Case Study
Dear Gavin
I booked to go on holiday to a country in Africa with a high incidence of yellow fever. When I went to get my travel vaccinations, I was told, in no uncertain terms, that I should abandon my trip since it was highly likely that the yellow fever vaccine I had in 2005 would no longer be active since I am on immunosuppressant drug for MS.
A large part of my life has been travelling, quite often as an ambassador of a global charity. I am despondent that I will no longer be able to revisit some of the projects I have sponsored in Africa and South America.
To make matters worse, since the yellow fever vaccine is live, I was warned not to have it, so I will no longer be able to visit any country with yellow fever.
As an aside, my travel insurance would not give me the money back for the trip to Africa since a clause states that it will not cover people who do not have the relevant vaccines.
I should have been made aware of this issue before starting ocrelizumab (Ocrevus) and, more recently, ofatumumab (Kesimpta); at least, I would have been able to choose to have the yellow fever vaccine and visit the countries before starting the DMT.
I indeed wasn’t forewarned this would be a problem - possibly it was in the small print?
I welcome your view on this matter.
With kindest regards,
Person J with MS
Prof G’s response
Dear J
To the best of my knowledge yellow fever vaccine is not mandatory to visit Kenya. You can get a letter from your GP saying you can't have it. As you know, yellow fever is transmitted by mosquitos and tends to occur in the rainy season (Jan-April). So if you take precautions and avoid being bitten, the risk is low. Yellow fever is transmitted by the Aedes aegypti mosquito, which tends to be a daytime biter (early morning and late afternoon). So if you go, make sure you use insect repellant.
Yes, you should have been told about vaccines before starting therapy.
With best wishes,
Gavin
Person J with MS reply
Hi Gavin,
Thank you for your prompt reply.
Whilst the yellow fever vaccine isn’t mandatory, the doctor at the travel clinic was adamant that I shouldn’t go to any countries with yellow fever as all it would take is that one mosquito bite to have possibly fatal consequences.
I was going in March to celebrate a family member’s birthday; from what you’ve indicated, the risk would be higher as it falls in the rainy season.
In the future, neurologists should advise their patients of this downside to being on immunosuppressants. Imagine the consequences, for example, of people with friends or family in a country with yellow fever - I don’t think I’m being over dramatic when I say they could now be putting their health/life at serious risk every time they visit.
Thanks for listening.
Best wishes,
Person J with MS
Prof G’s opinion
It is clear that vaccines, particularly travel vaccines, are a big issue with chronic immunosuppressive therapies. This is one of the reasons why it is prominent on my list of derisking strategies when discussing starting or switching DMTs. I have discussed vaccines many times on MS-Selfie, and it is one of the reasons why I am a big proponent of immune reconstitution therapies (alemtuzumab, cladribine and AHSCT) because once your immune system reconstitutes vaccines and live vaccines are possible. Have you thought about moving onto a therapy that will allow you to have vaccines in the future?
Please read the following case study that explains why cladribine may have been a better option for this patient than an anti-CD20 therapy (ocrelizumab or ofatumumab).
Yellow Fever
Yellow fever is a potentially severe viral infection of short duration. Symptoms include fever, chills, loss of appetite, nausea, myalgias (muscle pains) and headaches. Symptoms typically improve within 4-6 days. In ~15% of patients, within a day of improving, the fever reoccurs in association with abdominal pain due to hepatitis (liver inflammation) and results in jaundice or yellow skin colour. Liver failure may affect clotting factor production with a resulting risk of bleeding, and it also may affect renal function with possible kidney problems.
Yellow fever is caused by the yellow fever virus, which an infected mosquito spreads. Yellow fever infects humans, other primates and several types of mosquitoes. In cities, it is spread primarily by the Aedes aegypti mosquito, which is found throughout the tropics and subtropics. The yellow fever virus is an RNA Flavivirus.
Although a relatively safe and effective vaccine against yellow fever exists, it has been known to trigger CNS demyelinating events. Many countries require vaccinations for travellers, but this is not compulsory. You can usually get a doctor’s letter giving you an exception, but then you have to take your chances of getting yellow fever. Please note the management of yellow fever is symptomatic; no specific measures are effective against the virus, and death occurs in up to half of those who get severe disease, i.e. hepatitis.
For this patient, all may not be lost. Recent evidence shows that one vaccine dose may generate long-lasting immunity (see paper 3 below). I would suggest this patient checks to see if she has immunity to the virus, and if yes, her risk of getting yellow fever, particularly severe yellow fever, will be very low.
Hopefully, in the future, we will be able to give these kinds of patients passive immunity using a monoclonal antibody infusion against the virus with a very long half-life. The latter technology has come of age during COVID-19, and I know many Pharma companies that are developing monoclonal antibodies to different viruses to protect vulnerable patients from infection. As expected, I am trying to nudge some of these companies to develop monoclonal antibodies against EBV in the hope we can use the antibodies as a treatment for MS.
Does the yellow fever vaccine trigger MS relapses?
A small Argentinian study reported that yellow fever immunisation increased the subsequent risk of MS relapse (see paper below). However, this finding was not reproduced in a more extensive French study. Therefore, I don’t think we can claim that the yellow fever vaccine has been shown to trigger MS relapses.
