Vaccine schedule recommendations and updates for patients with hematologic malignancy post‐hematopoietic cell transplant or CAR T‐cell therapy

Abstract Revaccination after receipt of a hematopoietic cell transplant (HCT) or cellular therapies is a pillar of patient supportive care, with the potential to reduce morbidity and mortality linked to vaccine‐preventable infections. This review synthesizes national, international, and expert consensus vaccination schedules post‐HCT and presents evidence regarding the efficacy of newer vaccine formulations for pneumococcus, recombinant zoster vaccine, and coronavirus disease 2019 in patients with hematological malignancy. Revaccination post‐cellular therapies are less well defined. This review highlights important considerations around poor vaccine response, seroprevalence preservation after cellular therapies, and the optimal timing of revaccination. Future research should assess the immunogenicity and real‐world effectiveness of new vaccine formulations and/or vaccine schedules in patients post‐HCT and cellular therapy, including analysis of vaccine response that relates to the target of cellular therapies.

F I G U R E 1 Future approaches to vaccine research for hematopoietic cell transplant (HCT) and cellular therapies patients.[14][15] However, marrying vaccine studies with clinical outcomes remains challenging.The clinical relevance of reduced antibody titers post-HCT or cellular therapies is poorly understood, given that only a limited number of vaccine-preventable diseases have been reported.7][18][19] When interpreting results from published studies of vaccine response in HCT recipients, it is important to recognize the dominant focus of humoral (serologic) endpoints, the lack of measurement of cell-mediated responses and the lack of correlation between immunogenicity and clinical endpoints. 20,21An ongoing challenge that remains, including recent examples of vaccination against Respiratory syncytial virus (RSV) 22 and influenza, 23 is that the inclusion of HCT recipients in initial clinical trials is often delayed despite being one of the highest risk groups for disease and related complications.This review aims to comprehensively discuss the evidence for vaccination strategies in HCT patients, focusing on newer vaccine formulations, evidence for optimized dosing regimens, and vaccine adjuncts.It also aims to review the emerging evidence informing vaccination strategies following cellular therapies, highlighting questions around retained seroprevalence, vaccine response, and the interplay between immune reconstitution and vaccine timing.Potential future directions for translational vaccinology, including the individualization of revaccination approach in hematology patients, are discussed.

VACCINATION IN HCT RECIPIENTS
Infection after HCT is a major cause of morbidity and mortality, with vaccine-preventable infections being a potential contributor.[27][28][29] Therefore, it is recommended to consider HCT patients as "never vaccinated" and requiring a full revaccination schedule, considering age, country, and epidemiology.
2][33][34][35] There are no data to support any specific lymphocyte level for starting vaccines, however, and delaying vaccination increases the at-risk period for the patient. 32ter HCT, it may be reasonable to delay vaccination for at least 6 months after the last dose of anti-CD20 mAb therapy and/or other B-cell-depleting therapies. 24,32activated vaccines are safe after transplant, although immunogenicity may be reduced post-transplant compared with healthy individuals, with improvement over time and close to expected response at 2-3 years post-transplant. 31,37Inactivated vaccines are not inhibited by IVIg replacement. 24Patients with GvHD are at higher risk of infection and therefore benefit from vaccination; however, vaccine response may be impaired due to immunosuppression used to treat GvHD.2][33][34] Optimal vaccination of household contacts is encouraged, including live-attenuated measles, mumps, and rubella (MMR) and varicella zoster virus (VZV) vaccine if indicated, but not intranasal live-attenuated influenza vaccine or liveattenuated oral polio vaccine due to prolonged viral shedding and risk of transmission. 33,38[33][34][35][36]

Streptococcus pneumoniae
There is a recognized high risk of invasive pneumococcal disease after autologous and allogeneic HCT, related to low specific antibody titers, with approximately 85% of patients unprotected 6 months after transplantation. 10,39,40Of note, most patients are infected by vaccine serotypes. 9,41The current guideline recommendation is to provide three doses of pneumococcal conjugate vaccine (PCV) 1 month apart starting 3-6 months post-HCT.[44][45] This is then followed by a fourth dose of PCV if the patient has GvHD or one dose of PPSV23 6 months later to increase the spectrum of serotype coverage. 30,32,33Some centers may start pneumococcal vac-cination at 12 months post-HCT and check serology 1 month after the third or fourth dose of vaccine.
Newer vaccine formulations are now available in some countries, including 20-valent PCV (PCV20) and 15-valent PCV (PCV15), offering additional serotype coverage.There are no current studies of PCV20 in HCT recipients.An alternate strategy proposed by the Advisory Committee on Immunization Practices is to provide a fourth dose of PCV20 (in place of PPSV23) at least 6 months after the third PCV20 dose or 12 months after HCT, whichever is later.This specific recommendation has not been studied; however, it is based on two studies that assessed the use of four PCV13 doses and found improved humoral immunity from after the third dose to after the fourth dose. 45,46Local and systemic reactions however occurred more frequently after the fourth PCV13 dose than after the first to third dose of PCV13, although most were mild-moderate. 45

