according to a presentation at the American Headache Society’s 2021 annual meeting.
Dr. Amy Galfand
Amy Gelfand, MD, director of pediatric headache at University of California, San Francisco, reviewed common concerns migraine patients or their clinicians might have related any of the three vaccines, starting with a review of how the vaccines work – by targeting the spike protein of the SARS-CoV-2 virus.
“The vaccines induce response to that protein, but only that protein, so there’s no reason to think they’re going to cause the body to produce neutralizing antibodies against any of our migraine therapeutics,” Dr. Gelfand said. She added that the phase 3 clinical trials included participants from a wide range of ages and comorbidities, so there were likely many people in the trials who have migraine, though no subgroup analyses have been performed for this group or are likely to be performed.
Common questions
The two treatments people have the most questions about concerning the COVID-19 vaccine are onabotulinumtoxinA and CGRP pathway monoclonal antibodies (mAbs), likely because both of these are injections, as is the vaccine, Dr. Gelfand said. First, she reminded attendees that onabotulinumtoxinA is not a dermal filler, since some reports following administration of the Moderna vaccine suggested that some people with dermal fillers had swelling in those areas after vaccination.
In addition, “there’s no reason to think the onabotulinumtoxinA would influence our body’s immune response to any vaccine, so there’s no need to retime the onabotulinumtoxinA injections around COVID-19 vaccine administration,” Dr. Gelfand said.
Regarding mAbs, she acknowledged that some white blood cells have CGRP receptors, which may have a pro- or anti-inflammatory role, but clinical trials of mAbs did not show any evidence of being immunosuppressive or myelosuppressive.
“The monoclonal antibodies themselves have undergone engineering so that they are just going after their one target,” Dr. Gelfand said. “They’re not going to be expected to bind to anything else outside of their targets, so I don’t think there’s anything there to make us retime the monoclonal antibody administration relative to the COVID-19 vaccine.”
She did note that patients who choose to get mAbs injections in their arm instead of their thigh or abdomen may want to receive it in the opposite arm than they one they have gotten or will get the vaccine in since the vaccine can cause discomfort.
The other common question patients may have is whether taking any NSAIDs or acetaminophen before getting the COVID-19 vaccine will reduce their immune response to the vaccination. This concern arises because of past evidence showing that some infants tended to have lower immunologic responses when they received acetaminophen after their primary vaccines’ series, but the clinical significance of those reduced responses is not clear since they still had strong responses. Further, this effect was not seen with booster shots, suggesting it’s an age-dependent effect.
During the clinical trials of the AstraZeneca vaccine, several sites gave prophylactic paracetamol without any apparent detrimental effect on antibody response, Dr. Gelfand said. Further, the mRNA and adenovirus-vectored vaccines appear to induce antibodies far above what many believe is needed for protection.
“Even if there were a slight decrease, it’s not clear that that would have any kind of clinical significance for that person in terms of their level of protection against COVID-19,” she said. “Bottom line, it’s fine for patients to use either of these after administration of the COVID-19 vaccine.” The Centers for Disease Control and Prevention doesn’t recommend it prophylactically beforehand, but it’s fine to take it for a fever, aches or headache after getting the vaccine.
Migraine or vaccine reaction?
Dr. Gelfand then addressed whether it should affect physicians’ headache differential if seeing a patient who recently received an adenovirus-vectored vaccine, such as the Johnson & Johnson or AstraZeneca vaccines. The question relates to the discovery of a very rare potential adverse event from these vaccines: cerebral venous sinus thrombosis (CVST) with thrombocytopenia and thromboses in other major vessels, together called thrombosis thrombocytopenia syndrome (TTS). No TTS cases have been reported following mRNA vaccines.
TTS’s mechanism appears similar to autoimmune heparin-induced thrombocytopenia, where the body produces platelet-activating antibodies. TTS currently has three diagnostic criteria: new-onset thrombocytopenia (<150,000/microliter) without evidence of platelet clumping, venous or arterial thrombosis, and absence of prior exposure to heparin.
