Vaccine-preventable infections in Systemic Lupus Erythematosus

Abstract

Systemic Lupus Erythematosus (SLE) is characterized by abnormal autoantibody production and clearance. Infections are among the most important causes of morbidity and mortality in SLE patients; they have an increased frequency of severe bacterial and viral infections possibly due to inherited genetic and immunologic defects and to immunosuppressive therapies. In addition, infectious agents can switch on lupus disease expression and activity. Among the strategies to reduce the risk of infection, vaccination can be considered the most reliable option. Most vaccines are effective and safe in SLE patients, although in certain cases immunogenicity may be sub-optimal and vaccination can trigger a flare. Although these issues are currently unresolved, the risk benefit balance is in favor for vaccination to reduce the risk of infection in SLE patients. In the present review we discuss the preventive strategies currently recommended to reduce bacterial and viral infections in SLE.

Keywords:

• systemic lupus
• erythematosus
• vaccines
• vaccine-preventable
• infections

Introduction

Systemic Lupus Erythematosus (SLE) is a systemic autoimmune rheumatic disease characterized by abnormal autoantibody production and clearance. The etiopathogenesis of SLE is complex and still largely unknown. Genetic, environmental and hormonal factors (estrogen, in particular) contribute to disease susceptibility.¹ The disease is characterized by a variable clinical course with periodic episodes of inflammation and damage to the joints, tendons, other connective tissues, and organs as heart, lungs, blood vessels, brain, kidneys, and skin. Indeed, while in some patients the disease may be mild affecting only one organ or system, in others it is characterized by multi organ involvement. The heart, lungs, kidneys, and brain are the organs most affected.² Bacterial and Viral infections are the most common complications. Both unbalanced immunological background and immunosuppressive therapy has been suggested to play a role in the susceptibility of SLE patients to infections.³ The administration of corticosteroids, disease modifying anti-rheumatic drugs (DMARDs) and “biological” drugs as TNF-α inhibitors increase the risk of infections. Numerous studies demonstrated that corticosteroids, especially in doses higher than prednisone 20 mg daily (or its equivalent), increased the susceptibility to infections.^4-6 Steroids are often used together with DMARDs increasing their cytotoxic effects such as leukopenia.^7-9 Moreover, TNF-α inhibitors are also used in association with DMARDs and amplify the immunosuppression by additional lymphocyte toxicity and inhibition of important cytokine and noncytokine activation pathways.^10-16 Molecular mimicry after common infections has been suggested as a trigger for SLE because clinical observations have demonstrated that SLE onset or exacerbation frequently followed an infection. Cross-reactivity between viral antigens and SLE autoantibodies has been proven in several cases: viruses bind to chromatin of infected cells with the subsequent production of anti-chromatin antibodies including anti-dsDNA and anti-histone antibodies.¹⁷ Virus-induced microRNAs may cause the production of autoantibodies by infected B-lymphocytes. Finally, some genetically determined defects of the immune system such as functional asplenia,¹⁸ abnormalities in the expression of complement receptors and complement factor deficiency¹⁹ or deficit of mannose binding lectine (MBL) may favor the insufficient clearance of infectious agents, whose persistence in the host may give rise to autoimmunity.^16,20 Since MBL is structurally homologous to C1q, a low serum MBL as shown in certain gene polymorphisms²¹ can induce a defective activation of the complement system leading to impaired complement-mediated clearance of immune complexes. MBL deficiency not only increase the risk of infections, but might predispose to the development of SLE, in particular is associated with musculoskeletal and cutaneous manifestations, while higher and intermediate MBL levels were significantly associated with nephritis in combination with other systemic manifestations.^19-22 Infections are also among the most important causes of morbidity and mortality in SLE across all regions,^23-28 with several series in Asian countries ranking infections as either the first or second cause of mortality.^27,28 The most frequent types of infections in SLE patients are community acquired pneumonia, urinary tract, soft-tissue and systemic infections frequently caused by Streptococcus pneumoniae (S. pneumoniae), Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa.²⁹

The high burden of infections provides additional rationale for the use of effective vaccine strategies in patients with SLE. In this review, we report and discuss international recommendation (i.e. European League Against Rheumatism, EULAR, Tables 1 and 2) about the more appropriate active immunoprophylaxis in LES.

Bacterial infection vaccines

Notably, asplenic/hyposplenic patients suffering from autoimmune inflammatory rheumatic diseases (AIIRD) such as SLE are at risk of developing the so-called “overwhelming post-splenectomy infection” (OPSI) including encapsulated bacteria (i.e., S. pneumoniae, Haemophilus Influenzae type b (HIB), Neisseria meningitidis (N. meningitidis). OPSI can also occur as a secondary infection after influenza infection. Therefore, the general consensus is to vaccinate these patients against Influenza, S. pneumoniae, HIB and N. meningitidis type C. Furthermore, when asplenic/hyposplenic patients with AIIRD plan to travel to or live in areas where other meningococcal strains are endemic (A, Y, W135), vaccination for these meningococcal subtypes is also indicated.^30-32

Streptococcus pneumoniae vaccines

S. pneumoniae is a gram-positive bacterium which is an important cause of morbidity and mortality worldwide, particularly in young children and elderly subjects.

