Types of vaccines.
Psoriasis is a chronic, immune-mediated disease resulting from interactions of genetic background with environmental triggering factors, such as trauma, infections and drugs. Dendritic cells, activated T-cells toward a Th1 and Th17 response and inflammatory cytokines [tumor necrosis factor (TNF)-alpha, IL-6, -12, -17, -22 and -23] are the key factors in psoriasis pathogenesis. Patients diagnosed with psoriasis are at increased risk of infection due to the nature of disease and immunosuppressive therapies. Vaccination is recommended to prevent infections in patients with psoriasis. Additionally, vaccines such as Mycobacterium vaccae, live attenuated varicella zoster virus and Leishmania amastigotes have been reported to induce improvement in psoriasis patients. It has been suggested that vaccines, targeting molecules in the immunopathogenesis of psoriasis, may be a new treatment option for psoriasis patients without any serious side effects. However, induction or worsening of the psoriasis and psoriatic arthritis followed by some vaccines (e.g., influenza, rubella, tetanus, BCG) has also been reported in the literature. In this review, we focus on the vaccines in psoriasis in terms of their both triggering and therapeutic effects.
- antimicrobial vaccination
- recommended vaccines
- triggering vaccines
- therapeutic vaccines
Psoriasis is a chronic, immune-mediated disease with a prevalence of 2–3% in adult population. Psoriatic arthritis affects approximately 11% of psoriasis patients, and cardiovascular disease is increased . Psoriasis disease is caused by the interactions of genetic background with various environmental triggering factors. HLA-Cw6 allele in PSORS1, the most associated gene with psoriasis, encodes a major histocompatibility complex I allele that is the major factor for antigen presentation of intracellular peptides to the immune system .
Several environmental factors, such as trauma (Koebner effect), infections, obesity, smoking and some medications, play a role in the onset of psoriasis. Guttate psoriasis is related to streptococcal throat infections as two-thirds of patients have a history of throat infection nearly 2 weeks before the eruption [3, 4]. A homology between streptococcal M protein and human keratin 17, which is upregulated in the skin of psoriasis, has been reported. In the basis of this finding, T-cells cross-reacting with human keratin and streptococci have been detected in HLA-CW6-positive psoriasis patients, raising the possibility that psoriasis is an autoimmune disease .
In the initial phase of the disease, certain dendritic cell (DC) populations such as plasmacytoid DCs (pDC) and dermal myeloid DCs are activated and produce the key psoriasis effector cytokines IL-12 and IL-23. Self-DNA or self-RNA from damaged keratinocytes and the antimicrobial peptide LL37 stimulate pDCs, through Toll-like receptor (TLR) 9 or TLR7/8 and IFN-alpha production is triggered. The stimulation of pDCs is followed by differentiation and activation of myeloid DCs, which express cytokines IL-12, tumor necrosis factor (TNF)-alpha, TGF-beta and IL-6. These cytokines induce T-cells to polarize into Th1 and Th17 subtypes, with suppressing of regulatory T-cells [1, 2, 6, 7]. CD4+ T-cells secreting IL-17 are classified as a different T-helper population called Th17 cells, which are critical in psoriasis pathogenesis. Th17 cells produce IL-17A and IL-17F, and Th1 cells produce TNF-alpha, IFN-gamma, IL-12, IL-22 and IL-23 that promote the pathological changes in psoriasis skin lesions [2, 8].
For psoriasis patients with localized disease, topical treatments including corticosteroids, vitamin D derivatives, tazarotene, anthralin, tar, calcineurin inhibitors, keratolytic agents and urea are the first-line therapy . Phototherapy is a mainstay option particularly for patients resistant to topical treatments with widespread disease . In cases with moderate-to-severe psoriasis resistant to any of these treatments, conventional systemic therapy is done with methotrexate (MTX), cyclosporine, fumaric acid esters and acitretin. In patients who have failed to respond to conventional systemic therapies and phototherapy or the person is intolerant to, or has a contraindication to these treatments, biologic immunotherapy is used. There are several agents such as TNF-alpha inhibitors (etanercept, infliximab and adalimumab) and ustekinumab that are available in the treatment of psoriasis .
