Vaccination of Children and Adolescents With Rheumatic Diseases

Laura Dell'Era; Susanna Esposito; Fabrizia Corona; Nicola Principi


Rheumatology. 2011;50(8):1358-1365. 

In This Article

Immunogenicity, Efficacy and Tolerability of Vaccines in Children With RDs

Inactivated and Recombinant Vaccines

Diphtheria Vaccine The only published study of diphtheria vaccine in paediatric RD[38] is in 55 children aged 6–15 years, who were in clinical and laboratory remission, including some who were still receiving NSAIDs or immunosuppressive maintenance therapy. The results showed that diphtheria vaccination was immunogenic and safe in 95% of the children. Protective antibody levels were maintained for a long time, and simultaneous maintenance of immunosuppressive therapy at average age-related doses did not inhibit the production of protective antibodies.[38]

Tetanus Vaccine The only available data concerning paediatric RD was obtained from 40 children with SLE in whom immunosuppressive therapy did not seem to interfere with the development of immunity.[39] However, it has been suggested that immunosuppressive drugs given to mothers with a systemic autoimmune disease during pregnancy can affect the vaccination response of 17% of infants, although there does not seem to be any clear relationship between specific drug exposure and antibody response.[45]

Acellular Pertussis Vaccine The only study of the presence of antibodies against pertussis in paediatric RD involved 72 Russian children with RD and no history of pertussis,[46] 94.4% of whom were receiving immunosuppressive therapy. Immunoglobulin G (IgG) against pertussis toxin and the other antigens of an acellular pertussis vaccine were detected in, respectively, 98.6 and 100% of the children by means of ELISA.[46] The same authors also studied the vaccination history of 134 children with RD, and found that the incidence of pertussis was 116.3 per 1000 in 43 unvaccinated children and 62.5 per 1000 in 16 children with incomplete vaccinations; no clinically distinct pertussis was diagnosed in the 75 patients who received the entire vaccination and revaccination series.[46]

Inactivated Poliovirus Vaccine No data are available concerning children with RD.

Haemophilus Influenzae Type b Vaccine No data are available concerning children with RD.

Hepatitis B Vaccine The only published study of the immunogenicity and tolerability of HBV vaccination in paediatric RD patients[47] enrolled 39 children with JIA (all in remission and serologically negative for hepatitis B surface antigen) and 41 healthy controls. All the study population except for one subject with systemic JIA developed a significant antibody response (antibody titres >10 mIU/ml), although the antibody levels in the children with JIA were significantly lower than those in the healthy controls.[47] Vaccine responsiveness was not affected by either MTX or prednisolone treatment.[47] The authors acknowledged that the study had some limitations, particularly its small sample size and the fact that the clinical investigators were not blinded to the patients' clinical status.

Hepatitis A Vaccine No data are available concerning children with RD.

Pneumococcal Vaccines Although RD patients are more prone to respiratory infections than healthy controls,[2,7,8] and there is evidence that pneumococcal infections can be particularly severe during treatment with anti-TNF agents,[3–5] only a small number of studies have evaluated the immunogenicity, safety and tolerability of pneumococcal vaccines in subjects with these clinical problems. The only paediatric study used the heptavalent pneumococcal conjugate vaccine (PCV-7), which was administered to children with JIA and a mean age of 12.9 years, who were being treated with anti-TNF drugs plus conventional DMARDs or DMARDs alone.[48] After a single vaccine dose, geometric mean titres (GMTs) significantly increased above the level of 0.35 µg/ml, which was considered protective against invasive pneumococcal infections for all the serotypes included in the vaccine, regardless of anti-TNF treatment, disease type and duration and baseline titres.[48] However, ~50% of the children receiving anti-TNF drugs and 25% of those treated with conventional DMARDs did not develop a 4-fold increase in their baseline antibody titres against at least five serotypes.[48] These findings seem to suggest that children being treated for RD and vaccinated with PCV-7 can be protected from invasive pneumococcal infections regardless of the type of therapy, but this protection is less efficient than in otherwise healthy children, particularly when anti-TNF drugs are used. Obviously, other studies of larger numbers of patients with different RDs receiving different treatments are needed to confirm these results.