Patients with SLE have an increased frequency and severity of S. pneumoniae infections, accounting for 6–18% of all bacterial infections in these patients.³³ In patients with functional asplenia and/or deficiencies of the early components of the complement pathway S. pneumoniae causes mainly pneumonia, however sepsis and meningitis may occur. Goldblatt et al.³⁴ reported that the opsonisation of S. pneumoniae with complement factor 3b/inactiveC3b (C3b/iC3b) was significantly decreased in SLE patients, as compared with other rheumatic diseases patients and healthy controls, contributing to the increased susceptibility of SLE individuals to pneumococcal pneumonia. Furthermore, genetic polymorphisms that affect the affinity of immunoglobulin (Ig) binding to Fc receptors may also be a risk factor for infection (homozygous for the R131 allele of FcγRIIA, MBL variant alleles, genotype 0/0).^35,36 Moreover, some S. pneumoniae serotypes are associated with higher mortality.³⁷

Three vaccines against S. pneumoniae are currently commercially available. The first vaccine is a 23-valent polysaccharide vaccine which contains capsular polysaccharides antigens (PnPS) from the 23 most dominant serotypes among clinical isolates of S. pneumoniae accounting for approximately 90% of overall invasive infections in the adult population. These antigens induce specific antibody production by a T-lymphocyte-independent mechanism which increase opsonization, phagocytosis and killing of pneumococci by phagocytic cells.³⁸ Vaccination is recommended for subjects aged > 65 years, for patients with asplenia or chronic diseases regardless of age.³⁸ The second vaccine is a 13-valent pneumococcal CRM₁₉₇ conjugate vaccine (PCV13) which was licensed in the United States in February 2010 and replaced the heptavalent pneumococcal conjugate vaccine (PCV7) available until then. PCV13 contains serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F. These serotypes account for 92% of the serotypes that cause invasive pneumococcal disease in children of <5 years of age in the United States.⁴⁰ PCV13 was licensed for prevention of invasive pneumococcal disease (IPD) caused among infants and young children by the 13 pneumococcal serotypes covered by the vaccine and for prevention of otitis media caused by serotypes also covered by PCV7 (4, 6B, 9V, 14, 18C, 19F, 23F).⁴⁰ Moreover, PCV13 was approved for use among adults aged ≥50 years to prevent pneumonia and invasive disease caused by S. pneumoniae serotypes contained in the vaccine. The conjugate vaccines are characterized by the covalent linking of the polysaccharide to a protein, that enhances immunogenicity and increases serum antibody levels. These protein carriers are T-cell-dependent antigens and stimulate a T-helper cell response that primes the vaccinated individual for an anamnestic or booster response.⁴¹ The third vaccine is a 10-valent pneumococcal HiD-DiT protein conjugate vaccine (PCV10) which was approved first in Canada in December 2008 and then by the European Medicines Agency in March 2009. PCV10 contains serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F, conjugated to 3 binding proteins: nontypeable Haemophilus influenzae protein D (NTHi protein D), diphtheria toxoid and tetanus toxoid. PCV10 was licensed for prevention of invasive diseases and acute otitis media, by the 10 serotypes included in the vaccine, in infants aged between 6 weeks-<2 years.⁴²

The influence of corticosteroids and DMARDs on pneumococcal vaccine response has not been evaluated in patients with chronic autoimmune rheumatic diseases as SLE. However, corticosteroid treatment does not seem to impair the specific immune response to pneumococcal polysaccharide vaccine.^43-44 Pisoni et al.⁴⁵ reported that 30 of 37 SLE patients vaccinated with the 23-valent polysaccharide pneumococcal vaccine reached protective specific antibody levels without any significant impact upon the disease activity up to 3 months after the vaccination. McDonald et al.⁴⁶ followed 19 SLE patients for up to 3 years after pneumococcal vaccination and reported decreasing protective titers in 8 of them. Battafarano et al.⁴⁷ confirmed the efficacy of pneumococcal, tetanus toxoid (TT), and HIB vaccination, showing that 84% of the SLE patients developed a 4-fold titer increase in response to at least 1 vaccine and 51% developed a 2-fold titer increase with all 3 vaccines. Moreover, almost half of the patients (47%) developed a 4-fold antibody response to S. pneumoniae. Finally, the revaccination remains still a topic of dispute for healthy individuals and, thus, even more in immunocompromised patients. However, the conjugate pneumococcal vaccine which has been licensed only for children has been shown to induce protective antibody levels in children with generally impaired immune responses at 6–9 months after bone marrow transplantation.⁴⁸ These data support the notion that a booster dose may be recommended for patients with chronic inflammatory autoimmune diseases such as SLE with suboptimal immune responses.

