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1.
Third-party cytomegalovirus-specific T cells improved survival in refractory cytomegalovirus viremia after hematopoietic transplant
Prockop, S. E., Hasan, A., Doubrovina, E., Dahi, P. B., Rodriguez-Sanchez, I., Curry, M., Mauguen, A., Papanicolaou, G. A., Su, Y., Yao, J., et al
The Journal of clinical investigation. 2023;133(10)
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Editor's Choice
Abstract
BackgroundRefractory CMV viremia and disease are associated with significant morbidity and mortality in recipients of hematopoietic stem cell transplant (HCT).MethodsIn phase I/II trials, we treated 67 subjects for CMV viremia or disease arising after HCT with adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs). All were evaluable for toxicity and 59 for response. Evaluable subjects had CMV disease or persisting viremia that had failed at least 2 weeks of induction therapy with a median of 3 antiviral drugs; 84.7% had more than 3 of 11 high-risk features. CMVpp65-VSTs were specific for 1 to 3 CMVpp65 epitopes, presented by a limited set of HLA class I or II alleles, and were selected based on high-resolution HLA matching at 2 of 10 HLA alleles and matching for subject and subject's HCT donor for 1 or more alleles through which the CMVpp65-VSTs were restricted.ResultsT cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses.ConclusionsRecipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.Trial RegistrationNCT00674648; NCT01646645; NCT02136797 (NIH).FundingNIH (P01 CA23766, R21 CA162002 and P30 CA008748); Aubrey Fund; Claire Tow Foundation; Major Family Foundation; "Rick" Eisemann Pediatric Research Fund; Banbury Foundation; Edith Robertson Foundation; Larry Smead Foundation.
PICO Summary
Population
Adults and children with cytomegalovirus (CMV) viremia or disease arising after HSCT, treated in a single centre in USA (n=67)
Intervention
Adoptive transfer of banked, third-party, CMVpp65-sensitized T cells (CMVpp65-VSTs).
Comparison
None
Outcome
T cell infusions were well tolerated. Of 59 subjects evaluable for response, 38 (64%) achieved complete or durable partial responses Recipients responding to CMVpp65VSTs experienced an improved overall survival. Of the risk factors evaluated, transplant type, recipient CD4+ and CD8+ T cell levels prior to adoptive therapy, and the HLA restriction of CMVpp65-VSTs infused each significantly affected responses. In addition, CMVpp65-specific T cells of HCT donor or recipient origin contributed to the durability of both complete and partial responses.
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Outcomes and Management of SARS-CoV2 Omicron Variant in Recipients of Hematopoietic Cell Transplantation (HCT) and Chimeric Antigen Receptor T cell (CART) therapy
Infante, M. S., Nemirovsky, D., Devlin, S., DeWolf, S., Tamari, R., Dahi, P. B., Lee, Y. J., Chung, D. J., Politikos, I., Barker, J., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Hematopoietic cell transplantation (HCT) and chimeric antigen receptor T cell therapy (CART) recipients who develop COVID-19 can have decreased overall survival, likely due to disease-inherent and therapy-related immunodeficiency. The availability of COVID-19 directed therapies and vaccines have improved COVID-19 related outcomes, but immunocompromised individuals remain vulnerable. Specifically, the effects of SARS-CoV-2 variant infections, including Omicron and its sublineages, particularly in transplant recipients, are yet to be defined. The aim of this study was to compare the impact of SARS-CoV-2 Omicron infections in HCT/CART recipients with outcomes previously reported for ancestral SARS-CoV-2 infections early in the pandemic (March-June 2020). STUDY DESIGN Retrospective analysis adult HCT/CART recipients diagnosed with COVID-19 at Memorial Sloan Kettering Cancer Center (MSKCC), New York, between July 2021 and July 2022. RESULTS We identified 353 patients (172 auto, 49%; 152 allo, 43%; 29 CART, 8%) with a median time