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Figure 1.  Study Schema Diagram
Study Schema Diagram
Figure 2.  Human Papillomavirus (HPV)–Type-Specific Antibody Response to Quadrivalent Vaccine by Study Cohort Over Time, Measured by Enzyme-linked Immunosorbent Assay
Human Papillomavirus (HPV)–Type-Specific Antibody Response to Quadrivalent Vaccine by Study Cohort Over Time, Measured by Enzyme-linked Immunosorbent Assay

A, HPV-6. B, HPV-11. C, HPV-16. D, HPV-18. Geometric mean antibody levels with geometric SDs were plotted at day 1 (prevaccine baseline) and months 2, 6, 7, and 12 after the first vaccination. The blue circles represent hematopoietic stem cell transplant participants (HCT) receiving immunosuppression therapy (IST), the orange squares represent HCT not receiving IST, and the grey triangles represent healthy volunteers. Levels lower than the cutoff were given the value of 4 EU/mL.

Table 1.  Baseline Characteristics
Baseline Characteristics
Table 2.  Geometric Mean Level Ratio at Month 7 and Month 12 vs Baseline for HPV-6, -11, -16, and -18a
Geometric Mean Level Ratio at Month 7 and Month 12 vs Baseline for HPV-6, -11, -16, and -18a
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    1 Comment for this article
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    Quadrivalent human papillomavirus vaccination in women after hematopoietic allogeneic stem cell transplant
    Tomoyuki Kawada, MD | Nippon Medical School
    Stratton et al. determined the safety and immunogenicity of the quadrivalent human papillomavirus (HPV) vaccine (HPV-6, -11, -16, and -18) in women with post-allogeneic transplant (1). Among 64 vaccinated women, 23 were receiving immunosuppressive therapy, 21 were not receiving immunosuppression, and 20 were healthy volunteers, and there was a significant difference in the percentage of developing antibody responses to all quadrivalent HPV vaccine types, presenting 78.3%, 95.2%, and 100%, respectively. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 highly correlated at month 7, presenting Spearman's ρ of 0.92, and adverse events were mild in each group. The authors recommended HPV vaccination to women with posttransplant for reducing HPV infection and related neoplasia incidence. I have a concern about their study.

    Majeed et al. reported the role of HPV and other vaccines in immunocompromised hematopoietic stem cell transplant recipients (2). Although live vaccines should be avoided, transplant recipients should get inactive vaccinations to prevent the target infection and subsequent adverse health effect. They mentioned that there is paucity of clinical data in patients with receiving vaccination, and I think that more clinical trials, regardless of randomization, are needed to specify the efficacy and safety of the quadrivalent HPV vaccine in women with post-allogeneic transplant.


    References
    1. Stratton P, Battiwalla M, Tian X, et al. Immune Response Following Quadrivalent Human Papillomavirus Vaccination in Women After Hematopoietic Allogeneic Stem Cell Transplant: A Nonrandomized Clinical Trial. JAMA Oncol. 2020 May 1;6(5):696-705.
    2. Majeed A, Harris Z, Brucks E, et al. Revisiting Role of Vaccinations in Donors, Transplant Recipients, Immunocompromised Hosts, Travelers, and Household Contacts of Stem Cell Transplant Recipients. Biol Blood Marrow Transplant. 2020 Feb;26(2):e38-e50.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    Original Investigation
    February 27, 2020

    Immune Response Following Quadrivalent Human Papillomavirus Vaccination in Women After Hematopoietic Allogeneic Stem Cell Transplant: A Nonrandomized Clinical Trial

