key: cord-0857370-4f40ctvu authors: Fragoso, Yara D; Gomes, Sidney; Gonçalves, Marcus Vinicius M; Junior, Euldes Mendes; de Oliveira, Bianca Etelvina S; Rocha, Cristiane Franklin; Cruz dos Santos, Gutemberg A; Tauil, Carlos Bernardo; Araujo, Raquel Vassao; Peron, Jean Pierre S title: New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19 date: 2021-10-13 journal: Mult Scler Relat Disord DOI: 10.1016/j.msard.2021.103321 sha: 37170ad2b21b1479ad813625e1deba6a00a3211b doc_id: 857370 cord_uid: 4f40ctvu We report on nine patients (eight cases of MS and one case of NMOSD) who presented a disease relapse in close temporal association with their first AZD1222 vaccination dose against COVID-19. These patients had been stable for a median period of six years, with no evidence of disease activity and no change in their medication. After a median of 13 days (7 to 25 days) from vaccination, they developed a new relapse with increased disability and new lesions on magnetic resonance imaging. Although exceedingly rare, this might be an adverse event of AZD1222. The key point for controlling the coronavirus disease 2019 (COVID- 19) pandemic is vaccination. Several safe and effective vaccines have now been developed against COVID-19, which, together with wearing a face mask, social distancing and frequent hand sanitation, can potentially slow the spread of the virus. 1 Patients with multiple sclerosis (MS) are correctly encouraged to be vaccinated against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19. 2 Given the urgency generated by the COVID-19 pandemic, COVID-19 vaccines have been granted emergency-use authorization in several countries on the basis of results from ongoing trials. 3 There has been no trial on any vaccine for patients diagnosed with autoimmune diseases such as MS or neuromyelitis optica spectrum disorders (NMOSD). There are some recommendations regarding the diseasemodifying drug (DMD) that they are taking at the time of receiving the vaccine. 4 Hesitancy to receiving vaccinations has been reported among patients with MS, 5 with particular concern and unwillingness observed in relation to COVID-19 vaccination. 6 Vaccines rely on both the innate and the adaptive arm of the immune system, and interact in a complex and complementary manner to generate the immunological memory. 7 According to MS societies and specialists' recommendations, "there is no vaccine preference for those living with MS. A fever can make your MS symptoms worse temporarily, but they should return to prior levels after the fever is gone. Even WhatsApp started to post cases of patients with MS or NMOSD who had had no evidence of disease activity (NEDA) 11 for years, but then, a few days after anti-SARS-CoV-2 vaccination, presented a demyelinating relapse. A separate study group was created and neurologists who wanted to report on their cases sent detailed information on this adverse event in a file created for this purpose. Additional Ethics Committee approval was obtained whenever necessary. Patients were included if they had not presented a clinical relapse, a new lesion on MRI or an increased or new neurological disability for at least one year. The patient should be using the same medication for MS for the whole time he/she was stable. The new relapse, occurring post-vaccine, should be in close temporal relation to the inoculation and alter the neurological examination and the magnetic resonance image (MRI). The present report is essentially descriptive. Table 1 summarizes the data on the nine patients who presented a new relapse after a median period of six years of NEDA for MS and 10 years of stability for NMOSD. Briefly, there were three men and six women, of median age 33 years, comprising eight cases of MS and one case of NMOSD. All the patients presented a relapse after a median interval of 13 days (range: 7 to 25 days), following their first dose of AZD1222. None of the patients with MS had had COVID-19 prior to vaccination, but the patient with NMOSD had been infected with SARS-CoV-2 eight months before her vaccination and had recovered well. There were two patients inoculated with CoronaVac who were excluded from the study for not fulfilling the abovementioned inclusion criteria. The first patient had shown a small new T2 lesion in her MRI six months before vaccination. Therefore, she was not considered to be in NEDA for at least one year and her presence in this study could not be justified. The second patient did not show MRI changes during the post-vaccine relapse, which was mostly sensory and resolved within three weeks without