Vaccination is a proven way of reducing the incidence of serious or life-threatening infectious disease in general population and in patients with immune-mediated inflammatory disease. Vaccines are recommended for psoriasis patients due to their susceptibility to infections . The data emphasize that especially some types of vaccines may trigger an exacerbation of psoriatic skin lesions or induce improvement in psoriasis [1, 13].
In this review, we aim to summarize the vaccines in psoriasis in terms of their both triggering and therapeutic effects.
2. Vaccines recommended for psoriasis patients
Patients diagnosed with psoriasis are at risk of infections owing to the nature of disease and immunosuppressive therapies [12, 14]. Therefore, the medical board of the National Psoriasis Foundation recommends vaccinations in compliance with recommendations of the Advisory Committee for Immunization Practices to prevent infections . Types of vaccines can be categorized as live and inactivated vaccines (Table 1) [12, 14].
|Inactivated or inert vaccines||Live vaccines|
|Salk poliomyelitis vaccine||Vaccinia/smallpox|
|Most influenza vaccines (injectable)||Rotavirus|
|Hepatitis B||Yellow fever|
|Human papillomavirus||Oral poliomyelitis|
|Diphtheria-tetanus-pertussis||Varicella zoster vaccine|
|Haemophilus influenza type b conjugate vaccine||Herpes zoster|
|Pneumococcal||Intranazal influenza virus|
Live vaccines, which contain attenuated natural pathogens, are contraindicated in immunocompromised patients and should be given 2 or 4 weeks before the immunosuppressive therapy. Additionally, immunosuppressive medications should be stopped generally 3 months before the immunization with live vaccines [12, 14]. However, a few reports suggest that some live vaccines such as yellow fever vaccine in patients receiving MTX may be safe . More research is needed for safety of live vaccines in immunocompromised patients [12, 15]. Inactivated vaccines are safe for patients on immunomodulatory therapy due to their noninfectious content but vaccine response may be suboptimal [12, 14, 16]. It has been reported that the antibody response ratio following seven-valent conjugate pneumococcal vaccination was significantly higher in controls when compared to patients treated with MTX or MTX combined with TNF inhibitors. On the other hand, in the same study, patients treated with TNF inhibitors as monotherapy had numerically lower but not significantly different antibody levels, compared to controls . In a study, ustekinumab did not impair the immune response to pneumococcal and tetanus toxoid vaccines in psoriasis patients . In another study, efalizumab caused a nearly threefold decrease in the antibody response to tetanus toxoid vaccine while not changing the immune response to pneumococcal polysaccharide vaccine . Immune responses to pneumococcal polysaccharide vaccine in patients with chronic plaque psoriasis treated with alefacept were similar to those seen in healthy subjects .
In a study assessing the seasonal 2012 influenza vaccination among patients with psoriatic arthritis and psoriasis, usage of TNF-alpha blockers or disease-modifying antirheumatic drugs did not affect the response rate . Annual immunization with inactivated influenza vaccine is recommended for psoriasis patients on immunosuppressive treatment due to high mortality rates of seasonal influenza [12, 22]. In a French study on 1308 psoriasis patients, Sbidian et al. reported that 19% of patients received the 2009 monovalent H1N1 vaccine. Only 33% of the patients treated with biologics were vaccinated . The vaccination rate of influenza vaccine in 2010/2011 was found 28% among 1299 patients with psoriasis or psoriatic arthritis in Germany. Thirty-eight percent of the patients were on biological therapy at the time of vaccination . Despite the recommendations, the vaccination coverage was low in psoriasis patients in both studies [22, 23].
