What are the current recommendations for administration of live vaccines in patients receiving dupilumab?

Background
Dupilumab (Dupixent®), an antagonist of the interleukin-4 receptor alpha, was initially approved by the United States Food and Drug Administration (FDA) in March of 2017; at the time of approval, it was only indicated for the treatment of moderate to severe atopic dermatitis in adults.1 As of April 2024, dupilumab is now approved for multiple additional indications in patients of varying ages, including asthma (≥6 months), chronic rhinosinusitis with nasal polyposis (adults), eosinophilic esophagitis (≥1 year weighing ≥15 kg), and prurigo nodularis (adults); the indication for atopic dermatitis has also been expanded to include pediatric patients who are ≥6 months of age.2 The drug’s prescribing information states that patients should consider completing all age-appropriate vaccinations before initiating the drug, and it includes a warning to avoid administering live vaccines in patients taking dupilumab. This warning is likely based on the fact that A) administration of live vaccines was not authorized during phase 3 trials of dupilumab and B) patients receiving biologic agents, including dupilumab, have a suppressed immune response, which could lead to reduced vaccine efficacy and an increased risk of infection from the live virus or bacterium.3,4

Currently, the only live vaccine available in the United States is the oral adenovirus vaccine, which is primarily given to military personnel to prevent adenovirus.5 Routinely administered live-attenuated vaccines include the live-attenuated influenza vaccine, vaccines with components against measles, mumps, and rubella (MMR), rotavirus vaccines, and the varicella zoster vaccine (VZV). Other non-routine live attenuated vaccines are available, including travel vaccines to prevent typhoid, cholera, and yellow fever, among others; however, these vaccines will not be the focus of this review. Previously, a live-attenuated vaccine for the prevention of shingles (Zostavax®) was approved for patients aged ≥50 years; however, Zostavax was discontinued in November 2020. The currently available vaccine against shingles, Shingrix®, is not a live vaccine.6 Details on currently available live and live-attenuated vaccines in the United States are described in the Table below.

Table. Live and live-attenuated vaccines.5,7-22
Vaccine (brand name)Indicated populationDosing/administration
Live vaccines
Adenovirus type 4/7 vaccine (N/A)Military personnel aged 17-50 years2 tablets, administered orally x1 dose
Live-attenuated vaccines
Bacillus Calmette-Guerin substrain tice live antigen injection (BCG Vaccine)Peoplea not previously infected with M. tuberculosis who are at high risk for exposure0.2-0.3 mL, administered percutaneously using a multiple puncture device
Cholera vaccine, live, oral (Vaxchora®)2-64 years of age traveling to cholera-affected areasMix active drug powder into reconstituted buffer solution; administer ≥10 days prior to potential exposure to cholera
Dengue tetravalent vaccine, live (Dengvaxia®)6-16 years of age with laboratory-confirmed previous dengue infection and living in endemic areas0.5 mL, administered SC as 3 doses, each given 6 months apart
Influenza vaccine, live (Flumist® quadrivalent)2-49 years of age0.2 mL intranasally (0.1 mL per nostril), given annuallyb
Measles-mumps-rubella vaccine, live (M-M-R® II; Priorix)≥12 months of age0.5 mL, by IM (M-M-R II only) or SC injection, at the following recommended intervals:c

First dose: 12-15 months of age
Second dose: 4-6 years of age
Measles, mumps, rubella, and varicella virus vaccine live injection (ProQuad®)12 months to 12 years0.5 mL, by IM or SC injection, at the following recommended intervals:d

First dose: 12-15 months of age
Second dose: 4-6 years of age
Rotavirus vaccine, live, oral solution
(Rotarix®)		Infants 6-24 weeks of age1-1.5 mL, administered orally as a 2-dose series; first dose is administered beginning at 6 weeks of age, with subsequent dose separated by ≥4 weeks

Do not administer after 24 weeks of age
Rotavirus vaccine, live, oral, pentavalent solution (RotaTeq®)Infants 6-32 weeks of age2 mL, administered orally as a 3-dose series; first dose is administered at 6-12 weeks of age, with subsequent doses administered at 4- to 10-week intervals

