MS ECHO: Vaccines in MS

Gary Stobbe, MD Medical Director, MS Project ECHO

Clinical Assistant Professor, UW Neurology

Conflicts of Interest

• Dr. Stobbe has no conflicts of interest to disclose

Objectives • Understand current recommendations

regarding vaccines for MS patients • Review effect of disease modifying therapies

on effectiveness of vaccines and safety-related issues

Case • 60 yo female • Dx RRMS in 1991 • Interferon beta 1995-2013 (dc’ed after staph

infection); Dimethyl fumarate since 12/2013 • Last relapse – 2012 (vertigo) • Imaging – 11/2014 – unchanged compared to

1 year prior • JCV Ab positive (index – 3.03) • Lymphocytes – 0.68 – 1.09 range

Case (cont) • Pneumonia recently and multiple URI/sinus

infections • Mod-severe nausea ongoing with dimethyl

fumarate (weight loss) and flushing • VZV antibodies – 1:8

• VZV vaccine indicated if switching to

fingolimod – give while still on dimethyl fumarate? If need to be off, how long?

Why vaccinate MS Patients? • As many as 1/3 of MS relapses are associated

with infections • Increased relapse rate/MRI activity following

bacterial and viral infections (Correale, 2006; Buljevac, 2002)

• Relapses associated with infection more likely to result in EDSS rise (Buljevac, 2002)

• Patients on certain DMTs at risk for opportunistic infection

When not to vaccinate MS Patients? • Vaccines can worsen exacerbations if given

during the exacerbation • Certain DMTs may reduce effectiveness of

vaccination

• Evidence of triggering MS has been refuted by

US Institute of Medicine

2001 NEJM study

• 643 MS patients • Patients received hep B, tetanus, or influenza • Followed prospectively for 4 years • 2.3% relapse rate during periods receiving

vacinnation, vs. 2.8 – 4% during non-vaccinated periods

MS Council for Clinical Practice Guidelines, 2002

• Evidence supports strategies to minimize infections • Influenza, hep B, varicella, tetanus vaccines are safe • Non-live vaccines endorsed • Live, attenuated vaccines “generally not recommended” • Wait 4-6 weeks after relapse • Consult a physician prior to receiving live vaccine if on

immunosuppressive therapy • No consensus on risk for a person with MS whose close family

member receives a live-virus vaccine

2003 CDC study • Vaccination against hep B, influenza, tetanus,

measles, and rubella did not increase a person’s risk of developing MS or optic neuritis

Disease/Pathogen USA Standards Vaccine type Use in MS

Diphtheria All individuals Inactivated Reduce MS risk?

Influenza All individuals Inactivated Yes (at risk patients)

Human papilloma Females 11-12 yo Inactivated Evidence lacking

MMR At risk individuals Live attenuated No if immunosupp

Meningococcal At risk individuals Inactivated ? Consider pre-med

Pertussis All adults Inactivated Evidence lacking

Pneumococcus > 65 & at-risk Inactivated ? Consider pre-med

Tetanus All individuals Inactivated Reduce MS risk?

Varicella Low immune state Live attenuated Pre-med, no in immunosupp

Diptheria • Generally administered in combo with tetanus • Large scale studies in MS have not been

conducted • European MS database – no increase in

relapse rate • Possible reduced risk of developing MS?

(Farez, 2011)

Influenza • 180 patients with RRMS – 12 of 36 patients with

influenza developed a relapse within 6 weeks; only 4 of 80 patients receiving vaccination developed a relapse (De Keyser, 1998)

• Placebo-controlled, double-blind study of 104 MS patients showed no difference in relapse rate (Miller, 1997)

• Small case series suggest possible risk of relapse with both seasonal and H1N1 vaccine (McNicholas, 2011)

• Avoid live vaccine; high dose inactivated vaccine not studied – NMSS recommends standard dose only

• Lemtrada patients – give 6 wks prior to infusion

Human papilloma virus • Designed to prevent HPV6, 11, 16, and/or 18-

related cervical cancer/dysplasia • 3 cases of NMO/1 case of ADEM following

HPV vaccination • 5 cases of MS relapse • Nationwide registry in Denmark and Sweden –

showed no association of MS with the HPV vaccine – 800,000 individuals (Scheller, 2015)

Measles, mumps, and rubella • MMR is live attenuated • Immunosuppressed patients at risk for

vaccine-induced disease (avoid vaccine in patients on immunosuppression)

• Effect of MMR vaccine on MS disease course has not been established

Bacterial diseases • Pneumococcal and meningococcal vaccines • Not studied adequately in MS • Consider administering prior to starting

immunosuppression in at-risk patients

Tetanus • European MS database study showing

reduced relapse rate in patients receiving combined vaccine (Confavreux, 2001)

• Meta-analysis – case-control studies, 1966-2005 (963 MS patients; 3,126 healthy controls) – reduced risk of relapse in patients receiving tetanus (Hernan, 2006)

Varicella zoster virus • Live attenuated vaccines – Shingles vaccine (Zostavax) reduces risk

of zoster in 60-70% of adults over age 50 (efficacy reduced over age 70)

