The epidemiology of infectious diseases has changed dramatically in the last century. Thanks to vaccination, many diseases that were the leading causes of childhood death have been almost eradicated in developed countries. However, this trend has stalled over the past 10 years. A good example is diphtheria, the incidence of which rapidly declined after large-scale vaccine introduction and has increased again in the last few years. Seven thousand three hundred twenty-one confirmed cases worldwide were officially reported to the World Health Organization in 2014.1 There are several reasons for diphtheria outbreaks in developed countries: decreased immunization rates due to anti-vaccination movements, decreased immunity in people who have not received a booster doses, migration from regions of high diphtheria incidence and no vaccination.
Patients with autoimmune diseases, including inflammatory bowel diseases (IBD), are at increased risk of any infections, mainly due to immunosuppressive treatment. Inactivated vaccines may induce a weaker immune response in these patients, whereas live vaccines are contraindicated during immunosuppressive therapy. Therefore, evaluation of the vaccine response in patients with IBD is very important and fully supported by international associations focusing on autoimmune disorders.2
We designed this study to evaluate the immune response of booster diphtheria vaccine in adolescents with IBD.
MATERIALS AND METHODS
This was an open, multicenter and prospective study (NCT03998215). We enrolled patients 11–17 years of age with Crohn’s disease (CD) and ulcerative colitis. Disease activity was assessed on the basis of the Pediatric Crohn’s Disease Activity Index for CD and the Pediatric Ulcerative Colitis Activity Index for ulcerative colitis. Values <10 points were considered as remission.
The immunosuppressive therapy was defined as treatment with 6-mercaptopurine, azathioprine, methotrexate, cyclosporine or biologics for at least 2 months or high-dose corticosteroids (≥20 mg/day or ≥2 mg/kg/day of prednisone or equivalent) for at least 2 weeks.
All children, as a part of the basic vaccination course, had been previously vaccinated with 5 doses of diphtheria, tetanus and whole-cell pertussis vaccine (DTwP), but they did not receive a booster dose after 6 years of age.
Participants received 1 dose of the trivalent vaccine against diphtheria, tetanus and acellular pertussis intramuscularly in the deltoid muscle (Boostrix, GlaxoSmithKline Biologicals, Rixensart, Belgium, Tdap vaccine).
Blood samples were collected at baseline and 4–8 weeks postvaccination. The anti-diphtheria toxoid IgG antibody levels were determined by a standard ELISA kit (Euroimmun AG, Lübeck, Germany).
The primary endpoint of the study was to achieve seroprotective antibody concentration after booster vaccination. According to the World Health Organization and the manufacturer’s test recommendations, 2 cutoff points were used.3 Antibody concentrations ≥0.1 IU/mL indicated protection against diphtheria, while levels ≥1.0 IU/mL were considered to ensure long-term protection. The secondary endpoints included a booster response to vaccination and adverse effects or IBD exacerbation occurrence. Booster response was defined as a postvaccination antibody concentration ≥0.4 IU/mL in initially seronegative subjects or as a 4-fold increase of antibody concentration in initially seropositive subjects.4 All endpoints were assessed 4–8 weeks postvaccination.
To assess the potential effect of immunosuppressive therapy, analyses were performed on 2 subgroups, on and without immunosuppression treatment. To determine the statistical significance of sex and disease type, the χ2 test was used. In the case of long-term protection and comparing other percentage values, the χ2 test with Yates correction for continuity was used. For the other parameters in which the medians were compared, the Mann-Whitney U test was used. A P-value < 0.05 was considered statistically significant.
This study was approved by the Clinical Research Ethics Committee of the Medical University of Warsaw, Poland (number 188/2012). All parents and patients ≥16 years old signed an informed consent form.
We enrolled 46 patients with IBD, 61% (n = 28) of them had CD, 59% were males and the median age was 15.8 years. At the time of enrollment, 32 (69.6%) patients were on immunosuppressive therapy, of whom 3 were additionally treated with infliximab and none with systemic corticosteroids. There were no differences in sex, age, body weight and disease type between the 2 study groups (detailed data available in Table, Supplemental Digital Content 1, http://links.lww.com/INF/D715). The severity of the disease was lower in patients with CD on immunosuppressive therapy compared with those without it (Pediatric Crohn’s Disease Activity Index 5 points versus 15 points, respectively, P < 0.05). Diphtheria booster vaccine has induced both protection (93.5%) and long-term protection (56.5%) against the disease in patients with IBD, booster response was obtained in 56.5% of them (Fig. 1). There were no statistically significant differences in seroprotection rates (93.8% vs. 92.9%; P = 0.59) and booster response (56.3% vs. 57.1%; P = 0.79) between the groups with and without immunosuppression (detailed data available in Table, Supplemental Digital Content 2, http://links.lww.com/INF/D716).