from HCT/CART to SARS-CoV-2 infection of 1010 days (IQR, 300 to 2046). Forty-one (12%) patients were diagnosed with COVID-19 during the delta wave and 312 (88%) patients during the Omicron wave. Risk factors associated with increased odds of COVID-19 related hospitalization were the presence of 2 or more comorbidities (OR, 4.9; 95% CI 2.4-10.7, p< 0.001), CART therapy compared to allogeneic HCT (OR 7.7; 95% CI 3.0-20.0, p<0.001), hypogammaglobulinemia (OR 2.71; 95% CI 1.06-6.40, p=0.027), and age at COVID-19 diagnosis (OR 1.03; 95% CI 1.0-1.05, p= 0.04). In contrast, infection during Omicron variant BA5/BA4 dominant period compared to variant BA1 (OR 0.21; 95% CI 0.03-0.73, p =0.037), and more than 3 years from HCT/CART therapy to COVID-19 diagnosis, compared to early infection < 100 days (OR 0.31; 95% CI 0.12-0.79, p=0.011) were associated with a decreased odds for hospitalization. The overall survival (OS) at 12 months from COVID-19 diagnosis was 89% (95% CI: 84-94%), with 6/26 deaths attributable to COVID-19. Patients with the ancestral strain of SAR-CoV-2 had a lower overall survival at 12 months, with 73% (95% CI: 62-84%) vs 89% (95% CI: 84-94%), (p<0.001) in the Omicron cohort. Specific COVID-19 treatment was administered in 62% of patients, and 84% were vaccinated with mRNA COVID-19 vaccines. Vaccinated patients had significantly better OS than unvaccinated patients, being 90% (95% CI: 86-95%) vs 82% (95% CI: 72-94%) at 12 months, respectively (p=0.003). No significant difference in OS was observed in patients infected with the Omicron vs with Delta variant (p=0.4) or treated with specific COVID-19 treatments vs those not treated (p=0.2). CONCLUSIONS We observed higher overall survival in HCT and CART recipients infected with the Omicron variants compared to the ancestral strain of SARS-CoV2. Use of COVID-19 antivirals, monoclonal antibodies, and vaccines may have contributed to improved outcomes.
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Emergence of human CMV-induced NKG2C+ NK cells is associated with CD8+ T-cell recovery after allogeneic HCT
van der Ploeg, K., Sottile, R., Kontopoulos, T., Shaffer, B. C., Papanicolaou, G. A., Maloy, M. A., Cho, C., Robinson, K. S., Perales, M. A., Le Luduec, J. B., et al
Blood advances. 2023;7(19):5784-5798
Abstract
Cytomegalovirus (CMV) infection is associated with the expansion of a mature NKG2C+FcεR1γ- natural killer (NK) cell population. The exact mechanism underlying the emergence of NKG2C+ NK cells, however, remains unknown. Allogeneic hematopoietic cell transplantation (HCT) provides an opportunity to longitudinally study lymphocyte recovery in the setting of CMV reactivation, particularly in patients receiving T-cell-depleted (TCD) allografts. We analyzed peripheral blood lymphocytes from 119 patients at serial time points after infusion of their TCD allograft and compared immune recovery with that in samples obtained from recipients of T-cell-replete (T-replete) (n = 96) or double umbilical cord blood (DUCB) (n = 52) allografts. NKG2C+ NK cells were detected in 92% (45 of 49) of recipients of TCD HCT who experienced CMV reactivation. Although NKG2A+ cells were routinely identifiable early after HCT, NKG2C+ NK cells were identified only after T cells could be detected. T-cell reconstitution occurred at variable times after HCT among patients and predominantly comprised CD8+ T cells. In patients with CMV reactivation, recipients of TCD HCT expressed significantly higher frequencies of NKG2C+ and CD56neg NK cells compared with patients who received T-replete HCT or DUCB transplantation. NKG2C+ NK cells after TCD HCT were CD57+FcεR1γ+ and degranulated significantly more in response to target cells compared with the adaptive the NKG2C+CD57+FcεR1γ- NK cell population. We conclude that the presence of circulating T cells is associated with the expansion of a CMV-induced NKG2C+ NK cell population, a potentially novel example of developmental cooperation between lymphocyte populations in response to viral infection.
