COVID-19 and Vaccination in the Setting of Neurologic Disease

Mechanisms of Action

To lower overall viral transmission through herd immunity and decrease disease severity, particularly in vulnerable populations, 3 vaccines using distinct approaches have been approved by the FDA for emergency use. None of these vaccines utilizes inactivated or live-attenuated SARS-CoV-2 virus, nor do they use recombinant protein technology (the 3 most commonly used technologies for vaccine development in the past). Two of these (Pfizer and Moderna) utilize a novel messenger RNA (mRNA) approach, in which mRNA encoding a subunit of the SARS-CoV-2 spike protein is encapsulated within lipid nanoparticles to increase stability and augment uptake by antigen presenting cells.³⁶ After uptake, the mRNA is translated into antigenic spike protein, inducing cell-based and humoral immune responses. This technology has advantages with regard to vaccine production and potentially immunogenicity and has been shown to be effective in animal models and clinical trials against a wide variety of infectious agents.³⁷ Under emergency use authorization, it is now being used to vaccinate against SARS-CoV-2. The Johnson & Johnson vaccine, in contrast, utilizes a replication-deficient adenovirus vector to deliver DNA encoding the SARS-CoV-2 spike protein into host cells, which is then transcribed/translated into antigenic protein. Adenoviruses are common cold-causing viruses.³⁶ In the context of the Johnson & Johnson vaccine, the adenovirus has been genetically engineered to prevent replication, meaning it cannot produce an active adenovirus infection. A similar platform has been used in a prior Ebola virus vaccine approved for use in the European Union.³⁸ Because none of the currently approved vaccines utilize live-attenuated SARS-CoV-2 virus, none has the potential to cause SARS-CoV-2 infection.

Safety and Efficacy

mRNA-based vaccine approaches provide a novel, highly potent mechanism toward building immunity.³⁷ In a multinational randomized placebo-controlled trial of >40,000 people, the Pfizer vaccine was found to be 95% effective against development of symptomatic disease in recipients compared to controls.⁴ In their initial report to the FDA, fatigue and headache were the most frequent side effects of vaccination and initial severe systemic symptoms occurred in only about 2% of participants. Longer term severe events were rare, occurring in only 4 participants, and included shoulder injury, lymphadenopathy, ventricular arrythmia, and paresthesias. Similar results were seen with the Moderna vaccine.³

The most recent safety data are provided in the preliminary analysis of a multicenter phase 3 trial of >30,000 volunteers assigned to mRNA-1273 SARS-CoV-2 vaccine (Moderna) vs placebo. The trial showed high efficacy (94.1%) and a low rate of complications in individuals at high risk for infection and mortality due to COVID-19 who received active vaccine.³⁹ Whereas neurologic illness was not an inclusion criterion, other high-risk comorbidities such as heart failure, pulmonary hypertension, diabetes, and HIV infection resulted in a diverse population with multiple comorbidities that would be expected to encompass some patients with neurologic disease. The most frequent complications included injection site reactions, headache, and fatigue. Severe adverse events attributable to vaccine or placebo were uncommon, and similar between the vaccine and placebo groups (0.5% vs 0.2%).

The Johnson & Johnson vaccine phase 3 trial differed from the Moderna and Pfizer trials in its prespecified outcomes, timing, and setting. It found a 66% reduction in moderate to severe COVID-19 in its treatment arm, with 85% reduction in severe disease and no hospitalizations or COVID-19–related deaths compared to controls. Recently, blood clots occurring 7–14 days after administration have been reported, primarily in young women on oral contraceptive medications, though whether this is higher than the baseline rate of thrombosis in this group and whether the mechanism can be reliably linked to vaccine administration is under investigation. In these events, vaccination was typically followed by cerebral venous sinus thrombosis, which was associated with thrombocytopenia and antibodies to platelet activating factor-4.^40,41 In April 2021, the FDA instituted a 10-day pause in the use of the Johnson & Johnson vaccine for further evaluation of these events, which constituted 6 cases out of approximately 7.98 million doses given. Following review, the recommendation and emergency use authorization for this vaccine were reaffirmed for individuals aged 18 years and older, with a warning regarding rare clotting events primarily among women aged 18–49 years.⁴² Of note, similar rare clotting events that appear to share a pathophysiologic mechanism have been reported with the Oxford/AstraZeneca vaccine approved outside the United States, with an estimated incidence of 1 in 40,000.⁴³ This vaccine uses a similar adenovirus-based mechanism.

