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Article: Immune Responses to Varicella-Zoster Virus Vaccines.

Levin, Myron J / Weinberg, Adriana

Current topics in microbiology and immunology

2022 Volume 438, Page(s) 223–246

Abstract: The live attenuated varicella vaccine is intended to mimic the tempo and nature of the humoral and cell-mediated immune responses to varicella infection. To date, two doses of varicella vaccine administered in childhood have been very effective in ... ...

Abstract	The live attenuated varicella vaccine is intended to mimic the tempo and nature of the humoral and cell-mediated immune responses to varicella infection. To date, two doses of varicella vaccine administered in childhood have been very effective in generating varicella-zoster virus (VZV) immune responses that prevent natural infection for at least several decades. After primary infection, the infecting VZV establishes latency in sensory and cranial nerve ganglia with the potential to reactivate and cause herpes zoster. Although, the immune responses developed during varicella are important for preventing herpes zoster they wane with increasing age (immune senescence) or with the advent of immune suppression. Protection can be restored by increasing cell-mediated immune responses with two doses of an adjuvanted recombinant VZV glycoprotein E vaccine that stimulates both VZV-and gE-specific immunity. This vaccine provides ~85-90% protection against herpes zoster for 7-8 years (to date).
MeSH term(s)	Humans ; Herpesvirus 3, Human ; Chickenpox/prevention & control ; Herpes Zoster Vaccine ; Chickenpox Vaccine ; Herpes Zoster/prevention & control ; Vaccines, Attenuated ; Immunity, Cellular
Chemical Substances	Herpes Zoster Vaccine ; Chickenpox Vaccine ; Vaccines, Attenuated
Language	English
Publishing date	2022-10-28
Publishing country	Germany
Document type	Journal Article
ISSN	0070-217X
ISSN	0070-217X
DOI	10.1007/82_2021_245
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Article ; Online: Patient years lost due to cytomegalovirus serostatus mismatching in the scientific registry of transplant recipients.

Abidi, Maheen Z / Schold, Jesse D / Kaplan, Bruce / Weinberg, Adriana / Erlandson, Kristine M / Malamon, John S

Frontiers in immunology

2024 Volume 14, Page(s) 1292648

Abstract: Background: The cytomegalovirus (CMV) mismatch rate in deceased donor kidney transplant (DDKT) recipients in the US remains above 40%. Since CMV mismatching is common in DDKT recipients, the cumulative effects may be significant in the context of ... ...

Abstract	Background: The cytomegalovirus (CMV) mismatch rate in deceased donor kidney transplant (DDKT) recipients in the US remains above 40%. Since CMV mismatching is common in DDKT recipients, the cumulative effects may be significant in the context of overall patient and graft survival. Our primary objective was to describe the short- and long-term risks associated with high-risk CMV donor positive/recipient negative (D+/R-) mismatching among DDKT recipients with the explicit goal of deriving a mathematical mismatching penalty. Methods: We conducted a retrospective, secondary analysis of the Scientific Registry of Transplant Recipients (SRTR) database using donor-matched DDKT recipient pairs (N=105,608) transplanted between 2011-2022. All-cause mortality and graft failure hazard ratios were calculated from one year to ten years post-DDKT. All-cause graft failure included death events. Survival curves were calculated using the Kaplan-Meier estimation at 10 years post-DDKT and extrapolated to 20 years to provide the average graft days lost (aGDL) and average patient days lost (aPDL) due to CMV D+/R- serostatus mismatching. We also performed an age-based stratification analysis to compare the relative risk of CMV D+ mismatching by age. Results: Among 31,518 CMV D+/R- recipients, at 1 year post-DDKT, the relative risk of death increased by 29% (p<0.001), and graft failure increased by 17% (p<0.001) as compared to matched CMV D+/R+ group (N=31,518). Age stratification demonstrated a significant increase in the risk associated with CMV mismatching in patients 40 years of age and greater. The aGDL per patient due to mismatching was 125 days and the aPDL per patient was 100 days. Conclusion: The risks of CMV D+/R- mismatching are seen both at 1 year post-DDKT period and accumulated throughout the lifespan of the patient, with the average CMV D+/R- recipient losing more than three months of post-DDKT survival time. CMV D+/R- mismatching poses a more significant risk and a greater health burden than previously reported, thus obviating the need for better preventive strategies including CMV serodirected organ allocation to prolong lifespans and graft survival in high-risk patients.
MeSH term(s)	Humans ; Adult ; Transplant Recipients ; Cytomegalovirus ; Retrospective Studies ; Registries ; Cytomegalovirus Infections
Language	English
Publishing date	2024-01-09
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1292648
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Article ; Online: Understanding the mechanism of action of cytomegalovirus-induced regulatory T cells.

