Yellow Fever Vaccination Raises Multiple Sclerosis Relapse Rate

Patients with relapsing-remitting multiple sclerosis had a more than 10-fold increase in their relapse rate after they received vaccination against yellow fever, according to a small prospective study.

Although relapsing-remitting MS and yellow fever (YF) vaccination do not overlap often, "depending on specific patient travel plans, potential local epidemics, and length of stay, the final decision on whether to administer the vaccine should result from a careful balance between the risk of MS exacerbation and the likelihood of exposure to the YF virus, which can lead to death," Dr. Jorge Correale, one of the authors of the study, wrote in an e-mail (Arch. Neurol. 2011 June 13 [doi: 10.1001/archneurol.2011.131]).

Dr. Correale added that most other vaccines do not increase the risk of new exacerbations in MS patients (J. Neurol. 2011;258:1197-206).

"However, in contrast to other vaccines, YF vaccine is prepared with live attenuated virus, and probably for other vaccines prepared in the same way we need to consider this possibility," wrote Dr. Correale and his coauthor, Dr. Mauricio F. Farez. Both work in the department of neurology at the Dr. Raúl Carrea Institute for Neurological Research, Buenos Aires.

YF is a potentially deadly disease found in tropical regions of Africa and in parts of South America. It affects approximately 200,000 people each year and leads to 30,000 deaths annually. Although there are no treatments for the disease, the YF 17D-204 vaccine has been proven a safe and effective preventive measure.

Observations of two patients who presented with worsened MS after YF immunization prompted the authors to conduct the study. There is very little data available on the overlap of YF vaccination and MS. 

The authors recruited seven patients – five women and two men with an average age of 45 years – with relapsing-remitting MS who received a single dose of YF 17D-204 before traveling. After vaccination, the patients underwent clinical, radiological, and immunological evaluations every 3 months for 2 years. The investigators asked the patients to return for examination within 72 hours if they had a relapse. 

To serve as control subjects, the investigators recruited seven unvaccinated patients with MS of the same age and sex; seven patients with MS of the same age and sex who had received influenza vaccinations; and seven healthy individuals of the same age and sex.

They defined an MS exacerbation as the development of a new symptom or worsening of preexisting symptoms lasting at least 48 hours and preceded by stability or improvement lasting at least 30 days. They considered patients to be at risk between 1 to 5 weeks after immunization.

During the at-risk period, five of the seven patients who received YF 17D-204 had exacerbations. Four of those five patients had a significant and persistent increase in their Expanded Disability Status Scale score 1 year after the exacerbation, according to the study. Exacerbations were transient in the other 3 patients.

The annual exacerbation rate in the at-risk period was significantly higher than during the non-risk period (8.57 vs. 0.67, respectively). During 2 years of follow-up, the overall annual exacerbation rate was 0.99. In contrast, immunization against influenza did not affect the annual exacerbation rate. 

MRI showed a significantly higher mean number of new or enlarging T2 lesions at 3 months after YF vaccination, compared with the remaining follow-up period (2.6 vs. 0.1), as well as significantly more gadolinium-enhancing lesions (2.14 vs. 0).

The number of myelin basic protein- and myelin oligodendrocyte glycoprotein-peptide-specific cells that secreted the proinflammatory cytokines and chemokines IL-1alpha, IL-1beta, IFN-gamma, TNF, and IP-10 were significantly higher in samples collected from YF vaccinated patients with MS, compared with unvaccinated patients with MS, influenza-vaccinated patients with MS, or controls. The numbers of these cells reached maximum levels between 2 and 5 weeks after vaccination.

The study’s limitations were the small number of patients and its unblinded design for clinical and radiological assessments. 

The authors added that it is not clear how YF immunization can trigger autoimmune reactions. They proposed molecular mimicry, epitope spreading, bystander activation, and polyclonal activation as possible mechanisms.

"Whether the more than 10-fold increase in the relapse rate observed in these seven patients can be confirmed by larger studies remains to be seen," the authors wrote.

Dr. Correale is a board member of Merck Serono Argentina, Biogen Idec LATAM, and Merck Serono LATAM. He has received reimbursement to develop educational presentations for Merck Serono Argentina, Merck Serono LATAM, Biogen Idec Argentina, and Teva-Tuteur Argentina.