Although neurologic side effects were not more commonly observed following active vaccine over the extended follow-up period for any of the vaccines, a number of neurologic complications of these vaccines are now being reported in the most comprehensive registry, the Vaccine Adverse Events Reporting System (VAERS) database. These include strokes, cranial neuropathies including Bell palsy, tinnitus and trigeminal neuralgia, peripheral neuropathies, dysautonomia, acute disseminated encephalomyelitis, transverse myelitis, and AIDP.⁴⁴ Case reports are also starting to emerge in the published literature^45,46 and the popular press. Most recently, the possibility of increased risk of AIDP in the weeks following vaccination was formally added to the label for the Johnson & Johnson vaccine. These complications are rare when compared to the large number of vaccinated individuals; however, it is too early to know the true incidence and risk factors for these complications. They are thought to be immune-mediated and early recognition and treatment with immunomodulatory therapies might be warranted. There are little to no data regarding the safety or efficacy of the COVID-19 vaccines in patients with preexisting neurologic conditions or patients receiving immunomodulatory therapies. Based on COVID-19 vaccine data from the general population and extrapolations from other vaccines studied in patients with neurologic disease, statements from the American Academy of Neuromuscular and Electrodiagnostic Medicine and the National Multiple Sclerosis Society support vaccination.^47,48 As discussed further below, a single study has now reported no increased risk of complications in patients with MS receiving the Pfizer COVID-19 vaccine.⁴⁹

Neurologic Complications Associated With Prior Vaccines

Prior studies have shed light on the likelihood of neurologic complications following vaccination. These data can be difficult to interpret and are often seen as controversial, suffering from potential reporting bias and lack of clear causality, but illustrate theoretical concerns for both patients and physicians and must be acknowledged. The VAERS Database has reported adverse events affecting both the central and peripheral nervous systems, although clear causal relationships remain difficult to establish. AIDP is the most common neurologic syndrome and has been described in case reports following vaccination for influenza, polio, rabies, meningococcus, measles, mumps, and tetanus.⁵⁰ Vaccination for H1N1 in 1976 was associated with an increased risk of AIDP of 1 additional case per 100,000 vaccinated individuals.⁵¹ These cases occurred between 1 and 6 weeks following immunization. On this basis, the vaccine was discontinued in January 1977. However, one must also consider the baseline rate of Guillain-Barré and seasonal variability when interpreting these data. The 2009 H1N1 epidemic showed that individuals were actually more likely to experience AIDP after viral infection than after administration of the vaccine,⁵² and subsequent influenza vaccines have been considered safe with an excess risk of about 0.1 case per 100,000 vaccinations.^53,-,59 Case reports of AIDP have been reported with a number of vaccines such as hepatitis A, Japanese encephalitis, smallpox, yellow fever, and meningococcus.⁶⁰ Current guidelines by the advisory committee on immunization practices of the Centers for Disease Control & Prevention list AIDP within 6 weeks of previous influenza as a precaution for immunization against influenza. This means that while the risks may be elevated, individual risks vs benefits should be considered before recommending immunization.^e1 Vaccination has been associated with the development of chronic inflammatory demyelinating polyneuropathy (CIDP) in 1.5% of patients with CIDP within 6 weeks of administration^e2 and worsening symptoms were also reported after tetanus vaccination in 8.7% of patients.^e3 The overall rate of complications is rare and consideration of vaccination type is also important when considering risk.