treatment. Again, inclusion of this patient could have been a confounding factor in a group with distinctive relapses. The changes to the nine patients' disability status during the relapse are shown in Figure 1 . None of the drugs used for MS treatment and none of the clinical presentations of the disease seemed to influence the onset of a relapse ( Table 1) . None of the patients had interrupted their treatment or changed therapy at any time over the years in which they had remained stable regarding their MS/NMOSD. Here, we discuss the cases of nine patients with MS or NMOSD with NEDA for long periods, i.e. 1-8 years, who had relapses as early as 7-15 days after administration of the first dose of the AstraZeneca AZD1222 vaccine against COVID-19. The most common features were new Gd+ lesions and higher lesion loads, shown on MRI. Appearance of autoimmunity after administration of vaccines has already been described in the literature, including vaccines against SARS-CoV-2. Usually, these patients develop self-limiting symptoms that may include Guillain-Barré syndrome (GBS), 12,13 autoimmune thrombocytopenia, 14-16 encephalitis 17 or lupus, 18 among others. Moreover, the concept of autoimmune/inflammatory syndrome induced by adjuvants (ASIA), described by Shoenfeld in 2011, 19 has been extensively debated. A cohort study on 500 subjects who developed ASIA identified that around 35% had neurological manifestations, 73% arthralgia and 65% chronic fatigue. 20 It is noteworthy that some of these patients had ASIA after receiving the influenza vaccine, for which the adjuvant is the same one used in AZD1222. Vaccines may be developed on different bases, using living attenuated, nonreplicating or inactivated pathogens, for example. Specific components may also be introduced, such as purified proteins and, more recently, nucleic-acid vaccines made of mRNA, plasmid DNA or viral DNA vectors that code for a specific antigen. This latter category forms the basis for the current COVID-19 vaccines, for which the antigen is either the full length or a portion of the envelope SPIKE protein. 21 However, the presence of the adjuvants, another component of vaccines with an unquestionably essential function, must not be neglected. In association, the antigen and the adjuvants have the aim of inducing a robust and long-lasting specific response from both humoral and cellular components of the immune system. For this, three signals are essential: (1) specific antigens need to be recognized by the major histocompatibility complex -T cell receptor (MHC-TCR) interaction; (2) costimulatory engagement need to occur to favor TCR signaling pathways; and (3) pro-inflammatory signals supplied by cytokines lead to functional involvement of the T lymphocytes towards the Th1, Th2 or Th17 phenotypes. 22 Although the first signal is very specific, i.e., through recognition of the specific vaccinal epitope, the second and third signals are much more unspecific. 23 Adjuvants are known to activate innate immunity receptors, such as toll-like receptors (TLRs). 24 The TLR signaling pathway culminates in phosphorylation of the transcription factor NF-KB, for which responsive elements are found in more than 1500 inflammatory genes. 25 These elements include cytokines, chemokines, enzymes and also antigen presentation molecules like MHC I and II. 26 Moreover, the Nod-like receptor (NLR) triggers assembly of an inflammasome, which further activates caspase-1, for release of IL-1β and IL-18 by means of pyroptosis. 27 Together, these molecules correlate with the mild flulike symptoms that may be observed soon after administration of most vaccines. However, although essential, given that these molecules supply T lymphocytes with enough stimuli for B and T clonal activation and expansion for an appropriate immune response, they may also trigger undesired responses, such as autoimmune reactions. The human organism contains a very broad repertoire of lymphocytes. These lymphocytes are usually under the control of peripheral mechanisms of tolerance, a role that is mostly played by CD4+Foxp3+ regulatory cells. 28 In the case of immune-mediated diseases, such as MS and NMOSD, this repertoire is enriched by anti-myelin or anti-aquaporin-4 antigen-specific lymphocytes and, besides Treg suppression, they are also targets for immunomodulatory therapy. The inflammatory effect of adjuvants may blunt the mechanisms of tolerance, thereby allowing these self-reacting clones to surge. Thus, lymphocytes with specificities unrelated to the vaccinal antigen may be activated by the abundance of cytokines produced. This phenomenon is known as bystander activation and may be observed under many different circumstances. 