Zoster vaccine, a live attenuated vaccine, is recommended for use in immunocompetent individuals 60 years of age or older to reduce the risk and severity of herpes zoster (HZ) . Increased incidence of HZ has been reported in psoriasis patients receiving combination treatment with biologic medications and MTX while biologic or systemic agents as monotherapy did not increase the risk of HZ . Zhang et al. reported that zoster vaccination was not related to increased risk of HZ in patients with immune-mediated disease including psoriasis under biological therapy [25, 26]. However, it was emphasized that infliximab increases the risk of HZ in most of the cohort studies while the risk of HZ in patients receiving etanercept, adalimumab or ustekinumab therapy is not clear . Yun et al. indicated that the use of biologic agents and systemic steroids in patients with autoimmune and inflammatory diseases increased the risk of HZ . Consequently, HZ vaccination should be considered for patients who are going to receive biological agents especially infliximab and combination treatment with MTX therapy. Additionally, the vaccine should be administered before initiation of the immunosuppressive therapy [24, 27].
As a conclusion, it has been reported that immunization status, including
|Type of vaccine||Before therapy||On therapy|
|Influenza||Vaccinate with inactivated or live attenuated vaccine||Annual inactivated influenza|
|Human papillomavirus||Recommended for male and female < age 26 years||Same|
|Hepatitis A||For selected individuals at high risk (diabetes, liver disease, injecting drug users, homosexual men, employees or residents in institutional settings)||Same, test for serology after vaccination|
|Hepatitis B||For individuals at high risk and without evidence of disease and immunity||Use high-dose vaccine, test for serology after vaccination|
|Pneumococcal||Immunization with 23-valent pneumococcal polysaccharide vaccine||Immunization with 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine if not given prior|
|Haemophilus influenza type b||Unvaccinated individuals can be vaccinated||Same|
|Diphtheria-tetanus-pertussis||Booster is recommended every 10 years and for high-risk wounds, offer before therapy||Same|
|Meningococcal||For selected individuals at high risk (asplenia, complement deficiency, group living situation)||Same|
|Poliomyelitis||For selected individuals at high risk (healthcare workers or laboratory personnel)||Same|
|Varicella zoster||Test for serology before initiation of therapy, if negative, offer vaccination||Contraindicated|
|Herpes zoster||1 dose for adults ≥50 years||Contraindicated|
|Measles-mumps-rubella||Assessment of immunization by history and serology before initiation of therapy, if negative, offer vaccination||Contraindicated|
3. Triggering effect of vaccines on psoriasis
As mentioned above, basis on a genetic predisposition, various environmental factors may cause development of psoriasis in patients who are in latent period. Physical or chemical factors, infections and various types of medications are the most important among these, and they may affect the course of psoriasis by many different mechanisms . Triggering vaccines on psoriasis and psoriatic arthritis are summarized below.
3.1. Koebner effect
Various types of skin trauma with subsequent development of new psoriasis lesions about 10 days later are known as ‘Koebner-phenomenon’ . In a study evaluating the relation between ‘Koebner-phenomenon’ and intradermal antigens, 30 psoriasis patients and 20 control subjects were firstly determined for Koebner status and then were tested with intradermal injections of purified protein derivative, Candida, mumps, mixed respiratory vaccine and saline control solutions. Two psoriasis patients were Koebner positive and developed psoriasis at all five injection sites. Besides, in five Koebner negative patients, local psoriasis lesions were observed in at least one injection site of different antigens. These findings were interpreted that some psoriatic patients may have individually specific sensitivity to different antigens to trigger the cellular immune response in psoriasis .
Additionally, in a recent placebo-controlled study, evaluating the ‘nontypeable Haemophilus influenza protein vaccine’, a psoriasis case was reported to be associated with injection of saline placebo at 114 days post-dose 3 in the placebo group indicating the Koebner effect .
3.2. BCG vaccination
BCG is a live attenuated strain of
3.3. Tetanus-diphtheria (Td) vaccination
A case of 50-year-old psoriasis patient in remission was described as guttate psoriasis 1 week after the Td vaccination . Td vaccine has shown to induce IL-6 production, which stimulates Th17 cells, having a key role in psoriasis pathogenesis [37, 38]. It was suggested that this mechanism was the triggering cause in this case . In a case-control study evaluating the potential risk factors for the onset of psoriatic arthritis, exposure to rubella (OR = 12.4, 95% CI = 1.2–122.14) and tetanus (OR = 1.9, 95% CI = 1.0–3.7) vaccines was reported at a higher frequency in psoriatic arthritis group as compared to the psoriasis group without arthritis .
