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Three doses of COVID-19 vaccines in multiple sclerosis patients treated with disease-modifying therapies

Published:August 17, 2022DOI:https://doi.org/10.1016/j.msard.2022.104119

      Abstract

      Objectives and aims

      Disease modifying therapies used in multiple sclerosis can decrease humoral response after COVID-19 vaccines. This problem must be adequately addressed because new variants evolve, and COVID-19 still poses a risk to patients with comorbidities and immunosuppression. We aimed to evaluate the antibody response after the third dose of the COVID-19 vaccine in people with multiple sclerosis on disease-modifying therapies.

      Methods

      People with multiple sclerosis who received the third dose of either mRNA or inactivated vaccine after two doses of inactivated vaccine were recruited for the study. Blood samples were collected at least two weeks after the third dose.

      Results

      Blood samples of 339 (female 72.5%) people with multiple sclerosis and 52 (female 71.2%) healthy controls were evaluated. Healthy controls (mean: 4.07 ± 0.66) have higher antibody titers than people with multiple sclerosis (mean: 2.79 ± 2.95). Seronegative cases were observed only in the fingolimod and ocrelizumab treatment groups. Patients on fingolimod who received mRNA as a third dose had significantly higher antibody titer than those who had inactivated vaccines. Longer disease duration, having inactivated vaccine as a third dose, and DMT use was associated with lower antibody response.

      Conclusions

      The study shows that even after inactivated vaccine schedule, mRNA still offers more protection in people with multiple sclerosis on disease-modifying therapies.

