Humoral Immunity After MRNA SARS-CoV-2 Vaccination in Allogeneic HCT Recipients—Room For Improvement And Much To Learn

“Will the vaccine work? Should I check an antibody titer? How do I interpret the results”? Questions like these from hematopoietic cell transplant (HCT) recipients and their healthcare practitioners are currently a daily reality for hematologists/oncologists and infectious disease physicians. 

Our challenge is to provide evidence-based answers for immunocompromised patients about the fundamentals of how to resume their lives in the continuously evolving world in which SARS-CoV-2 is here to stay. For allogeneic HCT recipients, answers to these questions are particularly urgent given an observed overall survival rate of only 68% within 1 month after a COVID-19 diagnosis.

Allogeneic refers to the admixture between individuals from the same species but who differ genetically. Allotypes with the same blood type, usually have a higher degree of mutual recognition and lower rejection in terms of immunity. This is because their leukocyte antigens (HLA) are similar, making them less antigenically heterogeneous to each other. However, allografts of different blood types, usually have a high rejection reaction in terms of immunity. This is because their HLA differences are large, and they produce obvious antigenic heterogeneous reactions with each other, which triggers the immune system to produce inflammatory and rejection reactions. For allografts, recipients are given immunosuppressants to reduce rejection. 

In addition, the selection of an allogeneic donor with a high degree of HLA matching increases the likelihood of successful transplantation. Therefore, it can be said that the relationship between allogeneic and immunity is mainly determined by their HLA matching. So in our life, we need to understand the importance of improving immunity. Cistanche can enhance immunity in our life. Cistanche contains a variety of biologically active ingredients, such as polysaccharides, two mushrooms, and Huang Li. etc. These ingredients can stimulate various cells of the immune system and increase their immune activity.

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Le Bourgeois and colleagues2 provide some of the first data to inform these important questions. They conducted a single-center prospective observational study of 2 doses of the BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech) administered to 117 allogeneic HCT recipients more than 3 months post-HCT and without the active graft-vs-host disease (GVHD). Binding antibody (IgG) responses to the SARS-CoV-2 spike protein receptor-binding domain were tested with a semiquantitative assay (Elecsys® anti-SARS-CoV-2-S) immediately before and a median of 35 days after the second vaccine dose. 

After the first dose, 54% of participants were seroconverted (titer 0.8 arbitrary units [AU]/mL) with median titers of 15.8 AU/mL. After the second dose, 83% of participants were seropositive. Titers above the upper limit of quantitation (250 AU/mL) were observed in 3.4% of participants after the first vaccine compared to 61.5% after the second, although dilutions were not performed to determine the range of actual titers. 

All 4 patients with prior COVID-19 infection developed titers greater than 250 AU/mL. When stratified by clinical and immunologic characteristics, responses were substantially lower (50%-65%) in patients vaccinated within 12 months of HCT and those with lymphopenia (<1000 cells/μL) or on immunosuppression; these individuals also had lower absolute titers. There were no serious adverse events based on questionnaires administered for the first 7 days after each vaccine dose, although no details were provided about the incidence of GVHD exacerbations.

These data paint a similar picture compared with recently reported studies in allogeneic HCT recipients and other highly immunocompromised patients. In a comparably designed study including allogeneic HCT recipients receiving a 2-dose mRNA SARS-CoV-2 vaccine regimen and tested with the same serologic assay, seroconversion was observed in 75% of 57 tested participants, with median titers of 178 AU/mL.3 SARS-CoV-2–specific T-cell responses were documented by enzyme-linked immune absorbent spot assay in 19% of 37 tested individuals, all of whom also seroconverted. As in the current study, the majority of participants were also more than 12 months post-HCT, and seroconversion was positively associated with longer duration since HCT. The authors also demonstrated a positive association between seroconversion and higher CD19+ B-cell counts (but not CD4+ T-cell counts). 

Approximately 5% of patients developed transient grade 3-4 cytopenias, and 5% developed GVHD exacerbations after each vaccination, but manifestations were readily controlled with immunosuppressants. Another study demonstrated a similar spectrum of adverse effects and concluded that mRNA SARS-CoV-2 vaccines appear to be relatively safe after allogeneic HCT.4

The findings of these first observational reports are consistent with expected vaccine responses in allogeneic HCT recipients based on studies using other vaccines. Guidelines generally recommend administering routine nonlive vaccines at least 6 months after HCT gave the pattern of immune reconstitution and relatively poor response rates (<50%) at earlier time points, although earlier vaccination can be considered for pathogens such as influenza in the context of community outbreaks.5 

In a randomized noninferiority trial in which the 7-valent pneumococcal conjugate vaccine (PCV7; Prevnar) 3-dose series was administered at 3 months vs 9 months after allogeneic HCT, similar response rates of approximately 80% were demonstrated, although the humoral immune response appeared to be less durable in the early vaccination cohort. 

Among participants who did not have a response, subsequent vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) resulted in seroconversion in an additional 41%. Based on historical data such as these, the National Comprehensive Cancer Network and other foundations recommend consideration for SARS-CoV-2 vaccination as early as 3 months post-HCT.