In addition to peripheral nervous system effects, CNS involvement has been reported most often in the form of acute disseminated encephalomyelitis (ADEM). In the early 1990s, seizures and encephalitis were loosely linked to the diphtheria-tetanus-pertussis vaccine,^e4 although later studies reported no increased seizure frequency over baseline.^e5 ADEM has been reported in the form of case reports with the antirabies vaccine,^e6-e8 as well as vaccinations to yellow fever, Japanese encephalitis, measles, influenza, smallpox, anthrax, and others. The strongest association of ADEM has been with the Semple rabies vaccine, likely because it was made in cells derived from the nervous system.⁶⁰ With regard to MS, theoretical concerns about vaccines precipitating relapses have existed for decades,^e6 although published studies have failed to identify any correlation between vaccination and either initial or subsequent clinical attacks.^e7-e10 In contrast, several vaccines have been possibly linked to a lower risk of subsequent MS diagnosis.^e8 Thus far, a single study of adult patients with MS receiving the Pfizer COVID-19 vaccine (555 having received the first dose and 435 having received the second dose) demonstrated no safety concerns and no increased risk of relapse.⁴⁹

Vaccine Efficacy in Patients Receiving Immunotherapies

Studies of COVID-19 vaccine efficacy in patients receiving immunotherapies are limited. A recently published real-world study of the Pfizer COVID-19 vaccine found that 2 doses of the vaccine reduced SARS-CoV-2 infection by 71% in immunosuppressed patients compared to a 90% reduction among the nonimmunosuppressed.^e11 However, the specific therapies used and the definition of immunosuppression were not reported. A small study of patients with rheumatic and musculoskeletal diseases found a blunted antibody response to 2 doses of SARS-CoV-2 mRNA vaccine in those treated with glucocorticoids (82% seroconversion), mycophenolate (73% seroconversion), or rituximab (26% seroconversion).^e12

Despite limited data specific to COVID-19 vaccination, prior studies have been helpful in elucidating the effect of immunomodulatory and immunosuppressive therapies on vaccine response. In general, immunomodulatory therapies have less effect on vaccine response than immunosuppressive or cell-depleting therapies. For patients with MS, there appears to be preserved immunity postvaccination for those taking interferons.^e6,e8 Dimethyl fumarate was similarly found to have no effect on vaccine response, although only in a single study.^e13 Glatiramer acetate, teriflunomide, and natalizumab have demonstrated mixed results, with mildly attenuated immune responses in some but not all studies.^e14-e20 Based on mechanism of action and the at most modest effect on vaccine response in prior studies, the above therapies are not expected to substantially decrease the efficacy of COVID-19 vaccines. In contrast, fingolimod, anti-CD20 therapies, and alemtuzumab have been shown to significantly impair vaccine responses in prior studies.^e21-e23 A recent study in 23 patients showed that patients treated with cladribine had normal immune responses to the vaccine.^e24 For these therapies, timing considerations must be taken into account for vaccination, as outlined in recently released guidelines from the National Multiple Sclerosis Society (Table).^e25 However, it is important to note that partial immunity might still be achieved even with those therapies that blunt measured vaccine responses. Furthermore, many studies of vaccine response have evaluated only humoral (antibody-mediated) immunity, without consideration of cell-mediated T-lymphocyte responses.

In addition to the above MS therapies, other immunotherapies are commonly used in patients with inflammatory/autoimmune neurologic disease. Methotrexate acts by inhibiting lymphocyte activation and results in a decreased response to pneumococcal vaccine.^e26 Similarly, azathioprine, mycophenolate mofetil, and systemic corticosteroids generally have been associated with decreased immunologic response to vaccines.^e27 The anti-interleukin-6 monoclonal antibody tocilizumab has thus far not been shown to attenuate humoral responses to vaccination, at least after short durations of therapy.^e28-e30 However, the possibility of decreased vaccine response must still be considered. The effect of eculizumab on vaccine response has not been extensively studied. When possible, it is generally prudent to complete vaccinations 2–4 weeks prior to initiating the above therapies, but treatment with these therapies does not preclude vaccination except for live-attenuated vaccines.