3.4. Influenza vaccination
Shin et al. described a 26-year-old woman with multiple erythematous scaly macules scattered on the extremities and trunk compatible with guttate psoriasis following injection of an inactivated split-virus influenza A/H1N1 vaccine without adjuvant . Güneş et al. reported 43 patients suffering from psoriasis in that 36 of them had exacerbation of pre-existing psoriasis while disease first appeared in the remaining seven patients after influenza vaccination in the 2009–2010 season. Thirty-seven of these patients had mixed plaque type and guttate psoriasis, three of them suffered from palmoplantar psoriasis, and another three of them had scalp psoriasis. Although there is the lack of control group and follow-up evaluations in that study, they suggested that their observations may support the association between influenza vaccination and the development of psoriasis due to the short-time onset of psoriasis after vaccination and the lack of other possible triggers .
There is also a cross-sectional study investigating a total of 1125 cases for the onset or flare of psoriasis occurring within 3 months following the 2009 monovalent H1N1/seasonal vaccination through a national survey in France. The overall influenza vaccine coverage was found 19% in this population. Ten patients were reported with a psoriasis of new onset (
In another study, the effects of seasonal influenza vaccination in psoriatic arthritis patients under anti-TNF-alpha therapy were evaluated. 1 month after the vaccination (T1), patients (
3.5. Adenovirus vaccination
In a retrospective study, which evaluated the possible side effects related to adenovirus types 4 and 7 in military recruits, psoriasis (21 versus 7 cases) was found more frequently (RR = 2.44, 95% CI = 1.13–5.31) in the vaccinated group (
4. Therapeutic effects of vaccines on psoriasis
Both conventional systemic treatments and biologic agents are related to serious side effects. The biologic immunotherapy agents act by inhibiting over-expressed T-cell activity by reducing T-cell numbers, T-cell trafficking or immune deviation and blocking the activities of proinflammatory cytokines, which may lead to severe infections, myelodegenerative and autoimmune disorders . Additionally, over the past few years, various John Cunningham virus (JCV) associated brain syndromes have been reported as a result of increased usage of the immunomodulatory medications . The progression in the enlightenment of the immunopathogenesis of psoriasis may provide new therapeutic options that do not have immunosuppressive side effects. Vaccination is a progressing therapy option for psoriasis and the other chronic inflammatory disorders such as multiple sclerosis, rheumatoid arthritis and atherosclerosis, which are termed as noncommunicable diseases [1, 45, 46]. It has clearly demonstrated that vaccines have the ability to activate effectors such as dendritic cells and T lymphocytes, which are also involved in psoriasis pathogenesis . Noncommunicable disease vaccines target cells, proteins or other molecules that are related to these disorders and modulate the immune system, similar to traditional vaccines .
Approximately two-thirds of guttate psoriasis patients and a quarter of chronic psoriasis patients have an association with streptococcal throat infections. Fry et al. claimed that vaccination against Streptococcus pyogenes as well as the other possible microorganisms that trigger psoriasis may be a new way to prevent psoriasis [3, 4]. It has also been suggested that psoriasis may benefit from development of a T-cell receptor peptide vaccine .
As we mentioned before, IL-17 has been shown to play an important role as a proinflammatory cytokine in psoriasis. IL-17 is demonstrated as a ‘target antigen’ for the treatment of autoimmune disorders and psoriasis in preclinical experiments in animal models and in clinical trials . Dallenbach et al. showed that immunization with Qβ-IL-17, a virus-like particle-based vaccine, generated IL-17-specific IgG in mice. In order to evaluate the role of hypermutation and affinity maturation, they mutated the hypermutated antibody back to germline sequence, producing a set of two antibodies with VH regions differing in three aminoacids, but recognizing the same epitope. They showed that both the hypermutated and the germline antibody significantly neutralized IL-17 and blocked its biological activity
Over-expression of ß-defensin 2, known as a skin antimicrobial peptide, has been reported to be associated with psoriasis . In a recent study, serum ß-defensin 2 levels have been found to correlate with IL-17A levels and psoriasis area severity index (PASI) scores in psoriatic patients . Additionally, García-Valtanen et al. demonstrated that ß-defensin 2 improves the DNA vaccine efficacy due to its adjuvant-like effects besides its antiviral and immunomodulatory properties in a study of zebrafish. They claimed that this psoriasis-related peptide might be used as an adjuvant in DNA vaccination to improve the efficacy of viral vaccines .
