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. Author manuscript; available in PMC: 2023 Oct 1.
Published in final edited form as: Clin Microbiol Infect. 2022 Feb 10;28(10):1345–1350. doi: 10.1016/j.cmi.2022.02.001

Assessing and restoring adaptive immunity to HSV, VZV and HHV-6 in solid organ and hematopoietic cell transplant recipients

Madeleine R Heldman 1,2, Kaja M Aagaard 1, Joshua A Hill 1,2
PMCID: PMC9363517  NIHMSID: NIHMS1779291  PMID: 35150885

Abstract

Background:

Herpes simplex virus (HSV) 1 and 2, varicella zoster virus (VZV), and human herpesvirus 6 (HHV-6) cause severe infections in immunocompromised hosts. Interventions to optimize virus-specific adaptive immunity may have advantages over antivirals in the prophylaxis and treatment of these infections.

Aims:

We sought to review adaptive immune responses and methods for assessing and replenishing cellular and humoral immunity to HSV, VZV and HHV-6 in solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients.

Sources:

We searched PubMed for relevant studies on immune responses to HSV, VZV and HHV-6 as well as studies describing methods for evaluating and restoring cell-mediated immunity to other double stranded DNA viruses in transplant recipients. Recent studies, randomized controlled trials, and investigations highlighting key concepts in clinical virology were prioritized for inclusion.

Content:

We describe the mechanisms of adaptive immunity to HSV, VZV and HHV-6, and limitations of antivirals as prophylaxis and treatment for these infections in SOT and HCT recipients. We review methods for measuring and restoring cellular immunity to double stranded DNA viruses, their potential applications to management of HSV, VZV, and HHV-6 in immunocompromised hosts, and barriers to clinical use. Vaccination and virus-specific T cell therapies are discussed in detail.

Implications:

The growing repertoire of diagnostic and therapeutic techniques focused on virus-specific adaptive immunity provides a novel approach to management of viral infections in transplant recipients. Investigations to optimize such interventions specifically in HSV, VZV, and HHV-6 are needed.

Graphical Abstract

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Introduction

The human herpesviruses are a group of eight double stranded DNA viruses that establish lifelong latency in human cells following primary infection (1). Reactivation of latent herpesviruses is facilitated by loss of regulatory cellular immunity and may occur any time after primary infection. The immunocompromised state associated with solid organ transplant (SOT) and hematopoietic cell transplant (HCT) increases the risk for severe disease during both primary infection and viral reactivation, and transplant recipients are prone to frequent episodes of the latter (1). Decades of research have centered on immune responses to cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in transplant recipients, while adaptive immunity to non-EBV, non-CMV herpesviruses are seldom the focus of large investigations. The majority of adults worldwide are infected with herpes simplex virus (HSV) 1 and 2, varicella zoster virus (VZV) and/or human herpesvirus 6 (HHV-6), and these infections may cause significant morbidity and occasional mortality following SOT or HCT (2–4). Severe sequalae from human herpesvirus 7 (HHV-7) and human herpesvirus 8 (HHV-8) are rare in transplant recipients (3). In this review, we describe adaptive immunity to HSV, VZV and HHV-6, discuss methods for evaluating virus-specific cellular responses, highlight limitations of available antiviral therapies, and explore novel mechanisms for restoring humoral in SOT and HCT recipients.

Overview of adaptive immunity in HSV, VZV and HHV-6 infections

Herpes simplex viruses

The herpes simplex viruses are α-herpesviruses that most commonly infect the oral or genital mucosa during primary infection and establish latency in the trigeminal nerve (oral HSV) or sacral dorsal root ganglia (genital HSV). HSV-1 and HSV-2 infect approximately 60% and 15–20% of adults by age 50, respectively (5, 6). Most clinical HSV infections in human immunodeficiency virus (HIV)-negative immunocompromised adults are due to HSV-1 and are characterized by mucocutaneous disease in the orofacial region (6, 7). Immunocompromised hosts are predisposed to more severe manifestations of HSV, including dissemination with visceral organ involvement (6, 8).