Only 6 patients had any adverse reactions; 5 reported local symptoms such as pain and sensitivity at the injection site (n = 5) or redness (n = 1). One patient had low fever, and 1 had difficulty falling asleep/sleep disturbances. There were no cases of exacerbation of IBD during the study.
In this study, booster vaccination against diphtheria provided an excellent immune response in adolescents with IBD irrespective of therapy type.
There are no data concerning the immune response of diphtheria in patients with IBD. Therefore, our results can only be compared with the single study that assessed the serologic status of the diphtheria vaccine in this group of patients. deBruyn et al, in their Canadian study, evaluated 156 children with IBD and found overall serologic protection against diphtheria in 79.5% of children and in 85.1% of those who received the complete vaccine series.5 These rates are slightly lower than we found. However, there are significant differences between these studies that make a simple comparison difficult: different study design (interventional vs. epidemiologic study), different interval between vaccination and measurement of antibody concentration, and different types of vaccine used (some older of deBruyn patients received vaccination with reduced antigen diphtheria content, known as “dTap”).
Our results can also be compared with those obtained in patients with autoimmune diseases other than IBD. In a retrospective cohort of young patients with juvenile arthritis, the seroprotective rate against diphtheria was 90.5%.6 In adults with various rheumatic diseases, the immunogenicity of the booster diphtheria vaccine after 4 and 12 weeks was 78% and 73%, respectively.7 Despite many methodologic differences between all these studies, we can conclude that the overall seroprotection rate, defined as ≥ 0.1 IU/mL, was high.
We did not find a difference in diphtheria booster vaccination seroprotection rates between patients receiving and not receiving immunosuppressive therapy. The results of studies assessing the immunogenicity of vaccines, other than diphtheria vaccines, in patients with IBD are divergent. In some studies, similar to ours, no association between immunosuppressive treatment and postvaccination response rate was observed.8,9 However, most studies found lowered response rates in patients treated with immunosuppressive therapy, especially anti-TNF alpha agents.10
Our study showed that only 70% of children with IBD had the protective concentration of diphtheria antibodies before the booster dose, and <9% had the concentration considered to ensure long-term protection. Similar findings were obtained by Zasada et al.11 They showed that 36.9% of the healthy Polish population <18 years of age had no protective antibody concentration and that only 7.2% had the concentration considered to ensure long-term protection. Similarly, though slightly better, the proportion of seronegative individuals is rising, based on data from other Eastern European countries.12 It seems that, in all of Europe, the number of people with insufficient diphtheria status has been increasing, which may potentially lead to epidemics.
We can also compare our results with healthy children. Data from the Zepp et al study served us as a reference point.4 In this German study, 179 healthy children who had the same vaccination status as in our study—5 doses of diphtheria vaccine before the age of 6—were evaluated. Antibody concentration ≥1.0 IU/mL was found in 93%–99% of children and the booster response was observed in 77%–87% of them. Higher immune response rates in German children may be a result of younger age of study participants (mean age 11 years) and/or the use of another type of vaccine for primary vaccination. In the Zepp study, all children were vaccinated with 5 doses of diphtheria, tetanus and acellular pertussis vaccine, while in Poland, until 2008, only the DTwP vaccine was used. Some publications show comparable immunogenicity of both diphtheria vaccines, but there is also evidence of lower immunogenicity of DTwP vaccine against all antigens.11
Diphtheria vaccine seems to be very safe. We did not note any serious adverse events and flares of IBD during the study course. These results add new data to the growing evidence that inactive vaccines are very safe for patients treated with immunosuppressive therapy.
Our study is the first and thus far the only 1 that has evaluated the immunogenicity of the diphtheria booster vaccine in IBD patients. A shortcoming of the present study is a relatively small study group and a lack of controls.
1. Centers for Disease Control and Prevention information on diphtheria
. Available at: https://www.cdc.gov/diphtheria/about/index.html
. Accessed June 09, 2019.
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3. World Health Organization. Diphtheria
vaccine. Review of evidence on vaccine effectiveness and immunogenicity to assess the duration of protection ≥10 years after the last booster dose. Available at: https://www.who.int/immunization/sage/meetings/2017/april/2_Review_Diphtheria_results_April2017_final_clean.pdf
. Accessed June 09, 2019.
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