https://orcid.org/0000-0002-7939-0026
ABSTRACT
Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects approximately 20% of children and 10% of adults. The implication of vaccines as a trigger for the de novo onset of AD in children or as a cause of exacerbation in individuals with a history of AD has long been debated. We present a brief review of the literature on AD and traditional vaccinations, proposing in addition the main recommendations for the management of patients with AD undergoing the vaccine against the SARS-COV-2 virus. Live attenuated vaccines seem to be associated with a relapse of AD and/or complications, such as eczema vaccinatum. For non-live vaccines, no adverse events are noted in atopic subjects. Since the Covid-19 vaccine is mRNA or viral vectored vaccine and there are no other currently used vaccines of this type, the same recommendations are applied as for all other non-live vaccines.
Introduction
Atopic dermatitis (AD) is a chronic inflammatory skin disease that affects approximately 20% of children and 10% of adults. The peak of incidence is in childhood, but adult-onset variants are noticed with characteristic clinical phenotypes.Citation1,Citation2 AD is often associated with other atopic comorbidities such as asthma and allergic rhino-conjunctivitis especially in subjects with high circulating IgE levels and familial atopy.Citation3 The multifactorial etiology of AD includes genetic and environmental factors leading to an immune dysregulation and skin barrier dysfunction, which play a key role in the pathogenesis of AD.Citation3 The implication of vaccines as a trigger for the de novo onset of AD in children or as a cause of exacerbation in individuals with a personal history of AD has long been debated. Furthermore, it is unclear whether AD can affect the immunological response to vaccines. The Covid-19 pandemic and the recent introduction of vaccines have triggered the problem of managing patients with chronic inflammatory diseases ongoing systemic and immunosuppressive therapies. In this article, we present a brief review of the evidence literature from existing studies on AD and traditional vaccinations. In light of the recent knowledge about the SARS-CoV-2 and the currently available mRNA and viral vectored COVID vaccines, we summarize the main recommendations for the management of patients with AD.
Atopic dermatitis and vaccination: what we know
Among the vaccine categories currently available (), the live attenuated vaccines seems to be associated with a relapse of atopic dermatitis and/or complications such as eczema vaccinatum or eczema herpeticum.Citation4 Several studies have been conducted in order to establish a relationship between administration of the live attenuated vaccine and the occurrence of atopic dermatitis or related complications. In details, Schneider et al.Citation5 investigated the immune response to varicella-zoster virus (VZV) vaccine among a population of children aged from 1 to 3 years with moderate to severe AD or with no history of atopy. They noticed that controls and AD subjects had similar cell-mediated responses to the VZV vaccine, but AD subjects who experienced eczema herpeticum showed higher VZV-specific IgE, as a possible risk factor for adverse effects to booster doses of vaccine or to wild-type VZV exposure. Moreover, Beck et al.Citation6 have previously suggested that carefully phenotyping of AD subsets may help to identify at-risk individuals susceptible to EH. They recognized the following risk factors: a more severe disease, early age of onset, more frequent history of other atopic disorders, greater Th2 polarity, allergen sensitization to many common allergens and more frequent skin infections. A double-blind randomized study, conducted by Mark et al. to investigate the safety and immunogenicity of live attenuated yellow fever virus (YFV) vaccination, showed that high baseline IgE levels provides a potential biomarker for predicting reduced virus-specific immune memory following transcutaneus infection with a live virus, not found in cases in which the skin is bypassed by subcutaneus injection/infection.Citation7 Among the inactivated vaccines, particular attention has been paid to the smallpox vaccine, which has historically been associated with a high