    Author Affiliations
    • 1Office of the Clinical Director, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
    • 2Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
    • 3Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
    • 4Sarah Cannon Research Institute, Nashville, Tennessee
    • 5Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
    • 6Clinical Center, National Institutes of Health, Bethesda, Maryland
    • 7Riverside Regional Medical Center, Newport News, Virginia
    • 8Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    • 9GW Cancer Center, The George Washington University Hospital, Washington, DC
    • 10University of Kansas School of Medicine, Kansas City
    • 11Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
    • 12Experimental Transplant and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
    • 13Rapa Therapeutics, Rockville, Maryland
    • 14Infectious Diseases Division, Mayo Clinic Arizona, Phoenix, Arizona
    • 15Hematopoietic Stem Cell Transplant and Cell Therapy, Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
    • 16HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
    • 17Office of New Drugs, Center for Drug Evaluation and Research, Division of Anesthesia, Analgesia, and Addiction Products, US Food and Drug Administration, Silver Spring, Maryland
    • 18Office of the Clinical Director, National Human Genome Research Institute, Bethesda, Maryland
    • 19DDL Diagnostic Laboratory, Rijswijk, the Netherlands
    • 20Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
    • 21University of Virginia School of Medicine, Charlottesville
    • 22Rittenhouse Women's Wellness Center, Philadelphia, Pennsylvania
    • 23Department of Hematology/Oncology, MedStar Washington Hospital Center, Washington, DC
    • 24Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, Frederick, Maryland
    • 25Children’s Research Institute, Children’s National, Washington, DC
    • 26Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
    • 27PDS Biotechnology, Berkeley Heights, New Jersey
    JAMA Oncol. 2020;6(5):696-705. doi:10.1001/jamaoncol.2019.6722
    Key Points

    Question  Is the quadrivalent human papillomavirus (HPV) vaccine immunogenic in reproductive-aged women after hematopoietic stem cell transplant?

    Findings  In this open-label nonrandomized clinical trial that included 64 women, most of the clinically stable reproductive-aged women who underwent allogeneic hematopoietic cell transplant, including those receiving immunosuppression, developed robust anti-HPV neutralizing antibody responses after vaccination similar to those observed in healthy women.

    Meaning  These findings suggest that the full HPV vaccine series might be administered to reproductive-aged women after allogeneic hematopoietic stem cell transplant and that the current use of immunosuppression or prior use of rituximab after transplant does not preclude vaccination.

    Abstract

    Importance  Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms.

    Objective  To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post–allogeneic transplant compared with female healthy volunteers.

    Interventions  Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later.

    Design, Setting, and Participants  This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019.

    Main Outcomes and Measures  Anti-HPV-6, -11, -16, and -18–specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay.

    Results  Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P < .001) but not significantly different across groups. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 correlated at month 7 (Spearman ρ = 0.92; P < .001 for both). Adverse events were mild and not different across groups.

    Conclusions and Relevance  Treatment with the HPV vaccination was followed by strong, functionally active antibody responses against vaccine-related HPV types and no serious adverse events. These findings suggest that HPV vaccination may be safely administered to women posttransplant to potentially reduce HPV infection and related neoplasia.

    Trial Registration  ClinicalTrials.gov Identifier: NCT01092195

    Introduction

    Human papillomavirus (HPV) infection causes cancer of the cervix, anogenital area, and oropharynx as well as genital and cutaneous warts.1,2 Persistent infection with high-risk, oncogenic HPV types, particularly HPV-16 and -18, is an established prerequisite for the development of cervical cancer; low-risk types HPV-6 and -11 are responsible for most genital warts.1,3 In healthy individuals, infection to cancer development typically has a long latency.3,4

    Allogeneic hematopoietic stem cell transplant is a form of cellular therapy that replaces the recipient’s hematopoiesis, including the humoral and cellular immune compartments. Long-term survivors of allogeneic cell transplant are at risk for infections and malignancy.5-7 Human papillomavirus–associated genital neoplasia, a frequent late complication after hematopoietic cell transplant in women, and HPV infection elsewhere contribute substantially to the high burden of HPV-related comorbidity and secondary malignancy in these survivors.5,6,8 The HPV disease arises in the setting of immune dysregulation, impaired cell-mediated immunity, consequences of the transplant process, and the immunosuppressive treatment of graft vs host disease.9,10 Hysterectomy does not protect women from developing HPV-related neoplasia in other anogenital or extragenital sites.6

    While vaccination is encouraged following allogeneic hematopoietic cell transplant, the immunogenicity of vaccines in this immunosuppressed population is uncertain.9-11 Quadrivalent HPV vaccine to prevent acquisition of HPV-6, -11, -16, and -18 is safe and immunogenic in healthy reproductive-aged women conferring durable immunity.12-15 As sexual activity resumes after transplant and women remain immune-compromised, their risk of acquiring HPV is increased, especially with a new sexual partner. Reports of HPV disease developing years post–allogeneic transplant suggest a period to augment immunity through vaccination.6 We assessed the safety and immunogenicity of quadrivalent HPV vaccine in women after allogeneic hematopoietic cell transplant (including some taking immunosuppression) by measuring humoral and neutralizing HPV-specific immunity and compared them with healthy female volunteers.