Neisseria meningitidis vaccine

Meningococcal infection spans a wide spectrum of clinical presentations, ranging from transient fever to severe shock. N. meningitidis is pathogenic only in humans. It colonizes the nasopharynx asymptomatically in up to 40% of the adult population but occasionally causes invasive disease. Only 6 capsular groups (A, B, C, W-135, X and Y) are associated with invasive disease and serogroups B and C are implicated in the majority of N. meningitidis infections in industrialized countries.⁴⁹ The spleen is important in the clearance of particulate immune complexes, such as bacteria opsonized with antibody and complement component C3. Defective splenic clearance of particulate immune complexes has been reported in SLE patients.⁵⁰ Furthermore, patients with active SLE have low circulating levels of complement components C3 and C4 resulting in defective opsonization of immune complexes and a reticuloendothelial system (RES) saturated with immune-complexes. Therefore, it seems intuitive that SLE patients should be at risk for organisms whose removal depends either on RES activity or on complement opsonization. Despite the frequent finding of complement deficiencies in SLE, the association of N. meningitidis infections and SLE remains still uncommon. In SLE patients, serogroups Y and W-135 are found more frequently.^51-53 Feliciano et al.⁵⁴ reported 3 cases of SLE patients who developed disseminated meningococcal disease. N. meningitidis serogroup Y, which is considered to be an organism of relatively low virulence, was isolated from the blood or cerebrospinal fluid in each case. All 3 patients had long-standing SLE, were treated with prednisone and presented serum hypocomplementemia at the time of infection. Zenone et al.⁵⁵ also described the case of a female SLE patient with low C3 and C4 serum levels who developed meningococcal disease due to N. meningitidis serogroup Y. These findings confirmed that meningococcal infections are strongly associated with C3 deficiency, properdin and late complement components. Schenfeld et al.⁵⁶ reported 2 SLE patients who developed monoarticular infectious arthritis in which N. meningitidis was recovered from knee synovial fluid. Asplenic/hyposplenic SLE patients may be vaccinated against N. meningitides.⁵⁰ First developed vaccines against N. meningitidis were based on the use of polysaccharide antigen, either monovalent, bivalent (group A and C) or tetravalent (group A, C, W135 and Y). Major limitations of these vaccine include the absence of T-lymphocyte-related memory effects, the short-lived seroprotection, the weak immunogenicity in infants less than 2 years of age and the inefficacy with regards to preventing nasopharyngeal carriage.^57-60 The introduction of the conjugation technologies led to the development of new vaccines able to elicit a T-cell-dependent immune response, so overcoming the above mentioned disadvantages. The currently available conjugate vaccines against N. meningitidis are formulated as monovalent group A or C and tetravalent groups A, C, W135 and Y. Recently, a combined HIB and N. meningitidis serogroup C conjugate vaccine has been licensed.⁶¹ In January, 2013, the European Medicines Agency (EMA) approved for the European market and licensed a novel 4-component meningococcal serogroup B vaccine, 4CmenB, able to cover up to 88% strains of capsular group B meningococcus currently circulating in the UK.^62-64 Available meningococcal vaccines have never been formally tested in patients with SLE; however, low rate of recorded adverse events in vaccine recipients and increased susceptibility of SLE patients for infections caused by capsulated agents like N. meningitidis, make meningococcal vaccines an important and effective preventive measure in these subjects.^65,66

Haemophilus influenzae

H. influenzae belongs to gram-negative coccobacilli and colonizes the upper respiratory tract.^67,68 The presence or absence of a polysaccharide capsule segregates this bacterial species in 2 well defined groups: a group of encapsulated strains and a second group of noncapsulated strains, commonly referred as nontypeable H. influenzae.^68-69 However, before 1985, H. influenzae type B was the leading cause of bacterial meningitis and a common cause of other invasive diseases (e.g., epiglottitis, pneumonia, septic arthritis, cellulitis, purulent pericarditis, and bacteremia) among US children aged <5 years.^70-73 Meningitis occurred in approximately 2 thirds of children with invasive HIB disease; 15%–30% of survivors had hearing impairment or severe permanent neurologic sequelae. Approximately 4% of all cases were fatal. ⁷¹ H. influenzae type F has been shown to cause pericarditis and acute epiglottitis, sepsis and multi-organ failure and H. influenzae type E to cause necrotizing fasciitis in patients with SLE.⁷⁴ Finally, hyposplenism in patients with SLE increases the risk of infections with H. influenzae.⁷⁵ Similarly to vaccines against N. meningitidis, also the first licensed HIB vaccine was composed of polysaccharide, in particular of purified polyribosylribitol phosphate (PRP). As observed for other polysaccharide vaccines, this product showed several limitations, especially lack in immunogenicity.^76,77 The advent of conjugation technologies, and the introduction of HIB conjugate vaccines, significantly increased the ability of vaccine recipients to mount an effective immune response after vaccination. Since the late 1980s several HIB conjugate vaccines have been licensed with PRP conjugated to tetanus toxoid (PRP-T), meningococcal group B outer membrane protein (PRP-OMP), diphtheria toxoid (PRP-D) or non-toxic mutant diphtheria toxin (HbOC).^77,78 HIB conjugate vaccine has been examined in patients suffering from SLE. Indeed, Battafarano et al.⁴⁶ demonstrated that 64 of the 73 (88%) SLE patients who received HIB vaccination developed protective levels of antibody to HIB. The vaccine was well tolerated and had no effect upon disease activity.