Cell-mediated immunity (CMI) has a key role in maintaining HSV latency (9, 10). In both SOT and HCT recipients, risk of HSV-1 reactivation is highest in the early post-transplant period when cellular immunity is most impaired (6, 7). Prior to routine antiviral prophylaxis, HSV-1 mucocutaneous disease occurred in up to 80% of seropositive HCT recipients and 15% of seropositive SOT recipients in the first several months following transplant (6, 11–13). Impaired T cell immunity also facilitates emergence of acyclovir resistant HSV during appropriately dosed prophylaxis, reflecting opportunities for viral mutants to arise during unchecked viral replication and the persistence of less fit variants that would otherwise be eliminated in immunocompetent hosts (14, 15). Cross-placental transfer of maternal HSV antibodies is a major mechanism of protection against neonatal HSV among infants born to seropositive mothers, suggesting that humoral immunity (HI) plays a key role during primary infection (16, 17). HI likely has a lesser role in the maintenance of HSV latency and isolated hypogammaglobinemia has not been associated with an increased risk of HSV reactivation (8, 18).

Varicella Zoster Virus

VZV is a ubiquitous α-herpesvirus that infected nearly all children before the advent of childhood varicella vaccination (VARIVAX®) in 1995 (19). Primary infection (varicella) manifests as a characteristic chickenpox rash, after which VZV establishes latency in ganglionic neurons. Thirty percent of VZV-infected individuals experience viral reactivation, manifested as herpes zoster ([HZ], shingles) (20). The incidence of HZ is up to 10 times higher in immunocompromised patients (21). Approximately 15% of HZ cases result in post-herpetic neuralgia (PHN), which is carries significant morbidity and is more common among immunocompromised persons (22).

CMI has central role in maintaining VZV latency. The first investigation of VZV-specific donor T cell infusion for seropositive allogeneic HCT recipients demonstrated limited viral reactivation during the post-transplant period, supporting a model of HZ pathogenesis in which cyclical viral reactivation is subclinical when CMI is intact (23). VZV-specific CMI has been inversely correlated with HZ incidence and related complications, including PHN (24). The role of HI in the prevention of HZ is less clear and likely less critical. In a study of 12,522 adults of whom 401 developed HZ over a three year period, VZV-specific CMI, but not VZV-specific antibody titers, correlated with protection against HZ (24).

Human Herpesvirus 6

HHV-6 (roseolavirus) is a β-herpesvirus that consists of two subspecies, HHV-6A and HHV-6B. Nearly all clinical manifestations of HHV-6 are due to HHV-6B, which infects >95% of people during early childhood (25). Primary HHV-6B infection may be asymptomatic or present with a mild, rash-associated febrile illness known as “exanthema subitem” or “roseola” (26). HHV-6B reactivation occurs in 30–50% of allogeneic HCT recipients, often during the pre-engraftment and early post-engraftment periods (3). HHV-6B in HCT recipients is associated with a variety of complications, including limbic encephalitis (1–8% of HCT recipients), which, when not fatal, frequently leads to severe and prolonged disability (3). HHV-6B reactivation occurs in up to one-third of patients in the first 12 weeks after liver transplantation, but HHV-6B encephalitis in SOT recipients is rare (3, 27).

As with HSV and VZV, CMI plays a greater role in controlling HHV-6 reactivation compared to HI. CD8 knockout, but not B cell deficiency, causes rapidly fatal infection in mice infected with murine roseolavirus, a β-herpesvirus related to HHV-6 (28). In HCT recipients, post-transplant HHV-6B viral loads are inversely correlated with the absolute number of HHV6B specific CD4 T cells contained in the graft, and higher proportions of perforin-expressing CD8 T cells are associated with HHV-6B clearance in viremic patients (28–30).

Limitations of antivirals

In SOT recipients, prophylaxis with acyclovir, valacyclovir or famciclovir is recommended in HSV and/or VZV seropositive patients for 1 month post-transplant and during treatment for rejection (6). HCT recipients remain at risk for VZV reactivation for months to years following transplant, and antiviral prophylaxis is extended for at least one year after HCT (7). HHV-6 prophylaxis is not recommended in SOT or HCT recipients (25). Plasma surveillance and/or preemptive therapy is not recommended for HSV, VZV or HHV-6, though antivirals should be given when there is high suspicion for disease (6, 7, 25).