    Methods
    Study Design

    We conducted a prospective study of the immunogenicity and adverse effects of quadrivalent HPV vaccine in clinically stable, nonpregnant women and female healthy volunteers age 18 to 50 years (eAppendix in the Supplement). Healthy volunteers and participants who were at least 90 days post–allogeneic cell transplant were recruited across the Intramural Research Program at the National Institutes of Health Clinical Center from May 2010 to March 2016. We included posttransplant participants taking stable doses of immunosuppressive treatment. Women posttransplant with malignancy, life-threatening infections or uncontrolled chronic graft vs host disease, prior HPV vaccination, or HPV-related genital neoplasia requiring treatment were excluded. The study was approved by the National Institute of Child Health and Human Development institutional review board (NCT01092195). Written informed consent was provided by participants. Recording race/ethnicity was part of the National Institutes of Health policy regarding study participation and was classified by participants.

    Transplant history, immunosuppressive medication use, and examination for extent of chronic graft vs host disease (including genital graft vs host disease) were recorded.16 Posttransplant immunosuppressive treatment, generally used to prevent or treat graft vs host disease, varied but typically included low doses of prednisone (<0.5 mg/kg), calcineurin inhibitors, sirolimus, or mycophenolate mofetil either alone or in combination. Healthy volunteers underwent a history and physical examination to confirm eligibility. Participants underwent gynecologic genital examination to identify HPV-related condyloma or high-grade squamous intraepithelial lesions (SILs) and obtain exfoliated cervical cells for cytology, HPV cotesting for high- and low-risk types (Hybrid Capture Test; Quest Diagnostics Nichols Institute), and a cervical mucosal sample for HPV polymerase chain reaction (PCR). Abnormal cytology results were described using the Bethesda 2001 classification system17 and clinically apparent HPV-related disease was evaluated using the American Society for Colposcopy and Cervical Pathology guidelines, including colposcopy and biopsy where indicated.18

    Vaccine Dosing

    The quadrivalent HPV vaccine (HPV-6, HPV-11, HPV-16, and HPV-18; Gardasil; Merck) was administered using the US Food and Drug Administration (FDA)–approved regimen of 3 separate 0.5 mL intramuscular injections at 0, 2, and 6 months. At vaccination visits, vital signs were obtained before and after vaccine administration. Participants recorded oral temperatures daily for 5 days after vaccination, injection site reactions, and systemic adverse events on a vaccination report card. Participants were contacted 2 to 3 days after vaccination to assess adverse reactions.

    Follow-up

    Before each vaccination and at 1 and 6 months after completing the vaccine series (study months 7 and 12), peripheral blood was obtained for complete blood cell count with differential, lymphocyte subsets and serum for research laboratories. Sexual activity was assessed19 and buccal mucosal specimens obtained for HPV type–specific testing at baseline, 7 months, and 12 months. At 12 months, a pelvic examination was conducted for cytology, HPV cotesting, and HPV type–specific testing; transplant participants underwent systemic and genital graft vs host disease assessment.16

    Immunological Measurements

    Anti-HPV-6, -11, -16, and -18–specific antibody levels by enzyme-linked immunosorbent assay (ELISA) were measured pre- (day 1) and postvaccination at months 2, 6, 7, and 12. Neutralization titers for HPV-16 and -18 were determined by pseudovirion-based secreted alkaline phosphatase neutralization assays 1 month after the last dose (month 7) in a single batch as previously described.20 All virus-like particles and pseudovirions used were produced at the HPV Immunology Laboratory at the Frederick National Laboratory for Cancer Research (Frederick, Maryland) as previously reported.21 Antibody levels determined by ELISA were expressed as ELISA units (EU)/mL and the seropositivity cutoffs were 8 EU/mL for anti-HPV-16 and 7 EU/mL for the others (eMethods in the Supplement). The HPV-16 and HPV-18 ELISA has been calibrated with the respective World Health Organization International Standards (HPV-16: 1 IU/mL = 5.75 EU/mL and HPV-18: 1 IU/mL = 6.81 EU/mL).

