Zoster Vaccines

Localization of Latent Varicella-Zoster Virus in Sensory Ganglia

The VZV and herpes simplex viruses are α-herpesviruses that cause human infections. The molecular virology of VZV, a member of the Herpesviridae family, is described in Chapter 62. An essential and unique feature of α-herpesviruses is their ability to become latent in neurons in sensory ganglia during their initial (primary) infection. The primary infection with VZV is manifest clinically as varicella (chickenpox), which is endemic worldwide (see Chapter 63). Varicella usually occurs in childhood in temperate climates, generally as winter–spring epidemics. ^{, ,} In countries with widespread immunization against varicella, this pattern is disappearing. In tropical climates, the prevalence of varicella remains high in late adolescence or young adulthood. Because varicella vaccine was not introduced into the United States until 1995, more than 97% of adults >25 years old have had varicella.

VZV is transmitted by an airborne route as droplet spread from the pharynx or from aerosols from skin lesions of an index case of varicella or HZ (see Chapter 63). It is postulated that the initial replication of VZV occurs in epithelial cells lining the nasopharynx and subsequently spreads to adjacent lymphoid tissue, thereby infecting memory CD4 ⁺ T cells, such as those that are abundant in tonsillar lymphoid tissue. Dendritic cells have a central role in this process. Activated CD4 ⁺ T cells expressing cutaneous homing markers are preferentially infected and deliver VZV to cutaneous epithelia within a few days of infection. ^{, ,} Infection of cells at the dermal–epidermal junction leads to the most visible consequence of VZV viremia, which is the characteristic vesicular lesions. The incubation period prior to varicella symptoms after exposure may be explained by the time required for dissemination of VZV by circulating T cells, initial cell-to-cell spread in tissues, and innate immune responses that delay VZV replication. The development of specific immune-mediated pathogenesis also contributes to the formation of in skin lesions.

The significance of the varicella lesions for the pathogenesis of HZ is that the termini of sensory axons are located at the dermal–epidermal junction at the base of vesicles. It is hypothesized that from this locus VZV enters and ascends by retrograde axonal transport to become latent in the soma of neurons in sensory ganglia. This mechanism is suggested by the clinical observations that the dermatomes most frequently affected with HZ are also those that have the highest density of skin lesions during varicella and that vesicle fluid has very high titers of cell-free VZV. ^{, ,} Additional support comes from early studies with the varicella vaccine, wherein vaccine recipients were much more likely to develop subsequent HZ with the vaccine strain virus if they had a vaccine-related rash in the postvaccine period. In addition, vaccine-related HZ occurring in recipients of the varicella vaccine occurs most often in the dermatome where the vaccine is administered. However, this is not always the case, suggesting that viremia occurs after varicella vaccine administration. Since viremia is characteristic of varicella, this provides an alternative or additional mechanism for VZV to gain access to sensory ganglia. ^{, ,} The presence of VZV in autonomic ganglia and enteric neurons is additional evidence that the viremia of varicella can seed sensory ganglia. ^,

Nature of Latent Varicella-Zoster Virus DNA

Cranial and dorsal root sensory ganglia, autonomic ganglia, and enteric neurons contain VZV DNA detectable by polymerase chain reaction (PCR). This is true of more than 90% of adult trigeminal ganglia and 70% of thoracic ganglia, reflecting the prevaccine epidemiology of varicella; other cranial nerve and autonomic ganglia contain latent VZV DNA.

Approximately 2–5% of neurons in sensory ganglia contain latent VZV DNA, which is absent in non-neuronal satellite cells. ^, The VZV DNA in neurons is latent in the sense that infectious virus cannot be isolated from ganglia by tissue culture techniques. The latent VZV DNA is present in the nuclei of neurons in a circular form different from that present in intact virions. ^, Episomal DNA also characterizes the physical state of latent herpes simplex virus in sensory ganglia. The number of copies of VZV DNA in a neuron is 1000-fold lower than the burst size in infected fibroblasts, indicating rapid shut off of VZV replication in infected neurons. ^{, ,} This VZV DNA serves as a template during latency, resulting in the presence of a limited number of RNA transcripts in ganglia examined shortly after death. These include a unique latency-associated transcript (VLT), the ORF 63 transcript, and a VLT-63 fusion transcript colocated in the nuclei of neurons. One model suggests that a VLT-63 fusion protein induces VZV transcripts of all kinetic classes that lead to reactivation. It is not known how latency is established or how the VLT-63 transcript induces reactivation.

