To vaccinate or not?

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Should your vaccine status be checked and updated before you start treatment?

As part of our programme to derisk disease-modifying therapies (DMTs) for pwMS in our service, we are reviewing our vaccination policy. One issue that has emerged is the possible need to boost immunity to certain types of bacteria that are known to pose a risk in patients on long-term immunosuppression, in particular B cell depleters, such as rituximab, ocrelizumab and ofatumumab. Why?

Chronic B-cell depletion essentially prevents B-cells mounting an adequate antibody response to new antigens. It does this by preventing the formation of so-called germinal centres in the spleen and/or lymph nodes. In other words patients on longterm anti-CD20 therapy behave, from an immunological perspective, if they have had a functional splenectomy. This put patients with longterm B cell depletion at risk of hypogammaglobulinaemia (low immunoglobulin levels) in the future and predisposes them to infections caused by so-called encapsulated bacteria; these include pneumococcus, meningococcus and Haemophilus Influenzae.

When you review the rheumatoid arthritis literature in relation to longterm rituximab (anti-CD20) therapy both these problems have been documented. How do the rheumatologists deal with these problems? They appear to routinely monitor immunoglobulin levels and they proactively vaccinate their patients prior to starting long-term anti-CD20 therapy.

It seems pretty obvious to me, reading the rheumatology literature, that before you start long-term anti-CD20 therapy you should have your vaccination status checked and we should start vaccinating patients against pneumococcus, meningococcus and Haemophilus Influenzae B. In fact, pneumococcal vaccine is already recommended, if possible, for all patients before starting immunosuppressive treatments. It is clear for anti-CD20 therapies that the vaccines will need to be given prior to starting treatment (see Nguyen paper below).

We also recommend doing baseline immunoglobulin levels on all patients before starting treatment as a reference and then to start checking levels from year 3 onwards. I say year 3 because in the ocrelizumab trials we only saw a  significant drop in IgM and IgA levels over 2 years and IgG levels were stable. Based on the rituximab data a drop in IgG levels is, therefore, only likely to emerge after 2 years of treatment.

I would be interested to know if any of you had your vaccine status discussed before you started maintenance immunosuppression?

Makatsori et al. Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. QJM. 2014 Oct;107(10):821-8.

BACKGROUND: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature.

METHODS: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out.

RESULTS: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia.

CONCLUSION: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.

Nguyen et al. Initial Serological Response after Prime-boost Pneumococcal Vaccination in Rheumatoid Arthritis Patients: Results of a Randomized Controlled Trial. J Rheumatol. 2017 Dec;44(12):1794-1803.

OBJECTIVE: To evaluate the initial serological responses to pneumococcal vaccination with the 13-valent protein-conjugated pneumococcal vaccine (PCV13) followed by the 23-valent polysaccharide pneumococcal vaccine (PPV23) among patients with rheumatoid arthritis (RA) treated with biological disease-modifying antirheumatic drugs (bDMARD) according to dosing and intervals between immunizations.

METHODS: Investigator-initiated clinical trial. Patients with RA receiving bDMARD were randomized (1:1:1) to immunization with single dose PCV13 followed by PPV23 after 16 or 24 weeks, or double dose PCV13 followed by PPV23 after 16 weeks. A comparison group of patients with RA treated with conventional synthetic (cs)DMARD received single dose PCV13 followed by PPV23 16 weeks later. Pneumococcal antibodies were collected before and 4 weeks after each vaccination. The primary endpoint was the proportion of participants responding to ≥ 6/12 pneumococcal serotypes 4 weeks after both vaccinations.

RESULTS: Sixty-five participants receiving bDMARD and 35 participants receiving csDMARD were included. After PPV23 vaccination, 87% (95% CI 0.76-0.94) and 94% (95% CI 0.77-0.99), respectively, of participants treated with bDMARD and csDMARD had reached the primary endpoint. There was no significant difference in primary endpoint between the 3 randomization arms. The response for rituximab-treated participants was 25% compared to ≥ 89% in participants treated with bDMARD with other mode of action.

CONCLUSION: The early serological response to prime-boost vaccination with PCV13 followed by PPV23 was very similar among participants receiving bDMARD and csDMARD. However, notable differences in response were observed according to individual bDMARD. It is important to consider the RA treatment when planning pneumococcal vaccination in patients with RA.