    HPV DNA Measurements

    DNA from each oral specimen was extracted via the MagNAPure LC DNA isolation procedure (Roche Diagnostics) as previously described.22 The extracted DNA samples were then tested for HPV DNA by PCR amplification using the HPV short PCR fragment 10 PCR DNA enzyme immunoassay LiPA25 (line probe assay) 25, version 1 (Labo Biomedical Products), which uses short PCR fragment 10 primers and LiPA25 line probe assay to provide the genotype of 26 alpha HPV types, including 12 carcinogenic (HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, and -59) and 14 noncarcinogenic (HPV-6, -11, -34, -40, -42, -43, -44, -53, -54, -66, -68, -73, -70, and -74) types.23,24

    DNA from each cervical specimen was extracted after lysis and purified by ultrafiltration. Extracted DNA samples were then tested for HPV DNA by PCR amplification using the TypeSeq HPV genotyping assay, which targets 51 HPV types, followed by next-generation sequencing25 (eMethods in the Supplement).

    At baseline, participants were considered currently negative for HPV if they had normal cervical cytology results, negative pooled testing for HPV types, negative serology results for HPV-6, -11, -16, and -18 antibodies, and no history of cervical/genital treatment. Participants were classified as having HPV if they had abnormal cytology results (American Society for Colposcopy and Cervical Pathology criteria), HPV lesions on pelvic examination, or were positive on HPV pooled testing results. The HPV type–specific testing on oral and cervical specimens were ascertained as described previously.

    Statistical Methods

    The power and sample size were calculated based on the primary outcome of assessing the difference between anti-HPV-6, -11, -16, and -18 antibody levels at prevaccine (day 1) and postvaccination levels at month 7 (1 month after series completion) or month 12. We hypothesized that those receiving immunosuppressive treatment would have a significantly lower response than those off immunosuppression or healthy volunteers. With 20 participants in each cohort, we had more than 95% power to detect a 1.5-SD effect size between any 2 cohorts, using a 2-sided independent 2-sample z test at the significance level of .002. This adjusted α level allows for a conservative Bonferroni correction for multiple comparisons for the primary outcome. Anticipating loss to follow-up and missing samples, we planned to enroll up to 24 participants per group.

    The analysis was conducted according to the study group at enrollment regardless of changes in immunosuppression for clinical indications. For baseline patient and transplant-related characteristics, the Kruskal-Wallis test and Wilcoxon rank-sum test were used to compare the continuous variables and the Fisher exact test to compare the categorical variables between study cohorts.

    Because the ELISA antibody levels were not normally distributed, the geometric mean level with 95% confidence intervals was reported. The geometric mean level ratio (GMR) and 95% CIs were used to summarize the primary vaccine outcome between pre- and postvaccination. The Kruskal-Wallis test was used to compare the difference in GMR among 3 study groups and the Wilcoxon rank-sum test was used to assess the pairwise differences in GMR between study groups using a significance level of .002. As a secondary outcome, the vaccine response at months 7 and 12 was defined as any increase in antibody levels from baseline by ELISA. The Fisher exact test was used to compare the proportions of participants who developed antibody responses among the 3 study groups. Correlations between neutralizing anti-HPV-16 and -18 antibody titers and ELISA antibody levels at month 7 were assessed by the Spearman rank correlation. Baseline participant and transplant covariates, including age at vaccination, baseline HPV antibody level, time from transplant, stem cell source, donor sex and age, IgG, and cluster of differentiation (CD) 4 and CD19 levels at baseline or month 7 were examined to assess their effect on the immunogenicity of quadrivalent HPV using a multiple linear regression adjusted for the patient study group. Adverse events were analyzed by participant and vaccination. These events were categorized by the worst severity for each symptom after any vaccination. For each symptom, each participant was counted once. Individual participants could have more than one symptom.