Varicella zoster virus vaccines
The prevention of primary VZV infection in seronegative patients and reactivation in seropositive patients (zoster and postherpetic neuralgia) is of prime importance in patients post-HCT. 7,8Antiviral prophylaxis (acyclovir or valacyclovir) is usually administered for at least 24 months post-allogeneic HCT and 12 months after autologous HCT; however, may be longer if there is ongoing immunosuppression or GvHD. 7,8,47However, there are limitations to prophylaxis, including uncertainty around optimal duration, ongoing compliance, and lack of reconstitution of cellular immunity.9][50] There is an expected response rate of ∼65% with some clinical protection.9][50] The risks and benefit of this decision should be carefully considered, given reports of fatal cases of vaccine-related disseminated VZV. 6,51Patients should be aware of this risk within 3 weeks of vaccination and to seek antiviral treatment if required. 326][57][58][59] Zostavax is no longer marketed in the United States.An inactivated version of Zostavax was also studied in autologous HCT recipients and found to be efficacious against the prevention of herpes zoster; however, it has not been made commercially available. 60ingrix, an inactivated, adjuvanted recombinant zoster vaccine (aRZV) is now available and recommended to prevent reactivation in seropositive immunocompromised patients. 61,62It is a subunit vaccine

:
Acellular pertussis vaccine-ap (pertussis toxoid) Three doses of diphtheria-tetanus vaccine at 1-2-month interval, from 6 months after HCT for all ages 145 Full dose diphtheria (DT) vaccine preferred over reduced dose antigen formulation diphtheria toxoid (Td) to achieve adequate seroprotection Three doses (for pertussis) given in combination with each dose of the diphtheria-tetanus vaccine from 6 months after HCT Three doses of DTaP for patients   containing VZV glycoprotein E and the AS01b adjuvant system. 5,62In a large, international, multicenter phase III clinical trial, 1846 adult autologous HCT recipients were randomized to receive two doses of aRZV or placebo 50-70 days following HCT and then 1-2 months later. 5After a median of 21 months of follow-up, the vaccinated group had a lower incidence of herpes zoster compared with the placebo group, with reported efficacy of 68.2%. 5 Humoral immune response rates were in the range of 70%-80%, with similar rates reported in other immunocompromised patients, including those with HM, solid tumors, human immunodeficiency virus, and solid organ transplant. 5ere was also reduction in postherpetic neuralgia, herpes zoster virus-associated complications and hospitalization. 5r allogeneic seropositive HCT recipients, only observational data exists for the assessment of adjuvanted vaccines including the aRZV vaccine. 63,644][65] In one study, cell-mediated immunity was significantly enhanced in patients with prior shingles compared to those without prior shingles and male sex. 65The recommended aRZV vaccine schedule is with two doses 2-6 months apart and to continue antiviral prophylaxis 1 month after the first vaccination.The use of aRZV in allogeneic HCT recipients and optimal timing need to be defined through future studies.
For all zoster vaccines, it is important to acknowledge that efficacy is difficult to assess, given that most of the data are based on company-developed assays and are specific to these vaccine studies.
Currently, there are no commercially available methods for addressing the protection of herpes zoster.

COVID-19 vaccines
7][68][69] B-cell-depleting therapy within 12 months has been found to be a major determinant of impaired humoral immunity. 67,70,712][83][84] This may be dependent on timing of vaccination relative to the transplant and use of any concurrent immunosuppressive therapies. 69,77In allogeneic HCT recipients, lower seroresponse to three doses of vaccine has been found in HCT recipients of haploidentical donors, those with chronic kidney disease and lower lymphocyte count. 69,73Starting from 3 to 6 months after transplantation, it is recommended to revaccinate HCT recipients with a full primary series of three doses, following the recommended sched-ule for each specific vaccine. 75,79Immunogenicity analysis (humoral and cell-mediated immunity) from a recent observational cohort study of allogeneic HCT recipients supports the commencement of mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) revaccination at 3 months post-transplantation, immune responses were not influenced by concurrent GvHD or immunosuppressive regimen. 85e third dose should be given at least 28 days after the second dose.
77][78][79]86 Booster dose(s) are recommended after the three-dose primary course to optimize immunogenicity, and 86 the timing is suggested as per local guidelines but at least 3 months after the third dose. 76At the time of writing, updated variant-specific mRNA COVID-19 vaccines are now preferred as the booster dose. 79inical effectiveness studies have found reduced severity of COVID-19 in vaccinated patients with HM; however, there is still significant morbidity and mortality from breakthrough infection. 13,75,87 a study of four-dose vaccinated patients with HM, rates of hospitalization, oxygen requirement, and mortality of 38.2%, 21.6%, and 3.9%, respectively, were found with breakthrough COVID-19. 876][97] In a small study of hemato-oncological patients, Ad26.COV2-S appeared safe as a heterologous vaccine booster after two doses of BNT162b2 vaccine. 98In hematology malignancy patients with diseases and treatments impacting B-cell immunity, in those who received two doses of ChAdOx1 vaccination followed by an mRNA vaccine, even in the absence of seroconversion robust SARS-CoV-2-specific T-cell immunity was documented. 74