Maintenance of Latency by Varicella-Zoster Virus–Specific Immune Responses

Although the mechanism of latency is not understood, strong evidence suggests that it is related to the VZV-specific immunity of the host that initially developed at the time of, or shortly after, the appearance of skin lesions with varicella, and to the subsequent decline of this immunity with aging. These immune responses include polyclonal VZV-specific antibody and T-cell–mediated immune (CMI) responses, including CD4 ⁺ and CD8 ⁺ effector and memory T cells. They persist lifelong to protect the host against subsequent cases of varicella and to prevent HZ.

The central role of VZV-specific CMI in preventing HZ is consistent with observations that HZ incidence and severity increases with age, while VZV-CMI decreases with age at about the same rate. ^, In contrast, VZV-specific antibody is not greatly affected by age. ^, The relationship between VZV-CMI and HZ is evident from numerous and varied clinical observations. It was recognized early that the age-specific incidence and severity of HZ was greatly increased in patients with immune compromise resulting from underlying illness (e.g., HIV infection) or immunosuppressive therapies for malignancy, autoimmune disease, or organ transplantation. Natural and iatrogenic experiments indicated that VZV-CMI is necessary and sufficient to maintain latency of VZV and prevent HZ. For example, children born with isolated γ-globulin deficiencies do not develop severe varicella or experience an increased incidence or severity of HZ, whereas children with severe combined immune deficiency often suffer severe morbidity with VZV infections. ^, The likelihood that chemotherapy-treated patients with lymphoma developed HZ correlated with the preservation or recovery of VZV-CMI, whereas this risk did not correlate with the presence of anti-VZV antibody. In addition, the presence of anti–VZV antibody before bone marrow transplantation was not predictive of the occurrence of HZ. Moreover, recipients of allogeneic hematopoietic stem cell transplants, who have their immune responses totally ablated and then receive replacement therapy with intravenous γ-globulin (which has high levels of anti–VZV antibody), nevertheless have a high incidence of HZ, often with severe manifestations. The risk of HZ in this setting abates only with engraftment and return of the potential for pathogen-specific CMI. The essential role of VZV-CMI in maintaining latency was verified by the success of an experimental, inactivated vaccine evaluated after hematopoietic stem cell transplants. The frequency and severity of HZ after vaccination correlated with the appearance of VZV-CMI (but not anti–VZV antibody). ^,

Clinical Manifestations of Herpes Zoster

VZV, because of the global endemicity of varicella, is latent in many ganglia in most humans and has the potential to reactivate intermittently in a subclinical manner. This is suspected because unexplained increases in VZV-specific antibody and activated VZV-specific T cells are detected intermittently, and VZV DNA is intermittently detected in the blood of asymptomatic immunocompromised and immunocompetent people. Presumably these random events, of unknown frequency , are of no consequence because the VZV-CMI that is present when they occur is sufficient to prevent propagation of VZV infection in ganglia. The subsequent boost in immunity that accompanies subclinical reactivation may be a factor in maintaining VZV-CMI throughout life (termed “endogenous boosting”). When an immune person is exposed to someone with varicella or HZ, VZV-specific immunity may also be boosted (termed “exogenous boosting”). ^, The accumulation of activated VZV-specific CD4 ⁺ T cells in older people may reflect these phenomena. ^,