Friedman & Winthrop. Vaccinations for rheumatoid arthritis. Curr Opin Rheumatol. 2016 May;28(3):330-6.

PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients experience increased infectious disease-related morbidity and mortality, and vaccinations represent an important element in their care. However, vaccine immunogenicity can be affected by disease-modifying antirheumatic drug (DMARD) therapy, such that vaccine choice and timing can be clinically challenging. We review the indications, safety, and immunogenicity of vaccines in the setting of RA.

RECENT FINDINGS: Recent recommendations highlight the use of influenza, pneumococcal, and shingles vaccines in RA patients. Studies suggest influenza and pneumococcal vaccines are underutilized, but well tolerated in RA patients and generally immunogenic during DMARD use with the exception of rituximab. Though data for other nonlive vaccines are more limited, hepatitis B virus and human papilloma virus vaccines also appear well tolerated and immunogenic in this population. Live vaccines for shingles and yellow fever remain contraindicated in some RA patients; however, limited data suggest they might be well tolerated in certain individuals.

SUMMARY: The review updates rheumatologists on the optimal use and timing of routine vaccinations in the care of RA.

CoI: multiple

About the author

Gavin

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

22 comments

    • They should because the EMA approved summary of product characteristics says the following:

      Vaccinations

      The safety of immunisation with live or live-attenuated vaccines, following Ocrevus therapy has not been studied and vaccination with live-attenuated or live vaccines is not recommended during treatment and not until B-cell repletion (in clinical trials, the median time for B-cell repletion was 72 weeks). See section 5.1.

      In a randomized open-label study, RMS patients were able to mount humoral responses, although decreased, to tetanus toxoid, 23-valent pneumococcal polysaccharide with or without a booster vaccine, keyhole limpet hemocyanin neoantigen, and seasonal influenza vaccines. See section 4.5 and 5.1.

      It is recommended to vaccinate patients treated with Ocrevus with seasonal influenza vaccines that are inactivated.

      Physicians should review the immunisation status of patients being considered for treatment with Ocrevus. Patients who require vaccination should complete their immunisation at least 6 weeks prior to initiation of Ocrevus.

      See section 4.5 and 5.1 for further information about vaccinations.

      4.5 Vaccinations

      The safety of immunisation with live or live-attenuated vaccines, following Ocrevus therapy has not been studied.

      Data are available on the effects of tetanus toxoid, 23-valent pneumococcal polysaccharide, keyhole limpet hemocyanin neoantigen, and seasonal influenza vaccines in patients receiving Ocrevus. See section 4.4 and 5.1.

      After treatment with Ocrevus over 2 years, the proportion of patients with positive antibody titers against S. pneumoniae, mumps, rubella and varicella were generally similar to the proportions at baseline.

      5.1. Immunisations

      In a randomized open-label study in RMS patients (N=102), the percentage of patients with a positive response to tetanus vaccine at 8 weeks after vaccination was 23.9% in the ocrelizumab group compared to 54.5% in the control group (no disease-modifying therapy except interferon-beta). Geometric mean anti-tetanus toxoid specific antibody titers at 8 weeks were 3.74 and 9.81 IU/ml, respectively. Positive response to ≥5 serotypes in 23-PPV at 4 weeks after vaccination was 71.6% in the ocrelizumab group and 100% in the control group. In patients treated with ocrelizumab a booster vaccine (13-PCV) given 4 weeks after 23-PPV did not markedly enhance the response to 12 serotypes in common with 23-PPV. The percentage of patients with seroprotective titers against five influenza strains ranged from 20.0-60.0% and 16.7-43.8% pre-vaccination and at 4 weeks post vaccination from 55.6-80.0% in patients treated with ocrelizumab and 75.0-97.0% in the control group, respectively. See sections 4.4 and 4.5.

  • Are all these vaccines needed for those on Natalizumab as well? My understanding is that it isn’t immunosuppressive and only the annual flu jab is needed. Is that right?

    • No, see my comment above regarding ocrelizumab. You can still mount a vaccine response, it just won’t necessarily be as good or adequate to protect you from infection. This is why it is better to have the vaccines before starting treatment.