    All tests were 2-sided. For comparisons of secondary outcomes, adverse events and covariate differences among the study groups, P < .05 indicated a possible trend toward a significant association. The analysis was performed using R statistical software, version 3.6.1 (R Foundation for Statistical Computing).

    Results
    Participants

    Sixty-five nonpregnant women were enrolled; 1 withdrew prior to vaccination (Figure 1). Twenty-three of 44 women who were postallogeneic cell transplant (52.3%) were receiving systemic immunosuppressive treatment (eTable 1 in the Supplement) and 20 (31.3%) were healthy female volunteers (Table 1). All vaccinated participants completed the vaccine series and the 7- and 12-month follow-up visit. Groups were similar for age (median, 34.3 years [receiving immunosuppressive treatment; range, 18.6-48.1], 32.2 years [not receiving immunosuppression; range, 18.3-49.9], and 32.9 years [controls; range, 23.0-45.8]; P = .40). Other baseline characteristics were comparable, except for race/ethnicity (Table 1).

    Transplant Characteristics

    Baseline transplant-related characteristics were similar across cohorts (Table 1). Most underwent transplant for malignancy (27/44 [61.4%]), received peripheral blood stem cells (35/44 [79.5%]), and underwent reduced-intensity conditioning (30/44 [68.2%]). Factors identified that would potentially delay immune reconstitution included T-cell depletion (16/44 [36.4%]), development of either acute (17/44 [38.6%]) or active extensive chronic graft vs host disease (13/44 [29.5%]), or posttransplant treatment with rituximab before (8/44 [18.2%]) or during the study (2/44 [4.5%]). The vaccine was administered between 5 months to 12.5 years posttransplant (median, 1.3 years receiving and 2.3 years not receiving immunosuppressive treatment).

    Baseline HPV Status

    At baseline, 11 (17.2%), 9 (14.1%), 24 (37.5%), and 32 (50%) participants had detectable anti-HPV-6, -11, -16, and -18 antibodies by ELISA, respectively (eFigure 1 and eTable 2 in the Supplement). Fewer posttransplant participants not receiving immunosuppression had anti-HPV-18 antibodies (6 not receiving immunosuppression [28.6%] vs 12 receiving immunosuppression [52.2%] vs 14 health volunteers [70%]; P = .03).

    More than half were currently sexually active. Eighteen of 64 (28.1%) were currently negative for HPV and 21 others (32.8%) had prior or current evidence of HPV infection (Table 1); among women undergoing colposcopy, only low-grade SIL was identified. In baseline cervical samples, 4 of 64 women (6.3%) carried either HPV-16 (n = 3) or HPV-18 (n = 1), but none carried HPV-6 or -11 (eTable 3 in the Supplement). No quadrivalent HPV vaccine types occurred in buccal samples.

    Vaccine Adverse Effects

    Adverse events did not differ between healthy volunteers and women posttransplant (eTable 4 in the Supplement). Some posttransplant participants (7 receiving immunosuppression [30.4%]; 5 not receiving immunosuppression [23.8%]) received other vaccines concurrently. Adverse effects were predominately limited mild injection site reactions that resolved within a few days without treatment. No detectable flares of graft vs host disease occurred after vaccination.

    HPV Vaccine Response at 7 and 12 Months

    After vaccine series completion, 18 of 23 patients receiving immunosuppressive treatment (78.3%), 20 of 21 (95.2%) not, and all 20 healthy volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04 comparing across the 3 groups; eFigure 1 in the Supplement). The other 6 participants (5 posttransplant receiving immunosuppression and 1 not) had an antibody response to some but not all HPV types (eTable 1 in the Supplement).