frequency of skin complications including progressive vaccinia, eczema vaccinatum (EV), generalized vaccinia and autoinoculation.Citation8–10 Traditional smallpox vaccines contain replication-competent Vaccinia Virus (VACV), an orthopoxvirus related to Variola Virus (VARV).Citation11,Citation12 These vaccines are administered via scarification to the skin, causing a localized VACV infection that elicits a protective immune response to VARV. Regarding complications, EV occurred in the general population at a rate of 39 cases per million vaccinations, while the subjects with eczema or AD showed an increased risk of developing EV due to their underlying skin disease.Citation13–15 Moreover, the risk of developing EV has been documented, not only for the subject who received vaccination, but also for individuals in close contact, since a contact transmission of VACV is possible.Citation16 This has placed greater emphasis on smallpox vaccination on subjects with skin conditions such as atopic eczema and their cohabitants, leading to the development of Modified Vaccinia Ankara virus (MVA), a non-replicating vaccine in humans, with a favorable safety and immunogenicity profile, which makes it suitable also for subjects with a weakened immune system.Citation17 Currently, the vaccination campaign, conducted on a global scale, has led to the extinction of the disease. If we consider recombinant DNA vaccines, such as hepatitis B vaccine, in subjects with AD there was no increase in the incidence of adverse events as for live attenuated vaccines, but rather a reduction in the number of responders to the vaccine.Citation18 A study by Deepa et al. revealed that from the screening of the immunization profile of 75 patients, affected respectively by AD 36.1%, psoriasis 34.4% and morphea 29.5%, all vaccinated for HBV and candidates for MTX therapy, as many as 52 subjects had no anti-HBs levels and, in detail, the 53.8% of the non-responders were AD subjects. The hypothesis advanced by the authors is that the underlying chronic inflammatory process, together with the immunogenic factors investigated in previous studies, such as genetic predisposition, human leukocyte antigen (HLA) haplotypes, interleukin genotypes, and polymorphisms in cytokines or cytokine receptors, may be associated with low immunogenic responses to the HBV vaccine in subjects affected by AD.Citation18 Regarding vaccines with purified antigens and anatoxins or toxoids, there is no evidence in terms of increased adverse effects in individuals with AD, but considering the effectiveness of vaccines, opinions are conflicting. It seems that in subjects with AD, the response to immunization for tetanus and diphtheria does not change compared to healthy subjects, while as regards pertussis there is a higher percentage of non-responders in subjects with AD than in healthy subjects.Citation19 The possibility that the vaccination could affect the onset of AD in vaccinated subjects remains difficult to prove since often other variables, first of all familiarity, are confounding factors for the onset of AD after vaccination in children.Citation20 Grüber sustained that common childhood vaccines are unlikely to promote atopic disease and that the possible future development of atopic symptoms is most likely not causally related to vaccination but a mere coincidence.Citation21 A recent study in Denmark has put forward the hypothesis that delaying the start of vaccinations, in particular DTaP, may reduce the development of new cases of atopic dermatitis before 4 months of age.Citation22 The results of the studies currently available are not able to establish certain causality between the administration of vaccines and the onset of atopic dermatitis. Vaccines that have been, not without discussion, associated with a relapse of atopic dermatitis or complications such as eczema vaccinatum, belong to the category of live attenuated vaccines. For nonlive vaccines, no adverse events are noted in atopic subjects; some studies have reported a lower immunological response to the vaccine in atopic subjects than in the healthy population, but further studies are needed to confirm the relationship between atopic disease and immunological response to vaccination. summarizes the cited studies concerning AD and vaccines.
