Table 5.

Evidence and Recommendations on Immunization of Patients on Biologic and Targeted Immunomodulatory Therapies

TNF inhibitors	Immunization with inactivated vaccines during therapy with TNF inhibitors is recommended.98 Non-immunized patients who were at risk should ideally complete the HBV vaccine series ≥ two weeks prior to the initiation of TNF inhibitors.16 The EMA label of TNF inhibitors recommends that infants born from mothers on TNF inhibitors receive live vaccines after ≥ five months of last adalimumab injection,99 ≥ four months of last etanercept injection,100 ≥ six months of last golimumab injection,101 ≥ five months after certolizumab injection102 and ≥ six months after birth in infliximab treated mothers;66 however, vaccine response to Haemophilus influenzae in infants born from mothers on biologic therapies including infliximab, adalimumab, certolizumab pegol, and golimumab is not impaired. The Canadian Dermatology Association strongly recommends routine immunization schedule for infants exposed to biologic agents during pregnancy and lactation.103 EULAR recommends that live attenuated vaccines should be avoided during the first six months of life in newborns exposed to TNF inhibitors after 22 weeks of gestation.98
IL-1-targeted agents	In patients receiving IL-1 targeted agents, vaccination against Pneumococcus and Haemophilus influenzae type B should be considered. Infants born from mothers on canakinumab could receive live vaccines after ≥ 16 weeks of the last injection.68 If a live vaccine is required; patients on rilonacept could be vaccinated ≥ six weeks of the last dose and ≥ six weeks before the next dose.104
CD19-targeted agents	The recommendations on vaccination with anti-CD20 therapies could be extrapolated to anti-CD19 targeted agents such as blinatumomab.28 Live vaccines for infants born from mothers on CD19 targeted agents should be postponed until B cell recovery.105
Anti-CD20 monoclonal antibodies	Tetanus immunoglobulin should be administered in patients with contaminated wounds who have received anti-CD20 monoclonal antibodies in the past six months.98,106 Live attenuated vaccines should not be received within six months of anti-CD20 monoclonal antibody administration.10 For optimal immunization in patients on rituximab, vaccination should be deferred to at least 5–6 months after the last dose and at least one month before the next dose.98,103 If the time window is not possible inactivated vaccines could be administered considering suboptimal response.98 Administration of second booster dose of inactivated influenza vaccine is associated with superior immunity response.28 Non-immunized patients who are candidates for R-CHOP therapy should complete HBV vaccines ≥ 4 weeks prior to the initiation of rituximab.14 Patients should ideally complete the required vaccines ≥ six weeks prior to the initiation of ocrelizumab. Live vaccines are not recommended until B cell depletion in patients treated with ocrelizumab (may take up to 72 weeks).106,107 Case reports have demonstrated that immunization of infants born from mothers on rituximab therapy up to the third trimester was not attenuated.103 The Canadian Dermatology Association strongly recommends routine immunization schedule vaccines for infants exposed to rituximab during pregnancy and lactation;103,108 however, EULAR recommends that Live-attenuated vaccines should be avoided during the first six months of life in newborns exposed to biologic agents in the second half of pregnancy.98 The EMA label of ocrelizumab, obinutuzumab, and ofatumumab recommends that administration of live vaccines in neonates born from mothers receiving these agents during pregnancy should be postponed until B cell repletion.106,109, 110
Anti-CD52 monoclonal antibodies	Live vaccines should be avoided up to at least 12 months after discontinuation of MabCampath®.111 Poor response to vaccination is observed in patients with hematologic malignancies who have received alemtuzumab in the previous six months.77 Immunization requirements should be completed ≥ 6 weeks prior to the initiation of Lemtrada®. VZV seronegative patients should be immunized ≥ six weeks prior to the initiation of Lemtrada®.76
T-Cell Co-stimulation blockers	Live vaccines could be administered ≥ 3 months after discontinuation of abatacept.112
Monoclonal antibodies targeting α4-integrin and CD 11a	The EMA label recommends discontinuation of efalizumab eight weeks prior to vaccination and resumption of therapy two weeks after vaccination.78 Routine immunization schedule, including inactivated and live vaccines for infants exposed to natalizumab during pregnancy and lactation, could be considered.103 Vaccine response to Haemophilus influenzae in infants born from mothers on natalizumab was not impaired.
IL-12 and IL-23-targeted agent	Live vaccines could be administered ≥ 15 weeks after discontinuation of ustekinumab.113 Vaccine response to Haemophilus influenzae in infants born from mothers on ustekinumab was not impaired. The Canadian Dermatology Association strongly recommends routine immunization schedule, including both inactivated and live vaccines for infants exposed to ustekinumab during pregnancy and lactation.103
Component 5 (C5)-targeted agents	Unvaccinated patients should receive S. pneumonia and H. influenzae type b vaccine ≥ 2 weeks prior to treatment with eculizumab. Two-dose series with quadrivalent conjugate (MenACWY) at least two months apart and serogroup B (MenB) either two-dose series at least a month apart or three-dose series at 0,1, 2 and 6 months should be administered. Meningococcal immunization should be completed ≥ 2–4 weeks prior to eculizumab administration. Booster doses of tetravalent conjugate vaccine should be repeated every five years based on the duration of therapy.8
Proteasome Inhibitors	VZV seronegative patients should receive live attenuated vaccine ≥ 1 month prior to initiation of therapy.11 HSV subunit vaccine could be considered for VZV seropositive patients ≥ 50 years.11
BCR-ABL Tyrosine kinase inhibitors	ECIL guidelines recommend yearly seasonal influenza vaccine and PCV followed by PPSV 23 (8 weeks later) in CML patients on BCR-ABL tyrosine kinase inhibitors.23
JAK inhibitors	Vaccination with Shingrix® should be considered ≥ 2 weeks or (Zostavax® ≥ 4 weeks) prior to the initiation of tofacitinib.94
Sphingosine 1-phosphate receptor modulators	Live vaccines are not recommended until at least two months after discontinuation of fingolimod.97 The EMA label recommends vaccination against HPV prior to the initiation of fingolimod.97 VZV seronegative, non-immunized patients should receive live attenuated (2 doses of Varivax® separated by four weeks) ≥ 1 month prior to initiation of therapy.11,63 Adjuvant herpes zoster subunit (HZ/su) vaccine could be considered for VZV seropositive patients ≥ 50 years.63 The vaccine should not be administered while the patient is on antiviral agents against VZV. An antiviral agent should be prescribed for vaccinated patients who develop rashes.63 When treated with pulse dose corticosteroid, vaccination should be postponed for at least one month after the last dose of corticosteroid.63
Bruton Tyrosine kinase inhibitors	Pneumococcal vaccine and yearly inactivated influenza vaccine is recommended in CLL patients.23
Monoclonal antibody targeting CD25	Inactivated vaccines could be administered 3 months after induction of basiliximab. Inactivated influenza vaccine could be administered as early as one month after transplant.114

Abbreviations: CLL, Chronic lymphocytic leukemia; HBV, Hepatitis B virus; HPV,  human papillomavirus; H. influenzae, Haemophilus influenza; ECIL, European Conference on Infections in Leukaemia; EMA, European medicines agency; EULAR; European league against rheumatism; IL-1, interleukin-1; S. pneumonia, Streptococcus pneumonia; TNF, tumor necrosis factor; VZV, varicella-zoster virus.