this one may be abit scientific to grap a cuppa and read slowly
MORE COVID-19 VACCINATION STUDIES INDICATING A DELAY TO INCREASE CHANCE OF VACCINATION RESPONSE
I have long argued that the biology indicated that the best way to increase your SARS-COV-2 vaccine response if you were taking rituximab or ocrelizumab was to delay the infusion until more than 6 months between infusions. This allows the antibody (ocrelizumab, rituximab) to clear and the B cells capable of making a new vaccine antibody response to recover. This could be done because the memory B cells targeted by the MS drugs are depleted for longer than the naive/immature B cells.
For ocrelizumab it takes about 53 weeks to reach 40 cells/per microlitre. The standard dose is 600mg every 6 months for ocrelizumab meanig it hangs around at depleting doses for many months as 2 x 10mg depletes the B cells and half the dose is removed about every 4 weeks. Rituximab is often dosed at 500-1000mg so it is going to hang around even longer. In the study below a delay of at least 1 month in the standard interval reduced the risk of hospitalisation from COVID-19. The work below supports the view of a delay in infusion to allow a better vaccine response to develop. SARS-COV-2, flu and other vaccines are here to stay and since COVID-19 the importance of vaccination has entered the psyche. As such people are bringing extended dosing intervals into clinical practise.
Now you may think I’m happy that my science has gone into clinical practise so quickly. Yes and no.
I wanted to do this as a trial to make sure it was safe because there are reasons why I may not want to delay the infusion of the anti-CD20 depleting antibodies and I also wanted to test the “watch and wait” approach. Sadly this idea was ahead of its time and the referees didn’t like the concept….now so many people are bringing this idea into practise as a post-COVID-19 influence, it may no longer be possible to do the trial as you can’t allocate some people to not have the extended interval dosing.
Smith JB, Gonzales EG, Li BH, Langer-Gould A. Analysis of Rituximab Use, Time Between Rituximab and SARS-CoV-2 Vaccination, and COVID-19 Hospitalization or Death in Patients With Multiple Sclerosis. JAMA Netw Open. 2022 Dec 1;5(12):e2248664.
Importance: Rituximab and other B-cell-depleting therapies blunt humoral responses to SARS-CoV-2 vaccines, particularly when the vaccine is administered within 6 months of an infusion. Whether this translates into an increased risk of hospitalization or death from COVID-19 is unclear.
Objectives: To examine whether rituximab treatment is associated with an increased risk of hospitalization for COVID-19 among SARS-CoV-2-vaccinated persons with multiple sclerosis (MS) and whether delaying vaccination more than 6 months after rituximab treatment is associated with decreased risk.
Design, setting, and participants: This retrospective cohort study used Kaiser Permanente Southern California’s electronic health record to identify individuals from January 1, 2020, to February 15, 2022, who had MS and who had been vaccinated against SARS-CoV-2.
Exposures: Rituximab treatment compared with disease-modifying therapies (DMTs) that do not interfere with vaccine efficacy or being untreated (no or other DMT group). Among rituximab-treated patients, the exposure was receiving at least 1 vaccine dose more than 6 months after their last infusion compared with receiving all vaccine doses 6 months or less since their last infusion.
Main outcomes and measures: The main outcome was hospitalization due to COVID-19 infection. The odds of infection resulting in hospitalization following SARS-CoV-2 vaccination were adjusted for race and ethnicity, advanced MS-related disability; vaccine type; booster dose; and, among rituximab-treated only analyses, cumulative rituximab dose and dose at last infusion. Exposures, outcomes, and covariates were collected from the electronic health record.
Results: Among 3974 SARS-CoV-2-vaccinated people with MS (mean [SD] age, 55.3  years; 2982 [75.0%] female; 103 [2.6%] Asian or Pacific Islander; 634 [16.0%] Black; 953 [24.0%] Hispanic; 2269 [57.1%] White; and 15 [0.3%] other race or ethnicity), rituximab-treated patients (n = 1516) were more likely to be hospitalized (n = 27) but not die (n = 0) compared with the 2458 individuals with MS receiving no or other DMTs (n = 7 and n = 0, respectively; adjusted odds ratio [aOR] for hospitalization, 7.33; 95% CI, 3.05-17.63). Receiving messenger RNA (mRNA) SARS-CoV-2 vaccine (aOR, 0.36; 95% CI, 0.15-0.90; P = .03) and receiving a booster vaccination (aOR, 0.31; 95% CI, 0.15-0.64; P = .002) were independently associated with a decreased risk of hospitalization for COVID-19. Among vaccinated rituximab-treated individuals with MS, receiving any vaccination dose more than 6 months after the last rituximab infusion was associated with a reduced risk of COVID-19 hospitalization (aOR, 0.22; 95% CI, 0.10-0.49).