Tetanus toxoid-vaccine

Tetanus is an acute neurological disease caused by Clostridium tetani, a non-invasive, and spore-bearing anaerobic bacilli bacterium. C. tetani infects humans by contaminating wounds, broken skin, or mucous membranes from where it produces the potent toxin, which circulates into the human body to cause the muscle spasms that characterizes the disease.⁷⁹ Vaccination against tetanus toxoid represents an absolute necessity for everyone, especially for the elderly who are often inadequately immunized in many countries. Tetanus toxoid vaccine is an inactivated form of tetanospasmin. It is available in several forms, variably combined with diphtheria and pertussis vaccine at normal or reduced content: DTP, DtaP, Tdap, DT, and Td. The combination vaccines are generally recommended because concurrent immunization is typically appropriate. The Advisory Committee on Immunization Practices (ACIP) recommends a single Tdap dose for persons aged 11 through 18 years who have completed the recommended childhood diphtheria and tetanus toxoids and pertussis/diphtheria and tetanus toxoids and acellular pertussis (DTP/DTaP) vaccination series and for adults aged 19 through 64 years.⁸⁰ Kashef et al.⁸¹ determined the efficacy of anti-tetanus antibody response in young patients with SLE. Forty SLE patients and 60 age and sex matched normal controls received the complete schedule of tetanus toxoid vaccination consisting of 3 primary doses and 2 boosters. In all of the patients and controls anti-tetanus antibody titer was > 0.1 IU/ml, demonstrating that immunosuppressive therapy does not seem to interfere with development of consistent immunity to tetanus toxoid vaccine. Battafarano et al.⁴⁷ confirmed the efficacy and safety of tetanus toxoid vaccination. Indeed, 90% of SLE patients who received tetanus toxoid vaccination achieved protective levels of antibody to tetanus toxoid. Overall lupus disease activity was unaffected by immunization. Devey et al.⁸² demonstrated significant differences in both affinity and IgG subclass of antibodies produced after immunization with tetanus toxoid in patients with SLE and RA compared to healthy controls. Some patients with SLE produced very high affinity antibodies to tetanus toxoid with a response either restricted predominantly to IgG1 or more generally to all the IgG subclasses. Abe et al.,⁸³ Kashef et al.⁸⁴ and Csuka et al.⁸⁵ confirmed similar responses to tetanus toxoid vaccine in SLE patients as compared to healthy controls.

Diphteria vaccine

Diphtheria is an acute infectious disease caused by the bacterium Corynebacterium diphtheriae. Once in the body, this infectious agent release a toxin that can damage, or even destroy, organs and tissues. The organs involved vary depending on the type of bacteria, the most widespread type affects the throat, nose, and sometimes the tonsils, while another type, found mostly in tropical areas, causes skin ulcers. More rarely, the infection affects the vagina or the conjunctiva. Since the introduction of effective immunization, starting in the 1920s, diphtheria rates have dropped dramatically in the United States and other countries that vaccinate widely. Between 2004 and 2008, no cases of diphtheria were recorded in the United States. However, the disease continues to play a role globally. In 2007, 4,190 cases of diphtheria were reported, which is likely an underestimate of the actual number of cases.⁸⁶ No diphtheria-only vaccine is available. The diphtheria vaccine available are: DTaP (Diphtheria, Tetanus, acellular Pertussis vaccine); DTaP in combination with HIB vaccine; DTaP in combination with hepatitis B and inactivated polio vaccines; DTaP in combination with HIB, hepatitis B and inactivated polio vaccines; DT or Td (in combination with tetanus vaccine); Tdap (Tetanus, reduced diphtheria, acellular Pertussis). Vaccines containing the whole cell pertussis component (DTP) are no longer recommended for use in the United States although they are used in many other countries. Vaccines containing lower amounts of diphtheria toxoid—abbreviated with a small d—are utilized in persons 7 years of age or older. Maintaining seroprotection against tetanus and diphtheria through adherence to ACIP-recommended boosters is important for adults of all ages. Csuka et al.⁸⁵ demonstrated that the level of vaccine-induced immune responses against diphtheria in SLE patients were comparable to the healthy controls (60.6% vs 61.1%, respectively), even if the serum concentration of anti-diphtheria antibodies were significantly lower in <40-year-old SLE patients than in healthy controls. However, subjects with a titer ≥0.10 IU/ml were regarded as protected against diphtheria.

Bordetella pertussis

Pertussis (whooping cough) is a respiratory disease with serious consequences for newborns and populations at risk, such as smokers and seniors. This disease has long been responsible for severe morbidity and mortality worldwide.⁸⁶ In the middle of the last century, pertussis vaccination was introduced for young children. This led to a dramatic decrease in the mortality and morbidity due to this disease.⁸⁶ Pertussis vaccine is commonly administered to children in combination with diphtheria and tetanus toxoid. Pediatric acellular pertussis vaccines (i.e., diphtheria and tetanus toxoids and acellular pertussis antigens [DTaP]), less reactogenic than the earlier whole-cell vaccines, were first licensed for use in children in 1991.^87,88 ACIP recommended that pediatric DTaP replace all pediatric DTP doses in 1997.^88,89 Kostinov et al.⁹⁰ analyzed the serum levels of specific antibodies against pertussis in patients aged 1–18 years with immune-mediated diseases including SLE and without history of pertussis. They demonstrated that IgG to pertussis toxin and to antigens of acellular pertussis vaccine were detected in 98.6% and 100% of children. Most recent studies recommend immunization with pertussis vaccine for pregnant women between 28 and 38^th week in order to protect the newborn in the first 3 months.⁹¹

