#COVIDMS Can you respond to viral infections on ocrelizumab

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I came across this unpublished abstract. It shows that you immune responsiveness to new infectious agents is reduced, but clearly shows that it is not absent or anywhere near absent. Hope this is of use.

The results can be seen here at Clinical trials.gov https://clinicaltrials.gov/ct2/show/results/NCT02545868

Daniela Stokmaier, Kevin Winthrop, Cathy Chognot, Joanna Evershed, Marianna Manfrini, John McNamara, Amit Bar-Or Effect of Ocrelizumab on Vaccine Responses in Patients With Multiple Sclerosis (S36.002). April 10, 2018; 90 (15 Supplement), 2018

Objective: VELOCE (NCT02545868) is a randomized, open-label, Phase IIIb study to assess if ocrelizumab recipients with relapsing multiple sclerosis (RMS) raise adequate humoral responses to selected vaccines.

Background: Ocrelizumab selectively depletes CD20+ B cells while preserving the capacity for pre-existing humoral immunity. Vaccinations against infections are an important part of the management of patients with MS.

Design/Methods: Patients (N=102) were randomized 2:1 into Group A (n=68), receiving a single dose of ocrelizumab 600 mg; or Control Group B (n=34), on no disease-modifying therapy or interferon-beta. All patients received a tetanus toxoid-containing vaccine (most people have been vaccinated at some time), keyhole limpet hemocyanin (KLH) (This is a weird antigen (Blood juice from a limpet)used by immunologists along with hen egg lysozyme, ovalbumin and used to use sperm whale myoglobinshould be new), and a 23-valent pneumococcal polysaccharide vaccine (23-PPV). At randomization, Group A was subdivided into Groups A1 (n=33), receiving pneumococcal booster vaccine (13-PCV) 4 weeks after 23-PPV, and A2 (n=35), receiving seasonal influenza vaccine. Group B was treated the same as Group A2. Vaccinations in Group A started 12 weeks (3 months) after ocrelizumab. This would at a time when there are few CD19 B cells in the blood) treatment start, and in Group B on Day 1

Results: Positive response (% of patients; definition of response included in poster) to tetanus vaccine at 8 weeks was 23.9% in Group A (ocrelizumab) versus 54.5% in Group B (control). Positive response to ≥5 serotypes in 23-PPV at 4 weeks was 71.6% in Group A (ocrelizumab) and 100% in Group B (control). In Group A1 (ocrelizumab), booster vaccine (13-PCV) did not enhance the response to 12 serotypes in common with 23-PPV. The humoral response to the neoantigen KLH was decreased in Group A (ocrelizumab) versus Group B (control) at all time points measured. Seroprotective titers at 4 weeks against five influenza strains (season 2015/2016 and 2016/2017) ranged from 55.6% to 80.0% in Group A2 (ocrelizumab) and 75.0% to 97.0% in Group B (control).

Conclusions: As expected, ocrelizumab attenuated the humoral response to the studied vaccines.

Also there is published data with alemtuzumab that is not doom and gloom either

Immune competence after alemtuzumab treatment of multiple sclerosis. McCarthy CL, Tuohy O, Compston DA, Kumararatne DS, Coles AJ, Jones JL. Neurology. 2013 Sep 3;81(10):872-6.

Objective: To determine the immunocompetency of patients with multiple sclerosis treated with the lymphodepleting humanized monoclonal antibody alemtuzumab.

Methods: In this pilot case-control study, we assessed immunocompetence in 24 patients after alemtuzumab treatment by measuring antibody responses to 3 vaccines (diphtheria, tetanus, and poliomyelitis vaccine, Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and pneumococcal polysaccharide vaccine). In 20 patients, antibodies to common viruses (mumps, rubella, varicella-zoster, and Epstein-Barr virus) were measured before alemtuzumab treatment, then at 1 and 9-11 months after treatment. Results were compared with well-defined historical controls.