One model is that reactivation of VZV in ganglia is normally contained by the ambient specific immune response, and HZ only occurs following reactivation if there has been a decline below some (unknown) critical level of VZV-CMI. In this scenario, the appearance of infectious VZV in a ganglion, unchecked by the ambient VZV-CMI, leads to ganglionitis, during which many neurons and supporting cells are damaged by the widespread infection and/or the intense inflammatory response that follows. An alternative potential role of VZV-CMI is to directly prevent (rather than limit) VZV reactivation. There is insufficient information to distinguish between these two possibilities. An inadequate immune response to a VZV reactivation that culminates in HZ may result from therapy-related or disease-related immune suppression, but much more often it is the result of the decline in VZV-CMI that accompanies the normal aging process. ^{, ,} It is also likely that the level of VZV-specific immunity, at any age, can be temporarily blunted by changes in sense of well-being, depression, stress, or intercurrent infection with viruses that can alter CMI responses, such as Epstein-Barr virus and cytomegalovirus. ^, Trauma to a dermatome may also lower the threshold for symptomatic reactivation in the ganglion innervating that dermatome. These additional factors may explain why children sometimes develop HZ. ^, Race and family history also influence the age-specific incidence of HZ and its complications. ^,

The ganglionitis and related neuronal damage that accompany extensive VZV reactivation cause the neuropathic prodromal pain in the dermatome where skin lesions subsequently appear. Prodromal pain accompanies 70–80% of HZ cases in older adults. ^{, ,} The prodromal pain typically lasts 3–4 days, but may last a week or longer. Its character varies with the patient: shooting, boring, aching, and throbbing are some descriptors. The pain may be constant or intermittent. Intense itching is common. The cause of this localized pain in the involved dermatome is initially unclear to the medical provider, often leading to a search for visceral disease suggested by the location of the pain, such as myocardial infarction when a left upper thoracic dermatome is involved; renal stone or intervertebral disk disease when a lumbar dermatome is involved; or intra-abdominal disease (e.g., cholecystitis or appendicitis) when right-sided mid-lower thoracic dermatomes are involved. Approximately 12% of medical costs for HZ in the United States occur before the appearance of skin lesions. ^,

The duration of the prodrome is a function of the rate and extent of VZV replication in the ganglion and correlates with subsequent antegrade movement of VZV in the sensory nerve to the dermal–epidermal junction, where VZV replicates to induce the characteristic rash. The appearance of skin lesions reveals the origin of the prodromal pain and provides the diagnosis. Mild constitutional symptoms are infrequent (10–20%). The rash of HZ in immunocompetent patients characteristically involves a single dermatome; hence, the lesions do not cross the midline (see Fig. 66.1 ). Several contiguous dermatomes may develop lesions or individual variation in innervation may give this impression. Infection of epithelial cells causes a varicelliform rash that is limited to the dermatome involved. After brief sequential macular and papular stages, the characteristic rash (i.e., vesicles on an erythematous base) appears. New vesicles appear for 3–4 days in groups that tend to cluster where there are branches of the involved cutaneous sensory nerve. Pustulation of vesicles begins within 1 week, followed 3–5 days later by lesion ulceration, crusting, or both. The lesions may evolve over a longer time or become hemorrhagic in patients with advanced age or immune suppression. The rash is usually accompanied by the same pain experienced during the prodrome, but this acute phase pain can worsen, improve, or appear for the first time after the skin lesions appear. The acute pain and the preceding prodrome can be very severe, disabling, and a barrier to employment and activities of daily living. The nociceptive pain, which accompanies extensive skin involvement, is additive to the neuropathic pain. Itching may also increase in prominence. ^,

VZV frequently gains access to the bloodstream, as demonstrated by VZV DNAemia during the early stages of HZ. ^{, ,} This is of little consequence to most patients, but in immunocompromised patients, extensive viremia in the absence of a vigorous immune response can result in a disseminated form of HZ that includes severe, multiorgan disease. ^, VZV is also present in the saliva shortly after the onset of HZ. ^,

Additional insight into the age-related decline in VZV-CMI is gained from the observation that elderly patients with HZ frequently have cutaneous VZV lesions at a distance from the involved dermatome. This reflects their inability to muster adequate VZV-CMI in a timely manner after VZV reactivation, thereby permitting more extensive viremia and/or more extensive VZV replication at distant sites.