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SARS-CoV-2 vaccination in the first year after allogeneic hematopoietic cell transplant: a prospective, multicentre, observational study
Hill, J. A., Martens, M. J., Young, J. H., Bhavsar, K., Kou, J., Chen, M., Lee, L. W., Baluch, A., Dhodapkar, M. V., Nakamura, R., et al
EClinicalMedicine. 2023;59:101983
Abstract
BACKGROUND The optimal timing for SARS-CoV-2 vaccines within the first year after allogeneic hematopoietic cell transplant (HCT) is poorly understood. METHODS We conducted a prospective, multicentre, observational study of allogeneic HCT recipients who initiated SARS-CoV-2 vaccinations within 12 months of HCT. Participants were enrolled at 22 academic cancer centers across the United States. Participants of any age who were planning to receive a first post-HCT SARS-CoV-2 vaccine within 12 months of HCT were eligible. We obtained blood prior to and after each vaccine dose for up to four vaccine doses, with an end-of-study sample seven to nine months after enrollment. We tested for SARS-CoV-2 spike protein (anti-S) IgG; nucleocapsid protein (anti-N) IgG; neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains; and SARS-CoV-2-specific T-cell receptors (TCRs). The primary outcome was a comparison of anti-S IgG titers at the post-V2 time point in participants initiating vaccinations <4 months versus 4-12 months after HCT using a propensity-adjusted analysis. We also evaluated factors associated with high-level anti-S IgG titers (≥2403 U/mL) in logistic regression models. FINDINGS Between April 22, 2021 and November 17, 2021, 175 allogeneic HCT recipients were enrolled in the study, of whom all but one received mRNA SARS-CoV-2 vaccines. SARS-CoV-2 anti-S IgG titers, neutralizing antibody titers, and TCR breadth and depth did not significantly differ at all tested time points following the second vaccination among those initiating vaccinations <4 months versus 4-12 months after HCT. Anti-S IgG ≥2403 U/mL correlated with neutralizing antibody levels similar to those observed in a prior study of non-immunocompromised individuals, and 57% of participants achieved anti-S IgG ≥2403 U/mL at the end-of-study time point. In models adjusted for SARS-CoV-2 infection pre-enrollment, SARS-CoV-2 vaccination pre-HCT, CD19+ B-cell count, CD4+ T-cell count, and age (as applicable to the model), vaccine initiation timing was not associated with high-level anti-S IgG titers at the post-V2, post-V3, or end-of-study time points. Notably, prior graft-versus-host-disease (GVHD) or use of immunosuppressive medications were not associated with high-level anti-S IgG titers. Grade ≥3 vaccine-associated adverse events were infrequent. INTERPRETATION These data support starting mRNA SARS-CoV-2 vaccination three months after HCT, irrespective of concurrent GVHD or use of immunosuppressive medications. This is one of the largest prospective analyses of vaccination for any pathogen within the first year after allogeneic HCT and supports current guidelines for SARS-CoV-2 vaccination starting three months post-HCT. Additionally, there are few studies of mRNA vaccine formulations for other pathogens in HCT recipients, and these data provide encouraging proof-of-concept for the utility of early vaccination targeting additional pathogens with mRNA vaccine platforms. FUNDING National Marrow Donor Program, Leukemia and Lymphoma Society, Multiple Myeloma Research Foundation, Novartis, LabCorp, American Society for Transplantation and Cellular Therapy, Adaptive Biotechnologies, and the National Institutes of Health.