Some information regarding the protection offered by the 23-valent pneumococcal polysaccharide vaccine to older children can be drawn from studies of adult patients. Elkayam et al.[49] showed that average antibody titres in patients receiving conventional immunosuppressive agents and/or CSs between 1 month and 1 year after vaccination were the same as, or slightly lower than, those observed in control subjects. In a more detailed investigation, Elkayam et al.[50] found similar post-vaccination GMTs among the patients, regardless of treatment, but 33% of those with RA and 21% of those with SLE showed only minimal responses. Elkayam et al.[51] also compared antibody responses 1 month after pneumococcal polysaccharide vaccination in 16 patients treated with MTX plus etanercept or infliximab, and 17 matched patients treated with MTX alone. The patients receiving TNF antagonists showed a trend towards lower antibody responses to most of the tested antigens; 31% were poor responders compared with 18% of those receiving MTX alone.[51] In contrast, Kapetanovic et al.[52] compared responses to the 23F and 6B pneumococcal antigens in patients with RA receiving MTX alone or combined with TNF antagonists, and found that the former had significantly lower antibody responses. Mease et al.[53] investigated immune responses to 5 of the 23 antigens in the polysaccharide vaccine in 184 patients with PsA treated with MTX alone or combined with etanercept, and found that ~20% of the patients in both groups did not show a ≥2-fold increase in antibody titre against any of the antigens. Logistic regression analysis identified MTX therapy and older age (but not treatment with etanercept) as independent factors leading to the attenuated responses.[53] On the other hand, Visvanathan et al.[54] did not find any difference in antibody responses between patients with RA receiving MTX alone or combined with infliximab, but the responses of both groups were lower than those of healthy controls.

None of these studies[49–54] reported any safety problems, and the tolerability of both the PCV-7 and polysaccharide vaccine was always good in both children and adults with RD, and no different from that observed in healthy controls or subjects suffering from different diseases. No efficacy data are available for any of the pneumococcal vaccines, and it is not known how long protective titres last after vaccination in patients receiving immunosuppressive therapy, or when such patients should be revaccinated.

Meningococcal Vaccines Among the meningococcal vaccines, the meningococcal serogroup C conjugate vaccine was evaluated in a multicentre cohort study of children with RD in order to determine whether their immune response may be hampered by immunosuppressive therapy:[40] 234 children and adolescents with JIA were vaccinated, and adequate antibody levels were observed even in those receiving highly immunosuppressive medication.

Inactivated Influenza Vaccine Annual vaccinations against influenza are recommended throughout the world for children with impaired immune responses, including those with RD.[55,56] Although no randomized controlled trial has studied influenza vaccinations in these patients, there are some small studies but as most of them were carried out before 2000, they do not consider the effects of biological drugs such as anti-TNF preparations on immune responses to influenza vaccine.

Data have been collected from patients treated with CSs and/or other DMARDs. In a study by Malleson et al.[28] involving 34 children with JIA and 13 healthy controls, at least 95% of the patients developed presumably protective antibody levels. Pre-immunization titres, seroresponse rates and final titres against influenza antigens were similar in the patients and controls. Olson et al.[57] reported similar results from a small study of 14 subjects with JIA aged 5–20 years. The absence of any interference with antibody response to influenza vaccine by immunosuppressive drugs has also been demonstrated by Kanakoudi-Tsakalidou et al.,[58] who found no difference between 70 children with chronic RDs aged 4–17 years and five healthy siblings despite the fact that some of the patients had been receiving prednisone and/or other anti-rheumatic drugs for a long time.