Table 1. Type of vaccines categorized by their composition and formulation
Table 2. Articles cited concerning AD and vaccines
SARS-CoV-2 virus: m-RNA and viral vectored vaccine ()
The current Covid-19 pandemic has led to the rapid development of vaccines against SARS-Cov-2. In detail, two mRNA vaccines produced respectively by Pfizer and Moderna have been developed and approved by EMA as well as several viral vectored vaccine produced respectively by Vaxzevria (previously COVID-19 Vaccine AstraZeneca) (AZ) and Janssen (J&J). The EMA’s human medicines committee (CHMP) has started a rolling review of Sputnik V (Gam-COVID-Vac) (). Although apparently the mRNA vaccine seems like a novelty, in reality it is not. For several years, studies have been underway to develop strategies for the containment of the so-called emerging infectious diseases (EIDs), i.e. a timely interventional approach aimed at limiting the spread of dangerous infectious diseases as they were in the past the Black Death in the 14th century, smallpox and cocoliztli in the 16th century and Spanish influenza in 1918–1919. Epidemic outbreaks caused by virus infections are emerging or reemerging almost every year and in all cases are characterized by unpredictability, high morbidity, exponential spread, and substantial social impact.Citation23 The mRNA vaccines represent one of the potential solutions to stem the spread of viral pandemics. In particular, mRNA vaccines will be suitable for rapid response applications because of their ability to induce broadly protective immune responses and their potential of being produced by rapid and flexible manufacturing processes.Citation24 An interesting recent review of 2019 describes the characteristics of mRNA vaccines and shows the different fields of application including the recent Zika, Ebola, Nipah, and pandemic influenza epidemics, to underline the relative “novelty” of mRNA vaccines.Citation25 The Covid-19 pandemic was an opportunity to channel and unify the resources of scientists, the private sector, national governments, and international organizations in order to quickly reach a vaccine by exploiting recent important advances in biotechnology. The mRNA vaccines do not generate infectious particles or integrate in the genome of the host cells. They can be delivered for antigen expression in situ without the need to cross the nuclear membrane barrier for protein expression and can express complex antigens without packaging constraints.Citation26 The mRNA vaccines can be produced rapidly, possibly within days of obtaining gene sequence information, using completely synthetic manufacturing processes.Citation27 The technology is versatile and amenable to multiple targets, and thereby ideal for rapid responses to newly emerging pathogens.Citation28–30 Once the right target has been identified, the means to rapidly develop a vaccine are now available. SARS-CoV-2 is a virus consisting of a single RNA strand containing 13 genes encoding the proteins necessary for its own replication. The entry of the virus into the host cells occurs through the interaction between a viral protein of the capsid called spike (in particular the external portion RBD) that binds the membrane receptor of human host cells ACE-2. However, once entered, in order to transcribe its own viral proteins, the virus needs the host’s transcription system. In particular, it must first be able to transcribe the RNA-dependent RNA polymerase in order to duplicate itself. Currently available mRNA vaccines consist of nano-lipid particles containing only the mRNA that encodes the Spike structural protein. Due to its lipophilic nature, the vaccine diffuses into the outer membrane of the host cell; the lipid component degrades and releases mRNA into the cytoplasm. The host transcription system transcribes the spike protein of which only the RBD tract remains, while the rest of the protein undergoes proteosome degradation.Citation31,Citation32 This limits the reactogenicity of the vaccine since there are no antigens other than RBD that the host immune system can react with and it does not contain viral vectors. In addition, there is no risk that in some way the viral RNA integrates with the cell’s DNA since the vaccine does not contain genes encoding transcription enzymes in its sequence.