Viral infection vaccines

Influenza vaccine

Influenza (flu) is a contagious respiratory illness which can be mild to severe. Serious outcomes of flu infection can result in hospitalization or death. Some people, such as older people, young children, and people who belong to a specific group (i.e.diabetic and asthmatic patient) are at high risk for serious flu complications.^92-94 The best way to prevent the flu is by getting vaccinated each year. The season's flu vaccine contains most common influenza viruses: influenza A (H1N1) virus, influenza A (H3N2) virus, and one or 2 influenza B viruses, depending on the flu vaccine. Trivalent inactivated influenza vaccine (TIV) and live-attenuated influenza vaccine (LAIV) are currently commercially available. TIV can be used for any person aged ≥6 months, including those with high-risk conditions, while intranasally administered LAIV is indicated for healthy nonpregnant persons aged 2–49 years.^95-97

The frequency of influenza infection among patients with SLE has not been estimated. While prevention of influenza infections may reduce the risk of developing pneumonia, there has been concern that influenza vaccine may trigger SLE flares.^97,98 Moreover, B lymphocytes dysregulation and immunosuppressive treatment might favor an impaired humoral response to A/H1N1 and A/H3N2 influenza viruses vaccination in SLE patients.⁹⁹

Williams et al.¹⁰⁰ reported that 47% of the 19 SLE patients vaccinated with inactivated bivalent (A/NJ and A/Victoria) influenza vaccine presented seroconversion as compared with 94% in age-matched control group. In another study, Ristow et al.¹⁰¹ confirmed that only 48% of SLE patients vaccinated with chick-cell agglutinin units of A/New Jersey/76 HswINI influenza virus vaccine as compared to 62% of controls presented 4-fold increase in antibody titers. Moreover, in a recent study, 24 SLE patients were immunized with the split virion, inactivated vaccine of A/Beijing/262/95 (H1N1), A/Sydney/05/97 (H3N2), and B/Harbin/07/94. Among the SLE patients, only 58%, 63% and 38% responded to A/Beijing/262/95 (H1N1), /Sydney/05/97 (H3N2), and B/Harbin/07/94 vaccine, respectively.¹⁰² Of note, it has been reported that a median title of 28 seems to protect 50% of vaccinated healthy adults.¹⁰³ Further studies seem to confirm that patients with SLE have a humoral response to influenza vaccination lower than healthy controls.¹⁰⁴ Holvast et al.^104,105 reported that 56 SLE patients presented fewer seroconversions as compared to healthy controls: in particular, 43% of patients versus 94% of controls for A/H1N1, 39% of patients vs. 88% of controls for A/H3N2 and, finally, 41% of patients versus 71% of controls for B/Hong Kong. Notably, 75% of patients and 100% of controls achieved a titer ≥ 40 to both influenza A strains. Lu et al.¹⁰⁶ enrolled 21 SLE patients and 15 sex- and age-matched normal healthy controls who were vaccinated against A/H1N1 influenza virus. All subjects had a low SLEDAI score and were taking one or more immunosuppressive agents including prednisolone, hydroxychloroquine and DMARDs. The seroprotection and the seroconversion rates increased significantly in SLE patients and healthy controls and met the “Committee for Proprietary Medicinal Products” (CPMP) guidelines 3 weeks and 6 months after the vaccination.

Conflicting results have been reported on the induction of SLE flares by influenza vaccination. In fact, some studies reported mild flares of overall SLE activity ^107,108 or renal flares,^109-112 whereas other studies did not report SLE-flares.^{100,104,109,110} Finally, Saad et al.¹¹¹ included in a study a total of 1668 patients with autoimmune rheumatic diseases who were vaccinated with a non-adjuvanted influenza A/California/7/2009 (H1N1) virus-like strain flu. The choice of using non-adjuvant vaccines was to prevent triggering an “adjuvant disease” in genetically susceptible individuals. In fact, as adjuvants may act as ligands for Toll-like receptors (TLRs) and stimulate innate immune responses, their use is a potential risk in autoimmune-prone subjects.^112,113 Indeed, aluminum adjuvants commonly used in human vaccines were found associated with macrophagic myofasciitis which is an autoimmune disease.¹¹⁴ Of note, the onset of a syndrome named “Autoimmune (auto-inflammatory) Syndrome Induced by Adjuvants” or “ASIA” has been recently described, both in animal models and in humans, following silicone breast implants or injection of adjuvanted vaccines.^115-117

Polio vaccine

Poliomyelitis is a viral disease. There are 3 types of poliovirus and many strains of each type. The virus enters through the mouth and multiplies in the throat and gastrointestinal tract, then moves into the bloodstream and is carried to the central nervous system where it replicates and destroys the motor neuron cells.