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Patterns of CMV Infection After Letermovir Withdrawal in Recipients of Post-Transplant Cyclophosphamide Based Transplant
Lin, A., Brown, S., Chinapen, S., Lee, Y. J., Seo, S. K., Ponce, D. M., Shahid, Z., Giralt, S. A., Papanicolaou, G. A., Perales, M. A., et al
Blood advances. 2023
Abstract
Reactivation of latent cytomegalovirus (CMV) is increased in CMV seropositive (CMV+) recipients of allogeneic hematopoietic cell transplantation (allo HCT) using post-transplant cyclophosphamide (PT-Cy) based graft versus host disease prophylaxis. Letermovir, a novel DNA terminase complex inhibitor, reduces the incidence of clinically significant CMV infection (csCMVi) in this population; however, parameters that predict csCMVi after letermovir withdrawal are not well described. Here, we examined clinical and immunological parameters in 294 recipients of PT-Cy based allo HCT, including 157 CMV+ patients of whom 80 completed letermovir prophylaxis without csCMVi, and subsequently stopped letermovir. In this population, the median duration of letermovir exposure was 203 days (interquartile range (IQR): 160 - 250 days). After letermovir withdrawal, the 90-day cumulative incidence of csCMVi was 23.0% (14.3 - 32.8). There were no episodes of CMV end-organ disease. Hypo-gammaglobulinemia prior to letermovir discontinuation was predictive of csCMVi (hazard ratio: 0.33, 95% confidence interval: 0.12-0.93, p = 0.03), whereas T-cell and B-cell reconstitution prior to letermovir withdrawal were not predictive of csCMVi. Higher numbers of NK cells were found prior to letermovir withdrawal in patients that experienced csCMVi (median 202 versus 160, p = 0.03). In CMV+ recipients, CD3+CD4-CD8+ T-cell reconstitution was faster in CMV+ patients regardless of letermovir exposure. Taken together, these data suggest that csCMVi after letermovir withdrawal was frequent in patients treated with PT-Cy, despite prolonged exposure. Strategies to boost CMV specific adaptive immunity in patients with persistent hypo-gammaglobulinemia is a logical pathway to reduce csCMVi after letermovir withdrawal.
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Outcomes of refractory cytomegalovirus (CMV) infection in the first year after allogeneic hematopoietic cell transplantation
Karantoni, E., Zavras, P. D., Su, Y., Fang, J., Tamari, R., Cho, C., Perales, M. A., Stern, A., Papanicolaou, G. A.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND Outcomes of refractory (Rf) cytomegalovirus infection (CMVi) after hematopoietic cell transplantation (HCT) are poor due to limited treatment options and related toxicities. Maribavir, an orally bioavailable CMV antiviral was recently approved for treatment of Rf-CMVi. Real-world studies, quantifing the burden of Rf-CMVi prior to maribavir provide a benchmark for evaluation of the net value of novel treatments. OBJECTIVES We report the incidence, clinical outcomes and healthcare resource utilization (HRU) associated with Rf-CMVi in the first year after HCT in a cohort of CMV seropositive HCT from a single center. METHODS The retrospective cohort study included adult CMV seropositive (R+) HCT recipients between 1/1/2014 and 12/31/2017 at Memorial Sloan Kettering Cancer Center (MSKCC) managed exclusive by preemptive therapy. CMVi was defined as CMV viremia treated preemptively. Rf-CMVi was defined as <1 log(10) decrease and CMV viral load (VL) >1,000 U/mL after ≥14 days of appropriately dosed therapy. Well-days were calculated as alive days not hospitalized and off CMV antivirals by 1 year post-HCT. The impact of Rf-CMVi on EOD, mortality and HRU was examined in multivariable models. RESULTS Of 286 R+ patients, 145 (50.7%) developed CMVi (99 no Rf-CMVi and 46 Rf-CMVi). Compared with no Rf-CMVi, more patients with Rf-CMVi had CMV EOD (23.9% versus 10.1%, p=0.030); CMV-related mortality (9.5% versus 0.0%, p=0.002) and all-cause mortality (33.3% versus 15.6%, adjusted p=0.049). Rf-CMVi was an independent predictor for readmissions (adjusted odds ratio [aOR] [95% confidence interval, CI] 3.24 [2.19-4.87]; p<0.0001); CMV-related readmissions (aOR [95 CI] 9.48 [5.83-15.80]; p<0.0001) and decreased well days (adjusted arithmetic mean ratio [aAMR] [95% CI] 0.72 [0.58-0.89], p=0.001) in the first-year post-HCT. CONCLUSIONS Rf-CMVi is associated with increased mortality and increased HRU at 1 year after HCT. Improved therapies for Rf-CMVi have the potential of improving HCT outcomes and reducing HRU.