      Keywords

      1. Introduction

      Vaccines as a prophylactic source to fight the pandemic have shown their benefits by lowering the mortality and morbidity of the COVID-19 (
      • Chen X.
      • Huang H.
      • Ju J.
      • Sun R.
      • Zhang J.
      Impact of vaccination on the COVID-19 pandemic in U.S. states.
      ). Several vaccine types are available in different countries. The mounting evidence suggests that they are all effective, and the difference is with antibody titer that is elicited (
      • Dong Y.
      • Dai T.
      • Wei Y.
      • Zhang L.
      • Zheng M.
      • Zhou F.
      A systematic review of SARS-CoV-2 vaccine candidates.
      ). Although there is no clear evidence which antibody titer against COVID-19 is adequate, some vaccines manage to boost a more significant humoral response than others (
      • Ozakbas S.
      • Baba C.
      • Dogan Y.
      • Cevik S.
      • Ozcelik S.
      • Kaya E.
      Comparison of SARS-CoV-2 antibody response after two doses of mRNA and inactivated vaccines in multiple sclerosis patients treated with disease-modifying therapies.
      ;
      • Sormani M.P.
      • Inglese M.
      • Schiavetti I.
      • Carmisciano L.
      • Laroni A.
      • Lapucci C.
      • da Rin G.
      • Serrati C.
      • Gandoglia I.
      • Tassinari T.
      • Perego G.
      • Brichetto G.
      • Gazzola P.
      • Mannironi A.
      • Stromillo M.L.
      • Cordioli C.
      • Landi D.
      • Clerico M.
      • Signoriello E.
      • Frau J.
      • Ferrò M.T.
      • Sapio A.D.
      • Pasquali L.
      • Ulivelli M.
      • Marinelli F.
      • Callari G.
      • Iodice R.
      • Liberatore G.
      • Caleri F.
      • Repice A.M.
      • Cordera S.
      • Battaglia M.A.
      • Salvetti M.
      • Franciotta D.
      • Uccelli A.
      Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
      ). Studies show that immunocompromised patients can not mount good antibody response after a standard vaccine regime. Considering this fact and the knowledge that new variants are still causing a threat to the population and the humoral immunity against the COVID-19 vaccine is waning with time, a booster dose seems to be lifesaving for at least vulnerable members of the population (
      • Krause P.R.
      • Fleming T.R.
      • Peto R.
      • Longini I.M.
      • Figueroa J.P.
      • Sterne J.A.C.
      • Cravioto A.
      • Rees H.
      • Higgins J.P.T.
      • Boutron I.
      • Pan H.
      • Gruber M.F.
      • Arora N.
      • Kazi F.
      • Gaspar R.
      • Swaminathan S.
      • Ryan M.J.
      • Henao-Restrepo A.M.
      Considerations in boosting COVID-19 vaccine immune responses.
      ;
      • Kamar N.
      • Abravanel F.
      • Marion O.
      • Couat C.
      • Izopet J.
      • del Bello A.
      Three doses of an mRNA COVID-19 vaccine in solid-organ transplant recipients.
      ). At the start of the pandemic, it was shown that mortality and morbidity are related to age and some other comorbidities, immunosuppression being on the list (
      • Wang D.
      • Hu B.
      • Hu C.
      • Zhu F.
      • Liu X.
      • Zhang J.
      • Wang B.
      • Xiang H.
      • Cheng Z.
      • Xiong Y.
      • Zhao Y.
      • Li Y.
      • Wang X.
      • Peng Z.
      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China.
      ;
      • Wu C.
      • Chen X.
      • Cai Y.
      • Xia J.
      • Zhou X
      • Xu S.
      • Huang H.
      • Zhang L.
      • Zhou X
      • Du C.
      • Zhang Y.
      • Song J.
      • Wang S.
      • Chao Y.
      • Yang Z.
      • Xu J.
      • Zhou X
      • Chen D.
      • Xiong W.
      • Xu L.
      • Zhou F.
      • Jiang J.
      • Bai C.
      • Zheng J.
      • Song Y.
      Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.
      ). Though multiple sclerosis (MS) is an autoimmune disease whose pathology is tried to be explained by an altered immune system, it does not cause immunosuppression (
      • Titus H.E.
      • Chen Y.
      • Podojil J.R.
      • Robinson A.P.
      • Balabanov R.
      • Popko B.
      • Miller S.D.
      Pre-clinical and clinical implications of “inside-out” vs. “outside-in” paradigms in multiple sclerosis etiopathogenesis.
      ). But disease-modifying therapies (DMT) are potential candidates to diminish immune response after vaccines because they target immune cells directly or indirectly. Among the DMT, CD20 depleting agents were consistently associated with decreased antibody response against COVID-19. Other DMT show somewhat favourable results, but less than healthy people (
      • Garjani A.
      • Patel S.
      • Bharkhada D.
      • Rashid W.
      • Coles A.
      • Law G.R.
      • Evangelou N.
      Impact of mass vaccination on SARS-CoV-2 infections among multiple sclerosis patients taking immunomodulatory disease-modifying therapies in England.
      ;
      • Tallantyre E.C.
      • Vickaryous N.
      • Anderson V.
      • Asardag A.N.
      • Baker D.
      • Bestwick J.
      • Bramhall K.
      • Chance R.
      • Evangelou N.
      • George K.
      • Giovannoni G.
      • Godkin A.
      • Grant L.
      • Harding K.E.
      • Hibbert A.
      • Ingram G.
      • Jones M.
      • Kang A.S.
      • Loveless S.
      • Moat S.J.
      • Robertson N.P.
      • Schmierer K.
      • Scurr M.J.
      • Shah S.N.
      • Simmons J.
      • Upcott M.
      • Willis M.
      • Jolles S.
      • Dobson R.
      COVID-19 vaccine response in people with multiple sclerosis.
      ;
      • Achiron A.
      • Mandel M.
      • Dreyer-Alster S.
      • Harari G.
      • Magalashvili D.
      • Sonis P.
      • Dolev M.
      • Menascu S.
      • Flechter S.
      • Falb R.
      • Gurevich M.
      Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.
      ).
      Recent studies also showed that people with a history of COVID-19 infection have a greater immunologic response after vaccines (
      • Sormani M.P.
      • Inglese M.
      • Schiavetti I.
      • Carmisciano L.
      • Laroni A.
      • Lapucci C.
      • da Rin G.
      • Serrati C.
      • Gandoglia I.
      • Tassinari T.
      • Perego G.
      • Brichetto G.
      • Gazzola P.
      • Mannironi A.
      • Stromillo M.L.
      • Cordioli C.
      • Landi D.
      • Clerico M.
      • Signoriello E.
      • Frau J.
      • Ferrò M.T.
      • Sapio A.D.
      • Pasquali L.
      • Ulivelli M.
      • Marinelli F.
      • Callari G.
      • Iodice R.
      • Liberatore G.
      • Caleri F.
      • Repice A.M.
      • Cordera S.
      • Battaglia M.A.
      • Salvetti M.
      • Franciotta D.
      • Uccelli A.
      Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies.
      ), which supports the idea that revaccination could boost humoral immunity. This study aimed to evaluate antibody response after booster COVID-19 vaccines in people with multiple sclerosis (pwMS) treated with disease-modifying therapies.