    Mean antibody levels after vaccination were significantly higher than baseline at month 7 and 12 for each HPV type and study group (all geometric mean ratios >1; P < .001; eTable 5 in the Supplement; Figure 2). At month 7 or 12, the change in HPV antibody levels from baseline was not significantly different between the 2 posttransplant groups or between either posttransplant group and healthy volunteers (Table 2; Kruskal-Wallis test; all P > .05). Neutralization assay titers for anti-HPV-16 and -18 strongly correlated with ELISA antibody levels at month 7 (Spearman ρ = 0.92; P < .001 for both; n = 61; eFigure 2 in the Supplement).

    Patient Characteristics and Immunogenicity

    As observed in the general population, a lower magnitude of response was associated with increasing age among all women for anti-HPV-6 and -1126 (eFigure 3 in the Supplement). The time from transplant was not associated with the vaccine response for any anti-HPV antibody type (eFigure 4 in the Supplement). No other baseline parameters were associated with immunogenicity. In the transplant cohorts, lower CD19 T-cell subsets at month 7 were associated with a lower magnitude of response across anti-HPV antibody types (eFigure 5 in the Supplement). Among the 10 patients (22.7%) who had received rituximab posttransplant, 5 (1 receiving immunosuppression and 4 not) had an antibody response while the remaining 5 had either a poor response (3 receiving immunosuppression) or a blunted antibody response (2 receiving rituximab during the vaccination series).

    Discussion

    Most clinically stable reproductive-aged women who underwent allogeneic hematopoietic cell transplant, including those receiving immunosuppression, developed robust neutralizing anti-HPV antibody responses after vaccination that were not significantly different from those in healthy women. Although immune response to all 4 HPV vaccine types tended to be less likely in women posttransplant who were receiving immunosuppression than healthy women, the magnitude of response among those responding in the receiving immunosuppression and not receiving immunosuppression cohorts approached those of healthy controls after completion of the full vaccine series. Of the 6 patients with poor response to HPV vaccination (9.4%), 5 were receiving immunosuppression, including 3 who had received prior rituximab. Overall, antibody concentrations measured by ELISA were highly associated with neutralizing antibody titers as previously described.27 Adverse effects were time-limited and mild. Human papillomavirus vaccination was well tolerated after transplant and did not precipitate graft vs host disease flares, even when combined with other routine vaccinations.

    Predictably, posttransplant rituximab use, which results in B cell lymphopenia, was the strongest factor associated with impaired response to the HPV vaccine as observed in other vaccine studies after rituximab.28 These findings are consistent with the observations that rituximab eliminates peripheral B cell memory in a dose-dependent manner,29 a depletion that may be prolonged.30 Importantly however, 5 of 8 participants (63%), of whom 4 were not receiving immunosuppression, developed anti-HPV responses to vaccination despite rituximab exposure at least 6 months previously; other reports suggest that such patients may develop a vaccine response.31

    The HPV vaccination schedules used after allogeneic hematopoietic cell transplant were recommended by expert transplant and infectious disease committees following population-based age recommendations.9,10 Importantly, vaccination was recommended regardless of whether the recipient or donor had undergone previous HPV vaccination before the transplant. Generally, responses to vaccines comprising proteins like the quadrivalent HPV vaccine are more immunogenic than polysaccharide vaccines.32 To our knowledge, unlike other vaccinations, the lowest level of antibodies that provides protection following HPV vaccination is unknown. However, achieving antibody levels following vaccination that are greater than those observed following natural infection could be considered potentially efficacious.32 Additionally, HPV vaccines exhibit crossreactivity against nonvaccine HPV types.32 Although the HPV vaccine was shown to be highly immunogenic in the posttransplant setting, our study suggested that those who continued to receive immunosuppression or who had CD19 lymphopenia because of having received rituximab were less likely to mount antibody responses to all types in the vaccine. While these individuals might benefit from later or subsequent vaccination, studies are needed to confirm our findings and determine appropriate recommendations for these groups of patients.