• NMSS recommends discuss with HCP • For seronegative patients, varicella vaccine (Varivax) indicated

– Recommended before start of immunotherapy – Explicitly required with fingolimod (4 weeks prior) and alemtuzumab (6

weeks) • Immunocompromised individuals not vaccinated and exposed to

VZV should receive hyperimmunoglobulin for post-exposure prophylaxis

• Study of 47 MS patients receiving varicella vaccine – 14 individuals improved, 4 patients deteriorated, no change in 29 patients – 4 patients developed mild vaccine-associated chickenpox (Ross, 1997)

Experimental VZ vaccine

• HZ/su – experimental recombinant inactivated zoster vaccine (combines gE, a protein found on the virus, with an adjuvant system intended to enhance the immunological response to gE – 3 year, phase III trial – 15,411 adults over age 50 – Given 2 doses 2 months apart – 97.2% efficacy (98% in age 70 and over) – Studies ongoing in immunocompromised population

Tick-borne encephalitis • Small case-control study (15 MS patients, 15

controls) showed no increase in exacerbation rate in following 36 months or MRI lesion load at 45 days post-vaccination (Baumhackl, 2003)

Yellow fever • Live, attenuated vaccine • Vaccination required for entry into certain

countries (tropical/subtropical South America and Africa)

• Largely contraindicated in immunosuppressed patients and MS patients on DMTs

• Significant increase in relapse rate during 3 months post-vaccination (Farez, 2011)

Hepatitis B • Initial hep B vaccine program in France

showed associated CNS demyelination in MS; subsequent studies did not confirm this risk

• Case-crossover study of 643 MS patients showed no increased exacerbation rate during 2 months post-vaccination (Confavreux, 2001)

• National Academy of Sciences’ Institute of Medicine – determined no association (2002)

Poliomyelitis • Inactivated polio vaccine recommended in all

children and boosters for adults traveling to endemic areas

• Risk of MS relapse associated with vaccine has not been studied

Rotavirus • 2 live attenuated vaccines available for

vaccination of infants • Immunosuppressed patients with household

contact with recently vaccinated infants should follow strict personal hygeine (virus is shed after vaccination)

• No studies on impact of MS course

Rabies • No studies in MS • Immediate active immunization combined

with immunoglobulin recommended post-exposure

Are vaccines effective with patients on DMTs?

• Large prospective studies absent • DMTs generally do not appear to affect the

efficacy of vaccines • Fingolimod may be exception • IVIG and rituximab may impair

immunogenicity of live viral vaccines for 6-12 months

Are vaccines effective with patients on DMTs?

• Vaccinate an MS patient with varicella vaccine prior to starting on fingolimod if immune status is negative

Vaccines and specific DMTs • Interferon beta – normal humoral and cellular response to influenza

vaccine – vaccines considered safe including live vaccine • Glatiramer – no known negative effects – vaccines considered safe

including live vaccine • Natalizumab – normal humoral response to influenza and tetanus • Teriflunomide – normal immune responses to influenza and rabies

vaccines • Dimethyl fumarate – no data (NMSS recommends no live vaccines) • Fingolimod – decreases humoral response to influenza, tetanus, and

pneumococcal vaccines. Delay vaccines for 2 months after stopping drug. Delay drug for 1 month after administering vaccine.

• Alemtuzumab – live-virus vaccine contraindicated; influenza vaccine give 6 wks prior to infusion

Vaccines and specific DMTs (cont.) • Azothioprine – VZV is ok per recommendation of the Advisory Committee

on Immunization Practices (ACIP) – specific dose recommended

Resources • Review article by Loebermann, M. et al. Vaccination against infection in

patients with multiple sclerosis. Nature Reviews: Neurology, March 2012, vol 8: 143-151. link - doi:10.1038/nrneurol.2012.8

• Oral Presentation by Patricia Coyle, MD. CMSC Meeting, 2014. • NMSS Website - Vaccinations

Dr. Burgess’s Case

• 57 yo man with RRMS • Dx’d 2003 with optic neuritis and positive MRI • h/o copolymer • Failed natalizumab (developed anti-natalizumab Ab) • Dimethyl fumarate (DMF) started July 2013

Dr. Burgess Case (cont.)

• Last brain MRI January 2014 stable • Low lymphocyte count • Normal LFTs • JCV +, no titer available • LOVES being able to take a pill and not do

injections

Dr. Burgess Case (cont.) – Lymphocyte count

date WBC K/uL Lymph K/uL

5/6/15 7.5 0.4

3/19/14 6.6 0.5

12/18/13 7.3 0.4

12/23/12 11.4 2.0

Dr. Burgess Case (cont.)

• Uses walking stick • Previous used lofstrand crutches and bioness

estim • Got recumbant bike from rec tx • Bikes 4 times per week 15 min to 90 mins • Feels like he is getting stronger, no falls in 6

mos

Dr. Burgess’s case cont.

• Some fatigue • Has cooling vest but doesn’t use it • Bilateral neuropathic foot pain controlled

with gabapentin • Some right eye loss of vision

Psychosocial Sx

• Divorced • Living out of his van • Wanting to start a new relationship and

erectile dysfunction is a big problem

Imaging