27 In fact, investigation of the effects of adjuvants for induction of autoimmunity dates back to studies by Thomas Rivers, who took the observations made by Louis Pasteur after inoculation of rhesus monkeys with brain extracts and correlated these with the discovery of Freund´s adjuvant, by Jules Freund, as previously reviewed. 30 Whereas Louis Pasteur needed multiple inoculations for induction of paralysis, Rivers needed only one inoculation if he used brain extracts in association with Freund´s adjuvant. Importantly, it is known that both IL-1 and IL-6 are potent blockers of Treg function, 31 while they favor involvement of the encephalitogenic Th17 subtype. 32 The AZD1222 vaccine contains the adjuvant MF59 ® , which is an oil-in-water emulsion containing squalene (4.3%) in citric acid buffer with the surfactants Tween 80 (0.5%) and Span 85 (0.5%). This emulsion has been clearly shown to induce inflammation, given that it may induce secretion of cytokines such as IL-6 and IL-8, as well as the chemokines CCL2, CCL3 and CCL4. 33 Here, we hypothesize that bystander activation of reminiscent self-reactive clones may have been reactivated in our patients. Considering that they were previously in a state of NEDA for long periods, it is plausible to think that self- Recent reports have also shown that COVID-19 severity correlates with a broad spectrum of self-reacting antibodies, including against central nervous system antigens. Unexpectedly, these responses were found to be compartmentalized to the CNS. This was further confirmed in a murine experimental model. The candidate antigens are NRG3, SYNJ2 and DPYSL2. 34 Because no reports have so far demonstrated epitope similarities between SARS-CoV-2 and neuroantigens, molecular mimicry seems not to be the case, and the mechanisms still need to be unraveled. Moreover, AZD1222 is composed of SPIKE alone, and not a fully viral particle. Another interesting report using an experimental model has shown that the SARS-CoV-2 SPIKE protein is able to cross the blood-brain barrier by means of transcytosis via ACE-2 interaction and, furthermore, can reach the brain parenchyma, via the olfactory bulb. Our motivation in reporting these cases was that there may be other such cases around the world. Moreover, there are no recommendations regarding the merits of the second dose of vaccine for these patients. For the moment, since the second dose of AZD1222 leads to a relatively small increase in protection against COVID-19, we have suggested to these patients that they should not take it. Our aim in presenting this report was to bring this subject to discussion, especially with regard to cases of vaccination of autoimmune patients. We strongly support vaccination, and we believe in its importance for controlling the pandemic. We still believe that its benefits greatly outweigh the risks, given that the prevalence of adverse effects is very low. However, we also believe not only that this subject is relevant, but also that it must be brought to discussion between patients and physicians, in order to have a more transparent and trustful relationship. Legends to the figures Legend to the table Guillain-Barré syndrome and influenza vaccines: A meta-analysis. 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Cell Death Differ A local regulatory T cell feedback circuit maintains immune homeostasis by pruning self-activated T cells A distinct function of regulatory T cells in tissue protection Bystander CD4+ T cells: crossroads between innate and adaptive immunity Thomas Rivers and the EAE model The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells Immunology and efficacy of MF59-adjuvanted vaccines Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms COVID-19 vaccination in patients with multiple sclerosis: What we have learnt by Safety of the BNT162b2 COVID-19 vaccine in multiple sclerosis (MS): Early experience from a tertiary MS center in Israel Patient-reported safety and tolerability of the Sidney Gomes -included two patients, discussed the results Euldes Mendes Junior -included a patient, discussed the results Recovery* -when "not yet recovered" is stated, it means that the patient is still with some degree of neurological disability after at least 40 days from the onset of the relapse. All authors agreed with the final version of the paper, now submitted to the journal. ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. No private or public funding was provided for this study.