So far, TTS has been limited only to the vaccines that use an adenovirus vector. One male clinical trial participant experienced CVST with thrombocytopenia in Johnson & Johnson phase 3 trials, and 12 cases out of approximately 8 million Johnson & Johnson doses were reported to the Vaccine Adverse Event Reporting System between March 2 and April 21, 2021. Three TTS more cases followed these, resulting in 15 TTS events per 8 million doses.
In terms of clinical features, all 15 cases were females under age 60, mostly white, and all 11 who were tested were positive for the heparin-platelet factor 4 antibody test. TTS occurred 6-15 days after vaccination for these cases, and all but one had a headache. Their platelet count was 9,000-127,000. None were pregnant or postpartum.
“For us, as headache clinicians, the epidemiology of TTS overlaps with the epidemiology of migraine – they’re happening to the same group of patients,” Dr. Gelfand said. Most of the cases occurred in women aged 30-39 years, while the estimated incidence in women aged 50 or older is 0.9 cases per million doses.
The CDC has proceeded with the Johnson & Johnson vaccine because a risk-benefit analysis revealed that use of the vaccine will result in fewer hospitalization and deaths from COVID-19, compared with adverse events from the vaccine, Dr. Gelfand explained. However, the CDC notes that “women younger than 50 years old should be made aware of a rare risk of blood clots with low platelets following vaccination and the availability of other COVID-19 vaccines where this risk has not been observed.”
For clinicians, the existence of TTS raises a question when patients with a history of migraine call after having received the Johnson & Johnson vaccine, Dr. Gelfand said: “How do we know if this is a spontaneous attack, if it’s a headache provoked by receiving the vaccine, or they have one of these rare cases of [TTS]?”
Three things help with this differential, she said: timing, epidemiology, and headache phenotype. Headache after a vaccine is very common, but it usually happens within the first couple of hours or days after the vaccine. By day 4 after vaccination, few people had headaches in the clinical trials. Since TTS requires production of antibodies, a headache within a few hours of vaccination should not raise concerns about TTS. It should be considered, however, for patients who experience a headache within a week or 2 after vaccination.
Then consider the epidemiology: If it’s a woman between ages 18 and49 calling, the risk is higher than if it’s a male over age 50. Then consider whether there are any unusual headache features, positionality, encephalopathy, or clinical features that could suggest clots in other parts of the body, such as abdominal pain, shortness of breath, or pain in the legs.
“At the end of the day, if it’s a person who’s in this epidemiological window and they’re calling a week or 2 out from the Johnson & Johnson vaccine, we may just need to work it up and see,” Dr. Gelfand said. Work-up involves a CBC, a platelet count to see if they’re thrombocytopenic, and perhaps imaging, preferentially using MRI/MRV over CT since it’s a younger population. Treatment for CVST with thrombocytopenia is a nonheparin anticoagulant, and platelet transfusion should not occur before consulting with hematology.
Continue to vaccinate
“The big take home is that we should continue to vaccinate patients with migraine and that your current therapies do not interfere with the vaccine working and that the vaccine does not interact with our therapies,” Brian D. Loftus, MD, BSChE, immediate past president of the Southern Headache Society and a neurologist at Bellaire (Pa.) Neurology, said of the presentation. He also felt it was helpful to know that NSAIDs likely have no impact on the vaccines’ effectiveness as well.
“The most important new information for me was that the median onset of the CSVT was 8 days post vaccine,” Dr. Loftus said. “Typically, postvaccine headache is seen much sooner, within 1-2 days, so this is a useful clinical feature to separate out who needs to closer follow-up and possible neuroimaging.”
Given the epidemiology of those most likely to have TTS, Dr. Loftus said he would advise his female patients younger than 60 to simply get the Pfizer or Moderna vaccine since they appear safer for this demographic.
Dr. Gelfand is editor of the journal Headache but has no industry disclosures. Her spouse has received clinical trial grant support from Genentech and honoraria for editorial work from Dynamed Plus. Dr. Loftus has received grants or fees from Teva, Amgen, Abbvie, and Biohaven.