The two types of polio vaccines most widely used are inactivated polio vaccine (IPV), and the Sabin oral polio vaccine (OPV), a live attenuated vaccine. Oral poliovaccine should not be given to patients significantly immunocompromised. There is also a risk from household contacts receiving the oral poliovaccine: OPV is shed in the stool of vaccinated subjects and can then spread to other people in the community, so replicating long enough to revert to a neurovirulent form.¹¹⁸ Schattner et al.¹¹⁹ reported that the risk of flares in SLE patients immunized against poliomyelitis represented a real event. Indeed, both OPV and IPV vaccines were implicated in the flares (1/24 and 3/49 patients, respectively).

Hepatitis B vaccine

Hepatitis B virus (HBV) is transmitted through bodily fluids such as blood, semen and vaginal secretions. HBV vaccination is an universal recommendation of the World Health Organization (WHO) for all countries,¹²⁰ but this procedure has been implicated as a potential trigger for autoimmune diseases ¹²¹ or worsening of its symptoms.¹²² The active substance in the vaccine is the hepatitis B surface antigen (HBsAg), which is actually obtained by DNA recombination technique. The Second-generation recombinant vaccines contains variable fragments (d/y, w/r) and the ‘a’ determinant common to all HBsAg subtypes, that is recognized by B lymphocytes; the conservative character of this region allows cross-protection after vaccination anyway of HBsAg subtype used in the vaccine.¹²³

Hepatitis B vaccine is available as a single-antigen formulation and also in fixed combination with other vaccines, such as hepatitis A virus vaccine, HIB vaccine, diphtheria and tetanus toxoids and acellular pertussis adsorbed (DTaP) vaccine, IPV vaccine. Kuruma et al.¹²⁴ confirmed the efficacy and safety of HBV vaccine in 28 inactive SLE patients with negative serology for HBV. The patients were immunized with recombinant DNA HBV vaccine. An adequate seroconversion was achieved at the end of the study (93%), although a lower frequency after the first (4%) and second dose (54%) was observed. No significant change in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was observed after each vaccine-dose.

On the basis of these facts, we can say that inactive lupus patients may benefit by HBV vaccination reaching a satisfied production of protective antibody. Moreover, the response to the immunizing antigen does not seem to induce flares and autoantibodies. Therefore, HBV vaccine can be considered as part of the prevention program for patients at high risk of exposure (long stay in endemic countries,.medical profession, contacts of HBV infected people).¹²⁴

Hepatitis A vaccine

Hepatitis A virus (HAV) is transmitted by the fecal-oral route. Inactivated and attenuated hepatitis A vaccines have been developed; however, only vaccines made from inactivated HAV have been evaluated for efficacy in controlled clinical trials.^126-127 The vaccines containing HAV antigen currently available are single-antigen vaccines and the combination vaccine containing both HAV and HBV antigens. All currently available vaccines are inactivated. Vaccination against hepatitis A virus (HAV) is only recommended when the risk of contracting this infection is really increased (i.e., travel or residence in endemic countries for HAV) or when protective antibodies against HAV are absent. There are no data available to confirm this vaccine's safety and efficacy in patients with SLE.¹²⁷

Human papillomavirus vaccine

Human papillomavirus (HPV) is the primary cause of cervical cancer. Cervical cancer is the second most common cancer after breast cancer to affect women aged 15–44 years in the European Union. Persistent infection of the genital tract by some specific types of HPV is present in most cases of cervical lesions, which can further develop into cancer.¹²⁸

More than100 types of HPV have been described, about 40 of them can infect the genitals and at least 14 HPV types classified as ‘high risk’ can cause cervical cancer in women, and are associated with other anogenital and oral cancers both men and women. HPV 16 and HPV 18 are the most common types, causing about 70 percent of all cases of cervical cancer. ‘Low risk’ HPV types, most commonly HPV 6 and HPV 11, are responsible of about 90% of cases of genital warts.^128-130

Two HPV vaccines have been licensed in Europe, a bivalent and a quadrivalent vaccine: both have a good safety profile and protect against the high-risk HPV types 16 and 18. The quadrivalent vaccine also protects against HPV 6 and 11. Both vaccines have been shown to prevent more than 90% of precancerous lesions associated with HPV 16 and 18. Different adjuvants were added to these vaccines, the quadrivalent one utilizes the hydroxyphosphate sulfate adjuvant whereas the bivalent exploits a double adjuvant system, ASO4 composed of 3-O-desacyl-4′monophosphoryl lipid A and aluminum hydroxide. The vaccines are given in 3 intramuscular injections over a 6-month period. They do not cure existing infections and should therefore be given before onset of sexual activity. Both HPV vaccines are safe and effective in healthy females aged 9–26 years providing a long-lasting protection against HPV infection and premalignant lesions (90–100 % of cases prevented).^128-130

HPV vaccines are well tolerated in the general population, nevertheless some adverse effects were reported as mild local-site reactions, fatigue, headache, myalgia; a few serious adverse effects including venous thrombosis, hypersensitivity reactions, anaphylaxis, motor neuron disease, and even deaths, but only the rate of venous thrombosis was significantly higher than in the general population. An association between quadrivalent HPV vaccine and autoimmunity was suggested, in particular for systemic lupus erythematosus (SLE).^131,132

