 months, which was similar to healthy individuals. This indicates that while the antibody response might be reduced, the T cell response can still provide important protection. ^{1 2 3 4 5}

What data supports the effectiveness of the treatment 'Reduction in antimetabolite immunosuppression' for improving COVID-19 vaccine response?

Research shows that patients on immune-modifying therapies, like antimetabolite therapy, can still have a strong T cell response to COVID-19 vaccines, which may help protect against the virus even if their antibody response is weaker. ^{1 2 3 4 5}

What safety data exists for adjusting immunosuppression to improve COVID-19 vaccine response?

The safety data for adjusting immunosuppression, specifically through temporary antimetabolite treatment holds, suggests that it can boost humoral and cellular immunity in kidney transplant recipients. A study showed that a temporary hold of mycophenolate (MPA) or azathioprine improved seroconversion rates and immune responses after a fourth COVID-19 vaccine dose. This approach was associated with increased virus-neutralizing capacity and specific immune cell responses, without significant adverse effects reported. Further studies are suggested to explore this strategy in transplant recipients. ^{1 6 7 8 9}

Is it safe to adjust immunosuppression for better COVID-19 vaccine response?

Temporary reduction of certain immunosuppressants, like mycophenolate, in kidney transplant recipients has been shown to improve immune response to COVID-19 vaccines without reported safety issues in the study. However, specific safety data for other conditions or long-term effects were not detailed in the available research. ^{1 6 7 8 9}

Is the treatment in the trial 'Immunosuppression Adjustment for Improved COVID-19 Vaccine Response' a promising treatment?

Yes, the treatment is promising. Studies show that adjusting immunosuppression, like temporarily holding certain drugs, can improve the immune response to COVID-19 vaccines in patients who are usually immunosuppressed, such as transplant recipients. This approach has led to better vaccine responses, including increased antibody production and virus-neutralizing capacity. ^{1 4 8 10 11}

How does the treatment for improving COVID-19 vaccine response in immunosuppressed patients differ from other treatments?

This treatment involves temporarily holding antimetabolite drugs, like mycophenolate, to boost the immune response to COVID-19 vaccines in transplant recipients. This approach is unique because it specifically targets the impaired immune response caused by ongoing immunosuppression, unlike standard treatments that do not adjust immunosuppressive therapy. ^{1 4 8 10 11}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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]

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 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 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 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 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]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Seroconversion after COVID-19 vaccination for multiple sclerosis patients on high efficacy disease modifying medications. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Favorable vaccine-induced SARS-CoV-2-specific T cell response profile in patients undergoing immune-modifying therapies. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

Abatacept, Cenicriviroc, or Infliximab for Treatment of Adults Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. [2023]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Differential antibody response to COVID-19 vaccines across immunomodulatory therapies for multiple sclerosis. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Trajectories of host-response biomarkers and inflammatory subphenotypes in COVID-19 patients across the spectrum of respiratory support. [2023]

6. England 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. [2023]

7. England 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. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Temporary antimetabolite treatment hold boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Analysis of Side Effects Following Vaccination Against COVID-19 Among Individuals With Multiple Sclerosis Treated With DMTs in Poland. [2022]

10. Netherlands 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. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Response to SARS-CoV-2 vaccines in patients receiving B-cell modulating antibodies for renal autoimmune disease. [2022]