    As quadrivalent HPV vaccine is not a therapeutic vaccine, women warranting treatment for HPV were excluded. Study participants with low-grade SIL were followed closely to enable early treatment of worsening HPV disease. Only half of the posttransplant women were sexually active. Some showed prior immunity to HPV types or had undergone HPV treatment, yet few carried types found in the quadrivalent HPV (4 [6.3%]) or nonavalent HPV (10 [15.6%]) vaccine (Merck; eTable 3 in the Supplement). These study participants would potentially benefit from vaccination to protect them against new HPV infections. This approach follows clinical guidelines to administer HPV vaccine regardless of current HPV infection.33 The vaccine would not have a therapeutic effect against types currently causing HPV disease yet can boost immunity to other vaccine types26,34 and possibly protect against de novo exposure to new HPV infections.

    Strengths and Limitations

    One strength of our study was the adherence to the study schedule by participants because of multidisciplinary collaboration among investigators. Cohorts were well-matched for age and demographic characteristics; recipients were clinically stable at a median of 2.1 years after transplant. Importantly, despite heterogeneity in transplant regimens and a small sample size, the vaccine response across transplant survivors was similar in magnitude.

    Our study has several limitations; the cohort was relatively small and only included women, some of whom were recruited late after transplant. Disparities in the kinetics of immune recovery within the posttransplant group may be partially due to transplant diversity.9 Posttransplant participants were allowed but not required to receive other vaccinations, making it easier to recruit participants but more difficult to attribute adverse effects exclusively to quadrivalent HPV vaccination. Human papillomavirus carriage may be underestimated by sampling only the cervix and oral cavity with the sampling techniques used. We studied only the quadrivalent HPV vaccine, which is now replaced by a nonavalent HPV vaccine that protects against acquiring HPV-6, -11, -16, and -18 and 5 additional oncogenic HPV types.21,35 Given the small sample size and transplant diversity, it is unknown whether these results are generalizable to men, all types of allogeneic transplant, or other immunosuppression regimens.

    Conclusions

    To our knowledge, this prospective study is the first to show the immunogenicity and functional neutralizing antibody activity induced by HPV vaccination after allogeneic hematopoietic cell transplant. Human papillomavirus vaccination increases HPV-specific immunity, protects against incident HPV infection and related neoplasia, and thus may decrease HPV disease occurrence.3,32 As recommended after transplant, the full vaccine series should be administered. Reproductive-aged men who are at risk of oropharyngeal and anogenital HPV infection may also benefit from vaccination. Importantly, the current use of immunosuppression or prior use of rituximab after transplant should not preclude vaccination. However, to maximize vaccine immunogenicity, one could consider delaying HPV vaccination until immunosuppression is discontinued and CD19 lymphopenia has resolved. Given the high HPV incidence and generally later occurrence of HPV disease after transplant, our results suggest that vaccinating women up to age 50 years, an expanded age range recently approved by the FDA for HPV vaccine use,36 combined with periodic cytology/HPV screening37 could be a practical approach to reduce incident HPV infections and subsequent HPV-associated SIL and malignant disease in this population.

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    Article Information

    Accepted for Publication: December 4, 2019.

    Corresponding Author: Pamela Stratton, MD, National Institutes of Health, 10 Center Dr, Bldg 10, Room 7-4647, Bethesda, MD 20892 (strattop@mail.nih.gov).

    Published Online: February 27, 2020. doi:10.1001/jamaoncol.2019.6722

    Author Contributions: Dr Stratton had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Wood and Pinto are co–last authors.

    Concept and design: Stratton, Battiwalla, Barrett, Childs, Gea-Banacloche, Ito, Kemp, Pinto, Schiffman, Shenoy, Quint, Struijk, Tisdale, Wood.

    Acquisition, analysis, or interpretation of data: Stratton, Battiwalla, Tian, Abdelazim, Baird, Barrett, Cantilena, Childs, DeJesus, Fitzhugh, Fowler, Geo-Banacloche, Gress, Hickstein, Hsieh, Ito, Kemp, Khachikyan, Merideth, Pavletic, Quint, Schiffman, Scrivani, Shanis, Struijk, Tisdale, Wagner, Williams, Yu, Wood, Pinto.

    Drafting of the manuscript: Stratton, Battiwalla, Tian, Baird, Barrett, Childs, DeJesus, Scrivani, Wood, Pinto.