Table 3. Features of the vaccines against SARS CoV-2 currently available
Currently, safety and efficacy data of mRNA Covid-19 vaccines are available from clinical trials. As regard Pfizer, clinical trials were conducted on subject aged 16 and older and they showed a 95% reduction in the number of symptomatic COVID-19 cases in the people who received the vaccine. The trials also showed around 95% efficacy in the participants at risk of severe COVID-19, including those with asthma, chronic lung disease, diabetes, high blood pressure or a body mass index ≥30 kg/m2.Citation33 Phase 4 safety and effectiveness data are available for Israel, where the entire population is being vaccinated and Pfizer is accruing data with Israel Health groups. The latest analysis from the Israel Ministry of Health (MoH) proves that two weeks after the second vaccine dose protection is even stronger than clinical trials. Vaccine effectiveness was at least 97% in preventing symptomatic disease, severe/critical disease and death. Findings represent the most comprehensive real-world evidence to date demonstrating the effectiveness of a COVID-19 vaccine.Citation34 About Moderna the efficacy was calculated in around 28,000 people from 18 to 94 years of age who had no signs of previous infection. The vaccine demonstrated a 94.1% efficacy in the clinical trial. In addiction the trial also showed 90.9% efficacy in participants at risk of severe COVID-19, including those with chronic lung disease, heart disease, obesity, liver disease, diabetes or HIV infection.Citation35 Subsequent to the mRNA vaccine, several COVID-19 viral vector vaccines have also been approved. Viral vectored SARS-CoV-2 vaccines are made up of another virus belonging to adenovirus families. The viral vector is non-replicating and does not cause disease since it has been modified to contain the gene for the SARS-CoV-2 spike protein. Once it has been administered, the vaccine delivers the SARS-CoV-2 spike proteine gene into cells and the transcription of spike protein began; immune system of vaccinated subjects will recognize the spike protein as foreign and produce antibodies and activate T cells (white blood cells) to target it. Precedent vaccines include vectored Ebola vaccine, which is licensed and used for outbreaks in Africa and it demonstrated a good safety profile. The most common adverse have been pain, swelling and redness at the injection site, headache, fever, muscle pain, tiredness and joint pain. These AEs occourred almost in the 10% of vaccinated subjects, within 7 days after vaccination and there were mild to moderate in intensity and resolved in less than a week.Citation36 Nowadays several viral-vectored COVID vaccines (especially adenovirus vectored) have been approved (). Combined results from 4 clinical trials [study COV001 (UK, Phase I/II); study COV002 (UK, Phase II/III); study COV003 (Brazil, Phase II/III) and study COV005 (South Africa, Phase I/II)] showed that COVID-19 Vaccine AstraZeneca was safe and effective at preventing COVID-19 in people from 18 years of age. The vaccine demonstrated around a 60% efficacy in the clinical trials. Most of the participants in these studies were between 18 and 55 years old. There are not yet enough results in older participants (over 55 years old) to provide a figure for how well the vaccine will work in this group.Citation37 Due to the reporting of a suspected number of thrombo-embolic events following vaccination, the administration of Astrazeneca was temporarily interrupted in some countries at the end of March. On March 29, 2021, EMA published updated Safety data where a warning on very rare specific blood clot events has been included in the product information. These events include disseminated intravascular coagulation (DIC) and cerebral venous sinus thrombosis (CVST). A causal link of DIC and CVST with the vaccine is not proven but cannot be excluded and requires further investigation Based on all available data on embolic and thrombotic events, Pharmacovigilance Risk Assessment Committee (PRAC) considered that the benefits of Vaxzevria in preventing COVID-19 and related death continue to outweigh the risks, and that this vaccine can be used while further data collection and assessment are ongoing.Citation38
Results from a clinical trials involving people in the United States, South Africa and Latin American countries found that COVID-19 Vaccine Janssen was effective at preventing COVID-19 in people from 18 years of age. This is the first vaccine which can be used as a single dose. The trial found a 67% reduction in the number of symptomatic COVID-19 cases after 2 weeks in people who received COVID-19 Vaccine Janssen (116 cases out of 19,630 people) compared with people given placebo (348 of 19,691 people). This means that the vaccine had a 67% efficacy.Citation39 Promising results are expected from Sputnik V, which demonstrates 91% efficacy in clinical trials.Citation40 The most common side effects of all kind of vaccines are pain and tenderness at the injection site, headache, tiredness, muscle pain, general feeling of being unwell, chills, fever, joint pain and nausea which tend to appear 24–48 hours after vaccination and resolve in the short term. Real life data in literature are limited since the vaccination campaign on the population started less than a month ago.
