Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis (SJS/TEN)  During the COVID-19 Pandemic and SARS-CoV-2 Vaccines

Importance of vaccines in fighting the COVID-19 pandemic

Currently it is estimated that more than 90% of the US and global population is still susceptible to infection with SARS-CoV-2 which leaves a population vulnerable to a considerable amount of morbidity and mortality. We cannot rely on our communities at large becoming immune to SARS-CoV-2  as a result of natural infection (herd immunity).  Vaccines have the promise to be game changers in the fight against COVID-19, however high uptake in the population  will be necessary to make a dent in the number of cases in the community, the number of hospitalizations and the number of deaths.  Maintenance of social distancing, masking and routine infection control measures such as handwashing will continue be necessary and the mainstay  in the short to medium term after the initiation of national vaccination programs. In addition all of the vaccine studies to-date have been carried out in adults with safety and efficacy in children yet to be established.  Children have been known to be have less severe illness associated with COVID-19 including infection without symptoms.  Children still readily develop and transmit SARS-CoV-2 and they will also be amongst the last to be vaccinated.  Pregnant women have also not been included in the current SARS-CoV-2 vaccine studies and vaccine studies will soon be conducted in women in the second and third trimester of pregnancy.

What has been involved in the development of the SARS-CoV-2 vaccines?

In the wake of the COVID-19 pandemic development of diagnostic testing, new drugs and vaccines have all been expedited.  The process of developing vaccines which would normally take several years had been fast-tracked over several months. Fortunately,  attention to safety has not been sacrificed, and at every step the Food and Drug Administration, the Centers for Disease Control,  and independent safety monitoring committees have been involved in reviewing the data, making sure the vaccine is safe before progressing to the next stage.  This included early studies in animals that led to the first in human studies that more critically looked at the safety and immune response and the final phase III studies that randomized patients to either receive the vaccine or a placebo (either saline or the inactive ingredients in the vaccine preparation).  The Phase III studies are the most important studies to measure the actual efficacy of the vaccine which is the reduction in COVID-19 infections in those who received the vaccine versus those who received placebo. These studies have involved between 30,000 to over 40,000 participants.

Currently there are more than 40 vaccines being studied to prevent SARS-CoV-2 infection.  An updated list of vaccine candidates can be found here at this World Health Organization (WHO) website.

How have the vaccines been made?

The SARS-CoV-2 virus, like other coronaviruses to which it is closely related (SARS-CoV and MERS),  has a large spike protein that extends out from the surface of the virus and is the major mechanism by which the viruses attach and enter human cells.  The spike protein  also represents the major target or construct from which vaccines have been designed, since antibodies that are induced against the spike protein can prevent  SARS-CoV-2 from attaching to and infecting human cells.  However, there are a number different technologies involved in making vaccines designed against the spike protein.

What is the current state of vaccine research and how close are we to having a vaccine that will be administered to the population?

During emergency situations like the current COVID-19 pandemic,  the FDA is able approve the use of tests, treatments, and vaccines under an emergency use authorization (EUA).  The FDA will only issue an EUA if there is evidence of safety and effectiveness of the vaccine and this includes at least 2 months of follow-up data available on 50% of the vaccine recipients.

Currently there are three vaccines made by the companies, Pfizer, Moderna and Janssen that have been given an EUA.  Prior to the EUA being issued, the vaccine efficacy and safety of each of these vaccines must also be reviewed by an advisory committee to the FDA called the Vaccine and Related Biologic Products Advisory Committee.  (VRBPAC). However the ultimate decision on whether to extend an EUA is determined by the FDA The Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) is the committee that makes the ultimate recommendations for use of the vaccine, the recommended schedule and the groups who will be prioritized for SARS-CoV-2 vaccinations.

What is the experience of COVID-19 vaccines in the United States?

The Pfizer and Moderna vaccines will likely be amongst the first distributed more broadly in the US.  These vaccines are administered as two intramuscular injections spread several weeks apart (the specific schedule depends on the vaccine).

What side effects are associated with the SARS-CoV-2 vaccines?