Women with SLE have higher prevalence of persistent human papilloma virus (HPV) infections and precancerous lesions than healthy women. This is the reason for the aim that SLE may benefit from HPV vaccines and specific cervical cancer screening.¹³⁰

HPV vaccine should be recommended to SLE patients prior to sexual activity, depending on the prevalence of the infective disease, the safety of the individual vaccine and the activity stage of their autoimmune-rheumatic condition. A risk-benefits assessment before vaccination is strictly recommended together with close follow-up after each dose.^132,133

Measles, mumps, rubella and varicella vaccine

Measles, caused by a Paramyxovirus of the genus Morbillivirus, is transmitted by air and affects the respiratory system, the immune system and the skin. Two combination vaccines are licensed and available to prevent measles, rubella, mumps and varicella infections: trivalent MMR vaccine (measles-mumps-rubella) and quadrivalent MMRV vaccine (measles-mumps-rubella-varicella). MMRV vaccine was licensed on the basis of noninferior immunogenicity of the antigenic components compared with simultaneous administration of MMR vaccine and varicella vaccine. Monovalent measles, rubella, and mumps vaccines and other vaccine combinations are no longer commercially available.^132,133 MMR and MMRV vaccine should not be administered to persons receiving systemic immunosuppressive therapy, including corticosteroids ≥2 mg/kg of body weight or ≥20 mg/day of prednisone or equivalent for persons who weigh >10 kg, when administered for ≥2 weeks.^133,134 There are no series that directly assessed the safety and efficacy of MMR vaccination in patients with SLE. Miyamoto et al.¹³⁵ evaluated the influence on antibody response to measles and tetanus vaccine antigens in 30 children and adolescents with juvenile SLE and 14 healthy age-matched controls. Immunosuppressive therapy included cyclophosphamide or methylprednisolone pulses as well as oral mycophenolate mofetil, azathioprine, cyclosporine (2 mg/kg per day) or prednisone (20 mg/day) for more than 14 days and was considered to cause a significant degree of immunosuppression. The SLE group was divided according to disease activity into inactive SLE and active SLE. Measles antibody levels in the SLE groups were similar to the control group. Therefore, these findings confirmed the efficacy of measles vaccine in SLE patients.

Herpes zoster vaccine

Herpes zoster is still the most common viral infection in patients with SLE treated with cyclophosphamide and mycophenolate mofetil.¹³⁶

Chickenpox is a highly contagious infectious disease caused by the Varicella zoster virus (VZV), belonging to the family of herpes viruses, which is transmitted by air. SLE patients are at increased risk of herpes zoster (HZ). Although a vaccine for HZ has been approved by the US Food and Drug Administration, its use in immunocompromised individuals remains controversial. Guthridge et al.¹³⁷ analyzed the immunogenicity of the HZ vaccine in 10 SLE patients and in 10 control individuals aged ≥ 50 years. Immunogenicity was assessed with varicella zoster virus (VZV)-specific interferon-γ-producing enzyme-linked immunospot (ELISPOT) assays and with antibody concentrations. The proportion of subjects with a > 50% increase in ELISPOT results following vaccination was comparable between both groups, although absolute SLE responses were lower than controls. Finally, no herpetiform lesions or SLE flares were seen in this small cohort of patients.

Conclusions

As illustrated above, SLE patients have a major predisposition to infection with microbial agents, due to a range of predisposing factors, such as leukopenia, acquired hypocomplementaemia, genetic complement deficiency, mannose binding lectin deficiency, hypogammaglobulinaemia, splenectomy or functional hyposplenism, prednisolone dose, immunosuppressive medication, biologics (e.g.,, rituximab). Among the various strategies which can be applied to try and reduce the risk of infection in SLE patients, vaccination can be considered the most reliable option. Inactivated vaccines are safe to administer to SLE patients on immunosuppression and the induction of autoantibodies is usually of short term and of little clinical significance. Live vaccines are contraindicated in patients on immunosuppressive medication, although they may be considered in mildly immunosuppressed patients on a case-by-case basis. In order to obtain acceptable level of response and minimize adverse events, vaccines should be administered while disease activity is quiescent and, if possible, before starting immunosuppressive treatment, especially when high-dose corticosteroids or biologics are scheduled. Although immunogenicity may be sub-optimal and flare can be triggered, the risk benefit balance is in favor for vaccination to reduce the risk of infection as compared to the risk of flare.