The study was supported by a research grant from his institution.

Patients with relapsing-remitting multiple sclerosis had a more than 10-fold increase in their relapse rate after they received vaccination against yellow fever, according to a small prospective study.

Although relapsing-remitting MS and yellow fever (YF) vaccination do not overlap often, "depending on specific patient travel plans, potential local epidemics, and length of stay, the final decision on whether to administer the vaccine should result from a careful balance between the risk of MS exacerbation and the likelihood of exposure to the YF virus, which can lead to death," Dr. Jorge Correale, one of the authors of the study, wrote in an e-mail (Arch. Neurol. 2011 June 13 [doi: 10.1001/archneurol.2011.131]).

Dr. Correale added that most other vaccines do not increase the risk of new exacerbations in MS patients (J. Neurol. 2011;258:1197-206).

"However, in contrast to other vaccines, YF vaccine is prepared with live attenuated virus, and probably for other vaccines prepared in the same way we need to consider this possibility," wrote Dr. Correale and his coauthor, Dr. Mauricio F. Farez. Both work in the department of neurology at the Dr. Raúl Carrea Institute for Neurological Research, Buenos Aires.

YF is a potentially deadly disease found in tropical regions of Africa and in parts of South America. It affects approximately 200,000 people each year and leads to 30,000 deaths annually. Although there are no treatments for the disease, the YF 17D-204 vaccine has been proven a safe and effective preventive measure.

Observations of two patients who presented with worsened MS after YF immunization prompted the authors to conduct the study. There is very little data available on the overlap of YF vaccination and MS. 

The authors recruited seven patients – five women and two men with an average age of 45 years – with relapsing-remitting MS who received a single dose of YF 17D-204 before traveling. After vaccination, the patients underwent clinical, radiological, and immunological evaluations every 3 months for 2 years. The investigators asked the patients to return for examination within 72 hours if they had a relapse. 

To serve as control subjects, the investigators recruited seven unvaccinated patients with MS of the same age and sex; seven patients with MS of the same age and sex who had received influenza vaccinations; and seven healthy individuals of the same age and sex.

They defined an MS exacerbation as the development of a new symptom or worsening of preexisting symptoms lasting at least 48 hours and preceded by stability or improvement lasting at least 30 days. They considered patients to be at risk between 1 to 5 weeks after immunization.

During the at-risk period, five of the seven patients who received YF 17D-204 had exacerbations. Four of those five patients had a significant and persistent increase in their Expanded Disability Status Scale score 1 year after the exacerbation, according to the study. Exacerbations were transient in the other 3 patients.

The annual exacerbation rate in the at-risk period was significantly higher than during the non-risk period (8.57 vs. 0.67, respectively). During 2 years of follow-up, the overall annual exacerbation rate was 0.99. In contrast, immunization against influenza did not affect the annual exacerbation rate. 

MRI showed a significantly higher mean number of new or enlarging T2 lesions at 3 months after YF vaccination, compared with the remaining follow-up period (2.6 vs. 0.1), as well as significantly more gadolinium-enhancing lesions (2.14 vs. 0).

The number of myelin basic protein- and myelin oligodendrocyte glycoprotein-peptide-specific cells that secreted the proinflammatory cytokines and chemokines IL-1alpha, IL-1beta, IFN-gamma, TNF, and IP-10 were significantly higher in samples collected from YF vaccinated patients with MS, compared with unvaccinated patients with MS, influenza-vaccinated patients with MS, or controls. The numbers of these cells reached maximum levels between 2 and 5 weeks after vaccination.

The study’s limitations were the small number of patients and its unblinded design for clinical and radiological assessments. 

The authors added that it is not clear how YF immunization can trigger autoimmune reactions. They proposed molecular mimicry, epitope spreading, bystander activation, and polyclonal activation as possible mechanisms.

"Whether the more than 10-fold increase in the relapse rate observed in these seven patients can be confirmed by larger studies remains to be seen," the authors wrote.

Dr. Correale is a board member of Merck Serono Argentina, Biogen Idec LATAM, and Merck Serono LATAM. He has received reimbursement to develop educational presentations for Merck Serono Argentina, Merck Serono LATAM, Biogen Idec Argentina, and Teva-Tuteur Argentina.

