Varicella-zoster-virus vaccination in immunosuppressed children with rheumatic diseases using a pre-vaccination check list

A prospective single-center study was conducted at the German Center for Pediatric and Adolescent Rheumatology, Garmisch-Partenkirchen (ISRCRTN: 21654693, retrospectively registered). The study was approved by the Institutional Board of Ethics in Medical Research of the Bavarian Chamber of Physicians. Written informed consent was obtained from all parents and the patients. Within the inclusion period from April 2012 to Mai 2013, 2802 patients between the ages of 2 to 17 years were screened by reviewing their immunization records, a questionnaire asking about prior chickenpox or herpes zoster and, in case of absence of chickenpox, herpes zoster and vaccination, by VZV-IgG screening. Inclusion criteria for the intervention part of the study were: (1) negative medical history for chickenpox and herpes zoster, (2) ≤ 1 prior dose of the VZV vaccine, (3) in case of first VZV vaccination, laboratory evidence of susceptibility for chickenpox defined as VZV-IgG either classified as negative (<160 mIU/ml) or equivocal (160-200 mIU/ml) (test system: VZV-IgG-ELISA (medac GmbH, Wedel) calibrated based on WHO reference preparation allowing quantitative measurements), (4) diagnosis of an inflammatory PRD, (5) clinically inactive disease as defined by the American College of Rheumatology (ACR) criteria in case of JIA [18] or a physician’s global score of <1 in case of other PRDs, and (6) no change of IS for at least 3 months prior to the vaccination. Exclusion criteria were as follows: (1) acute febrile disease, (2) current clinical or laboratory evidence for lack of immunologic reactivity (see pre-vaccination checklist below), (3) known hypersensitivity to constituents of the varicella vaccine, (4) measles, mumps, rubella (MMR) vaccination within 4 weeks prior to VZV vaccination, (5) treatment with IS other than those mentioned in the pre-vaccination checklist, i.v. glucocorticoid pulse therapy or a prednisone-equivalent dose of ≥2mg/kg/day or ≥20mg/day for > 2 weeks within less than 4 weeks prior to vaccination, cyclophosphamide pulse <6 months ago, rituximab without B-cell reconstitution, intravenous immune globulins (IVIG) <6 months ago (high-dose IVIG (2g/kg) <11 months), therapy with aspirin until 6 week post-vaccination or vi) any blood products <3 months prior to vaccination.

After consultation with the German Standing Committee on Vaccination (STIKO), we graded the intensity of the IS by applying laboratory testing to determine the current immunologic reactivity that should allow control of the OKA vaccine strain. Definitions regarding the level of IS were based on available recommendations [17, 19]. Medications for which no previous grading or sufficient experience regarding live virus vaccination existed, such as biologic DMARDs, mycophenolate mofetil and mechanistic Target of Rapamycin (mTOR) inhibitors, e.g. sirolimus and everolimus, were considered to represent HIIS.

A checklist was developed, consisting of items regarding medical history, physical examination, contraindications, grading the level of IS and basic laboratory examinations for all patients (Table 1). Basic laboratory testing included white blood cells (WBC) and lymphocyte count, serum IgG and IgM levels and tetanus toxoid antibody level. Cut-off levels were WBC ≥3000/mm³, lymphocytes ≥1200/mm³, serum IgG ≥500 mg/dl, IgM ≥20 mg/dl, tetanus toxoid antibody ≥0.1 IU/ml [20]. If tetanus antibody-level was <0.1 IU/ml, tetanus (booster) vaccination was administered and antibody testing repeated 4 weeks later. Additional (extended) laboratory examinations were pursued for patients receiving HIIS or patients on LIIS with abnormal basic laboratory test results and included the following parameters and cut-off levels: normal CD4+ T cell count (cut-off ≥200/mm³ if age >5 years or ≥500/mm³ if age 2-5 years) and a positive T cell function test (CMI). As an easy-to-obtain T cell function test we used a commercial interferon-gamma release assay (IGRA), the TB-EliSpot® test, which contains a mitogen as positive control (phytohemagglutinin). Patients exceeding the respective cut-off levels had adequate immunologic reactivity for the purpose of this study and VZV vaccination was offered.

Patients stratified to fullfill the pre-vaccination criteria, also met the immunological precautions requested by the manufacturer of Varilrix® (Glaxo-Smith-Kline) for the in-label application of the VZV vaccine on IS (absolute lymphocyte count >1200/mm³ and/or adequate CMI). Varilrix® contains the live attenuated Oka strain at a concentration of at least 10^3.3 plaque-forming units per 0.5ml. Participants received a standard dose of the vaccine 0.5ml subcutaneously. A second dose was given at an interval of at least 6 weeks on LIIS and 3 months on HIIS [19]. Patients, parents and the primary care pediatrician received a written instruction to initiate treatment with acyclovir in case of VZV disease with >50 skin lesions or a rash lasting >7 days and to contact their pediatric rheumatologist to decide on A reduction of the IS.