Neuromuscular and Neuroinflammatory Disorders

The weakness and disability associated with neuromuscular and neuroinflammatory disorders can result in increased symptomatology with viral infection, though there is no clear evidence that infection is associated with increased risk of flare or disease progression. These patient populations are most likely to be treated with immunotherapies, which are discussed above in the context of SARS-CoV-2 infection and vaccination. Despite a paucity of data specifically evaluating the currently available COVID-19 vaccines in these groups, vaccination is expected to be safe. Both the American Academy of Neuromuscular and Electrodiagnostic Medicine and the National Multiple Sclerosis Society are in favor of vaccination for patients with neuromuscular disease and MS, regardless of immunosuppressive status. Although consensus guidelines from these groups discuss optimal timing of vaccination in relation to treatment with certain immunotherapies, it is important to note that vaccination should not necessarily be delayed if immediately available, as in some cases the risk of delaying even partial immunity may outweigh the benefit of waiting to achieve optimal vaccine response.^47,48,e25

For those patients treated with immunotherapies known or suspected to decrease vaccine response, patients should be counseled to remain vigilant about infection mitigation efforts even after vaccination due to the possibility of absent or diminished immunity. Evidence-based guidance does not exist regarding COVID-19 risk and appropriate ongoing safety measures for vaccinated patients on immunocompromising therapies. These issues are becoming increasingly relevant and challenging as a greater share of the population becomes vaccinated, leading to lifting of state- and locally mandated safety measures and recommendations regarding the return to normal activities for the fully vaccinated.^e31 Some providers may choose to measure postvaccination antibody levels against the SARS-CoV-2 spike protein to assess vaccine response and aid in counseling these patients, although the clinical significance of such testing with regard to COVID-19 risk remains uncertain. Further studies are needed regarding how best to evaluate postvaccination immunity in this patient population and whether additional measures (such as booster vaccines) may be useful.

Dementia, Cerebrovascular Disease, and the Elderly

The possibility of side effects from vaccination is a significant concern in the elderly population, given that it includes many individuals with potential vulnerability due to cognitive impairment or cerebrovascular disease. However, the risk of viral infection is also highest in this demographic and the Alzheimer's Association is recommending vaccination for elderly individuals and their caregivers.^e32 More research is required to determine whether individuals with neurodegenerative cognitive disease are at risk for accelerated decline after COVID-19. Vaccine administration for the majority of patients with stroke and cardiovascular disease is also supported by the American Heart Association,^e33 as infection with COVID-19 can exacerbate neurologic sequelae of prior strokes. There are rare case reports of increased risk of stroke in young individuals with COVID-19 without traditional vascular risk factors,^e34 as well as reports of clotting in individuals with severe COVID-19.^e35 There is as yet no evidence to suggest that those with traditional risk factors are at an increased risk of stroke. As of this writing, 75% of the elderly population of the United States have received at least 1 vaccine dose and 55% are fully vaccinated. Careful surveillance will be required to determine whether there are age-related vaccination risks, but in the absence of clear data indicating increased risk, the clear impetus is to vaccinate that portion of the population that has constituted 80% of US deaths due to COVID-19 to date.

Epilepsy

Although seizures are not a common presentation of COVID-19, infection can increase seizure frequency in those at increased risk and the Epilepsy Foundation recommends the vaccine for eligible patients as there does not appear to be worsening of epileptic seizures following vaccine administration.^e36 There has been no evidence of increased risk of seizures following vaccination in those with a history of epilepsy.

Children and Pregnant Women

Recently, the first mRNA vaccine was approved for administration in children over 12 years of age; however, this review focuses on the ramifications of COVID-19 and evidence regarding safety of vaccination in the adult population, as the risk–benefit ratio is likely different between the 2 groups. Data are also sparse, although emerging, regarding the vaccine’s use in pregnant women.^e37 Although “no obvious safety signals” were seen, we await further evidence of safety and efficacy.

Underrepresented Populations

Underrepresented populations, including the Black, Latinx, and indigenous communities, also merit special consideration due to disproportionate risk of morbidity and mortality related to SARS-CoV-2 infection^e38-e41 and disparities in access to available vaccines,^e42-e44 although no data exist specifically regarding the interaction between COVID-19 and preexisting neurologic illness in these groups. An additional challenge is vaccine hesitancy related to relative mistrust of the medical community, which stems from a variety of historical events and experiences.^e45,e46 Of course, it is important to note that vaccine hesitancy is not restricted to underrepresented populations and transcends age, sex, race, and socioeconomic class, although the historical experiences producing hesitancy are often unique to these groups. Given the challenges facing underrepresented and underserved groups, strategies to increase vaccine access and advocacy within these communities remain critical.