Tovar-Salazar, Adriana / Weinberg, Adriana

Virology

2020 Volume 547, Page(s) 1–6

Abstract: We previously showed that CMV-induced ... ...

Abstract	We previously showed that CMV-induced CD4
MeSH term(s)	CD4-Positive T-Lymphocytes/immunology ; Cell Proliferation ; Cytomegalovirus/genetics ; Cytomegalovirus/physiology ; Cytomegalovirus Infections/immunology ; Cytomegalovirus Infections/physiopathology ; Cytomegalovirus Infections/virology ; Humans ; Leukocytes, Mononuclear/immunology ; Lymphocyte Activation ; Programmed Cell Death 1 Receptor/immunology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	PDCD1 protein, human ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2020-05-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	200425-2
ISSN	1096-0341 ; 0042-6822
ISSN (online)	1096-0341
ISSN	0042-6822
DOI	10.1016/j.virol.2020.05.001
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Article ; Online: Immune responses to zoster vaccines.

Levin, Myron J / Weinberg, Adriana

Human vaccines & immunotherapeutics

2019 Volume 15, Issue 4, Page(s) 772–777

Abstract: There are two licensed herpes zoster vaccines. One is a live vaccine (ZVL) based on an attenuated varicella-zoster virus (VZV). The other is a recombinant vaccine (RZV) based on the VZV glycoprotein E (gE) combined with AS01B, a multicomponent adjuvant ... ...

Abstract	There are two licensed herpes zoster vaccines. One is a live vaccine (ZVL) based on an attenuated varicella-zoster virus (VZV). The other is a recombinant vaccine (RZV) based on the VZV glycoprotein E (gE) combined with AS01B, a multicomponent adjuvant system. RZV is superior to ZVL in efficacy, and differs from ZVL in that protection is not diminished by the age of the vaccinee and has not waned significantly during 4 years of follow-up. Immunologic studies demonstrated higher peak memory and persistence of T cell responses in RZV compared with ZVL recipients. RZV recipients also showed development and persistence of polyfunctional T cell responses. Taken together, we conclude that the immunologic data parallel and support the higher efficacy over time of RZV compared with ZVL.
MeSH term(s)	Adjuvants, Immunologic ; Clinical Trials as Topic ; Herpes Zoster/prevention & control ; Herpes Zoster Vaccine/immunology ; Humans ; Immunologic Memory ; T-Lymphocytes/immunology ; Vaccination ; Vaccines, Attenuated/immunology ; Vaccines, Synthetic/immunology ; Viral Envelope Proteins/immunology
Chemical Substances	Adjuvants, Immunologic ; Herpes Zoster Vaccine ; Vaccines, Attenuated ; Vaccines, Synthetic ; Viral Envelope Proteins ; glycoprotein E, varicella-zoster virus
Language	English
Publishing date	2019-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2664176-8
ISSN	2164-554X ; 2164-5515
ISSN (online)	2164-554X
ISSN	2164-5515
DOI	10.1080/21645515.2018.1560918
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Article ; Online: Adjuvanted Recombinant Glycoprotein E Herpes Zoster Vaccine.

Levin, Myron J / Weinberg, Adriana

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2019 Volume 70, Issue 7, Page(s) 1509–1515

Abstract: The adjuvanted recombinant glycoprotein E herpes zoster (HZ) vaccine is superior to the live attenuated HZ vaccine, with an efficacy >90% against HZ in healthy immunocompetent adults aged ≥50 years after vaccination. In pivotal studies, the efficacy of ... ...