VACCINATION FOLLOWING CELLULAR THERAPIES
Less is known about the burden of vaccine-preventable infections and the role of revaccination in patients treated with cellular therapies. 11,99,1005][106][107] The field is currently aiming to determine the extent to which antibody immunity is preserved following cellular therapies, optimize timing of revaccination following treatment, and identify key predictors of vaccine response from hematological markers of immune reconstitution.

Preservation of immunity: the retention of pathogen-specific antibodies following cellular therapies
Few studies have systematically explored the persistence of pathogenspecific IgGs after CAR-T therapy.Available seroprevalence data is often adjunctive and exploratory; for example, comparing the prevalence of existing antibodies to vaccine-preventable infections between CAR-T treated patients and healthy controls to explore reasons for poor humoral response following SARS-CoV-2 vaccination. 108,109udies specifically aiming to characterize the effect of CAR-T therapy on circulating pathogen-specific IgGs are summarized in Table 2. [110][111][112][113][114][115] Studies differ in the timing of antibody measurement post-CAR-T, the exclusion or inclusion of patients receiving Ig replacement, and data are aggregated across mixed populations of leukemia, lymphoma, and myeloma patients.[110][111][112][113][114][115][116] Data regarding seroprevalence in patients treated with bispecific or non-CD19+ directed CAR-T (e.g., B-cell maturation antigen [BCMA]) therapies are lacking.117

3.1.1
The effects of CAR-T target Significant discussion surrounds how CAR-T patients retain antibodies after B-cell aplasia.One theory is that although CD19 directed CAR-T cells deplete memory-B and CD19+ plasma cells, they spare a CD19plasma cell population, which replenish antibody production against previously encountered pathogens. 118BCMA CAR-T, used in the treatment of multiple myeloma, depletes all BCMA-expressing plasma cells and could therefore be associated with lower antibody positivity after treatment compared to the CD19+ product. 103At present, seroprevalence studies in BCMA treated patients are very limited, but a small study demonstrates (BCMA = 4) a lower rate of aggregated seropositivity (48%) compared to CD19+ treated patients (67%). 115

Streptococcus pneumoniae
Fewer than 14% of patients, not receiving IVIg replacement after CAR-T, demonstrated antibodies against tested serovars of S. pneumoniae at 3-20 months post-infusion. 114,115These estimates reflect predominantly patients with lymphoma receiving CD19+ depletion.There is a lack of baseline data on S. pneumoniae seroprevalence prior to CAR-T infusion. 110Similarly, reference data for healthy population seroprevalence for S. pneumoniae were not available. 115Small subgroups (N = 13) with S. pneumoniae IgG detected prior to CAR-T infusion have demonstrated reduction in mean titers of IgG 3-6 months post-infusion, although a proportion remained seroprotection throughout. 109,1101.3Diphtheria, tetanus, and pertussis Studies demonstrate a high rate of circulating IgG specific to tetanus (100% of patients) prior to CAR-T infusion that was maintained, or comparable to healthy controls, at 3-20 months post-infusion in 90%-100% of sampled patients. 108,110,111,116,119,120Similarly, diphtheria antibodies were detected in 88%-95% of patients pre-infusion, with similar seroprevalence maintained at post-infusion follow-up (median 3-20 months). 110,112Pertussis data were sparse, with low seroprevalence rates identified at pre-infusion in small samples, and equally low rates of detection at 12-and 20-month follow-up. 112,114,1151.4Measles, mumps, and rubella 2][113] If enduring response was achieved, patients maintained expression of MMR IgG. 111,112,114,1151.5

Varicella zoster virus
Within the limitations of a single study with pre-infusion results, a high proportion of CAR-T treated patients had demonstrable antibodies against VZV (82%). 111Post-infusion serosurveys have demonstrated similar seroprevalence (87%-96%). 114,115Seropositive patients are currently prophylaxed against VZV reactivation for between 6 and 12 months depending on center. 121-123