Table 1. EULAR Recommendation.^30,134

Pathogens	Vaccines	Recommended
Streptococcus pneumoniae	PPV-23,PCV7,PCV13	Good immunogenicity and safe
Neisseria meningitides	MenC	Good immunogenicity and safe
Haemophilus influenzae	Anti-HIB	Good immunogenicity and safe
Clostridium tetani, Corynebacterium diphtheriae, Bordetella pertussis	DTaP, DT, TT	Good immunogenicity and safe
Influenza Virus	Anti-Flu	Good immunogenicity and safe
Polio Virus	IPV/OPV	NA- some flares
Hepatitis A and B Virus	Anti-HAV/HBV	Good immunogenicity and safe
Human papillomavirus	Anti-HPV	NA-Safe
Measles, Mumps, Rubella Virus	MMR	Good immunogenicity and safe
Varicella Zoster Virus	VZV	Good immunogenicity and safe

HAV, hepatitis A virus vaccine; HBV, hepatitis B virus vaccine; Hib, Haemophilus influenzae type B vaccine; HPV, human papillomavirus vaccine; IPV, inactivated poliovirus; MMR, measles, mumps, rubella vaccine; MenC, meningococcal serogroup C conjugate vaccine; OPV, oral poliovirus vaccines PCV7, 7-valent pneumococcal conjugate vaccine; PPV-23, 23-valent pneumococcal polysaccharide vaccineTD, tetanus-diphtheria vaccine; TDaP, tetanus-diphtheria-acellular pertussis vaccines; TT, tetanus toxoid vaccine; VZV, varicella zoster virus vaccine;NA not applicable.

Table 2. Recommendation for vaccine with grade, adapted from EULAR.^30,134

NON LIVE BACTERIAL VACCINE	RECOMMENDATION GRADE
The TT vaccine should be administered to patients with juvenile SLE according to the national vaccination guidelines.	B
It is recommended to adhere to national vaccination guidelines for vaccination against tetanus, diphtheria, pertussis, Hib, pneumococci and meningococci in pediatric patients.	C
In the case vaccinations against Hib, pneumococci and meningococci are recommended for patients with low complement levels or functional asplenia.	D
Pneumococcal vaccination, PPV23 or PCV7/PCV13 prior then rituximab use.	C
To assure adequate immune responses, it is recommended to determine pneumococcal strain-specific antibody concentrations after the PPV23+methotrexate	C
NON-LIVE VIRAL VACCINES	RECOMMENDATION GRADE
It is recommended to adhere to national vaccination guidelines for vaccination against hepatitis B virus in pediatric patients with SLE.	C
It is recommended to adhere to national vaccination guidelines * for vaccination against hepatitis A virus and poliovirus.	D
Annual influenza vaccination should be considered in all patients.	D
Influenza vaccination is recommended prior to rituximab use whenever possible.	C
It is recommended to adhere to national vaccination guidelines* for vaccination against HPV.	D
LIVE-ATTENUATED VIRAL VACCINE	RECOMMENDATION GRADE
It is recommended to withhold live-attenuated vaccines in patients on high-dose DMARD, ^† high-dose corticosteroids ^† or biological agents. Strictly Risk assessment is required.	D
It is recommended to adhere to national vaccination guidelines for live-attenuated vaccines unless patients are on high-dose DMARD, ^† high-dose corticosteroids ^† or biological agents.	C
In case of a negative history for VZV infection or vaccination, VZV vaccine should be considered, ideally before initiation of immunosuppressive therapy.^†	D

* National vaccination guidelines worldwide can be found on http://apps.who.int/immunization_monitoring/en/globalsummary/scheduleselect.cfm.

^† High-dose DMARD are defined as intravenous pulse therapy, cyclosporine >2.5 mg/kg per day, sulphasalazine >40 mg/kg per day or 2 g/day, azathioprine >3 mg/kg, cyclophosphamide orally >2.0 mg/kg per day, lefl unomide >0.5 mg/kg per day, or 6-mercaptopurine >1.5 mg/kg per day. High-dose glucocorticosteroids are dosages ≥2 mg/kg or ≥20 mg/day for 2 weeks or more. In patients chronically treated with 20 mg/day glucocorticosteroids, dosages below 2 mg/kg per day are also considered high dosages.

^† Generally 2–4 weeks is recommended before immunosuppressive therapy is commenced.

DMARD, disease-modifying antirheumatic drugs; Hib, Haemophilus infl uenzae type B; HPV, human papillomavirusMMR, measles, mumps, rubella; PPV23, 23-valent pneumococcal polysaccharide; RC, recommendation; SLE, systemic lupus erythematosus; TNF, tumor necrosis factor; TT, tetanustoxoid; VZV, varicella zoster virus.

Table 2. (Continued)

Code	Quality of Evidence	Definition
A	High	Further research is very unlikely to change our confidence in the estimate of effect. Several high-quality studies with consistent results In special cases: one large, high-quality multi-center trial
B	Moderate	Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. One high-quality study Several studies with some limitations
C	Low	Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. One or more studies with severe limitations
D	Very Low	Any estimate of effect is very uncertain. Expert opinion No direct research evidence One or more studies with very severe limitations

GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group 2007

Take-Home Messages

1. Patients with SLE are at an increased risk of infection, especially if they are taking immunosuppressive medication.

2. Although the history of vaccination in SLE patients had been controversial, the risk benefit balance is in favor for vaccination to reduce the risk of infection as compared to the risk of flare.

3. Inactivated vaccines are safe to administer to SLE patients on immunosuppression whereas live vaccines are contraindicated in patients on immunosuppressive medication.

4. If possible, vaccination should be administered before starting immunosuppressive medication, as once it is started then live vaccines are contraindicated and responses to non-live vaccines may be suboptimal.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.