Antivirals are not universally successful in preventing or treating herpesvirus infections. Breakthrough HSV infections occur in up to 10% of SOT and HCT recipients receiving prophylaxis, particularly if antivirals are underdosed for renal function or when absorption of oral agents is inadequate (6, 7). Emergence of HSV antiviral resistance while on adequately dosed prophylaxis may render pharmacotherapy ineffective, and HHV-6 encephalitis is associated with prolonged morbidity even in patients who receive targeted antiviral therapy (2, 4, 31). HZ after discontinuation of routine prophylaxis is common late after HCT and occurs in 26% of umbilical cord blood transplant recipients within 5 years of transplant (4). While acyclovir and valacyclovir are relatively safe and inexpensive, high pill burden, medication fatigue and transitions between healthcare teams limit long-term adherence (4).

Antiviral prophylaxis may have other unintended consequences that result in poor immune reconstitution. For example, CMV prevention with prophylactic letermovir (HCT) or valganciclovir (SOT) is associated with reduced CMV-specific polyfunctional T cell responses beyond day 100 compared to preemptive treatment approaches, potentially leaving patients vulnerable to a higher incidence of late CMV reactivation and disease (32–34). Clinically, such rebound effects have not been demonstrated after prolonged antiviral prophylaxis for VZV or HSV despite reduced VZV-specific lymphocyte proliferation among HCT recipients exposed to acyclovir (35, 36). Diagnostic tools that assess virus-specific immunity could identify patients at highest risk for viral infections and guide the necessary duration of prophylaxis, and therapies that restore immune function offer an alternative to antivirals for both prophylaxis and treatment of herpesviruses (Table 1).

Table 1:

Methods for assessing and restoring adaptive immunity to HSV, VZV, HHV-6

Diagnostics Prophylaxis and therapeutics
HI assay (serologies) CMI assays Vaccines Immunoglobulins Virus-specific T cells
HSV-1 & 2 Widely available; used to assess for evidence of latent infection prior to SOT and HCT Not available for routine clinical use Limited to clinical trials for prevention of primary infection Not indicated for primary prevention, prophylaxis, or treatment Not developed for use in humans
VZV Widely available; used to assess for evidence of latent infection prior to SOT and HCT Not available for routine clinical use Primary infection (varicella): live-attenuated varicella vaccine either alone (VARIVAX®) or in combination with measles, mumps, and rubella (MMRV, ProQuad®) Varicella zoster globulin (VARIZIG®) or pooled intravenous immunoglobulin (IVIG) for post-exposure prophylaxis in VZV seronegative immunocompromised persons Not developed for use in humans
Reactivation (herpes zoster): RZV (SHINGRIX®); ZVL (ZOSTAVAX®) no longer available in the US Not indicated for prevention of reactivation or treatment of zoster
HHV-6 Not recommended for routine clinical use Not available for routine clinical use Not available for prevention of primary infection or reactivation Not indicated for primary prevention, prophylaxis, or treatment Under investigation for prophylaxis and treatment in HCT recipients
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Abbreviations: cell mediated immunity (CMI), hematopoietic cell transplant (HCT), herpes simplex virus (HSV), human herpes virus 6 (HHV-6), humoral immunity (HI), recombinant zoster vaccine (RZV), solid organ transplant (SOT), varicella zoster virus (VZV), zoster vaccine live (ZVL)

Assessing humoral and cellular immune responses

Assessing humoral immunity

Measurement of virus-specific immunoglobulins in clinical practice is rarely performed to evaluate humoral immunity. Instead, HSV and VZV-specific immunoglobulins are used to detect latent infection and identify patients at risk of reactivation following HCT and SOT (6). Antibody tests for HHV-6 are not readily available and not recommended in transplant recipients (25). Furthermore, titers of HSV, VZV or HHV-6-specific immunoglobulins measured by enzyme-linked immunoassay (ELISA) do not necessarily correlate with neutralizing activity (16, 37, 38). Some experts use total immunoglobulin G (IgG) levels as a marker of global infection risk, but hypogammaglobulinemia without concurrent lymphopenia does not correlate with risk of VZV, HSV or HHV-6B reactivation or disease (39, 40).