Vaccine response
Most research examining vaccine response following CAR-T therapies have focused on response to SARS-CoV-2 vaccines and are synthesized in existing systematic reviews. 81,84,124,1250][131] Furthermore, mRNA vaccines elicited improved vaccine responses in this population compared to non-mRNA vaccines. 125Predictors of vaccine response were heterogeneously modeled between studies.Steroid use and underlying non-Hodgkin lymphoma predicted poor vaccine response. 84,126,132Higher numbers of circulating B cells were predictive of improved vaccine response in two studies. 129,133Across studies, absolute lymphocyte count, Ig replacement, time since CAR-T, and age of the patient were not predictive. 84,132,134st vaccine studies have examined CD19+ directed CAR-T therapies.Mechanistically, it is plausible that CD19+ and BCMA CAR-T TA B L E 2 Summary of studies examining seroprevalence of circulating immunoglobulin G against vaccine-preventable infections.Additionally, Walti et al. 117 prospectively examined response to the quadrivalent influenza vaccine in a mixed lymphoma/myeloma population treated with CD19+ and BCMA directed CAR-T.Partial response to inactivated influenza vaccine was appreciated in 60%-70% of the cohort, defined as a twofold increase in antibody response to a vaccine strain, while 31%-40% of the cohort had robust antibody response (fourfold increase). 117There was no association between vaccine response and age, time from CAR-T, IgG level, or underlying malignancy. 117

Vaccination guidelines
Vaccine studies in patients undergoing treatment with cellular therapies remain limited.Thus, vaccination schedules are derived largely from expert opinion and mirror the advice surrounding autoHCT.

Vaccinations prior to CAR-T
As demonstrated by the seroprevalence surveys, most patients who demonstrated humoral antibody response to vaccine-specific pathogens prior to CAR-T, maintained seropositivity at followup. 110,111,116Optimizing timely revaccination following autoHCT or HCT might potentially improve seroprotection in the event of relapse and subsequent need for CAR-T therapies.
Considering the epidemic nature of both influenza and SARS-CoV-2, the EBMT/JACIE/EHA and ASH-ASTCT consensus guidelines advocate for vaccination against SARS-CoV-2 and influenza at least 2 weeks prior to lymphodepletion, citing the likely lack of vaccine response after CAR-T infusion due to B-cell aplasia. 75,138Expert commentary has extended this recommendation to include pre-CAR-T vaccination against S. pneumoniae and hepatitis B in high endemicity areas and consideration of vaccination of household contacts. 100

Vaccinations following CAR-T
Vaccine selection and dosing intervals for CAR-T patients mimic guidelines for HCT summarized in Table 1.Revaccination post-CAR-T is derived from expert consensus, center and physician opinion, with general recommendations summarized in Table 3 and an example vaccination schedule in Table 4. 99 Consensus guidelines advise that killed or inactivated vaccines be administered ≥3 months after CAR-T administration.Patients should demonstrate immune reconstitution prior to vaccination, defined as CD4+ >0.2 × 10 9 /L, CD19 or CD20+ B cells >0.2 × 10 9 /L. 99,138,139tients should not be receiving concomitant immunosuppressive treatment including cytotoxic chemotherapy, systemic corticosteroids, T-cell-depleting or anti-lymphocyte agents, or IVIg within the previous 2 months. 99,138,139Certain immunotherapies may not be considered additionally immunosuppressive in the context of inactivated vaccines, such as checkpoint inhibitors, or immunomodulatory agents. 139 The exception is the influenza vaccine, which should be given annually prior to the expected influenza season, and ideally 2 weeks prior to lymphodepleting chemotherapy. 93ve vaccines should be different until at least 1 year following CAR-T and require demonstration of immune reconstitution.Several expert groups suggest that live vaccines are contraindicated within 8 months of receiving IVIg replacement. 138Expert centers, for example, the Fred Hutchinson Cancer Center, recommend delaying live and non-live adjuvant vaccines until ≥5 months from last IVIg replacement. 139Further expert commentary has suggested that before live and non-live adjuvant vaccines, vaccine responses to killed/attenuated vaccines should be demonstrated. 99,139

Future directions
For HCT recipients, owing to differences in conditioning regimen, stem cell source, and underlying disease, there is an opportunity to refine and personalize revaccination schedules for autologous HCT recipients rather than extrapolating from allogeneic HCT recipients.Ongoing Methods to heighten immunogenicity, including booster regimens, should also be explored.

CONCLUSION
In summary, there are well-recognized vaccine schedules for the HCT population, with new vaccine formulations including PCV20, aRZV, and bivalent booster COVID-19 vaccines that require ongoing assessment.
Revaccination post-cellular therapies at present mostly follow the HCT schedule, but further research is required to optimize the timing of vaccine delivery and clarify which vaccines would be of most benefit to the cellular therapy patients.

TA B L E 1
Recommended vaccines and timing post-hematopoietic cell transplant (HCT) from established international guidelines.