Conclusions and relevance: This cohort study’s findings suggest that rituximab-treated people with MS should be strongly encouraged to receive mRNA SARS-CoV-2 vaccines and boosters more than 6 months after their last rituximab infusion whenever possible. The low absolute risk of hospitalization for COVID-19 among mRNA-vaccinated individuals with MS should not preclude use of rituximab, which has marked efficacy, cost, and convenience advantages over other DMTs.
Are there some hypothectical issues to think about when using delayed-dosing
(1) Disease breakthrough
If you extend the interval between dosing there is a risk of disease activity in the extra time taken before dosing. The arguments of this have been discussed
van Kempen ZL et al. Extended dosing of monoclonal antibodies in multiple sclerosis. Mult Scler. 2022; 28:2001. PMID: 34949134.
Stable multiple sclerosis patients on anti-CD20 therapy should go on extended interval dosing Commentary-PMID: 35365058, Yes-PMID: 34931903; No-PMID: 34994665
There are many papers indicating the risk of disease breakthrough is low.
Starvaggi Cucuzza C et al. Neurol Neuroimmunol Neuroinflamm. 2022;10:e200056. PMID: 36411076 Maarouf A et al. Neurol Neuroimmunol Neuroinflamm. 2020; 7:e825. PMID: 32587103
However, there are some risks of disease breakthrough
Zanghì A et al. Is It Time for Ocrelizumab Extended Interval Dosing in Relapsing Remitting MS? Evidence from An Italian Multicenter Experience During the COVID-19 Pandemic. Neurotherapeutics. 2022; 19:1535. PMID: 36036858. “Extened interval dosing was associated with an increased risk of MRI activity. p = 0.028)
However, there are people on standard interval dosing that show disease breakthrough and CD20-depleting antibody acts quickly even if there is sub-clinical MRI activity. Also one has to think how much the vaccine response is enhanced given that despite seroconversion antibody levels are often deminished. It is about weighing up the risk/benefit of extended interval dosing.
van Kempen et al. Ocrelizumab Concentration Is a Good Predictor of SARS-CoV-2 Vaccination Response in Patients with Multiple Sclerosis. Ann Neurol. 2022. PMID: 36250739.
(2) Anti-Drug Antibodies (ADA)
If ADA appear they can stop the the drug from working and can also be associated with infusion related allergies and a problem called serum sickness (Karmacharya P et al. 2015). If you read the blurb about anti-drug antibody response of rituximab used in autoimmunity and cancer, to my surprise it is less than 5% (Mabthera=rituximab smPC). This is odd because in Sweden they estimate the rate of ADA is up to over 35%. (Dunn N et al. 2018. PMID: 28762877). In some of these individuals this will stop the drug working. These ADA may disappear with time and dosing (Dunn et al. 2018) and this is known as high-zone immunological tolerance.
The risk of ADA after ocrelizumab is less than 1% (Hauser et al. 2017) and for ofatumumab it is less than 0.5% (Hauser et al. 2020). This is due to the fact that rituximab contains more mouse than ocrelizumab. All therapeutic antibodies even if they are human can induce an antibody response now by delaying the antibody infusion you allow vaccine responses to form. However, you may also allow ADA to form. Why because you are delaying the infusion the antibody hangs around longer and whilst it depletes it stops antibody responses but eventually there will be a sweet spot where the antibody levels drop such that there is not enough to kill B cells but enough is present to allow activation of a T and B cell response but because there is not enough antibody to kill them ADA could form and these can eventually stop the drug working. This would be more of a risk for rituximab as it contains more mouse protein.
This is a theorectical issue but when you see higher ADA levels after rituximab it is often where they do not have standard dosing schedules and the cases where there are high levels of ADA response is where there is a long gap. The ADA frequency can be very high (Wincup et al. 2022. PMID: 36370065)
However in some cases rituximab is dosed according to size and maybe “size matters” and by extending the dosing interval one has to think if there is going to be be brain shredding. So by trying to do good, extending the dosing interval could they be doing bad…shredding the brain and then triggering litigation following off-label drug use
(3) Underdosing to cause progressive disability.