Abstract	The adjuvanted recombinant glycoprotein E herpes zoster (HZ) vaccine is superior to the live attenuated HZ vaccine, with an efficacy >90% against HZ in healthy immunocompetent adults aged ≥50 years after vaccination. In pivotal studies, the efficacy of the new vaccine varied very little with the age of the vaccinee and decreased only by 5-10% in the 3.5 years after immunization. This nonlive vaccine was successfully administered to small cohorts of immunocompromised individuals; initial trials showed efficacy of >60-80% in several such settings. Potential drawbacks include the requirement for 2 vaccine doses separated by 2-6 months, local and systemic reactogenicity that is significantly greater than observed with commonly used vaccines, and the inclusion of a strong adjuvant that has been minimally studied in clinical settings where it might be problematic, such as in people with autoimmune diseases. Postmarketing studies are underway to address some of the drawbacks.
MeSH term(s)	Adjuvants, Immunologic ; Glycoproteins ; Herpes Zoster/prevention & control ; Herpes Zoster Vaccine ; Herpesvirus 3, Human ; Humans ; Vaccination
Chemical Substances	Adjuvants, Immunologic ; Glycoproteins ; Herpes Zoster Vaccine
Language	English
Publishing date	2019-09-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciz770
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Article ; Online: Effect of high dose vitamin D supplementation on subsequent immune responses to administration of the live herpes zoster vaccine to long-term care residents.

Levin, Myron J / Ginde, Adit A / Schmid, D Scott / Lang, Nancy / Canniff, Jennifer / Schwartz, Robert S / Weinberg, Adriana

Vaccine

2024 Volume 42, Issue 9, Page(s) 2278–2281

Abstract: Thirty-three long-term care residents (mean age 76.5 years), who were participating in a study in which they were randomized to receive either oral daily standard dose (400-1000 IU/day) 25-hydroxy vitamin D (vitamin D3) (SD) or high dose (3000-4000 IU/ ... ...

Abstract	Thirty-three long-term care residents (mean age 76.5 years), who were participating in a study in which they were randomized to receive either oral daily standard dose (400-1000 IU/day) 25-hydroxy vitamin D (vitamin D3) (SD) or high dose (3000-4000 IU/day) (HD) vitamin D3, were vaccinated with the live, attenuated herpes zoster vaccine. Blood was drawn at vaccination and three weeks later to determine varicella-zoster virus (VZV) antibody and T-cell mediated immune responses. ELISA and neutralizing antibodies increased significantly, but to the same extent, in both groups. The antibody avidity significantly increased from pre- to post-vaccination only in the HD group. VZV-CMI, as measured by FLUOROSPOT significantly increased post-vaccination in both groups, but the difference in interferon-γ spot-forming cells (SFC) and interleukin-2 SFC was lower in the HD than SD group. The increase in VZV-CMI correlated inversely with circulating regulatory T cells in the HD group. We conclude that pre-treatment with HD vitamin D3 does not appreciably enhance the antibody response to a live vaccine and that VZV-CMI responses were diminished in HD vitamin D3 recipients.
MeSH term(s)	Humans ; Aged ; Herpes Zoster Vaccine ; Long-Term Care ; Immunity, Cellular ; Herpesvirus 3, Human ; Herpes Zoster/prevention & control ; Antibodies, Viral ; Vitamin D ; Cholecalciferol ; Vaccines, Attenuated ; Dietary Supplements
Chemical Substances	Herpes Zoster Vaccine ; Antibodies, Viral ; Vitamin D (1406-16-2) ; Cholecalciferol (1C6V77QF41) ; Vaccines, Attenuated
Language	English
Publishing date	2024-02-28
Publishing country	Netherlands
Document type	Randomized Controlled Trial ; Journal Article
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2024.02.055
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Article ; Online: Predictors of 5-Year Persistence of Antibody Responses to Zoster Vaccines.

Weinberg, Adriana / Scott Schmid, D / Leung, Jessica / Johnson, Michael J / Miao, Congrong / Levin, Myron J

The Journal of infectious diseases

2023 Volume 228, Issue 10, Page(s) 1367–1374

Abstract: Background: Protection against herpes zoster is primarily conferred by cell-mediated immunity. However, anti-varicella-zoster virus (VZV) glycoprotein (anti-gp) antibody responses to zoster vaccine live (ZVL) are correlated with protection, suggesting a ...

