University of Groningen Ageing and vaccination in transplant patients Wang, Lei

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University of Groningen

Ageing and vaccination in transplant patients

Wang, Lei

DOI:

10.33612/diss.160954435

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Publication date: 2021

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Wang, L. (2021). Ageing and vaccination in transplant patients. University of Groningen. https://doi.org/10.33612/diss.160954435

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Chapter 1

Introduction

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1 Introduction

The first human lung and kidney transplantations were performed by James Hardy in 1963 and Joseph Murray in 1954, respectively. Since then, along with the advances in surgical operation and therapy, kidney and lung transplantation have become well established treatments for end-stage renal disease (ESRD) and end-stage pulmonary disease (ESPD), with improving survival rates, better quality of life, and cost-effectiveness compared to other treatments (1, 2). Meanwhile, with the ageing tendency of the general population, the proportion of elderly lung/kidney transplant recipients is also increasing in recent years. Worldwide, 17% of the lung transplant recipients were over 65 years old in 2016, which was an increase of more than 6 times compared to 2004 (3). Although advanced age is no longer considered a barrier to transplantation, recipient age has a substantial impact on the morbidity and mortality. Leading causes of transplantation mortality are graft failure, cardiovascular disease, malignancies and infectious complications (4). Higher rate of infection is observed in older transplant patients and cytomegalovirus (CMV) infection is one of the most prevalent infectious complications (5). Interestingly, fewer acute rejections but more chronic graft dysfunction developed in elderly recipients, which was considered to be attributed to the declined function of immune system with ageing, or so called immunosenescence (6-8).

Immunosenescence can affect all compartments of innate and adaptive immunity (6). Although it is still controversial what the effect of immunosenescence is on absolute lymphocyte counts, the changes in distribution within T cell populations are often reported. Studies have shown that thymic involution leads to diminished output of new naïve T cells and there is a shift from naive to memory T cells, which causes accumulation of the memory T cell pool in the lymphoid system (7, 9). T cell phenotypic changes during ageing have been characterized. The expression of CD28, a co-stimulatory surface receptor, is found decreased on both CD4+ and CD8+ T cells and seems to be related to functional impairment and less proliferative ability in response to antigenic and mitotic stimuli. This could also lead to poor vaccine responses (10, 11). Like as for T cells, peripheral B cell total numbers stay relatively stable while impaired B cell development in the bone marrow has been found in the elderly. This alteration is attributed to the changes of both intrinsic cell problems as well as problems in the lymphoid organ

9 Introduction

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microenvironments and it eventually leads to decreased numbers of recirculating antibody-secreting plasma cells and reduced ability of antibody production (12). A growing number of studies has been published, focused on a mature B cell phenotype, termed age associated B cells (ABCs), characterized by the expression of CD11c+/CD11b+/CD21-/CD23-/T-bet+. Evidence of accumulation of ABCs in aged mice and elderly humans has been shown (13-15). ABCs have an exhausted, terminal differentiated B cell feature and are reported to be more prevalent in patients with autoimmunity disease and elderly people, and to be related to diminished antibody response to vaccine (16). In transplant patients, the increased rates of infections such as bacterial pneumonia and human herpes viruses, and impaired host defense against tumors were suggested to be related to the effects of ageing in different components of the adaptive immune system (7, 8).

Varicella zoster virus (VZV) is a highly contagious human α-herpes virus. Primary infection mainly occurs in children and causes varicella (chickenpox), after which VZV establishes a lifelong latency in dorsal root ganglia. Reactivation of VZV can occur decades later and cause herpes zoster (HZ). Although many triggering factors have been described such as trauma, X-ray irradiation and infection which could result in reactivation, increasing age leading to decreased cell-mediated immunity specific to VZV is considered to be the leading risk factor for HZ (17). In transplant patients, due to their lifetime maintenance of immunosuppression, the incidence of HZ and consequent complications such as postherpetic neuralgia (PHN) is much higher than in the healthy populations. Due to high doses of continuous immunosuppression, the risk of HZ in lung transplant patients is even higher than in other solid organ transplants (18). Considering the side effects and partial effectiveness of current treatment for HZ and PHN, prophylactic HZ vaccination while awaiting transplantation may be a proactive strategy for transplant patients (18).

Currently, there are two licensed HZ vaccines on the market. One is an attenuated live virus vaccine-Zostavax®_{and the other one is a recombinant} subunit vaccine-Shingrix®_{. Zostavax}®_{has been approved by the Food and Drug} Administration (FDA) in 2006. In a 4-year post-vaccination follow-up study, 38,546 adults over 60 years were enrolled and Zostavax®_{reduced the incidence} of HZ by 51.3% (19). However, the efficacy of Zostavax®_dramatically

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decreased with advanced age, with efficacy of 41% in adults over 70 years old and 18% in adults over 80 years old (9). Vaccination of transplant patients with Zostavax®_{is controversial due to the live attenuated characteristic of this} vaccine. The Advisory Committee on Immunization Practices (ACIP) recommended administration at least 14 days before immunosuppressive therapy and more than 4 weeks before hematopoietic stem cell transplantation (20). As for Shingrix®_{, which is approved by the FDA in 2017, 89.8% of} vaccine efficacy was reported in adults over 70 years old and there was no decline in efficacy with age (21). Of note, Shingrix®_{is a two-dose vaccine, and} it evokes local and systemic adverse events such as fatigue and myalgia mostly assigned to the added adjuvant (22). Currently, there are limited studies about HZ vaccine usage in transplant patients and how the ageing of immune system affects the efficacy of prophylactic HZ vaccine in transplant patient is still not very well known.