Other vaccines
Whilst we are on the issue of vaccines, please be aware that the focus should not only be on travel vaccines. We screen for varicella zoster and MMR immunity in all of our patients about to start immunosuppressive therapy, and if seronegative, we offer them these vaccines. I am also increasingly offering my patients the option of having or upgrading their HPV immunity as well. Please see the following MS-Selfie Newsletters for more specific information on these vaccines.
Please note that Shingrex, GSK’s vaccine to boost immunity against the varicella-zoster virus, has been licensed for all adults before starting immunosuppressive therapy to reduce their risk of shingles. From September this year, all pwMS who are about to start immunosuppressive therapies, in particular anti-CD20 therapies and S1P modulators, should not only be offered the pneumococcal vaccine but the Shingrex vaccine as well (see ‘Shingles vaccination programme: changes from September 2023 letter’, 04-July-2023). They should be up-to-date with their flu and COVID-19 vaccines assuming they are in the necessary seasonal window for these vaccines. I generally don’t delay starting treatment for these vaccines if the person is out of the window for these vaccines.
Other vaccines on the list need to be personalised based on the individuals with MS. These include the meningococcal and, for children, Haemophilus influenzae vaccines. The meningococcal vaccine is now mandatory and part of the childhood vaccination schedule. It is only indicated if patients missed out on this vaccine as children and are high-risk, i.e. students living in close quarters with other students or military recruits.
Please be aware of the rise of vaccine hesitancy and the anti-Vaxx community, and an increasing number of patients who did not have childhood vaccines developing MS. So, please check your vaccine records, and if you haven’t been vaccinated, please ask for the option of having your childhood vaccines before starting on chronic immunosuppressive therapy. The latter is important for the MMR vaccine.
Found wanting
This patient makes a valid point about her team being found wanting for not warning her about the blunted vaccine responses on anti-CD20 therapies (ocrelizumab and ofatumumab). I suspect this will have changed because of COVID-19, and I think vaccine awareness and the need for vaccinations before starting immunosuppressive therapies is now common practice in the field of MS. Or am I wrong? How many of you on continuous immunosuppressive therapies were offered vaccines and discussed them with you before starting treatment?
Argentinian study
Objective: To investigate the effect of yellow fever (YF) immunization on the subsequent multiple sclerosis (MS) relapse risk.
Design: Self-controlled case series study.
Setting: An MS outpatient clinic.
Patients: Seven patients with clinical relapsing-remitting MS traveling to endemic YF areas who received the YF 17D-204 vaccine were studied.
Intervention: The YF 17D-204 vaccine.
Main outcome measure: Number of relapses. Secondary outcomes included the number of new lesions on magnetic resonance imaging and peripheral mononuclear cell cytokine and chemokine production.
Results: The annual exacerbation rate during risk periods following immunization was 8.57, while the relapse rate outside the risk period was only 0.67 (rate ratio = 12.778; P < .001). Three months after immunization, patients showed a significant increase in new or enlarging T2-weighted lesions and gadolinium-enhancing lesions compared with 12 months prior to vaccination and 9 months after immunization (both P < .001). Moreover, blood myelin basic protein and myelin oligodendrocyte glycoprotein responses showed significant increases in interferon γ-induced protein 10 kDa-, interferon γ-, interleukin 1α-, interleukin 1β-, and tumor necrosis factor-secreting cell numbers as well as complement component C1qB production after YF vaccination in patients with MS compared with unvaccinated patients with MS, patients with MS vaccinated against influenza, and healthy control subjects (P = .01 and P < .001, respectively).
Conclusion: For patients with MS traveling to endemic YF areas, vaccination should be recommended on the basis of carefully weighing the risk of exacerbation against the likelihood of exposure to the YF virus.
French study
Background: Yellow fever vaccine (YFV) is not advised for multiple sclerosis (MS) patients because of the potential risk of post-vaccine relapses.
Objective: To assess the risk of relapsing-remitting multiple sclerosis (RR-MS) worsening after YFV.
Methods: Non-interventional observational retrospective, exposed/non-exposed cohort study nested in the French national cohort including MS.
Results: 128 RR-MS were included. The 1-year annualized relapse rate (ARR) following YFV did not differ between exposed: 0.219 (0.420) and non-exposed subjects: 0.208 (0.521) (p = 0.92). Time to first relapse was not different between groups (adjusted hazard ratio (HR) = 1.33; 95% confidence interval (CI) = 0.53-3.30, p = 0.54).
Conclusion: These results suggest that YFV does not worsen the course of RR-MS.
Paper 3 - durability of vaccine response
In accordance with the World Health Organization, one dose of yellow fever vaccine may guarantee protection lifelong in healthy adults. However, relatively little information is still available from ad hoc studies. We evaluated the persistence of neutralizing antibodies, which are considered to be an immune correlate of protection, in a large number of military personnel vaccinated up to 47 years before. Overall, 322 individuals were studied. The median time from vaccination to blood collection for neutralizing antibody evaluation was 9 years, ranging from <1 to 47 years. Of the 322 participants, 319 had neutralizing antibodies (99.1 %). The highest median PRNT50 value was observed in those vaccinated ≤1 year before (median PRNT50 = 320). In conclusion, our study confirms on a larger scale that, in healthy adults, neutralizing antibodies may persist as long as 47 years after a single yellow fever vaccines dose.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your own healthcare professional, who will be able to help you.
Yellow fever vaccination