Abstract	Background: Protection against herpes zoster is primarily conferred by cell-mediated immunity. However, anti-varicella-zoster virus (VZV) glycoprotein (anti-gp) antibody responses to zoster vaccine live (ZVL) are correlated with protection, suggesting a potential protective role for antibody. Detailed studies of antibody responses to the recombinant zoster vaccine (RZV) are provided. Methods: We compared enzyme-linked immunosorbent assay-measured anti-VZV glycoproteins (anti-gp) and glycoprotein E (anti-gE) antibody levels and avidity in 159 participants randomized to RZV (n = 80) or ZVL (n = 79) recipients over 5 years after vaccination and identified predictors of antibody persistence. Results: The comparison between vaccine groups showed higher anti-gE and anti-gp antibody levels after RZV than after ZVL over the 5-year study duration. RZV recipients also had higher anti-gE avidity for 5 years and higher anti-gp avidity in the first year after vaccination. Compared with prevaccination levels, RZV recipients maintained higher levels of anti-gE antibodies and avidity for 5 years, whereas ZVL recipients only maintained higher anti-gE avidity. Anti-gp antibody levels and avidity decreased to prevaccination levels or below beyond 1 year after vaccination in both groups. Independent predictors of persistence of antibody levels and avidity included vaccine type, prevaccination and peak antibody levels and avidity, prevaccination and peak cell-mediated immunity, and age. Sex or prior ZVL administration did not affect persistence. Conclusions: Antibody responses and avidity were higher and more persistent in RZV than in ZVL recipients. The effect of age on antibody persistence in RZV recipients is novel.
MeSH term(s)	Humans ; Herpes Zoster Vaccine ; Antibody Formation ; Herpes Zoster/prevention & control ; Herpesvirus 3, Human ; Glycoproteins ; Vaccines, Synthetic
Chemical Substances	Herpes Zoster Vaccine ; Glycoproteins ; Vaccines, Synthetic
Language	English
Publishing date	2023-05-04
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiad132
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Article ; Online: Cytomegalovirus Immune reconstitution in cord blood transplant recipients on letermovir prophylaxis.

Abidi, Maheen Z / Molina, Kyle C / Garth, Krystle / Gutman, Jonathan A / Weinberg, Adriana

Transplant infectious disease : an official journal of the Transplantation Society

2023 Volume 25, Issue 5, Page(s) e14104

Abstract: Introduction: Cytomegalovirus (CMV) can cause significant morbidity and mortality in cord blood transplant (CBT) recipients. Development of CMV-specific cell-mediated immunity (CMV-CMI) has been associated with protection against CMV clinically ... ...

Abstract	Introduction: Cytomegalovirus (CMV) can cause significant morbidity and mortality in cord blood transplant (CBT) recipients. Development of CMV-specific cell-mediated immunity (CMV-CMI) has been associated with protection against CMV clinically significant reactivation (CsCMV). In this study, we evaluated CMV-CMI reconstitution during letermovir prophylactic therapy, which prevents CsCMV without complete suppression of CMV reactivation. Methods: We measured CMV-CMI in CMV-seropositive CBT recipients pre-transplant after Day+90 of letermovir prophylaxis and at Days +180, and +360- post-transplant using a dual color CMV-specific IFNγ/IL2 FLUOROSpot. CsCMV and nonCsCMV reactivations were abstracted from medical records. CsCMV was defined as CMV viral load ≥5,000 IU/ml using a whole blood assay. Results: Among 70 CBT recipients, 31 developed CMV-CMI by Day+90 and an additional eight and five participants by Days +180 and +360, respectively. Thirty-eight participants developed CMV reactivation, including nine with CsCMV. Most reactivations (33 of 38) occurred before Day+180. Early CMV-CMI was present in six out of nine participants with CsCMV, indicating a lack of protection against CsCMV. Moreover, the magnitude of CMV-CMI at Day+90 did not differ between participants with CsCMV and nonCsCMV. Conclusion: Approximately 50% of CBT recipients reconstituted CMV-CMI during letermovir prophylactic therapy. However, CMV-CMI did not reach levels protective against CsCMV. Extension of CMV prophylaxis beyond Day+90 may be considered in CMV-seropositive CBT recipients.
MeSH term(s)	Humans ; Cytomegalovirus ; Cytomegalovirus Infections/drug therapy ; Antiviral Agents/therapeutic use ; Cord Blood Stem Cell Transplantation/adverse effects ; Immune Reconstitution ; Transplant Recipients ; Hematopoietic Stem Cell Transplantation/adverse effects
Chemical Substances	Antiviral Agents ; letermovir (1H09Y5WO1F)
Language	English
Publishing date	2023-07-12
Publishing country	Denmark
Document type	Journal Article
ZDB-ID	1476094-0
ISSN	1399-3062 ; 1398-2273
ISSN (online)	1399-3062
ISSN	1398-2273
DOI	10.1111/tid.14104
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Article ; Online: Impaired functionality of antigen presenting cells in HIV- exposed uninfected infants in the first six months of life.