      2. Methods

      This is a cross-sectional observational study of patients who already received two doses of inactivated COVID-19 vaccines and were enrolled in the comparative research after two doses of SARS-CoV-2 vaccines. Details reported previously (
      • Ozakbas S.
      • Baba C.
      • Dogan Y.
      • Cevik S.
      • Ozcelik S.
      • Kaya E.
      Comparison of SARS-CoV-2 antibody response after two doses of mRNA and inactivated vaccines in multiple sclerosis patients treated with disease-modifying therapies.
      ). The inclusion criteria for this study was having a third dose of either inactivated Sinovac or mRNA BNT162b2 vaccine. Patients from the previous survey were contacted by phone or e-mail, and eligible patients were invited to participate. The relatives and partners of patients and healthcare workers were recruited as healthy controls. University's Ethics Committee approved the study (2021/15-14). All participants gave the written informed concept. The blood samples were collected at least two weeks after the third vaccine dose.

      2.1 Measurement

      The primary outcome was quantifying antibody response after three doses of the COVID-19 vaccine. Antibody levels were transformed on a Log10 scale to normalize their distribution, and the ‘AU/mL Log’ name was used after that. For antibody titer less than the detectable limit of 21 AU/mL, to prevent missing data during Log10 transformation, a titer of 0.01 Au/mL was used. Vaccines were grouped into two categories: three-dose of inactivated vaccines and two doses of inactivated plus one dose of mRNA BNT162b2. Using the cut-off titer for seropositivity defined by the manufacturer, the antibody response was divided into two categories: seropositive (antibody titer ≥ 50 AU/mL) and seronegative (antibody titer< 50 AU/mL). CIS and RRMS were classified as a relapsing group, SPMS with PPMS as a progressive group for multivariable analyses. Each DMT group and HC were compared in seropositivity, antibody titer, and vaccine type.
      For all multiple comparisons, Bonferroni corrections were made. Two-sided hypothesis testing with a significance set at p < 0.05 was used. Statistical analysis was run on IBM SPSS STATISTICS software version 26.

      3. Results

      In total, 339 pwMS (329 pwMS using DMT, ten pwMSw/oT) and 52 healthy controls were enrolled in this study. Detailed information regarding clinical and demographic characteristics was presented in Table 1 according to DMT groups.
      Table 1Demographic and clinical characteristics of the participants.
      Sex (%)Age-Mean (SD)Disease duration Mean-year (SD)MS type (%)EDSS (SD)Vaccine Type (%)TBVS Mean-day (SD)
      FemaleMaleCISRRMSSPMSPPMS2 dose Inactivated Vaccine+1 dose mRNA BNT162b23 dose Inactivated Vaccine
      pwMS DMT239 (72.6)90 (27.4)44.26 (12.1)13.25 (8.3)0 (0)271 (80.4)55 (16.3)11 (3.3)2.21 (2.1)234 (71.1)95 (28.9)77.46 (56.8)
      pwMS w/o T7 (70.0)3 (30.0)40.20 (16.8)7.97 (8.6)2 (20.0)5 (50.0)2 (20.0)1 (10.0)2.25 (2.4)3 (30.0)7 (70.0)76.40