Recommendations for dermatologist treating patients with AD who undergo the COVID-19 vaccine
When a patient with AD has to undergo a vaccine, what may worry the dermatologist and consequently the patient too is: whether the vaccine is safe for the patient, i.e. in detail whether it will not cause a flare of the dermatitis or the onset of cutaneous complications; if the vaccine is effective and people with AD will develop an immunological response comparable to the health population. Due to the characteristics of the vaccine, since it is not a live attenuated vaccine and considering its poor reactogenicity due to the presence of a single viral protein and the absence of viral vectors, there does not seem to be any particular risk of developing skin complications or disease flares for individuals with AD to undergo vaccination for SARS-CoV-2. Currently the pediatric population is excluded from vaccination because children are not considered at risk for Covid-19 and therefore it is not possible to establish whether the vaccine can act as a trigger for the de novo onset of AD. With regard to efficacy, we do not know if AD can influence the immune response to the vaccine against Covid-19. However, we know that the vaccine is administered intramuscular (IM) and this seems to be the most effective route of administration in patients with AD as demonstrated by studies conducted on the influenza vaccine in which intradermal administration was associated with a poorer immune response than intramuscular administration.Citation41 If we consider patients with AD undergoing topical or systemic treatment who wish to undergo the vaccine against the SARS-CoV-2 virus, there are currently no contraindications, nor are there any data on the efficacy and safety of the vaccine, as these patients with chronic inflammatory diseases on immunosuppressive therapy are naturally excluded from clinical trials. Studies conducted in subjects with AD undergoing topical treatment with calcineurin inhibitors, who received the classic childhood vaccinations, have shown that the immunomodulatory effect of the topical treatment remained confined to the skin so there were no systemic effects that can interfere with the immune vaccine response.Citation42–45 In detail, Papp et al.Citation42 showed that for patients receiving pimecrolimus for 2 years, the proportions of patients with protective antibody titers against tetanus, diphtheria, measles and rubella, regardless of vaccination history, were similar to those observed in pediatric populations of similar age. Furthermore, also short-term treatment with tacrolimus ointment doesn’t seem to affect levels of immunoglobulin, antibodies to H. influenzae and tetanus toxoid, lymphocytes and/or subsets, or lymphoproliferative responses, nor interfere with the antibody response to pneumococcal vaccine in children with moderate to severe AD.Citation46 In subjects undergoing systemic immunosuppressive or biological therapy we know that live vaccine can be administered either 2–4 weeks before starting therapy or after temporary therapy interruption of 1 to 3 months. There is no indication to discontinue treatment for non-live vaccines, however, systemic immunosuppressive therapies can attenuate the response to vaccines.Citation47 For example, treatment with prednisone-equivalent doses ≥10 mg/d diminished humoral responses to influenza H1N1, H3N2, and B vaccines in patients with SLE.Citation48 Cyclosporine is shown to reduce antibody titers post-vaccination. Studies on cyclosporine-treated transplanted patients showed lower humoral response to vaccine stimulation for influenza, keyhole limpet hemocyanin, tetanus, and hepatitis B Virus.Citation49,Citation50
On the basis of these evidences, whenever possible, even in patients with AD for whom a course of therapy with systemic corticosteroids or cyclosporine is planned, it is advisable that also the vaccination for SARS-CoV-2 will be performed and completed 2 weeks before starting immunosuppressive therapy, in order to boost an adequate immune response. For patients who are already being treated, the choice falls on the physician, as a protocol for this type of mRNA vaccine has not yet been defined. For live attenuated vaccines, suspension is recommended, while all other non-live vaccines can be administered without needing to discontinue treatment even knowing that a poorer immunological response may be incurred.Citation51
Alternatively, immunosuppressive therapy may be temporarily discontinued prior to vaccination. The length of treatment discontinuation should take drug pharmacokinetics and dosage into consideration.Citation52 A frequent recommendation is for the washout period to be at least 5 times the half-life of the drug.Citation52 In detail, Cyclosporine half-life: 18 hours;Citation53 Prednisolone half-life: 2–4 hours.Citation54