    Critical revision of the manuscript for important intellectual content: Stratton, Battiwalla, Tian, Abdelazim, Baird, Barrett, Cantilena, Childs, DeJesus, Fitzhugh, Fowler, Gea-Banacloche, Gress, Hickstein, Hsieh, Ito, Kemp, Khachikyan, Merideth, Pavletic, Quint, Schiffman, Shanis, Shenoy, Struijk, Tisdale, Wagner, Williams, Yu, Wood, Pinto.

    Statistical analysis: Tian, DeJesus, Quint, Schiffman.

    Obtained funding: Stratton, Childs, Schiffman, Shanis, Shenoy, Pinto, Wood.

    Administrative, technical, or material support: Stratton, Battiwalla, Tian, Abdelazim, Baird, Barrett, Cantilena, Childs, Gea-Banacloche, Gress, Ito, Khachikyan, Pavletic, Schiffman, Scrivani, Shanis, Struijk, Wagner, Yu, Wood, Pinto.

    Supervision: Stratton, Tian, Battiwalla, Childs, Wood.

    Conflict of Interest Disclosures: Dr Stratton reported grants from the National Institutes of Health (NIH) Intramural Research Program and Allergen, being an employee of the National Institute of Child Health and Human Development (NICHD) Intramural Research Program, research funding from the National Cancer Institute (NCI), research support from ACOG and Hologic, and personal fees from UpToDate. Dr Wood reported personal fees from PDS Biotechnology outside the submitted work. No other disclosures were reported.

    Funding/Support: This NIH intramural clinical trial was funded as a Bench to Bedside Award in 2008 to Drs Stratton, Shenoy, Wood, and Pinto (the NIH Clinical Center, NICHD, National Heart, Lung, and Blood Institute [NHLBI], NCI, and National Human Genome Research Institute) with additional research funding from an ACOG/Hologic research award during 2011 to 2012 to Drs Stratton and Shanis. This project has been funded with federal funds from the NCI under contract HHSN261200800001E.

    Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The human papillomavirus vaccine was provided by funds from the Bench to Bedside award.

    Disclaimer: The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

    Meeting Presentation: This paper was presented at the Society for Reproductive Investigation; March 15, 2017; Orlando, FL; and the BMT Tandem Meetings; February 24, 2018; Salt Lake City, UT.

    Additional Contributions: Contributors to the study recruitment and coordination of study visits included Daniele Avila, MSN, CRNP, ANP-BC, Bazetta Blacklock-Schuver, BS, BSN, RN, Kristen Cole, DNP, RN, Tiffani Taylor Farrey, PA-C, MMS, MSPH, Brenna Hansen, BSN, RN, David Halverson, MD, Stephanie Hicks, BSN, RN, Jennifer Hsu, BSN, RN, and Brenda Roberson BSN, RN, OCN of the Intramural Research Program of the NCI and Elena Cho, MSN, RN, Wynona Coles, MPH, CCRP, Lisa Cook, BSN, RN, Theresa Donahue Jerussi, MS, PA-C, Eleftheria (Libby) K. Koklanaris, RN, BSN, Beth (Mary) Link, BSN, RN, Catalina Ramos, BSN, RN, Jeanine Superata, MSN, CRFNP, of the Intramural Research Program of the NHLBI. Contributors to the processing, management, and storage of the research specimens included Maria (Ruth) Burley, Nancy F. Hensel, BS, Susan Wong, BS, and Fariba Chinian, MS, of the Intramural Research Program of the NHLBI. Contributors to the web-based forms for patients in the study included Asma Idriss, MS, and Patricia Pullen, MBA, of the Intramural Research Program of the Eunice Kennedy Shriver NICHD. Suhasini Kaushal, MD, Intramural Research Program of the NHLBI, contributed to the writing of the original protocol. Margaret Bevans, PhD, RN, Intramural Research Program, Clinical Center, NIH, contributed to the inclusion of the sexual function assessment. We thank the patients, their families and caregivers, and all investigators involved in this study. No individuals earned additional compensation for their contributions.

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