If you look at ocrelizumab there is a standard dose used at 600mg and it appears that this can influence the level of B cell depletion. As such the small people deplete their B cells more than larger/heavier people because volume (size) matters. Baker D et al. Mult Scler Relat Disord. 2022; 57:103448. PMID: 34902760; Signoriello E et al. PMID: 32450508). Gibiansky et al. 2021. PMID: 33202059]. Exposure (area under the serum concentration–time curve) was 26% higher in patients with relapsing less than 60kg and 21% lower in those greater than 90kg versus a 75kg reference patient. Higher ocrelizumab exposure led to greater B-cell depletion, but clinical benefit on annualised relapse rate was independent of exposure [Kletzl et al. 2019 Neurology ;92(Suppl 15) N4.001; Gibiansky et al. 2021]. The good news is that his doesnt appear impact on the relapse rate (Turner B et al. Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis. J Neurol. 2019; 266:1182. PMID: 30820738).
This is seen in Hauser et al. 2019 https://www.quantpharm.com/pdf_files/Ocrelizumab_MS_poster_2019.pdf
Body mass index is associated with influence on B cell depletion but not on efficacy of relapsing MS for ofatumumab. Likewise, it is evident that BMI can impact on the level of antibody with ofatumumab but no impact on control relapsing MS [Yu et al. 2022 PMID: 35233753
However, some alarm bells have been raised when it comes to confirmred disability progression in the OPERA and OPEROTORIO cohorts.
Although, patients with relapsing MS obtained similar benefit with regards to annualised relapse rate (ARR) independent of exposure, however, risk reductions in 12/24-week confirmed disability progression (CDP) was exposure-dependent in patients with RMS (12-week confirmed disability progression (CDP) hazard ratios by exposure quartile 1–4: 0.77, 0.80, 0.45 and 0.33 versus interferon-beta 1a, respectively) and PPMS (12-week CDP hazard ratios by exposure quartile 1–4: 0.87, 0.83, 0.78 and 0.59 versus placebo, respectively) [Kletzl et al. 2019]
It was seen that smaller people deplete progress slower suggesting that the larger people are being underdosed.
This is seen in Hauser et al. 2019 https://www.quantpharm.com/pdf_files/Ocrelizumab_MS_poster_2019.pdf
Whilst relapsing MS occurs due to entry of lymphoid cells into the CNS and therefore this is likely to be a peripheral effect, control of progression may have an inflammatory effect within the central nervous system requiring central efficacy. BMI limits the dose available for entry into the CNS or the B cells available to enter the CNS.
This suggests that there may be under-dosing with ocrelizumab.
Trials fully recruited and ongoing these are:
A study to evaluate the efficacy, safety and pharmacokinetics of a higher dose of ocrelizumab in adults with relapsing multiple sclerosis (RMS). NCT04544436 (n=865) and
A study to evaluate the efficacy, safety and pharmacokinetics of a higher dose of ocrelizumab in adults with primary progressive multiple sclerosis (PPMS) NCT04548999 (n=699 participants).
People will be randomised to standard 600mg dosing or based on body weight assigned to either 1200 mg (Body weight <75 kg) or 1800 mg (participant’s body weight ≥75 kg) every 24 weeks for a minimum of 5 treatment doses and then in the open label extension phase people will be assigned to either 1200mg or 1800mg ocrelizumab for 4 doses (96weeks), with the primary outcome to measure 12 weeks confirmed disability progression defined events in relation to EDSS, timed 25 foot walk or 9 hole peg test.
ProfG called these trials the DoDO (Double Dose) trials
However one thing I will say is that the effect is only really in the smallest people in the forest plot (graph on the right) only the bottom quartile is significantly different as there is no dose response. However it hasn’t been properly presented
So extending the dose is effectively going to reduce B cell, could that be bad news. It needs to be monitored. I wonder if this is part of the thought process on extended interval dosing or is vaccine reponsivenss all that is thought about. Maybe worth asking your neuro when they offer extended dose interval
COI: Multiple but not considered relevent
Disclaimer: These are the views of the author