The TNF-alpha-induced protein 3 (TNFAIP3) is an anti-inflammatory factor that inhibits NF-κB activation in T-cells. In a few studies, it was reported that expression of TNFAIP3 mRNA was significantly higher in patients with mild psoriasis than in the patients with severe psoriasis, suggesting that TNFAIP3 gene may be a ‘target’ molecule for psoriasis therapy [52, 53]. There are also reported studies, which are mentioned below, about the usage of vaccines on psoriasis.
4.1. Mycobacterium vaccae
A placebo-controlled study in patients with chronic plaque psoriasis evaluated the potential beneficial effects of
A study performed on 36 patients with psoriatic arthritis randomized the patients to receive two intradermal injections of 50 µg delipidated, deglycolipidated
Mycobacterium w is a nonpathogenic, rapidly growing, cultivable strain of atypical mycobacteria and has been used as an adjuvant immunotherapy for leprosy, tuberculosis and human immunodeficiency virus, like
The mechanism of mycobacterium immunotherapy leads to improvement in psoriasis is not known exactly. Lehrer et al. suggested that the decreasing effect of TNF-alpha might cause clinical improvement in psoriasis patients treated with
4.2. Leishmania amastigotes
In a trial about a vaccine for cutaneous leishmaniasis, O’Daly et al. observed 100% clinical remission of a psoriatic lesion in one patient after third vaccination. After this discovery, they performed an open-label, single-center study to evaluate the leishmaniasis vaccine (AS100®) in 2770 psoriasis patients. When baseline PASI values were compared with the post-treatment values, PASI 100 was achieved in 23%, PASI 75 in 45%, PASI 50 in 13%, PASI 10 in 9% and <PASI 10 was determined in 3% of patients. The most common adverse effects were pain and nodule formation, which were injection side related. The other systemic adverse effects were considered as mild and moderate in severity. Similar results were observed in a second, double-blind, placebo-controlled study, performed by the same group . In a subsequent study, O’Daly et al. evaluated further purified vaccines, resulting in seven chromatography fractions per four Leishmania species. They suggested that three fractions from
4.3. Live attenuated varicella vaccine
A placebo-controlled study was conducted by El-Darouti et al. to evaluate the adjuvant effect of live attenuated varicella vaccine (Varilrix®) in patients with resistant severe psoriasis after their observation of improvement in one patient with severe psoriasis following a chickenpox infection. Study group received four doses of Varilrix® once every 3 weeks before low-dose cyclosporine (2.5 mg/kg/day) while control group received four doses of subcutaneous saline as placebo. Study group demonstrated significantly higher improvement in their PASI values. According to El-Darouti et al., the hypotheses explaining the mechanism of live attenuated varicella vaccine on psoriasis are given as below :
The stimulating effect of varicella zoster virus on the humoral response by Th-2 cells and subsequent downregulation of the Th-1 response,
The inhibitory effect of IFN-alpha on Th-17 cells by peripheral blood cells exposed to varicella zoster virus antigen,
The upregulation of regulatory T-cells that have inhibitory effects on psoriasis after receiving varicella vaccine.
Subsequently, El-Darouti et al. reported that live attenuated varicella vaccine is effective in psoriasis when used with low-dose cyclosporine by acting possibly on the Th17/ regulatory T-cells balance .
Vaccination is an effective tool for reducing the incidence of serious or life-threatening infectious disease . Patients diagnosed with psoriasis are at risk of infections due to the nature of disease and immunosuppressive therapies [12, 14]. For this reason, the medical board of the National Psoriasis Foundation recommends vaccination for patients diagnosed with psoriasis in compliance with recommendations of the Advisory Committee for Immunization Practices . Besides, vaccines such as