Do not administer after 32 weeks of age
Smallpox vaccine, live
(ACAM2000®)		Persons determined to be at high risk for smallpox (eg, laboratory workers who handle the variola virus)Percutaneously administered (ie, scarification) every 3 years
Typhoid Vi polysaccharide vaccine for intramuscular use (Typhim Vi®)≥2 years of age0.5 mL by IM injection x1 dose; reimmunization recommended every 2 years with repeated/continued exposure to S. typhi
Typhoid vaccine live, oral ty21a (Vivotif®)≥6 years of ageSwallow 1 capsule by mouth on alternate days (eg, days 1, 3, 5, and 7); complete all 4 doses at least 1 week prior to potential exposure to S. typhi
Varicella-zoster virus vaccine live injection (Varivax®)≥12 months of age0.5 mL, by IM or SC injection, at the following recommended intervals:

12 months to 12 years:e
First dose: 12-15 months of age
Second dose: 4-6 years of age

≥13 years:
2 doses administered ≥4 weeks apart
Yellow fever virus strain 17d-204 live antigen injection (YF-Vax®)≥9 months of age and falling into one of the following categories:

  1. Living in or traveling to endemic areas (eg, South America and Africa)
  2. Traveling internationally through countries with yellow fever
  3. Laboratory personnel
0.5 mL, by SC injection, x1. For most, a single dose provides long-lasting protection; an additional dose may be given in select individuals

A booster dose may be given to those vaccinated ≥10 years prior at increased risk of yellow fever
Abbreviations: IM=intramuscular; N/A=not applicable; SC=subcutaneous.
aSpecific age not specified; dosing recommendations includes infants <1 month old
bFirst administration requires 2 doses given ≥1 month apart
cIf not administered following recommended schedule, allow a minimum of 4 weeks between doses
dFirst dose may be given anytime through 12 years of age. Allow at least 1 month between a measles-containing vaccine and ProQuad and at least 3 months between a varicella-containing vaccine and ProQuad
eIn children <13 years of age, doses should be administered ≥3 months apart

General recommendations for the administration of live vaccines in immunocompromised individuals
Recommendations from the Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP) on best practices for vaccination of persons with altered immunocompetence (last updated in 2023) generally recommend administration of both non-live and live vaccines at least 2 weeks prior to initiating therapy with immunosuppressive medications, including interleukins.23 Further, the CDC/ACIP recommends withholding administration of live vaccines for 3 months after discontinuation of such therapies. These recommendations largely reflect the 2013 guidelines for vaccination of the immunocompromised host, which were initially published by the Infectious Diseases Society of America but have since been archived.24 The archived IDSA guidelines further suggest that live vaccines should be administered at least 4 weeks prior to initiating immunosuppressive medications.

The IDSA makes more specific recommendations for vaccinating patients with chronic, inflammatory diseases who are being treated with immunosuppressant agents.24 For instance, the VZV vaccine may be considered for patients being treated for chronic inflammatory diseases with long-term, low-level immunosuppression; however, other live-attenuated vaccines (ie, live attenuated influenza vaccine, MMR, and MMR with varicella) are not recommended in patients with chronic inflammatory diseases who are receiving maintenance immunosuppression. A variety of patient-specific factors can impact the degree of immunocompetence; therefore, it is recommended that the treating physician (sometimes in consultation with an infectious diseases or immunology specialist) make this determination for each patient when determining the most appropriate vaccine schedule.23

Recommendations for administration of live vaccines in patients on dupilumab
In 2024, a position paper was published by the American College of Allergy, Asthma, and Immunology to make recommendations for the use of vaccines in patients receiving dupilumab.3 Dupilumab was chosen as a specific focus due to the lack of guidance present in the drug’s prescribing information and the recent expansion of indications in the pediatric population (who are more likely to require live vaccines). The authors first conducted a systematic review of literature describing vaccination in patients receiving dupilumab from inception through January of 2022. Nine articles were included in the systematic review (5 cohort studies, 1 randomized controlled trial, 2 retrospective case-control studies, and 1 case series), which included patients ranging in age from 8 months to 64 years. Most of the included studies involved patients with atopic dermatitis (n=6) or asthma (n=2); 1 study included patients with both atopic dermatitis and asthma. Meta-analysis could not be performed due to a lack of data overall and heterogeneity within the included studies. A modified Delphi panel of 28 specialists with expertise in allergy/immunology and immune response/adverse reactions to vaccines was then organized to evaluate the literature and provide consensus recommendations regarding vaccination in patients receiving concurrent dupilumab.