Patients/parents and pediatricians completed a separate questionnaire between 4-12 weeks following vaccination asking for vaccination-associated side effects or signs for flare of the PRD. If any sign of side effect was present, further details were obtained by telephone interview.

VZV-IgG response was measured using a blood sample drawn between 4 to 12 weeks after vaccination. Furthermore, patients were interviewed after a longer interval (median 3 years) to determine if post-vaccination contact to VZV and/or breakthrough chickenpox or HZ had occurred.

Statistical analysis was performed using GraphPad Prism 6 (GraphPad Software, La Jolla, CA, USA) and Microsoft Excel 2010 (Microsoft, Redmond, WA, USA). Demographic and baseline laboratory characteristics were described using medians and range. Differences between patients receiving LIIS and those receiving HIIS were estimated with the chi-squared test for proportions and with the Mann-Whitney test for interval variables.

Within a period of 13 months 2802 patients with PRD were screened for their VZV-susceptibility by a questionnaire. Sixty patients (2.1%) reported a history of chickenpox while 2580 patients (92.1%) had received two doses of the VZV vaccine as recommended in Germany by the STIKO. Of the remaining 162 patients (5,8%) potentially susceptible for VZV, 116 had clinically active PRD and 46 had clinically inactive disease. Of 46 patients with clinically inactive disease, 11 refused further study participation. Of the 35 potentially VZV susceptible patients willing to further participate in the study, 12 had a VZV-IgG >200 IU/ml indicating prior contact to VZV. Additionally, we observed titers classified as negative (<160 mIU/ml) in 4 out of 9 patients that had received a single VZV vaccination prior to the study (median 230 mIU/ml, range 57-1003 mIU/ml). Twenty-three patients entered the interventional part of this study (Fig. 1).

Demographic data, disease type, current treatments and baseline laboratory test results of the patients vaccinated in the study are shown in Table 2. One patient had a low tetanus toxoid antibody level and received a successful tetanus booster-vaccination. All other parameters were above the predefined thresholds in all patients.

Nine patients who had previously received one dose of the VZV vaccine received a second dose in the context of this study (2 in the LIIS group, 7 in the HIIS group). Of the 15 patients naïve for VZV, six only received one vaccination (3 in the LIIS group, 3 in the HIIS group) while nine received two (4 in the LIIS group, 5 in the HIIS group). Among the six patients who received only one vaccination, one patient refused a second vaccination, and five patients (and their local pediatricians) deferred a second vaccination due to an increase in VZV-IgG-level after just one vaccination. We suggested to repeat VZV-IgG level measurements in these instances and to offer the booster vaccine in case of a negative or borderline VZV-IgG level.

Among patients who had received a single dose of the VZV vaccine before start of IS, the VZV-IgG baseline levels were 230 (57-1003) mIU/ml (median (range)). Figure 2 shows post-vaccination titers. Following the first VZV vaccination within this study, the median VZV-IgG level across all patients was 224 (59-1219) mIU/ml (LIIS subgroup 203 (159-707) mIU/ml, HIIS subgroup 430 (59-1219) mIU/ml). After the second vaccination, VZV-IgG levels increased to 882 (30-4685) mIU/ml (LIIS group 1035 (627-2671) mIU/ml, HIIS group 684 (30-4685) mIU/mL). The difference in the VZV-IgG levels between the LIIS and the HIIS groups was not significant (Mann-Whitney test p=0.67 after first vaccination, p=0.26 after second vaccination). Similarly, the absolute (Δ) and the relative (fold-) increase in VZV-IgG after first to after second vaccination (LIIS Δ796 mIU/ml and 4.9-fold, HIIS Δ393 mIU/ml and 3.5-fold, respectively) were not significantly different between these groups (Mann-Whitney test p=0.26 and p=0.49, respectively). Among participants only receiving a booster vaccination, all achieved VZV-IgG levels >500 mIU/ml, i.e. 1117 (513-4685) mIU/ml. Two participants in the HIIS group did not achieve an increase in VZV-IgG >200 mIU/ml despite two vaccinations. Patient 1 (on MMF monotherapy) and patient 2 (on leflunomide and abatacept therapy) both had VZV-IgG ELISA values in the negative range of the assays.

The VZV vaccinations were generally well tolerated. There were only minor adverse events, Table 3. There were no cases of rash or other vaccine-induced varicella disease symptoms and no evidence of PRD flare following vaccination.

After a median follow-up of three years, no patient had suffered from breakthrough chickenpox or from HZ. A known exposure to VZV was documented in three cases (one to herpes zoster and two to chickenpox).