SARS-Cov-2 vaccines  have been associated with mild to moderate but short-lived symptoms that occur within 24-48  hours after vaccination.   These include fever, chills, headache, muscle and joint pain and short-term fatigue that occurs in approximately 10% of vaccine recipients.  These symptoms appear to be worse after the second injection.  Injection site reactions are common with both vaccines, appear to be slightly more enhanced with the Moderna vaccine and worse after the second dose.  Anaphyalxis (an immediate allergic reaction not related to SJS) has been described to occur in approximately 4.5 per million doses of the Pfizer vaccine and 2.5 per million of the Moderna vaccines.  Rare cases of anaphylaxis have been reported with the Janssen and Astra Zeneca vaccines.  The Janssen single dose vaccine and the Astra Zeneca vaccine (not available in the US) are viral vector vaccines.  The Astra Zeneca vaccine is currently being investigated for a possible associated with clotting events that also are thought to occur rarely in < 3 per million doses (vaccine induced immune thrombotic thrombocytopenia).  Click Here  for more information on common side effects associated with the COVID-19 vaccines and some helpful tips.

Is there a cost associated with the SARS-CoV-2 vaccines?

The SARS-CoV-2  vaccine will be offered free of charge to all insured and uninsured individuals based on ACIP recommendations.

What processes are in place to monitor the ongoing safety and efficacy of the SARS-CoV-2 vaccines?

The EUA is issued based on the phase III clinical trial data but the FDA will mandate careful studies after the EUA is issued.  In addition, since it is not known how long protection from the SARS-CoV-2 vaccine will last, whether it will prevent transmission in the community and how well it works in populations that have not been studied. Processes are also in place to monitor post-EUA safety and effectiveness of the of the SARS-CoV-2 vaccine through the individual pharmaceutical companies and the CDC.

Does Rash Occur in Association with COVID-19 Illness and Can this be Confused with SJS/TEN?

Approximately 1/5 will develop a skin rash in associated with COVID-19 illness.  These rashes are generally either hives, measles like (erythematous rash) or COVID fingers or toes (chilblains) that presents with reddish purplish bumps on the fingers and toes. The latter appears more common in children and young adults and appears related to damage of the lining of vessels. Erythema multiforme (EM), a disease typically triggered by viral infection (most commonly Herpes simplex virus I) can be difficult to differentiate from SJS/TEN but is characterized by a more typical rash with target lesions (that resemble a bullseye) and  distribution of rash that favors  the extremities versus the truncal distribution characteristic of early SJS/TEN.  In EM there is also less mucosal involvement and less common constitutional features such as fever and sore throat which are common prodromal symptoms of SJS/TEN.  There have been case reports of EM in association with COVID-19 illness. Drug-induced SJS/TEN is related to a distinct genetic predisposition  and would not be expected to predispose to COVID-19 related EM or other rashes.

Should a patient who has recently experienced SJS/TEN or is a survivor of SJS/TEN have any concerns about receiving a SARS-CoV-2 vaccine?

The SARS-CoV-2 vaccines to-date have been safe and efficacious in the populations that they have been studied which include adults >65 years of age. The vaccine induces a predictable immune response against the SARS-CoV-2 spike protein that does not lead to the hyperinflammatory environment seen in some patients with acute COVID-19 disease.  It would thus be predicted that dosing of the SARS-CoV-2 vaccines would be safer for current or past SJS/TEN patients than going through acute SARS-CoV-2 clinical illness which in moderate to severe disease is associated with activation of the immune system and release of cytokines that lead to a proinflammatory and hypercoagulable state.   In addition to the inflammation associated with acute COVID-19 illness rarely a multi-inflammatory syndrome has been described more commonly in children (MIS-C) than adults (MIS-A) that occurs 2-4 weeks following acute COVID-19 illness.  This has not been described following vaccination. 

It is also much easier to treat mild to moderate vaccine related side-effects than it is to treat moderate to severe COVID-19.   The immune response to the SARS-CoV-2 vaccine has not been studied in immunocompromised patients or those on high dose steroids and this will need to be evaluated.  However, there are a number of studies of other vaccines in this population and immune responses have not been impacted greatly.