Assessing cellular immunity

Absolute CD4 T cell count is often measured as a global assessment of immune reconstitution in transplant recipients but may not accurately reflect virus-specific CMI (4, 41). Cytokine release assays that measure virus-specific CMI have potential to predict risk of herpesvirus infections. Commercial and in-house enzyme-linked immunospot (ELISPOT) assays, which detect interferon-γ release by purified peripheral blood mononuclear cells (PBMCs) after incubation with virus-specific peptides or antigen lysates, have been developed to assess CMV-CMI, though are unable to differentiate CD4 and CD8 responses (42, 43). The ratio of IFN- γ producing cells to PBMC is measured, but thresholds for positivity vary between individual assays (42). Prospective studies of CMV-ELISPOT assays in HCT and kidney transplant recipients have demonstrated that positive results, indicative of in vitro CMV-CMI, have high negative predictive values (>93%) but low positive predictive values (<30%) for CS-CMVi (43, 44). Among 241 CMV seropositive allogeneic HCT recipients, CMV-CMI was low in 94% of patients who experienced CS-CMVi in the first 6 months after transplant (43).

Such CMI assays for HSV, VZV and HHV-6 are not clinically available but could help providers understand an individual’s risk for viral infections and guide duration of HSV and VZV pharmacologic prophylaxis following transplant or after immunization, particularly among HCT recipients with profound T cell dysfunction. VZV-CMI has been correlated with protection against HZ in vaccine clinical trials, suggesting that VZV-CMI assays may predict safe termination of VZV prophylaxis after HCT (24). Specific thresholds associated with protection need to be established before CMI assays for non-CMV herpesviruses can be integrated into clinical practice.

Restoring humoral and cellular immunity

Active immunization (vaccination)

Vaccination to promote endogenous humoral and cellular immunity is one approach to restoring virus-specific immune responses. VZV is the only herpesvirus for which licensed vaccines are currently available. Vaccines for the prevention of HSV and HHV-6 primary infection have been developed but efforts have not focused on immunocompromised populations (16, 38). In addition to the live attenuated vaccine given to children to prevent varicella, two vaccines have been developed for the prevention of HZ in adults: a live attenuated vaccine (zoster vaccine live [ZVL], ZOSTAVAX®) and an adjuvanted recombinant glycoprotein E subunit vaccine (recombinant zoster vaccine [RZV], SHINGRIX®). RZV has greater vaccine efficacy than ZVL for the prevention of HZ and is the only zoster vaccine available in the United States (45, 46). Unlike ZVL, RZV does not carry the risk of disseminated VZV infection and is therefore safer in immunocompromised populations. The United States Food and Drug Administration has approved RZV for immunocompromised adults aged 18 and older (47).

SOT and autologous HCT recipients receiving RZV in clinical trials demonstrated similar or slightly reduced humoral and cellular immune responses compared to immunocompetent adults (20, 45, 48–52). In a placebo-controlled clinical trial of RZV in autologous HCT recipients, vaccine efficacy was ~70% and RZV elicited humoral and cellular responses in 67% and 93% of vaccinees, respectively (48). RZV may be less immunogenic and less effective in allogeneic HCT recipients. In an observational series of allogeneic HCT recipients who received RZV at a median of 7 months post-transplant, humoral response occurred in only 3/18 (18%) patients (53). In a separate cohort of allogeneic HCT recipients who received 2 doses of RZV and subsequently discontinued antiviral prophylaxis, 3 (2%) developed HZ within 6 months of the second dose (53). Notably, data on the safety, immunogenicity, and efficacy of RZV in the first 6–12 months after allogeneic HCT or SOT are limited, and RZV has not eliminated the need for antiviral prophylaxis in the early post-transplant periods. Passive immunization strategies may be more effective in the early periods after HCT and SOT until adequate immune reconstitution is achieved and documented with virus-specific assays.

Immune globulins

Passive immunization with pooled intravenous (or subcutaneous) immune globulin (IVIG) replenishes humoral immunity and is used to prevent bacterial and sinopulmonary infections in patients with a variety of immunocompromising conditions but does not have a major role in management of HSV, VZV or HHV-6 (6, 7, 25, 39). Immune globulin preparations containing high titers of anti-VZV IgG are recommended to reduce the attack rate and prevent complications of varicella in VZV-seronegative immunocompromised patients after VZV exposure but are not routinely used to prevent reactivation of or treat infections due to HSV, VZV or HHV-6 in seropositive immunocompromised populations (6, 7, 25, 54).