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Impact of letermovir primary Cytomegalovirus (CMV) prophylaxis on 1-year mortality after allogeneic hematopoietic cell transplantation (HCT): a retrospective cohort study
Su, Y., Stern, A., Karantoni, E., Nawar, T., Han, G., Zavras, P., Dumke, H., Cho, C., Tamari, R., Shaffer, B., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2022
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Abstract
BACKGROUND CMV seropositive (R+) hematopoietic cell transplant (HCT) recipients have a survival disparity compared with CMV seronegative recipient/donor (R-D-) pairs. We hypothesized that primary letermovir prophylaxis (LET) may abrogate this disparity. We investigated the relationship between LET and mortality at 1year post-HCT. METHODS In this retrospective cohort study, we included adult R-D- or R+ patients who received HCT pre-LET (between January 1, 2013 through December 15, 2017) and post-LET (between December 16, 2017 through December 2019). R+ were categorized by LET receipt as R+/LET or R+/no-LET. Cox proportional hazard models were used to estimate the association of LET with all-cause mortality at one-year post-transplantation. RESULTS Of 848 patients analyzed, 305 were R-D-, 364 R+/no-LET and 160 R+/LET. Because of similar mortality (adjusted hazard ratio [aHR] [95% confidence interval]); 1.29 [0.76-2.18; p=0.353] between pre-LET/R-D- and post-LET/R-D-, R-D- were combined into one group. Compared with R-D-, the aHR for mortality was 1.40 [1.01-1.93] for R+/no-LET and 0.89 [0.57-1.41] for R+/LET. Among R+, LET was associated with decreased risk of death (aHR 0.62 [0.40-0.98]); when conventional and T-cell depleted HCT were analyzed separately, the aHR was 0.86 [0.51-1.43] and 0.21 [0.07-0.65] respectively. CONCLUSIONS At one-year post HCT, LET was associated with closing the mortality disparity between R-D- and R+. Among all R+, LET was associated with decreased mortality; driven by 79% reduced incidence of death in T-cell depleted HCT.
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CMV viral load kinetics predict CMV end-organ disease and mortality after hematopoietic cell transplant (HCT)
Stern, A., Su, Y., Dumke, H., Fang, J., Tamari, R., Jakubowski, A., Cho, C., Giralt, S., Perales, M. A., Papanicolaou, G. A.
The Journal of infectious diseases. 2021
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Abstract
BACKGROUND We investigated the association between time-averaged area under the curve (AAUC) of CMV viral load (VL) by D100 and overall survival (OS) at one-year post-hematopoietic cell transplantation (HCT). METHODS A retrospective cohort study, including patients receiving HCT between 2010.6 and 2017.12 from Memorial Sloan Kettering Cancer Center. AAUC was calculated for patients with detected VL. Patients were categorized into "non-controllers" (Q4) and "controllers" (Q1-3) using the highest AAUC quartile as cutoff. Kaplan-Meier analyses and Cox models were used to estimate the association between AAUC and OS. Patients with non-detected CMV VL were categorized into "elite-controllers" (R+ or R-/D+) and "R-/D-". RESULTS The study (N=952) included 282 controllers, 93 non-controllers, 275 elite-controllers, and 302 R-/D-. OS was 80.1% and 58.1% for controllers and non-controllers, respectively. In multivariable models, non-controllers had worse OS versus controllers (adjusted hazard ratio [HR] 2.65, 95% CI 1.71-4.12). In landmark analyses, CMV controllers had similar OS as elite-controllers (HR 1.26, 95% CI 0.83-1.91) or R-/D- (HR 0.98, 95% CI 0.64-1.5). CONCLUSION CMV non-controllers had worse OS at one-year post-HCT. CMV controllers had similar OS as elite-controllers or R-/D-. Future studies are needed to validate our AAUC cutoff across different cohorts and CMV management strategies.