Results: Serum antibodies against common viruses remained detectable after treatment (CD52 is not expressed much by long-lived antibody producing cells that live in the Bone Marrow and may be shielded to some extent) , and vaccine responses were normal to T-cell-dependent recall antigens (tetanus, diphtheria, and polio), a T-cell-dependent novel antigen (meningococcus C), and T-cell-independent antigens (pneumococcal). There was no evidence for a diminished response to vaccinations in 5 patients studied within 6 months of alemtuzumab treatment.

Conclusion: In this small historically controlled pilot study, we demonstrated i) retained humoral immunologic memory (in the form of antibodies against common viruses and response to recall antigens), and ii) the retained ability to mount a humoral immune response against a novel antigen after treatment with alemtuzumab.

However to put this claim in context people were vaccinated 18 months after alemtuzumab (1.5months-86 months)

Five patients received all 3 vaccines within 6 months of alemtuzumab treatment. Of these, 2 were “responders” . This was not significantly different from 12 “responders” of 15 patients vaccinated more than 6 months after alemtuzumab treatment, although the number of patients vaccinated within 6 months was small and more patients would be needed to confirm this finding. (Therefore, not every one responded…So alemtuzumab is not without issues early after treatment either)

This data is in relation to vaccination with component vaccines and does not refer to live viral infections.

The following is the information that the Roche medical team sent ProfG earlier this week about serious viral infections on ocrelizumab. Although it is reassuring you still want to take the necessary precautions to prevent yourself from being exposed to COVID-19.

CAN YOU RESPOND TO VIRAL INFECTIONS ON OCRELIZUMAB

4 Min readMore scientificIn ArchiveBy MouseDoctorMarch 12, 20203 commentsC

I came across this unpublished abstract. It shows that you immune responsiveness to new infectious agents is reduced, but clearly shows that it is not absent or anywhere near absent. Hope this is of use.

The results can be seen here at Clinical trials.gov https://clinicaltrials.gov/ct2/show/results/NCT02545868

Daniela Stokmaier, Kevin Winthrop, Cathy Chognot, Joanna Evershed, Marianna Manfrini, John McNamara, Amit Bar-Or Effect of Ocrelizumab on Vaccine Responses in Patients With Multiple Sclerosis (S36.002). April 10, 2018; 90 (15 Supplement), 2018

Objective: VELOCE (NCT02545868) is a randomized, open-label, Phase IIIb study to assess if ocrelizumab recipients with relapsing multiple sclerosis (RMS) raise adequate humoral responses to selected vaccines.

Background: Ocrelizumab selectively depletes CD20+ B cells while preserving the capacity for pre-existing humoral immunity. Vaccinations against infections are an important part of the management of patients with MS.

Design/Methods: Patients (N=102) were randomized 2:1 into Group A (n=68), receiving a single dose of ocrelizumab 600 mg; or Control Group B (n=34), on no disease-modifying therapy or interferon-beta. All patients received a tetanus toxoid-containing vaccine (most people have been vaccinated at some time), keyhole limpet hemocyanin (KLH) (This is a weird antigen (Blood juice from a limpet)used by immunologists along with hen egg lysozyme, ovalbumin and used to use sperm whale myoglobinshould be new), and a 23-valent pneumococcal polysaccharide vaccine (23-PPV). At randomization, Group A was subdivided into Groups A1 (n=33), receiving pneumococcal booster vaccine (13-PCV) 4 weeks after 23-PPV, and A2 (n=35), receiving seasonal influenza vaccine. Group B was treated the same as Group A2. Vaccinations in Group A started 12 weeks (3 months) after ocrelizumab. This would at a time when there are few CD19 B cells in the blood) treatment start, and in Group B on Day 1

Results: Positive response (% of patients; definition of response included in poster) to tetanus vaccine at 8 weeks was 23.9% in Group A (ocrelizumab) versus 54.5% in Group B (control). Positive response to ≥5 serotypes in 23-PPV at 4 weeks was 71.6% in Group A (ocrelizumab) and 100% in Group B (control). In Group A1 (ocrelizumab), booster vaccine (13-PCV) did not enhance the response to 12 serotypes in common with 23-PPV. The humoral response to the neoantigen KLH was decreased in Group A (ocrelizumab) versus Group B (control) at all time points measured. Seroprotective titers at 4 weeks against five influenza strains (season 2015/2016 and 2016/2017) ranged from 55.6% to 80.0% in Group A2 (ocrelizumab) and 75.0% to 97.0% in Group B (control).