2 Aims and outline of the thesis

This thesis is mainly focused on ageing of the immune system in elderly and transplanted patients, and the influence of ageing on VZV infection. In the University Medical Center Groningen, lung transplant candidates were vaccinated with HZ vaccine as a pre-transplantation work-up when they were newly screened for lung transplantation since November 2016. At that time, Zostavax®_{was the only vaccine available in the Netherlands. To study the} efficacy and immunogenicity of HZ vaccination and the relation to immunosenescence, we prospectively collected blood samples from patients who were on the waiting list or had undergone lung transplantation either with or without HZ vaccination. Besides, we also retrospectively studied ageing of cells and immunity to VZV in kidney transplant patients.

In Chapter 2, we reviewed the literature on diagnosis and treatments for HZ as

well as for PHN in immunocompromised adults, especially in transplant patients. Besides, the efficacy and safety of prophylactic strategies for HZ and PHN, including antiviral prophylaxis and two HZ vaccines, were discussed. The recommendations of the Centers for Disease Control and Prevention with respect to Varicella-zoster immunoglobulin as the post-exposure prophylaxis in VZV seronegative patients were introduced at the last part of this chapter.

11 Introduction

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In the study described in Chapter 3, we investigated the safety, efficiency and

immunogenicity of a HZ vaccine in lung transplant candidates before and after transplantation. In total, 68 patients received one dose of Zostavax®_{and 37} patients without vaccination were enrolled as control. The humoral and cellular immune response to the vaccine before and after vaccination, and before and after transplantation were evaluated and compared by an in-house glycoprotein (gp) VZV enzyme-linked immunosorbent assay and a VZV-specific interferon (IFN)-γ enzyme-linked immunospot (ELISpot) assay respectively. In addition, we studied whether the vaccination had impact on outcomes of lung transplantation such as rejection. The results showed that Zostavax®_{was safe and that it induced a robust response to the vaccine in both} humoral and cellular immunity in patients with ESPD before lung transplantation. VZV-specific cellular immunity was significantly affected by immunosuppressant treatments shortly after transplantation but returned to a relatively high level at 6 months after transplantation in vaccinated patients. In Chapter 4, the frequencies of T and B subsets before and after vaccination

with Zostavax®_{in patients waiting for lung transplantation were measured by} flow cytometry, compared to the humoral and cellular immune response to the vaccine before and after vaccination. This chapter aimed to assess whether the frequencies of specific T and B cell subsets before vaccination, especially of aged cell subsets (CD28- T cells and ABCs) had influence on the immune responses to Zostavax®_{. We found that frequencies of ABCs rather than CD28-} T cells before vaccination were related to the vaccine response in the patients.

Chapter 5 aimed to analyze the effect of transplantation on ageing of T and B

cells in kidney transplant patients. We investigated the frequencies of T and B cells in kidney transplant patients before and around 3 years after transplantation, and compared these to healthy age-/sex- matched controls. The relation between aged T and B cells and age and CMV latency in transplant patients was discussed in this chapter. The results showed that after transplantation a redistribution of T cell subsets was seen, with less naïve CD4+ and CD8+ cells, but higher proportions of terminally differentiated memory cells. The proportions of CD28- T cell and ABCs both increased after transplantation, especially in elderly patients, and were related to CMV seropositivity.

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In Chapter 6, both humoral and cellular immunity to VZV was determined in

62 healthy controls and 60 adult patients before and 2-3 years after kidney transplantation. Besides, cytokine-expressing VZV-specific T cells were studied by flow cytometric analysis. We assessed the effect of kidney transplantation, infection and rejection after transplantation on the VZV-specific immunity. We concluded that VZV-VZV-specific cellular immunity did not significantly change after kidney transplantation and that ESRD patients might benefit from HZ vaccination before transplantation.

In Chapter 7, we established a replication-induced senescence in vitro model

using human skin fibroblasts to simulate the process of VZV infection in the skin of elderly people. After VZV infection, phosphorylation levels in signal transduction pathways such as JNK and p38 MAPK and their downstream substrates were evaluated and compared between young and senescent skin cells. We aimed to study the interaction of VZV with JNK and p38 signaling networks during skin ageing to gain a better understanding of the mechanism of the immune response to VZV infection during cellular immunosenescence. This in-vitro model can serve as a start to a more complex model were the effect of VZV-specific T cells on prevention of the infection of skin cells during reactivation can be studied.

Finally, the results and implications of this thesis were summarized, and future perspectives were discussed in Chapter 8.

13 Introduction

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15 Introduction

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