      (55.6)
      Healthy Controls37 (71.2)15 (28.8)41.04 (11.3)0 (0)46 (88.5)6 (11.5)75.05 (69.9)
      Glatiramer Acetate35 (92.1)3 (7.9)45.82 (14.3)11.47 (10.4)0 (0)36 (94.7)2 (5.3)0 (0)1.57 (2.0)25 (65.8)13 (34.2)90.11 (60.6)
      Interferons26 (72.2)10 (27.8)41.78 (9.3)12.78 (7.4)0 (0)36 (100)0 (0)0 (0)1.13 (1.4)24 (66.7)12 (33.3)77.94 (55.0)
      Teriflunomide14 (73.7)5 (26.3)49.47 (11.8)13.9 (8.9)0 (0)17 (89.5)2 (10.5)0 (0)1.42 (1.8)15 (78.9)4 (21.1)92.79 (54.3)
      Dimethyl Fumarate9 (60.0)6 (40.0)39.27 (13.2)3.67 (5.6)0 (0)15 (100)0 (0)0 (0)1.47 (1.2)13 (86.7)2 (13.3)70.67 (100.5)
      Cladribine5 (83.3)3 (16.7)40.33 (10.1)10.0 (8.0)0 (0)6 (100)0 (0)0 (0)0.50 (0.5)6 (100)0 (0)42.0 (44.4)
      Fingolimod77 (72.6)29 (27.4)42.02 (10.5)13.71 (7.6)0 (0)101 (95.3)5 (4.7)0 (0)1.50 (1.6)74 (69.8)32 (30.2)85.21 (53.7)
      Natalizumab28 (84.8)5 (15.2)37.12 (8.1)9.94 (5.1)0 (0)32 (97.0)1 (3.0)0 (0)1.62 (0.9)27 (81.8)6 (18.2)65.30 (53.3)
      Ocrelizumab44 (60.3)29 (39.7)51.22 (11.0)17.69 (7.4)0 (0)21 (28.8)43 (58.9)0 (0)4.84 (1.8)47 (64.4)26 (35.6)64.47 (49.9)
      Azathioprine1 (33.3)2 (66.7)54.0 (15.4)15.67 (9.0)0 (0)2 (66.7)0 (0)1 (33.3)2.50 (0.5)3 (100)0 (0)64.33 (23.7)
      Total283 (72.4)108 (27.6)43.82 (12.0)2 (0.5)271 (69.3)55 (14.1)11 (2.8)283 (72.4)108 (27.6)81.39 (65.0)
      The distribution of seronegative and seropositive participants regarding DMT groups is shown in Table 2. All participants have seropositivity in every DMT group except the fingolimod and ocrelizumab groups. While there was a significant difference between vaccinations in the fingolimod group (seropositive rate was higher in two doses of inactivated vaccine plus one mRNA BNT162b2), there were no significant differences in the ocrelizumab group.
      Table 2Comparison of having seropositivite and seronegative regarding vaccine groups.
      2 Dose Inactivated Vaccine+ 1 dose mRNA BNT162b23 Dose Inactivated VaccineP
      seropositiveseronegativeseropositiveseronegative
      pwMS w/o T3 (100)0 (0)7 (100)0 (0)NA
      Healthy Controls46 (100)0 (0)6 (100)0 (0)NA
      Glatiramer Acetate25 (100)0 (0)13 (100)0 (0)NA
      Interferons24 (100)0 (0)12 (100)0 (0)NA
      Teriflunomide15 (100)0 (0)4 (100)0 (0)NA
      Dimethyl Fumarate13 (100)0 (0)2 (100)0 (0)NA
      Cladribine6 (100)0 (0)NA
      Fingolimod57 (77.0)17 (23.0)15 (46.9)17 (53.1)0.002
      Natalizumab27 (100)0 (0)6 (100)0 (0)NA
      Ocrelizumab20 (42.6)27 (57.4)9 (34.6)17 (65.4)0.507
      Azathioprine3 (100)0 (0)NA
      The mean antibody titer Log level was higher in healthy controls (mean: 4.07 ± 0.66; minimum/maximum: 2.15/4.60) compared to pwMS (mean: 2.79 ± 2.95; minimum/maximum: −0.70/4.60). The AU/mL Log level of the participants is illustrated in Fig. 1.
      Fig 1
      Fig. 1The AU/mL Log level of the participants.
      When the analyses were repeated according to vaccination groups, healthy controls had higher titer in both three-dose inactivated vaccines (p = 0.01) and two doses of inactivated vaccine plus one dose of mRNA BNT162b2 (p = 0.029) than pwMS.
      Multivariable regression analysis showed that the type of vaccine (the favor of mRNA BNT162b2), disease duration and DMT used by pwMS are significantly associated with the COVID-19 AU/mL Log level. Only ocrelizumab was found significantly differ among DMTs’ (Table 3).
      Table 3Multivariable regression analysis assessing factors associated with antibody levels (AU/mL Log).
      Variableβ (SE)%95 CIP
      Sex (female vs male)−0.046 (0.137)−0.315–0.223.737
      Age−0.004(0.007)−0.018–0.009.501
      Vaccine type
      2 Dose Inactivated Vaccine+1 Dose mRNA BNT162b2 Vaccinereference
      3 Dose Inactivated Vaccine−0.671 (0.133)−0.933 – −0.409<0.001
      TBVS0.000 (0.001)−0.002–0.002.761
      EDSS−0.031(0.043)−0.115–0.053.472
      Disease duration−0.019 (0.010)−0.038–0.000.044
      MS course (Relapsing vs progressive)−0.223 (0.212)−0.640–0.195.295
      DMT<0.001
      Mean difference
      No treatmentReference
      Glatiramer acetate−0.379 (0.347)−1.496–0.739>0.99
      Interferons−0.694 (0.352)−1.829–0.440>0.99
      Teriflunomide−0.743 (0.379)−1.966–0.481>0.99
      Dimethyl fumarate−0.413 (0.397)−1.694–0.869>0.99
      Fingolimod0.957 (0.328)−0.102–2.0160.138
      Cladribine−0.588 (0.493)−2.179–1.003>0.99
      Natalizumab−0.441 (0.354)−1.583–0.701>0.99
      Ocrelizumab1.957 (0.327)0.901–3.013<0.001