Conclusions: As expected, ocrelizumab attenuated the humoral response to the studied vaccines.

Also there is published data with alemtuzumab that is not doom and gloom either

Immune competence after alemtuzumab treatment of multiple sclerosis. McCarthy CL, Tuohy O, Compston DA, Kumararatne DS, Coles AJ, Jones JL. Neurology. 2013 Sep 3;81(10):872-6.

Objective: To determine the immunocompetency of patients with multiple sclerosis treated with the lymphodepleting humanized monoclonal antibody alemtuzumab.

Methods: In this pilot case-control study, we assessed immunocompetence in 24 patients after alemtuzumab treatment by measuring antibody responses to 3 vaccines (diphtheria, tetanus, and poliomyelitis vaccine, Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and pneumococcal polysaccharide vaccine). In 20 patients, antibodies to common viruses (mumps, rubella, varicella-zoster, and Epstein-Barr virus) were measured before alemtuzumab treatment, then at 1 and 9-11 months after treatment. Results were compared with well-defined historical controls.

Results: Serum antibodies against common viruses remained detectable after treatment (CD52 is not expressed much by long-lived antibody producing cells that live in the Bone Marrow and may be shielded to some extent) , and vaccine responses were normal to T-cell-dependent recall antigens (tetanus, diphtheria, and polio), a T-cell-dependent novel antigen (meningococcus C), and T-cell-independent antigens (pneumococcal). There was no evidence for a diminished response to vaccinations in 5 patients studied within 6 months of alemtuzumab treatment.

Conclusion: In this small historically controlled pilot study, we demonstrated i) retained humoral immunologic memory (in the form of antibodies against common viruses and response to recall antigens), and ii) the retained ability to mount a humoral immune response against a novel antigen after treatment with alemtuzumab.

However to put this claim in context people were vaccinated 18 months after alemtuzumab (1.5months-86 months)

Five patients received all 3 vaccines within 6 months of alemtuzumab treatment. Of these, 2 were “responders” . This was not significantly different from 12 “responders” of 15 patients vaccinated more than 6 months after alemtuzumab treatment, although the number of patients vaccinated within 6 months was small and more patients would be needed to confirm this finding. (Therefore, not every one responded…So alemtuzumab is not without issues early after treatment either)

This data is in relation to vaccination with component vaccines and does not refer to live viral infections. The following is the information that the Roche medical team sent ProfG earlier this week about serious viral infections on ocrelizumab. Although it is reassuring you still want to take the necessary precautions to prevent yourself from being exposed to COVID-19.

“We have gone back to our original clinical study reports capturing the controlled period of our pivotal trials as well as checked the latest data from our ongoing clinical trials and open-label extensions, and can provide the following answer:

Infections overall:

A higher proportion of OCREVUS-treated patients experienced non-serious infections compared to patients taking REBIF (58.5% vs. 53.4%) or placebo (71.4% vs. 69.9%). These infections were predominantly mild to moderate, were equally likely to be bacterial or viral, resolved with standard treatments and did not lead to the discontinuation of ocrelizumab.

Serious infections:

Ocrelizumab was not associated with an increased risk of serious infections in MS patients, i.e. there was no signal for serious infections in Ocrelizumab-treated people with MS. For the serious infections observed, the vast majority were bacterial (very few were viral infections, though some were never identified), they responded well to treatment and resolved, and did not last longer than the serious infections which occurred in the comparator groups. Continued observation beyond the controlled data (through our open-label extension) has revealed no new or particular pattern of serious infections by year of treatment in RMS or PPMS patients treated with Ocrelizumab.”