The study was supported by a research grant from his institution.

Patients with relapsing-remitting multiple sclerosis had a more than 10-fold increase in their relapse rate after they received vaccination against yellow fever, according to a small prospective study.

Although relapsing-remitting MS and yellow fever (YF) vaccination do not overlap often, "depending on specific patient travel plans, potential local epidemics, and length of stay, the final decision on whether to administer the vaccine should result from a careful balance between the risk of MS exacerbation and the likelihood of exposure to the YF virus, which can lead to death," Dr. Jorge Correale, one of the authors of the study, wrote in an e-mail (Arch. Neurol. 2011 June 13 [doi: 10.1001/archneurol.2011.131]).

Dr. Correale added that most other vaccines do not increase the risk of new exacerbations in MS patients (J. Neurol. 2011;258:1197-206).

"However, in contrast to other vaccines, YF vaccine is prepared with live attenuated virus, and probably for other vaccines prepared in the same way we need to consider this possibility," wrote Dr. Correale and his coauthor, Dr. Mauricio F. Farez. Both work in the department of neurology at the Dr. Raúl Carrea Institute for Neurological Research, Buenos Aires.

YF is a potentially deadly disease found in tropical regions of Africa and in parts of South America. It affects approximately 200,000 people each year and leads to 30,000 deaths annually. Although there are no treatments for the disease, the YF 17D-204 vaccine has been proven a safe and effective preventive measure.

Observations of two patients who presented with worsened MS after YF immunization prompted the authors to conduct the study. There is very little data available on the overlap of YF vaccination and MS. 

The authors recruited seven patients – five women and two men with an average age of 45 years – with relapsing-remitting MS who received a single dose of YF 17D-204 before traveling. After vaccination, the patients underwent clinical, radiological, and immunological evaluations every 3 months for 2 years. The investigators asked the patients to return for examination within 72 hours if they had a relapse. 

To serve as control subjects, the investigators recruited seven unvaccinated patients with MS of the same age and sex; seven patients with MS of the same age and sex who had received influenza vaccinations; and seven healthy individuals of the same age and sex.

They defined an MS exacerbation as the development of a new symptom or worsening of preexisting symptoms lasting at least 48 hours and preceded by stability or improvement lasting at least 30 days. They considered patients to be at risk between 1 to 5 weeks after immunization.

During the at-risk period, five of the seven patients who received YF 17D-204 had exacerbations. Four of those five patients had a significant and persistent increase in their Expanded Disability Status Scale score 1 year after the exacerbation, according to the study. Exacerbations were transient in the other 3 patients.

The annual exacerbation rate in the at-risk period was significantly higher than during the non-risk period (8.57 vs. 0.67, respectively). During 2 years of follow-up, the overall annual exacerbation rate was 0.99. In contrast, immunization against influenza did not affect the annual exacerbation rate. 

MRI showed a significantly higher mean number of new or enlarging T2 lesions at 3 months after YF vaccination, compared with the remaining follow-up period (2.6 vs. 0.1), as well as significantly more gadolinium-enhancing lesions (2.14 vs. 0).

The number of myelin basic protein- and myelin oligodendrocyte glycoprotein-peptide-specific cells that secreted the proinflammatory cytokines and chemokines IL-1alpha, IL-1beta, IFN-gamma, TNF, and IP-10 were significantly higher in samples collected from YF vaccinated patients with MS, compared with unvaccinated patients with MS, influenza-vaccinated patients with MS, or controls. The numbers of these cells reached maximum levels between 2 and 5 weeks after vaccination.

The study’s limitations were the small number of patients and its unblinded design for clinical and radiological assessments. 

The authors added that it is not clear how YF immunization can trigger autoimmune reactions. They proposed molecular mimicry, epitope spreading, bystander activation, and polyclonal activation as possible mechanisms.

"Whether the more than 10-fold increase in the relapse rate observed in these seven patients can be confirmed by larger studies remains to be seen," the authors wrote.

Dr. Correale is a board member of Merck Serono Argentina, Biogen Idec LATAM, and Merck Serono LATAM. He has received reimbursement to develop educational presentations for Merck Serono Argentina, Merck Serono LATAM, Biogen Idec Argentina, and Teva-Tuteur Argentina.

The study was supported by a research grant from his institution.