No data are available concerning the possible impact of cytotoxic or biological drugs (e.g. TNF antagonists, rituximab or abatacept) on the immune response of children with RD to influenza vaccination. However, some findings in adults (although not entirely transferable to children) do indicate that the responses of RD patients treated with these drugs may be similar to or only slightly lower than those observed in untreated patients or healthy subjects, depending on the prescribed drug and the characteristics of the patients.[58–62] It has been shown that the response of subjects receiving adalimumab is not different from that of matched healthy controls,[59] and that the serological responses of patients with RA treated with MTX without TNF antagonists are significantly better than those of patients receiving TNF antagonists alone or combined with MTX and/or other drugs,[60] although the majority developed protective antibody levels after vaccination (from 52% against H1N1 to 94% against B antigen).[60] Similarly, Gelinck et al.[61] found that 80% of patients with various autoimmune diseases receiving TNF antagonists developed protective antibody titres, a percentage that was slightly but not significantly lower than those of the patients receiving conventional drugs (82–93%) and healthy controls (89–94%). In contrast, van Assen et al.[62] found that rituximab reduced the humoral responses of RA patients to influenza vaccination, which slightly recovered 6–10 months later. As previous influenza vaccination in rituximab-treated patients increases pre- and post-vaccination titres, it is not possible to foresee the immune response of children who have to be treated with the more recent anti-rheumatic drugs, and so specific studies are required before they can be routinely prescribed influenza vaccine.

All the studies[58–62] found that the local and systemic tolerability of influenza vaccine in children with RD was no different from that observed in healthy paediatric subjects. Solicited and unsolicited reactions are equally frequent in patients and controls, and the total number of severe adverse events is very small in all groups;[28,38,57] only Malleson et al.[28] found that their JIA patients felt unwell for longer than the controls.

HPV Vaccine No data are available concerning children with RD.

Live Attenuated Vaccines

Oral Poliovirus Vaccine Immunization coverage against poliomyelitis and the post-vaccination level of immunity have been assessed in 136 children with RD who had previously received oral poliovirus vaccine.[63] The proportion of children with RD who were seropositive to all three serotypes was 75.8%.[63] Although international guidelines state that live vaccines are contraindicated in patients receiving anti-TNF therapy, there is a report of one such patient who inadvertently received live polio vaccine without suffering from any infectious sequelae.[64]

MMR Vaccine There are two published studies of MMR vaccine in paediatric RDs, both involving children with JIA. The first was a retrospective observational multicentre cohort study of 314 patients born between 1989 and 1996.[65] Disease activity and medication use were compared during the 6 months before and 6 months after vaccination between patients vaccinated at the age of 8 and 9 years and those who had not been vaccinated by that age. In the second study, the effect of low-dose MTX therapy alone or combined with etanercept on the immunogenicity and tolerability of an MMR booster was evaluated in 15 children.[66] Neither study observed any overt MMR or secondary severe infections. Borte et al.[66] also found that low-dose MTX therapy following MMR vaccination did not interfere with T-cell-mediated immunity in vitro, and that neither low-dose MTX nor etanercept given simultaneously with revaccination markedly interfered with the generation of long-lived virus-restricted T cells or protective levels of virus-specific IgG antibodies. Arthralgia and acute transient arthritis have been described in children receiving MMR vaccines (see above).[35–37]

Varicella Zoster Virus Vaccine A number of reports show that complicated varicella and herpes zoster are very common in patients with RD.[67–70] However, varicella vaccination is contraindicated in patients taking glucocorticoids at prednisone-equivalent doses of 2 mg/kg/day or 20 mg/day for >14 days.[71] Consequently, Athreya and Lindsley[72] suggested measuring serum antibody levels and immunizing seronegative patients with varicella zoster virus (VZV) vaccine 3 weeks before starting the therapy. However, although this approach can be adopted in some cases, RD therapy is begun during the acute phase in the majority of situations and cannot be postponed until after the administration of VZV vaccine.

The immunogenicity and tolerability of VZV vaccine have been assessed in only one study of 25 susceptible children with juvenile RDs and 18 controls.[44] All the patients were receiving MTX, 13 were also receiving prednisone and five other DMARDs. Positive VZV IgG titres were detected in 50% of the seronegative patients and 72.2% of the controls 4–6 weeks after vaccination.[44] No episodes of overt varicella and no severe adverse reactions were observed during the follow-up.[44]

Live Influenza Vaccine No data are available concerning children with RD.


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