Therefore, while a washout period before vaccine administration may improve the patient’s immune response to the vaccine, clinicians should use their judgment to evaluate the risks vs benefits of treatment disruption. In patients receiving intermittent treatment in whom optimal vaccine immunogenicity is desired and the clinical situation allows, vaccination can be given at the nadir of immunosuppression.Citation51
For non-live vaccine, a more favorable safety profile of biologic agents compared to conventional systemic agents is described as the humoral response to vaccines is in general well-preserved.Citation47 Dupilumab is the only one biologic drug currently approved for the treatment of moderate to severe AD. Dupilumab is a fully human, monoclonal antibody directed against the IL-4 receptor α subunit that inhibits signaling of both IL-4 and IL-13.Citation55 Dupilumab has been shown to significantly improve signs and symptoms of moderate-to-severe AD, asthma, chronic sinusitis with nasal polyposis, and eosinophilic esophagitis and is approved in the European Union, United States, and Japan as well as other countries for the treatment of adults with inadequately controlled moderate-to-severe AD.Citation56,Citation57 During the covid 19 pandemic, patients with atopic dermatitis treated with dupilumab were recommended not to discontinue ongoing therapy since IL-4 and IL-13 pathways have not been implicated in the host defense mechanism against viral infections, neither cytokine storm in COVID- 19.Citation58–60
Currently there are no contraindications to the vaccineCitation61 even if the only data available on the efficacy and safety of vaccines undergoing therapy with Dupilumab are extrapolated from studies on other vaccines. In details, Blauvelt et al.Citation62 have conducted phase 2, randomized, double-blinded, multicenter, placebo-controlled, parallel-group study, with the aim to evaluate the effects of tetanus toxoid with reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) and quadrivalent meningococcal polysaccharide vaccine (MPSV4), in adult patients receiving Dupilumab. They noted that non-live vaccines such as Tdap and MPSV4 could be safely administered to patients with moderate to severe AD treated with Dupilumab ensuring adequate immunological response.Citation62 The only recommendation is to schedule the vaccine in the week interval between dupilumab dosing. Finally, the same recommendations as previously seen for Dupilumab could be applied to patients treated with Jak inhibitors. Upadacitinib is a selective inhibitor of JAK1 undergoing clinical trials to determine its benefit for several inflammatory diseases, including AD; Baricitinib is a first-generation inhibitor of JAK1 and JAK2 and is furthest along the development pathway for treatment of moderate-to-severe AD.Citation63 Few countries approved Jak inhibitors for the treatment of AD, but there are many patients undergoing treatment participating in clinical trials. Since the covid-19 vaccine is a non-live vaccine, treatment should not be suspended and the drugs do not interfere with the immune response to the vaccine.Citation51 It is advisable to prefer a vaccine with a higher efficacy (e.g. mRNA vs AZ or J&J) for patients on immunosuppressive therapy (systemic corticosteroid, cyclosporine) and in patients treated with jak inhibitors, since the ongoing therapy could further reduce the immune response to the vaccine.
Conclusion
In conclusion we can say that currently there are no data on the efficacy and safety of the covid-19 vaccine for patients with AD, both because people with chronic inflammatory diseases have been excluded from preliminary studies, and because vaccination on the general population has recently been introduced and limited to selected subjects. Since the Covid-19 vaccine are mRNA and viral vectored vaccine and there are no other vaccines of this type used routinely against ongoing infections, the same recommendations are applied as for all other non-live vaccines, with particular attention to subjects undergoing systemic immunosuppressive or biological therapy. Further studies to better understand the immunological response of AD patients to Covid-19 vaccination, as well as the possible occurrence of adverse events are needed. In the meantime, the proposed guidelines for non-live vaccines to which the dermatologist can refer together with his experience and common sense, for the management of the patient with AD during the Covid-19 pandemic, remain valid. In particular in pediatric patients, also in consideration that families of AD children often report fear and anxiety regarding just topical treatments,Citation64 which may lead to reduced compliance.
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
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