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Human herpes virus 6 DNAemia is associated with worse survival after ex vivo T-cell depleted hematopoietic cell transplant
Lee, Y. J., Su, Y., Cho, C., Tamari, R., Perales, M. A., Jakubowski, A. A., Papanicolaou, G.
The Journal of infectious diseases. 2021
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Abstract
BACKGROUND We examined the correlation between persistent HHV-6 DNAemia (p-HHV-6) and absolute lymphocyte counts (ALC), platelet counts (PLT) and all-cause mortality the 1-year after ex vivo T-cell depleted (TCD) hematopoietic cell transplant (HCT). METHODS We analyzed a cohort of adult TCD HCT recipients 2012-2016 prospectively monitored for plasma HHV-6 by qPCR from day +14 post-HCT (D+14) through D+100. P-HHV-6 was defined as =2 consecutive values of =500 copies/mL by D+100. PLT and ALC were compared between patients with and without p-HHV-6 using mixed model analysis of variance. Multivariable Cox proportional hazard models were used to identify the impact of p-HHV-6 on 1-year mortality. RESULTS Of 312 patients, 83 (27%) had p-HHV-6 by D+100. P-HHV-6 was associated with lower ALC and PLT in the first year post-HCT. In multivariable models, p-HHV-6 was associated with higher mortality by 1-year post-HCT (adjusted hazard ratio 2.97, 95% confidence intervals: 1.62-5.47, P=0.0005), after adjusting for age, antiviral treatment, and ALC at D+100. CONCLUSIONS P-HHV-6 was associated with lower ALC and PLT in the first year post-HCT. P-HHV-6 was an independent predictor of mortality in the first year after TCD HCT.
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10.
Predictors of Humoral Response to SARS-CoV-2 Vaccination after Hematopoietic Cell Transplantation and CAR T-cell Therapy
Tamari, R., Politikos, I., Knorr, D. A., Vardhana, S. A., Young, J. C., Marcello, L. T., Doddi, S., Devlin, S. M., Ramanathan, L. V., Pessin, M. S., et al
Blood cancer discovery. 2021;2(6):577-585
Abstract
Cellular therapies including allogeneic hematopoietic cell transplant (allo-HCT) and autologous hematopoietic cell transplant (auto-HCT) and chimeric antigen receptor (CAR) T-cell therapy render patients severely immunocompromised for extended periods after therapy, and data on responses to COVID-19 vaccines are limited. We analyzed anti-SARS-CoV-2 spike IgG Ab (spike Ab) titers and neutralizing Ab among 217 recipients of cellular treatments (allo-HCT, n = 149; auto-HCT, n = 61; CAR T-cell therapy, n = 7). At 3 months after vaccination, 188 patients (87%) had positive spike Ab levels and 139 (77%) had positive neutralization activity compared with 100% for both in 54 concurrent healthy controls. Time from cellular therapy to vaccination and immune recovery post-cellular therapy were associated with response. Vaccination against COVID-19 is an important component of post-cellular therapy care, and predictors of quantitative and qualitative response are critical in informing clinical decisions about optimal timing of vaccines and the requirement for booster doses. SIGNIFICANCE Identifying predictors of response to vaccination against SARS-CoV-2 in patients following cellular therapy is critical to managing this highly vulnerable patient population. To date, this is the most comprehensive study evaluating quantitative and qualitative responses to vaccination, providing parameters most predictive of response and potentially informing booster vaccination strategies.See related article by Chung et al., p. 568. This article is highlighted in the In This Issue feature, p. 549.