In addition to the acute pain, complications occur in approximately 8% of patients with HZ who are 50–59 years old and in more than 12% of persons 70 years of age or older. Complications include bacterial superinfection of the skin (2%); segmental motor nerve damage, including nerves of the face, limb weakness, and other neurologic complications (3–5%); and dysfunction of bowel or bladder when sacral nerves are involved. ^{, ,}

The presence of motor involvement may exceed 10% if this finding is carefully sought by a neurologist. Motor deficits are rarely permanent, although recovery is less likely to be complete in older patients. The occurrence of motor deficits is consistent with data that VZV often extends through the ganglionic root to the central nervous system. Lymphocytic pleocytosis and VZV DNA are commonly found in the cerebrospinal fluid of patients with HZ, and magnetic resonance imaging studies obtained during HZ often demonstrate inflammation in the spinal cord at the level of HZ involvement. Spread to the spinal cord has been confirmed histologically in patients who had HZ at the time of death from unrelated diseases. ^{, ,} While these abnormalities are generally inconsequential, they probably explain why contiguous dermatomes are often involved and why the uncommon complications of transverse myelitis and bilateral dermatomal involvement are occasionally seen in both immunocompetent and immunocompromised patients. ^, VZV meningitis and meningoencephalitis can occur with HZ. ^{, ,} Because the ophthalmic branch of the trigeminal nerve is involved in 10–15% of cases, damage to ocular structures is a common occurrence (5% of HZ in older patients). ^{, ,}

The most common complication of HZ is the persistence of significant pain for months after onset of the rash. ^, The frequency of this postherpetic neuralgia (PHN) is strongly influenced by the age of the patient. PHN is defined as pain persisting for an extended period after the onset of HZ (i.e., prodromal pain) or after the onset of HZ rash. Thus, the age-specific frequency of PHN varies with its definition. The postevent interval used to define PHN has most often been between 30 and 90 days after rash appears, because the onset of rash is easily recognized and remembered. Most investigators now use this starting point and many now define PHN as pain being present at 90 days after the rash appears. ^{, , ,}

Age is the strongest prognostic factor for the occurrence of PHN, which is uncommon in people younger than age 40 years, and becomes common when HZ occurs in people older than age 50 years. The various definitions, and various populations reported, have led to estimates of PHN ranging from 7% to 25% of HZ cases. HZ cases occurring during the large trial of the live HZ vaccine in subjects at least 60 years old resulted in significant pain lasting or beginning at least 30 days after rash onset in 30% of placebo recipients; lasting 60 days in 17%; and lasting 90 days in 12%. In some patients, PHN may last for a year or longer.

PHN may be intermittent or constant, stabbing or lancinating, deep burning or throbbing, or allodynia, which is a painful sensation resulting from an otherwise normal stimulation of the skin. PHN is the third most common cause of chronic neuropathic pain in the United States, with a point estimate of 500,000 cases annually. Acute and chronic pain strongly influence the quality of life, with effects on physical, psychological, social, and functional domains. These effects are particularly profound in elderly patients.

Rationale for a Herpes Zoster Vaccine

When Hope-Simpson showed in his seminal monograph that the frequency of HZ increased with age, he also suggested that this was the consequence of an age-related decline in VZV-specific immunity. His conclusion was consistent with the clinical information available at that time, since corroborated, that immunocompromising diseases and therapies are associated with a large increase in the frequency and severity of HZ. We now know that the essential component in protection against HZ is VZV-CMI. Distinct humoral and T cell–mediated immunity had not been defined when Hope-Simpson discerned the relationship between age and HZ frequency. The hypothesized progressive decline in VZV-specific immunity has been identified repeatedly as VZV-CMI, and not as antibody. This immunosenescence is now considered characteristic of the normal aging process. ^{, , ,} The close relationship between the decline in VZV-CMI and the increasing frequency of HZ with aging is assumed to represent cause and effect. This relationship and the continuing decline in VZV-CMI are maintained into the sixth, seventh, and eighth decades. ^{, ,} Anti–VZV antibody levels do not decline with age. ^{, , ,} In addition, Hope-Simpson noted that second cases of HZ were rare in elderly patients, suggesting that the occurrence of HZ in most cases sufficiently stimulated VZV-specific immunity to prevent second attacks. Many investigators have documented that second attacks of HZ are uncommon (2–5%), ^{, ,} although a recent study questioned this conclusion. Overall, the data available in the 1980s led many investigators to suggest that a vaccine capable of boosting VZV-CMI in elderly subjects might prevent or attenuate HZ in this population. A similar hypothesis, suggested for transplant recipients at high risk for HZ, was confirmed by boosting VZV-CMI with an inactivated VZV vaccine. ^,