    • No, the term time-bomb means it is inevitable in everyone. I do predict the same that has happened for rituximab will happen with ocrelizumab. A proportion of ocrelizumab-treated patients will develop low immunoglobulin levels and infections as a result of continuous ocrelizumab treatment. We just need to be prepared for it and to manage the risk as it emerges.

  • Starting Ocrevus next week. I am in US – no offer or discussion of running through vaccine status. Neurologist did mention that I should not get live vaccines, and that if I go to travel restricted area where I need travel vaccines, that vaccines may take some time to have effect, and that I would need to consult w travel clinic.

    I believe I am out of date on tetanus vaccine. Should I be pushing for this before first infusion? Or can I have infusion and get tetanus shot later this year?

    I am unclear from article whether there is routine labs that needs to be happening. If so, what?

    Also, re my neuro, no mention of need to screen for HBV, prior to first infusion. I pushed to have screening done, based on reading through FDA and Genentech drug info sheet stating that patients need HBV screen prior to infusion.

    • Please see comments on the EMA SmPC; I suspect the FDA version mentions vaccines. We have widened our baseline screen for ocrelizumab so as it overlaps with other immunosuppressive DMTs:

      Routine bloods: FBC, LFTs, U&E
      Serum immunoglobulin levels
      Immune status: VZV, measles, mumps and rubella
      Infection screen: Hepatitis B&C, HIV1&2, Syphilis and TB Elispot

  • Yes, my doctor and I reviewed my vaccination history, but we didn’t do any boosters before going on Ocrevus. The only decision taken was to get the yellow fever live vaccine before starting, since future work travel may require it. She’s also monitoring IgG, IgA, and IgM concentrations at each infusion (but not specific to pathogens).

  • What about NIRTs (Alem) and SIRTs (Cladribine)? After reconstitution phase it is probably not needed, but in some cases, reconstitution takes years… is it maybe advisable to do that anyway?

    • With IRTs the immune system is competent when it has reconstituted so vaccines, inactivated and live, are fine. The SmPC cautions against live vaccines, but this applies to the phase when the patients are lymphopaenic.

      • About to start cladribine, was screened for VZV, hep B&C, HIV, TB.
        Decided to have pneumococcal, shingles and hep B vaccines when we first started talking about DMTs. Was asked whether I thought I might need yellow fever, but declined it.

    • Fingolimod (Gilenya)

      Vaccination

      During and for up to two months after treatment with Gilenya vaccination may be less effective. The use of live attenuated vaccines may carry a risk of infections and should therefore be avoided (see sections 4.4 and 4.8).

      Dimethyl fumarate (Tecfidera)

      Concomitant administration of non-live vaccines according to national vaccination schedules may be considered during Tecfidera therapy. In a clinical study involving a total of 71 patients with relapsing remitting multiple sclerosis, patients on Tecfidera 240 mg twice daily for at least 6 months (n=38) or non-pegylated interferon for at least 3 months (n=33), mounted a comparable immune response (defined as ≥2-fold increase from pre- to post-vaccination titer) to tetanus toxoid (recall antigen) and a conjugated meningococcal C polysaccharide vaccine (neoantigen), while the immune response to different serotypes of an unconjugated 23-valent pneumococcal polysaccharide vaccine (T-cell independent antigen) varied in both treatment groups. A positive immune response defined as a ≥4-fold increase in antibody titer to the three vaccines, was achieved by fewer subjects in both treatment groups. Small numerical differences in the response to tetanus toxoid and pneumococcal serotype 3 polysaccharide were noted in favour of non-pegylated interferon.

      No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking Tecfidera. Live vaccines might carry an increased risk of clinical infection and should not be given to patients treated with Tecfidera unless, in exceptional cases, this potential risk is considered to be outweighed by the risk to the individual of not vaccinating.

  • My Rituximab treatment has been monitored by a rheumatologist along with the neurologist

    The first infusion was delayed a few months to catch up on vaccinations and for a course of TB treatment

    The immunoglobulin level is checked before every infusion.

    • Not live vaccines. Some can have the inactivated vaccines on ocrelizumab and hope they respond. However, for Pneumovax, the response rate is likely to be poor on ocrelizumab, similar to what has been found with rituximab.

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