Contribution from the Field
Yellow fever revaccination during infliximab therapy
Yellow fever vaccinations in patients receiving immunosuppressive therapy have been shown to be contraindicated due to the increased risk of viscerotropic disease in nonimmunocompetent patients (1). Biologic therapy such as anti–tumor necrosis factor (anti-TNF) has the capacity to block antibody development postvaccination, which is of concern to clinicians (2). Yellow fever vaccination is important in controlling this disease.
Immunization of the native population and travelers is advisable in countries where this disease is endemic. Yellow fever vaccination uses a live attenuated virus (17-D strain) that induces low-grade viremia in ∼50% of the vaccinated people and elicits neutralizing antibody levels in 99% of all the vaccinated individuals (3, 4).
Recently an outbreak of yellow fever occurred in Brazil and, following a massive advertising campaign by the health authorities in the media, several patients receiving anti-TNFα therapy were vaccinated without previously consulting their doctors. In Brazil, yellow fever vaccination is recommended every 10 years for those living in endemic areas. In view of this outbreak, there was a group of patients who had exceeded the 10-year revaccination period, and they demanded yellow fever vaccination in spite of receiving anti-TNF therapy.
In this study we describe the clinical observations and laboratory findings of 17 rheumatoid arthritis patients receiving infliximab therapy while receiving the yellow fever vaccination and of paired controls.
Subjects and Methods
Serology results pre– and post–yellow fever vaccination were available for 15 patients; 2 patients only had post-YF vaccination results available. The mean disease duration was 6.7 years, and the patients' age range was 26–58 years. Thirteen patients were women and 4 were men. Twelve patients were receiving 15 mg of methotrexate (MTX) weekly, 1 patient was receiving 17.5 mg MTX weekly, and 4 patients were receiving 20.0 mg MTX weekly. The control group consisted of 15 randomly selected healthy individuals; 8 men and 7 women with an age range of 29–51 years.
The patients received the yellow fever vaccination 1 month after the last anti-TNF infusion (a time when the half-life of the medication is known to be decreasing). Fifteen patients had their serum levels checked before and after the vaccination for IgG and IgM antibodies. None of the patients were receiving steroids at the time of revaccination and all were receiving MTX. The anti-TNF infusions in our population ranged from 1–3 years. Infliximab was administered every 2 months (3 mg per kilogram of body weight).
The immunofluorescence assay (biochip technology; Euroimmun) was used to detect antibodies against yellow fever vaccination. The results were reported from negative to positive with multiple dilutions. None of the patients or the controls reported the symptoms of yellow fever or any specific symptom that could be related to the administration of the yellow fever vaccination. The kit (Euroimmune, Anti-Yellow Fever Virus, IIFT) is the first commercial indirect immunofluorescence assay using biochip technology for the detection of IgG and IgM antibodies. In a previous publication comparing its sensitivity and specificity with the gold standard plaque reduction neutralization test, the overall correlation between the tests was 98.7% based on the analysis of 150 sera from vaccines and 150 sera from healthy blood donors (5). The assay used showed a very minor cross reactivity with flaviviruses, most of which are nonexistent in Brazil, with the exception of the dengue virus. The study was approved by the ethics committee of the Universidade de Brasilia.
The number of years after the previous vaccination of the patient population and the respective serology results (expressed in dilution titers) as well as the magnitude of the response before and after the yellow fever vaccination are shown in Tables 1 and 2.
Table 1. Number of years since previous vaccination for patients living in endemic areas and receiving biologic therapy
Table 2. Serologic response before and after yellow fever vaccination*
|Before revaccination|| || || || || |
|After revaccination|| || || || || |
The anamnestic response was similar between patients and controls. Fifteen patients had IgG detected before and after yellow fever vaccination, and 2 patients had neither IgG nor IgM detected. After yellow fever vaccination, 1 patient remained serum negative, and 1 patient was positive for both IgG and IgM. All controls were IgG positive before and after revaccination.
All of the patients and controls (with the exception of 1 in each group) received the initial vaccine after the 10-year revaccination period (range 11–22 years). All but 2 had antibodies after immunization, even after the 10-year period recommended by the local health authorities. None of the patients or the controls reported the symptoms of yellow fever or any specific symptom that could be related to the administration of the yellow fever vaccination. A comparison between the antibody test titers seen in patients and controls showed a trend toward lower response in patients, but due to the small number of patients we did not perform a formal statistical analysis.
Attenuated live virus injections similar to the yellow fever vaccination are not recommended for patients receiving TNF-blocking agents. However, in the endemic areas of Brazil, several patients were being revaccinated without any undesirable reaction. For this study we obtained permission to have patient serum samples collected before and after the yellow fever vaccination and stored (included in the analysis). This was not the case in several patients who notified their physicians after receiving the yellow fever vaccination (data not shown). This latter group of patients prompted our interest in studying in more detail the effects of revaccination in this patient population. It appears that patients vaccinated after long periods still display neutralizing immunity, which may explain the lack of adverse reactions. We have no information on the titers that will be protective with the assay used in our study, but based on our results and clinical evidence it appears that 1:100 seems to confer protection from viremia after administration of the yellow fever vaccination. As mentioned previously, the study by Niedrig et al showed that the plaque assay displayed a very high concordance with the assay used in our study (5). Further refined assays, such as reverse transcriptase polymerase chain reaction, were described by Neidrig et al and should be used in future investigations (5).
Our study results differ from those reported in influenza studies, where some authors described the negative influence of the combination of MTX and TNF-blocking agents on the development of an efficacious immune response; other authors saw no difference in the magnitude of the response (2, 6–8). We cannot determine whether the single patient in our study who failed seroconversion experienced vaccine failure during infliximab therapy unless a larger field study that investigates this specific question is performed.
Conversely, the studies by Amanna et al showed that several vaccines with replicating and nonreplicating antigens induced very stable responses of long-lived immunity (≥26 years) in a group of healthy control subjects (9, 10). The yellow fever vaccination was not included in the studies by Amanna et al. However, a study by Gaucher et al showed that the yellow fever vaccination induces a broad polyfunctional integrated humoral and cellular immune response (11). These findings may explain some of our results where the presence of a persistent immune response after prime vaccination led to the absence of significant adverse events and the development of a humoral immune response in the majority of the patients (10–12).
Patients living in endemic areas should be tested for immunity before revaccination. In our study, however, the 17-D strain vaccine appears to confer protective immunity for long periods of time (>10 years) and is associated with the lack of adverse reactions in patients taking infliximab therapy. Our study indicates that patients receiving anti-TNF therapy mount an adequate humoral response when revaccinated with a live attenuated vaccine like the yellow fever vaccination. Although we did not observe untoward effects of the vaccine in our cohort, further studies with larger numbers of patients are needed to establish the risk of revaccination in this setting. Studies using historic data and other techniques for antibody detection should strengthen the current findings. The data, although derived from a rather small number of patients, support the use of infliximab therapy and the yellow fever revaccination. Finally, our findings should not be extrapolated to travelers who receive a first de novo immunization while receiving infliximab or any other biologic therapy.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Scheinberg had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Scheinberg, Guedes-Barbosa, Mota, Oliveira, Lima.
Acquisition of data. Guedes-Barbosa, Mangueira, Rosseto, Mota, Oliveira, Lima.
Analysis and interpretation of data. Scheinberg, Guedes-Barbosa, Mangueira, Rosseto, Mota, Oliveira, Lima.