Two Vaccines to Prevent Herpes Zoster

There are two HZ vaccines licensed - one is a live-attenuated VZV vaccine and the other is a recombinant glycoprotein E vaccine. Although they are both discussed in this chapter, the recombinant HZ vaccine is currently available in a limited number of countries. This will remain true for several years. It is likely that, once the recombinant vaccine becomes available in any location, it will be the preferred preventative vaccine. The two vaccines are discussed in the order of their development.

Composition of the Live HZ Vaccine

This HZ vaccine contains the Oka strain of VZV developed for the varicella vaccine (see Chapter 63). This is provided as a lyophilized powder and solvent for suspension for injection in a prefilled syringe. The reconstituted vaccine (0.65 mL) contains not less than 19,400 PFU. This can be administered subcutaneously or intramuscularly; the latter has less local side effects. After reconstitution, the vaccine should be used immediately, although in-use stability has been demonstrated for 30 minutes when stored at 20–25°C. The vaccine should be stored and transported refrigerated (2–8°C). It should not be frozen.

The live HZ vaccine is produced by Merck & Co, and marketed as Zostavax®. It was licensed in the United States in May 2006. Because of the preferred recommendation of the recombinant HZ vaccine (discussed below) in the United States, the live HZ vaccine was withdrawn from the U.S. market. However, it remains an important HZ vaccine for most of the world. It is licensed in 60 countries, including the European Union, Canada, Australia, and much of Asia and the Middle East. It is available in 38 countries, where it is the sole option for preventing or attenuating HZ. In 2020, 2.2 million doses were distributed, primarily in the United Kingdom, European Union, Australia/New Zealand, and Korea.

Phase I/II Trials With the Live HZ Vaccine

Relevant trials with a live VZV vaccine were undertaken from 1984 to 1999. It was appreciated that the participants had preexisting VZV-specific immunity and that an investigational vaccine would be unique in preventing reactivation of an endogenous latent infection , rather than preventing a new infection . An important positive feature for the live and the recombinant HZ vaccines is that they will likely boost immune memory developed during childhood varicella, possibly further maintained by endogenous and exogenous boosting.

There were two important concerns when the live HZ vaccine was being developed: (1) that preexisting immunity in vaccinees might limit replication of the administered live vaccine; and (2) that this live vaccine was being administered by a non-natural route, with a quantity of infectious VZV that might not mimic the natural challenge of reactivation, to a target population known to have waning immunity to VZV.

Two studies of vaccine immunogenicity were especially important. ^, These each had more than 200 participants who were ≥55 years old. These and subsequent studies demonstrated the safety of the vaccine and provided dose-response data, based on immune responses, that determined the composition of the vaccine. ^, The number of VZV-specific CD4 ⁺ memory T cells in vaccinees was increased approximately twofold. For all age groups combined, the half-life for the booster effect was 56 months. At the highest dose, the vaccine effect declined little over 5 years. ^{, ,} Injection-site reactions were similar in frequency and severity to those occurring with the pneumococcal vaccine. No age effect on the vaccine-induced boost was observed in these pilot studies. Subsequent studies determined that VZV-spacific cytotoxic CD8 ⁺ T cells were also increased in number following vaccine. ^, Safety was demonstrated in older subjects with comorbidities, specifically persons with controlled diabetes mellitus or chronic obstructive pulmonary disease.

Prior to embarking on a definitive efficacy trial of the live HZ vaccine, a questionnaire to record HZ pain and discomfort was validated and laboratory methods were chosen and validated for measuring VZV-CMI. The pain assessment methods became a standard tool for current studies of HZ and related vaccines/therapies.