In general, a useful rule is that inactivated vaccines can be administered safely to IBD patients, irrespective of the degree of immunosuppression. However, patients on higher doses of immunosuppression (especially those receiving biologics) may not mount the same degree of antibody response to vaccines as patients on less immunosuppression. The best studied vaccine in children with IBD is the trivalent influenza vaccine, which is both safe and immunogenic in children and young adults. This vaccine is usually administered in the fall and protects against three strains of influenza. The trivalent influenza vaccine has generated protection against two strains of influenza A and one strain of influenza B. (In recent years, the quadrivalent influenza vaccine was developed which included a second strain of influenza B.) Three prospective studies have demonstrated that the trivalent influenza vaccine is usually well tolerated in children with IBD, including those receiving immunosuppressive therapy. However, immunogenicity may be reduced, especially in patients receiving biologic therapy. Mamula et al. performed a prospective study using the 2002–2004 vaccine, in which 51 children with IBD and 29 healthy children were immunized. Compared to the healthy controls, children with IBD receiving combination therapy (with immunomodulators and biologics) were less likely to respond to two of the three strains in the influenza vaccine [20]. In contrast, Lu et al. demonstrated a good response to the 2007–2008 influenza vaccine and a high prevalence of seroprotection to both of the influenza A strains in the vaccine. The less immunogenic influenza B strain, however, resulted in a decreased rate of seroprotection in patients receiving anti-TNF therapy [21]. DeBruyn and colleagues again demonstrated excellent safety and good response to the two A strains in the vaccine, but decreased immune response to the B strain [22]. A more recent study by deBruyn of 137 children with IBD receiving maintenance infliximab therapy demonstrated that timing of vaccination relative to infliximab infusion (immunization at time of infliximab versus midway between infusions) did not impact serological protection [23]. None of these studies demonstrated any increase in adverse events or increase in IBD flares. In summary, data from influenza vaccine studies in pediatric IBD support the recommendation that children with IBD receive annual influenza immunizations. Even patients on immunosuppressive therapies respond well to the two A strains in the vaccine, though antibody titers to the B strain may be reduced.

Hepatitis B vaccination has also been studied in children with IBD. Patients with latent hepatitis B who are treated with anti-tumor necrosis factor inhibitors are at risk for viral reactivation leading to severe viral hepatitis or even liver failure [24, 25]. Urganci et al. administered the hepatitis B vaccine series to children with IBD who were not previously vaccinated. Seroconversion was achieved in 70% of IBD patients compared to 90% of healthy controls (p = 0.02). Of children who did not achieve seroconversion, a subsequent booster dose resulted in an adequate response in 50% (7/14) of IBD patients and 60% (3/5, p = NS) of controls. There were no vaccine-associated adverse events [26]. Moses and colleagues conducted a prospective study of hepatitis B status in their pediatric IBD population on infliximab therapy and documented that 13% had never been immunized against hepatitis B and that approximately half of patients who were previously immunized did not have protective levels of anti-HBs. The investigators then administered a booster vaccine to 34 of these patients without protective titers and noted a 76% response rate. Children and young adults receiving infliximab more frequently (approximately every 5.9 weeks) were less likely to respond to the booster dose of hepatitis B [27]. In the adult IBD literature, Gisbert and colleagues found that therapy with anti-TNF was associated with a suboptimal vaccine response, but not with immunomodulators [28]. In another study, Gisbert et al evaluated two types of hepatitis B vaccination schedules in 148 adult IBD patients with negative hepatitis B antibodies. Seventy percent of the subjects received immunosuppressive therapy (22% thiopurines, 23% anti-TNF, and 25% both). One group (46%) received the standard vaccination protocol (single dose at 0, 1 and 6 months) and other group (54%) received the double dose protocol (double dose at 0, 1 and 2 months). Anti-HBs titers were drawn 1-3 months after the last dose. The double dose group had a higher seroconversion rate (defined as anti-HBs >10 IU/L) compared to the standard dose group (75% vs 41%, p < 0.001) [29].

Studies evaluating the immunogenicity of hepatitis A vaccine suggest that both children and adult IBD patients mount an excellent response (97–100%) after receiving two doses [26, 30, 31]. However, the rate of seroconversion was lower in adult patients on anti-TNF therapy compared to those who were not on anti-TNF therapy (92.4% vs 99.1%, p = 0.001) and in patients treated with ≥ 2 immunosuppressants compared to those on <2 immunosuppressants (92.6% vs 98.4%, p = 0.03). There was no difference in rate of seroconversion between patients on TNF inhibitor monotherapy and those on TNF inhibitor combined with another immunosuppressant [31]. The vaccine was safe and did not exacerbate IBD [26, 30].

The theme of suboptimal immunogenicity associated with TNF inhibitor therapy extends to pneumococcal vaccine as well. Several studies within the adult IBD literature agree that the immune response to 23-valent pneumococcal polysaccharide vaccine (PPSV23) is decreased in patients receiving TNF inhibitor therapy (either as monotherapy or in combination with immunomodulators, 45–63%) compared to patients not receiving immunosuppressive therapy (78–89%) and to healthy controls (85%) [32–34]. Immunomodulator monotherapy was not associated with a hindered immune response (79%). One pediatric study immunized IBD patients aged 5–18 years with no history of pneumococcal immunization with one dose of pneumococcal conjugate vaccine (PCV13). Immunogenicity was similar between IBD patients and healthy controls (90.4% vs 96.5%, p = NS). However, the geometric mean titer was higher in patients who were not on immunosuppressive therapy compared to those who were treated with TNF inhibitors or immunomodulators [35]. The vaccine was well tolerated without serious adverse events [32, 34, 35].

In contrast, the immunogenicity of human papillomavirus vaccine (HPV) does not appear to be diminished by immunosuppressive therapy. Jacobson and colleagues administered three doses of Gardasil to girls and young women aged 9–26 years while being treated with immunomodulator or TNF inhibitor therapy for IBD. All patients developed an excellent immune response with 96–100% seropositivity to HPV types 6, 11, 16, and 18. The geometric mean titers for each serotype were similar to those of healthy historical female controls from Merck. The IBD patients did not experience serious adverse events or worsened disease activity related to the vaccine [36]. Similarly, immunosuppressive therapy does not hinder the immune response to Haemophilus influenzae type b vaccine. A smaller study by Dotan and colleagues concluded that thiopurine monotherapy generally does not impair the cellular or humoral response to the vaccine in adults with IBD [37].

When a child is newly diagnosed with IBD, the ideal time to immunize is before the start of any immunosuppressive therapy. However, as many children with IBD are acutely ill, treatment can often not be withheld. Thus, the clinician is often caught between the “rock and the hard place”: should the patient be immunized and treatment postponed, or should treatment be instituted with plans to immunize at a later time? Making these decisions involves a careful assessment of the risk/benefit ratio and an informed discussion with the parents.