It is recommended that the administration of live-attenuated vaccines be deferred in patients on steroids > 10 mg prednisone equivalent for greater than 2 weeks until 3 months following steroid discontinuation. (e.g. measles/mumps/rubella(MMR) or chickenpox (Varicella) vaccines). The current SARS-CoV-2 vaccines in late stage studies likely to receive EUA in the near future do not contain live virus products. 

It is understandable that survivors of SJS/TEN would be hesitant to take drugs and vaccines even outside the drug that was implicated in their reaction given the randomness and severity of the disease. However, those who have recently experienced SJS/TEN and survivors of SJS/TEN can be reassured that receiving the SARS-CoV-2 vaccine is a safer option than natural infection.

Currently there have been two reports of anaphylaxis associated with the Pfizer vaccine in the United Kingdom which as of December 9. Anaphylaxis suspected due to the SARS-CoV-2 vaccine has now been described in approximately 21 individuals out of approximately 1.8 million doses administered or approximately 11.5 per million doses administered.  This is considered very uncommon although it appears to be up to  10 fold more common than other licensed vaccines. Currently it is not known what is driving this or what the mechanism is.  Part of the carrier vehicle for the active part of the vaccine or mRNA is made of polyethylene glycol (PEG2000) a component of both the Moderna and the Pfizer-BioNTech vaccines.  PEG has rarely been associated with anaphylaxis and one hypothesis is that it could be the component driving the rare cases of anaphylaxis that have been seen with the mRNA vaccines.

There is no association between anaphylaxis and SJS/TEN either in clinical presentation or mechanism.  Anaphylaxis is an immediate reaction that occurs within 30 minutes of vaccine injection and is associated with multiple symptoms that progress rapidly together including hives, flushing, itching, swelling of the face tongue and difficulty swallowing, shortness of breath or wheezing, low blood pressure, fast heart rate and nausea and vomiting. The treatment for anaphylaxis is epinephrine and if it is treated rapidly it is completely reversible without any long-term effects.  If anaphylaxis does occur it is possible this is due to one of the excipients (inactive ingredients)  in the vaccine such as PEG of which there is no association with these excipients and SJS/TEN.

 Although rare immunological events maybe reported in the future under the scrutiny of post-licensure vaccine safety programs there is no reason to believe that patients who have experienced SJS/TEN would be at higher risk for these events.  The genetic factors predisposing to SJS/TEN are specific for a specific drug or chemically related drugs and there is no reason to believe these predisposing factors would increase the risk of an adverse reaction to a SARS-CoV-2 vaccine.

Currently there are only two main safety reasons in adults not to get the COVID-19 mRNA vaccine: 1) known immediate or severe reaction to a component of the vaccine (e.g. PEG and PEG derivatives such as polysorbates) 2) Severe or immediate reaction associated with the first dose of the COVID-19 mRNA vaccine.  In the case of (2) although the advice is currently not to get the second dose some patients may experience milder symptoms such as hives. If reactions occur to the vaccine it is recommended to see an allergist who can do specialty testing and do risk assessment as to best future management.

If I have a safety reason that prevents me from getting a COVID-19 mRNA vaccine is it safe for me to get the Janssen (Johnson & Johnson) vaccine?

The J&J vaccine is a single dose vaccine that is viral vector vaccine also based on the spike protein construct.  The J&J vaccine does not contain PEG but does contain polysorbate which is closely related to PEG.  If you have had previous anaphylaxis associated with a vaccine or injectable drug or have had anaphylaxis to a PEG product you should talk with your doctor who may refer you to a specialist to determine if it is safe for you to get the J&J vaccinee.

Here are some quotes from an SJS survivor who has now completed vaccination and very relieved to have done so:

“ I was nervous, as I am sure many SJS survivors are, but the thought of getting the virus itself scared me more.”

“ I was a little sore and had a headache for a day or too, but otherwise was fine! I had no rash or reaction in my eyes, which is something I’ve struggled with throughout the year following my SJS diagnosis. I am scheduled to receive the second dose on Tuesday. Overall, I am very happy I chose to receive the vaccine. I’ve struggled with a long-term cough and congestion for the last year, so I have been very worried about COVID complications”