Jalbert, Emilie / Ghosh, Tusharkanti / Smith, Christiana / Amaral, Fabiana R / Mussi-Pinhata, Marisa M / Weinberg, Adriana

Frontiers in immunology

2022 Volume 13, Page(s) 960313

Abstract: HIV-exposed uninfected infants (HEU) have increased morbidity and mortality due to infections in the first 6 months of life that tapers down to 2 years of life. The underlying immunologic defects remain undefined. We investigated antigen-presenting cells ...

Abstract	HIV-exposed uninfected infants (HEU) have increased morbidity and mortality due to infections in the first 6 months of life that tapers down to 2 years of life. The underlying immunologic defects remain undefined. We investigated antigen-presenting cells (APC) by comparing the phenotype of unstimulated APC, responses to toll-like receptor (TLR) stimulation, and ability to activate natural killer (NK) cells in 24 HEU and 64 HIV-unexposed infants (HUU) at 1-2 days of life (birth) and 28 HEU and 45 HUU at 6 months of life. At birth, unstimulated APC showed higher levels of activation and cytokine production in HEU than HUU and stimulation with TLR agonists revealed lower expression of inflammatory cytokines and activation markers, but similar expression of IL10 regulatory cytokine, in APC from HEU compared to HUU. Differences were still present at 6 months of life. From birth to 6 months, APC underwent extensive phenotypic and functional changes in HUU and minimal changes in HEU. TLR stimulation also generated lower NK cell expression of CD69 and/or IFNγ in HEU compared with HUU at birth and 6 months.
MeSH term(s)	Antigen-Presenting Cells ; Cytokines ; HIV Infections ; Humans ; Interleukin-10
Chemical Substances	Cytokines ; Interleukin-10 (130068-27-8)
Language	English
Publishing date	2022-08-12
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.960313
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Article ; Online: Development of antibody-dependent cellular cytotoxicity in response to recombinant and live-attenuated herpes zoster vaccines.

Park, Seong Yeon / Levin, Myron J / Canniff, Jennifer / Johnson, Michael / Schmid, D Scott / Weinberg, Adriana

NPJ vaccines

2022 Volume 7, Issue 1, Page(s) 123

Abstract: Zoster vaccines generate antibody responses against varicella-zoster virus (VZV). We compared antibody-dependent cell cytotoxicity (ADCC) elicited by zoster vaccine live (ZVL) and recombinant zoster vaccine (RZV). ADCC mediated by antibodies against VZV ... ...

Abstract	Zoster vaccines generate antibody responses against varicella-zoster virus (VZV). We compared antibody-dependent cell cytotoxicity (ADCC) elicited by zoster vaccine live (ZVL) and recombinant zoster vaccine (RZV). ADCC mediated by antibodies against VZV lysate (VZV-ADCC) and recombinant glycoprotein E (gE-ADCC) was measured using plasma from 20 RZV- and 20 ZVL-recipients, including half 50-60-years-old and half ≥70-years-old. Solid phase-bound anti-VZV antibodies stimulated TNFα in NK cells as measured by flow cytometry or ELISA. VZV-ADCC pre- and post-immunization was higher in younger vaccinees. ZVL did not appreciably increase VZV-ADCC, whereas RZV increased VZV-ADCC in older vaccinees. ELISA-measured gE-ADCC was similar across groups pre-immunization; significantly increased after ZVL; and RZV and was higher in younger RZV than ZVL recipients. IgG3 antibodies increased after RZV and ZVL, with greater anti-gE than anti-VZV responses. Moreover, gE-ADCC strongly correlated with anti-gE antibody avidity, but there were no appreciable correlations between VZV-ADCC and avidity. NK cells stimulated by anti-gE antibodies showed increased IFNγ and CD107a expression, which was not observed with anti-VZV antibodies. In conclusion, anti-gE antibodies generated more robust ADCC than anti-VZV antibodies. RZV induced higher ADCC antibodies than ZVL depending on the antigen and age of vaccinees. Older adults had lower ADCC antibodies before and after vaccination than younger adults.
Language	English
Publishing date	2022-10-25
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-022-00545-2
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