The existing evidence revealed that there are currently no data to suggest that administration of live vaccines is dangerous or ineffective in patients receiving dupilumab (low certainty evidence, high risk of bias).3 The review further describes 2 studies that administered the yellow fever-17D vaccine or MMR/VZV vaccines to patients receiving dupilumab with no associated reports of disseminated infection or reduced antibody response. Patients in these studies temporarily interrupted treatment with dupilumab (yellow fever vaccination administered at a mean of 22.3 days following the last dupilumab dose; MMR/VZV vaccinations administered anywhere from 7 to192 days following the last dose) and reinitiated therapy between 2 to 43 days following vaccination.

The Delphi panel convened in October 2023, and panelists were asked to agree or disagree with 3 questions related to administration of vaccines in patients taking dupilumab based on their review of the literature: 1) it is safe to administer live vaccines to patients receiving dupilumab; 2) patients mount appropriate antibody response to vaccines while on dupilumab; 3) I would recommend giving live vaccines to patients on dupilumab after a shared decision-making discussion with the patient and/or their family.3 Responses to all 3 questions exceeded the threshold for agreement in the first round of voting, with more than 89% of panelists agreeing to each question.

Conclusion
According to the prescribing information of dupilumab and recommendations from various organizations, live vaccines are not recommended in patients receiving immunosuppressive therapy. Ideally, live vaccines should be administered at least 4 weeks before initiating dupilumab; however, this may be less feasible in certain populations, such as pediatric patients, who require multiple routine live vaccinations. Based on the results of a recent systematic review and modified Delphi panel, there is limited literature describing administration of live vaccines in patients receiving dupilumab. However, experts on this panel agreed that the use of live vaccines in patients receiving dupilumab is likely to be safe and effective, suggesting that such vaccines can be administered to patients using shared decision-making.

References

  1. Drugs@FDA: FDA-approved drugs. US Food and Drug Administration. Accessed June 21, 2024. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm
  2. Dupixent. Package insert. Regeneron Pharmaceuticals, Inc; 2024.
  3. Lieberman JA, Chu DK, Ahmed T, et al. A systematic review and expert Delphi consensus recommendation on the use of vaccines in patients receiving dupilumab: A position paper of the American College of Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol. Published online June 5, 2024. doi:10.1016/j.anai.2024.05.014
  4. Fan R, Cohen JM. Vaccination recommendations for psoriasis and atopic dermatitis patients on biologic therapy: a practical guide. Yale J Biol Med. 2022;95(2):249-255.
  5. Timing and spacing of immunobiologics: general best practice guidelines for immunization. Centers for Disease Control and Prevention. Updated August 1, 2023. Accessed June 23, 2024. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/timing.html#t-05
  6. Shingles vaccination. Centers for Disease Control and Prevention. Updated May 8, 2023. Accessed June 23, 2024. https://www.cdc.gov/vaccines/vpd/shingles/public/shingrix/index.html
  7. Clinical Pharmacology. Elsevier; 2024. Accessed June 24, 2024. https://www.clinicalkey.com/pharmacology/
  8. Adenovirus type 4 and type 7 vaccine, live. Package insert. Teva Women’s Health Inc; July 2022.
  9. BCG vaccine. Package insert. Merck Sharp & Dohme LLC; 2022.
  10. Vaxchora. Package insert. Bavarian Nordic A/S; 2024.
  11. Dengvaxia. Package insert. Sanofi Pasteur Inc; 2023.
  12. Flumist quadrivalent. Package insert. MedImmune, LLC; 2023.
  13. M-M-R II. Package insert. Merck Sharp & Dohme LLC; 2023.
  14. Priorix. Package insert. GlaxoSmithKline Biologicals SA; 2024.
  15. ProQuad. Package insert. Merck Sharp & Dohme LLC; 2023.
  16. Rotarix. Package insert. GlaxoSmithKline Biologicals SA; 2024.
  17. RotaTeq. Package insert. Merck Sharp & Dohme LLC; 2023.
  18. ACAM2000. Package insert. Emergent Product Development Gaithersburg Inc; 2018.
  19. Typhim Vi. Package insert. Sanofi Pasteur Inc; March 2020.
  20. Vivotif. Package insert. Emergent Travel Health Inc; 2020.
  21. Varivax. Package insert. Merck Sharp & Dohme LLC; 2023.
  22. YF-Vax. Package insert. Sanofi Pasteur Inc; March 2020.
  23. Altered immunocompetence: general best practice guidelines for immunization. Centers for Disease Control and Prevention. Updated August 1, 2023. Accessed June 24, 2024. https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html
  24. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):309-318. doi:10.1093/cid/cit816

Prepared by:
Jessica Elste, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois Chicago College of Pharmacy

July 2024

The information presented is current as of June 23, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.