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5 comments

  • Thank you! How might this differ for someone who has been on Ocrevus for 2-3 years? And what would it say about delaying one’s next infusion?

    • This data is in relation to vaccination with component vaccines and does not refer to live viral infections. The following is the information that the Roche medical team sent me earlier this week about serious viral infections on ocrelizumab. Although it is reassuring you still want to take the necessary precautions to prevent yourself from being exposed to COVID-19.

      “Thank you for your question regarding our observations of bacterial vs viral aetiology of serious infections in ocrelizumab-treated patients. We have gone back to our original clinical study reports capturing the controlled period of our pivotal trials as well as checked the latest data from our ongoing clinical trials and open-label extensions, and can provide the following answer:

      Infections overall:

      A higher proportion of OCREVUS-treated patients experienced non-serious infections compared to patients taking REBIF (58.5% vs. 53.4%) or placebo (71.4% vs. 69.9%). These infections were predominantly mild to moderate, were equally likely to be bacterial or viral, resolved with standard treatments and did not lead to the discontinuation of OCREVUS.

      Serious infections:

      OCREVUS was not associated with an increased risk of serious infections in MS patients, i.e. there was no signal for serious infections in OCREVUS-treated patients in MS. For the serious infections observed, the vast majority were bacterial (very few were viral infections, though some were never identified), they responded well to treatment and resolved, and did not last longer than the serious infections which occurred in the comparator groups.

      Continued observation beyond the controlled data (through our open-label extension) has revealed no new or particular pattern of serious infections by year of treatment in RMS or PPMS patients treated with OCREVUS.”

  • Last but not least Hsct

    🙂

    Infections
    As expected, infections were frequent in the first month, when multiple components of
    immunity were abnormal. Surprisingly, infections between day 31 and 730 were infrequent in
    spite of the profound initial lymphopenia (in particular CD4 lymphopenia) (Table 1). Two fatal
    infections occurred, both due to Epstein–Barr virus (EBV)-associated lymphoproliferation at
    approximately 2 months posttransplant. These occurred in two patients who at 1 month
    posttransplant had undetectable T cells (at that time point, 4/48 patients analyzed by
    immunophenotyping had undetectable T cells whereas the remaining 44 patients had detectable
    T cells). Details on these two patients were previously reported [25].
    Day 181–730 infections attributable to T-lymphopenia (as counts of other immune cells have
    recovered by day180) occurred with a low frequency of 0.21 total infections per patient year
    (0.07 severe infections and 0.09 documented infections per patient year). The day 181–730
    total infections were less frequent in <43-year-old patients than in ≥43-year-old patients (0.07
    vs. 0.36 per patient year, P = 0.03). There were no statistically significant differences in the
    day 181–730 total infection rates between patients with above vs. below median values of CD4
    or CD8 T cell counts, naïve CD4 or CD8 T cell counts, TREC+ CD4 or CD8 T cell counts, or
    numbers of CD4 or CD8 spectratype peaks (average of the 3 families measured) at 1 year
    posttransplant. However, the power to detect these differences at a statistically significant level
    was lower than the power to detect the difference in infection rates between the <43- and ≥43-
    year-old patients—the laboratory parameters at 1 year posttransplant were available for only
    ≤36 patients, whereas the data on infections and age were available for all 44 patients surviving
    without relapse/disease progression/pulmonary toxicity beyond day 180.

    Recovery from and consequences of severe iatrogenic
    lymphopenia (induced to treat autoimmune diseases)

    doi:10.1016/j.clim.2004.07.006.

    • Neutrophils are your first line of defence during the early months this is when you are most at risk. They and the rest of your immune system is replace with myeoablative therapy. You have no past memory and there is a procedural risk of death from infection. Yes this risk is low. Discuss this with your HCP before undertaking this procedure as you should with all changes of treatment

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