      4. Discussion

      In this study, we found that after the booster vaccine, there were no seronegative cases in pwMS except for those treated with fingolimod and ocrelizumab. mRNA vaccine is associated with higher antibody response even if given as a booster after the inactivated vaccine. These results are not surprising because studies have shown that fingolimod and ocrelizumab are responsible for the diminished immunologic response after COVID-19 vaccines (
      • Garjani A.
      • Patel S.
      • Bharkhada D.
      • Rashid W.
      • Coles A.
      • Law G.R.
      • Evangelou N.
      Impact of mass vaccination on SARS-CoV-2 infections among multiple sclerosis patients taking immunomodulatory disease-modifying therapies in England.
      ). The mechanism beyond this effect is that CD20 depleting agents such as ocrelizumab alter the new humoral response by decreasing the number of B-cells (
      • Bar-Or A.
      • Calkwood J.C.
      • Chognot C.
      • Evershed J.
      • Fox E.J.
      • Herman A.
      • Manfrini M.
      • McNamara J.
      • Robertson D.S.
      • Stokmaier D.
      • Wendt J.K.
      • Winthrop K.L.
      • Traboulsee A.
      Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis.
      ). On the other hand, fingolimod keeps lymphocytes from entering the circulation by holding them hostage in lymph nodes (
      • Mehling M.
      • Johnson T.A.
      • Antel J.
      • Kappos L.
      • Bar-Or A.
      Clinical immunology of the sphingosine 1-phosphate receptor modulator fingolimod (FTY720) in multiple sclerosis.
      ). Taking this notion further, we expect patients on azathioprine and cladribine to have lower antibody titer on comparative analyses, considering both as immunosuppressants (
      • Corsini E.
      • la Mantia L.
      • Gelati M.
      • Dufour A.
      • Milanese C.
      • Massa G.
      • Nespolo A.
      • Salmaggi A.
      Long-term immunological changes in azathioprine-treated MS patients.
      ;
      • Sipe J.C.
      • Romine J.S.
      • Koziol J.A.
      • McMillan R.
      • Zyroff J.
      • Beutler E.
      Development of cladribine treatment in multiple sclerosis.
      ). Though we did not observe these predictions, having fewer patients treated with these agents (three and six, respectively) prevented us from making statistically supported conclusions.
      Study results show that mRNA as a booster after two doses of inactivated vaccine resulted in a statistically significantly higher number of seropositive cases in the fingolimod group but not in ocrelizumab. This positive effect could be attributed to the fact that although fingolimod prevents lymphocytes from egressing into the circulation, it does not deter B-cells from building the humoral response, although for this effect to happen, a more potent trigger such as an mRNA vaccine might act on those lymphocytes.
      We observed that pwMS treated with DMT had lower antibody titer than healthy controls. Of 339 patients, 73 were treated with ocrelizumab and 106 with fingolimod, making up 53% of the total study population on DMT. These two groups could shift the mean antibody titer of pwMS to the lower side.
      By looking at the association of antibody titer after the third dose of the COVID-19 vaccine, we found that having inactivated vaccine as a booster, longer disease duration, and DMT use were correlated with lower antibody response. These findings are valuable because even if a patient has an inactivated vaccine as a standard dose, mRNA as a booster in these populations of MS patients could still mount an antibody response. We explained the relation of disease duration to lower antibody response by the negative effect of ocrelizumab, which is our choice of treatment in the progressive form of MS, and longer disease duration increases the odds of progression. This hypothesis is further supported by the finding that we did not find a significant relationship between age and antibody titer because longer disease duration could also mean advanced age.
      Among the limitations of the study are the observational design of the research and the lower number of participants in DMT groups. Also, we did not record the information about previous COVID-19 infections, which could influence the antibody response after the vaccines. This is also true for asymptomatic encounters. This bias could have been prevented by looking at the antibody titer before the vaccination.

      5. Conclusions

      A vaccination strategy is vital for protection during the pandemic. MS is not a condition that causes immunosuppression per se; however therapeutic choices to treat the disease can alter the function of immune cells. Study results favor the mRNA vaccine as a booster for pwMS on DMT, even if the first two doses were the inactivated vaccine.

      Declaration of Competing Interest

      The authors report no declarations of interest.

      Funding sources

      None.

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