Virus-specific T cells (VSTs)

Single or repeated virus-specific T cell (VST) infusions are a promising passive immunization strategy to replenish cellular immunity in immunocompromised patients. In HCT recipients, donor lymphocyte infusions are limited by graft versus host reactions due to the population of donor T cells recognizing recipient antigens. Selected infusion of CD4 and CD8 VSTs, or other approaches such as virus-specific NK cells or T cells with engineered receptors, may provide CMI while avoiding off-target T cell alloreactivity (55, 56). VST products were first designed to target individual viruses, including CMV, EBV, BK virus, and adenovirus (57). More recently, multivirus VST products that recognize a collection of double stranded DNA viruses, including HHV-6B, are being studied for prophylaxis and treatment of viral infections in high-risk HCT recipients, and have been administered for drug-refractory HHV-6B encephalitis in a limited number of patients (56, 58, 59). HSV-1 specific VSTs have been generated in vitro, but there are no reports of HSV or VZV specific T cell use in humans to date (56, 60). No serious adverse events have been causally linked to VST infusion, though GVHD and cytokine release syndrome are theoretical risks (56). Despite VSTs’ potential to revolutionize the management of viral infections in immunocompromised populations, evidence from placebo-controlled trials is not yet available, and there are several challenges to VST implementation in clinical practice (Table 2).

Table 2:

Advantages and limitations of virus-specific T cells (VSTs) for the prophylaxis and treatment of HSV, VZV and HHV-6 in immunocompromised hosts

Advantages of VSTs Limitations of VSTs
Implementation No pill burden, intended for short-term use as a “bridge” to immune reconstitution Costs associated with production and storage
Does not require enteral absorption or dose adjustment for renal function Infusion center needs (logistics of scheduling, travel for patients)
Stored banks of “off the shelf” products from third party donors with a variety of HLA types avoid treatment delays related to finding a suitably matched donor (56) HLA matching between VST donor, HCT donor, and recipient
Safety Well-tolerated in small clinical trials Theoretical risk of GVHD or CRS
Efficacy Option for HHV-6 prophylaxis; complementary or alternative strategy for treatment of HHV-6 or acyclovir resistant HSV Existing antivirals have established efficacy in management of HSV and VZV
Enthusiasm for research on cell-based therapies following the success of CAR-T cells for treatment of B cell malignancies Impact of corticosteroids, T cell depleting antibodies and other immunosuppressants on efficacy
Reported success in treatment of HHV- 6B encephalitis, under active investigation for prophylaxis in allogeneic HCT recipients (56, 59) Large, placebo-controlled trials lacking
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Abbreviations: chimeric antigen receptor modified-T (CAR-T), cytokine release syndrome (CRS), graft versus host disease (GVHD), human herpesvirus 6 (HHV-6), herpes simplex virus (HSV), varicella zoster virus (VZV), virus-specific T cell

Conclusions

HSV, VZV and HHV-6 continue to cause severe disease in patients with impaired cellular immunity. While antiviral prophylaxis has reduced the incidence of VZV and HSV infections following HCT and SOT, there are several limitations of antivirals in terms of safety, efficacy, and implementation. Laboratory methods assessing virus-specific CMI immunity have potential to guide the duration VZV prophylaxis following HCT, but clinical correlates of protection need to be established before routine use. Interventions focusing on measuring and optimizing an individual’s cellular immunity offer a precision medicine approach for infection prevention and management. Highly immunogenic vaccines may be valuable in some immunocompromised patients, and initiatives to develop vaccines that prevent HSV and HHV-6B reactivation are needed. However, in patients with the most profound deficits in CMI, active immunization is unlikely to induce protective immunity. VSTs are a promising tool to reduce viral reactivation and replication in highly immunocompromised patients awaiting CMI recovery. Overcoming the impact of immunosuppressants on VST expansion and function should be a focus of future investigations.

Funding:

This work was supported by the National Institute of Allergy and Infectious Diseases (T32AI118690 to M.R.H) and the National Cancer Institute (U01CA247548 to J.A.H) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest disclosures:

M.R.H. received speaking honoraria from Cigna LifeSource and Thermo Fisher Scientific. J.A.H received consulting fees from Gilead Sciences, Allovir, Takeda and research support from Takeda, Allovir, Deverra Thereapeutics, and Gilead. K.M.A. has no relevant interests to disclose.

Footnotes

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