With well over 10 000 allogeneic HCTs performed per year in the United States alone, there remains a large population of patients at high risk for morbidity from COVID-19. While overall vaccine response rates are encouraging in the reported studies, the cohorts were dominated by patients more than 12 months post-HCT, and vaccine responses were less reassuring in the earlier periods after HCT. Additionally, the absolute antibody titers achieved among those who seroconverted are substantially lower than those in healthy controls, which are typically greater than 1000 AU/mL.6 

While we have learned a lot about SARS-CoV-2 vaccination in healthy and immunocompromised patients, many questions remain to be answered. The search for an antibody titer threshold that accurately predicts protection from infection and disease is ongoing, but a dose-response relationship is likely. None of the available studies in HCT recipients report neutralizing antibody titers, which may not completely correlate with binding antibody titers but are better surrogates for protection from severe COVID-19.7 

Our understanding of the frequency and nature of SARS-CoV-2-specific T-cell responses remains limited in this patient population. Furthermore, there are no well-established clinical or immunologic variables that predict vaccine responsiveness for any vaccine in HCT patients. Finally, all the available data after HCT are derived from patients receiving mRNA SARS-CoV-2 vaccines; the immunogenicity of other formulations may differ.

The available data collectively demonstrate that SARS-CoV-2 vaccination should continue to be a priority after allogeneic HCT but is only one aspect of a broader management strategy. 

For now, patients who are in the first year after HCT or remain otherwise immunosuppressed should regard SARS-CoV-2 as a serious threat despite vaccination and follow behaviors with which they are already familiar: avoiding high-risk exposures, masking, hand hygiene, and ensuring that their close contacts are vaccinated. Strategies to better protect HCT recipients from SARS-CoV-2 infection remain a high priority for the medical community. Approaches under investigation include homologous or heterologous booster vaccination(s), for which there is clinical precedent using standard (eg, hepatitis B virus) or SARS-CoV-2 vaccines in other contexts. Trials of prophylactic monoclonal antibody or T-cell infusions are also underway. 

For infected individuals, a variety of therapies are currently available, but efficacious antivirals that can be easily administered both inside and outside of hospital settings are still desperately needed. The preliminary findings reported here are reasons for optimism, yet there is clearly room for improvement and much more to learn about preventing and managing COVID-19 after allogeneic HCT.

ARTICLE INFORMATION

Published: September 14, 2021. doi:10.1001/jamanetworkopen.2021.27454

Open Access: This is an open-access article distributed under the terms of the CC-BY License. © 2021 Hill JA. JAMA Network Open.

Corresponding Author: Joshua A. Hill, MD, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Mail Stop E4-100, Seattle, WA 98109 (jahill3@fredhutch.org).

Author Affiliations: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Allergy and Infectious Diseases, University of Washington, Seattle.

Conflict of Interest Disclosures:

Dr. Hill reported grants and personal fees from Gilead Sciences; personal fees from Amplyx; grants and personal fees from Allovir; personal fees from Allogene therapeutics, CRISPR therapeutics, CSL Behring, Optum Health, and Octapharma; grants and personal fees from Takeda; and grants from Karius outside the submitted work.

Additional Contributions:

The author thanks Paul Carpenter, MBBS, and Ashley Sherrid, Ph.D. (both of Fred Hutchinson Cancer Center, Seattle, Washington), for their insights and review of the manuscript. They were not compensated.

REFERENCES

1. Sharma A, Bhatt NS, St Martin A, et al. Clinical characteristics and outcomes of COVID-19 in hematopoietic stem-cell transplantation recipients: an observational cohort study. Lancet Haematol. 2021;8(3):e185-e193. doi:10. 1016/S2352-3026(20)30429-4 

2. Le Bourgeois A, Coste-Burel M, Guillaume T, et al. Safety and antibody response after 1 and 2 doses of BNT162b2 mRNA vaccine in recipients of allogeneic hematopoietic stem cell transplant.JAMA Netw Open. 2021;4(9): e2126344. doi:10.1001/jamanetworkopen.2021.26344 

3. Ram R, Hagin D, Kikozashvilli N, et al. Safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients after allogeneic HCT or CD19-based CART therapy—a single-center prospective cohort study. Transplant Cell Ther. 2021;(June):S2666-6367(21)01027-7. doi:10.1016/J.JTCT.2021.06.024 

4. Ali H, Ngo D, Aribi A, et al. Safety and tolerability of SARS-CoV-2 emergency-use authorized vaccines allogeneic hematopoietic stem cell transplant recipients. Transplant Cell Ther. 2021;(July):S2666-6367(21)01073-3. doi:10. 1016/j.jtct.2021.07.008 

5. Tomblyn M, Chiller T, Einsele H, et al; Center for International Blood and Marrow Research; National Marrow Donor Program; European Blood and MarrowTransplant Group; American Society of Blood and Marrow Transplantation; Canadian Blood and Marrow Transplant Group; Infectious Diseases Society of America; Society for Healthcare Epidemiology of America; Association of Medical Microbiology and Infectious Disease Canada; Centers for Disease Control and Prevention. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009;15(10):1143-1238. doi:10. 1016/j.bbmt.2009.06.019 

6. Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood. 2021;137(23):3165-3173. doi:10.1182/blood.2021011568 

7. Dispinseri S, Secchi M, Pirillo MF, et al. Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival. Nat Commun. 2021;12(1):2670. doi:10.1038/s41467-021-22958-8

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