Herpes Zoster Vaccines

Abstract

Background

Immunization for herpes zoster (HZ) aims to reverse the decline in cell-mediated immunity to varicella zoster virus that occurs with advancing age or immunocompromise. There are 2 vaccines available, one live attenuated (Zoster vaccine, live attenuated [ZVL]) and, recently, a recombinant subunit vaccine (HZ/su).

Methods

The literature relevant to the two HZ vaccines was reviewed.

Results

ZVL has overall efficacies of 51% and 65% against HZ and postherpetic neuralgia, respectively, with a prominent decline in efficacy with advancing age of the vaccinee. This compares to approximately 90% efficacy against HZ for HZ/su that is minimally affected with advancing age. The efficacy of ZVL against HZ declines over 4 and 8 years, compared with minimal decline so far over 4 years with HZ/su, and immunogenicity that is maintained for 9 years. Local and systemic reactogenicity to HZ/su is much greater than to ZVL.

Conclusions

HZ/su establishes an important principle—that a single recombinant viral protein with an effective adjuvant combination can stimulate immunogenicity superior to that of a live attenuated vaccine, and that this can diminish immunosenescence. This provides hope for improvement of other vaccines for aging patients. However, key questions remain unanswered, including the durability of the efficacy of HZ/su, its efficacy as a booster for previous recipients of ZVL, and its efficacy in immunocompromised patients.

Immunosenescence limits the magnitude, and generally the durability, of vaccine-induced immune responses [1]. Deficits in antibody responses to polysaccharide [2] and protein [3] antigens are limited by aging. In addition, and especially relevant to this presentation, is the effect of aging on varicella zoster virus (VZV) T-cell–mediated immunity (CMI), both magnitude and duration, in recipients of the live attenuated herpes zoster (HZ) vaccine [4]. This is noteworthy because these responses are essential for maintaining latency of the VZV and preventing HZ [5]. They are also important in limiting the severity of HZ once it has occurred [6]. VZV-CMI declines progressively with increasing age starting in the fourth decade of life [7].

EXPERIENCE WITH THE LIVE ATTENUATED HERPES ZOSTER VACCINE (ZOSTAVAX)

Despite the immune response barriers resulting from immunosenescence, the licensed HZ vaccine was an important advance. Overall, 51% of vaccine recipients ≥60 years of age were protected against HZ. Age-specific efficacy was 64% for those 60–69 years of age at the time of vaccination, fell to 41% for those 70–79 years of age, and was even lower for older vaccinees [8, 9] (Table 1; NCT00007501). It is noteworthy that the live zoster vaccine prevented postherpetic neuralgia (PHN) in 67% of vaccinees even into the eighth decade of life, demonstrating an attenuating effect even when it failed to prevent HZ. It also largely preserved the quality of life of the older vaccinees, as measured by standardized measures of life activities. Thus, even given a low vaccination uptake rate (currently ~34% in the United States), the HZ vaccine prevents >120000 cases of severe HZ in the United States annually (M. Levin, unpublished data).

In addition to these limitations on efficacy, 2 studies suggest that efficacy/effectiveness falls to 20%–40% at 4–8 years after vaccination [10, 11]. However, a subsequent large effectiveness study found that protection remained at approximately 50% for at least 4 years and protection against PHN remained at the 60%–70% range regardless of age at the time of vaccination [12].

Attempts to improve upon these results are complicated by the absence of a specific immune response target of protection (surrogate for protection) to guide potential interventions. While it is established that measures of antibody and VZV-CMI at various times before and after HZ vaccination correlate with protection on a population basis, no level of immune markers clearly predicted protection for a given vaccine recipient [4]. The exception to this is the suggestion that fold-rise in VZV antibody titer at 6 weeks postvaccination predicts protection [13]. This nonmechanistic correlate of protection was determined in a study limited to individuals 50–59 years of age.

Improving VZV Responses in Older Vaccinees

Using VZV-specific immune responses to evaluate approaches to improving the utility of the live HZ vaccine, it was determined that much higher doses than present in the vaccine did not appreciably enhance immune responses, although there is some evidence that duration of immunity was increased with larger doses (Merck Research Laboratories, unpublished data; M. Levin, unpublished data). Giving 2 doses, with varying intervals, also failed to significantly increase the immune response [14, 15]. Administration by the intradermal route was clearly dose sparing and suggested that VZV-CMI central memory responses were enhanced compared to subcutaneous administration [16].

In an attempt to reverse the waning of protective responses, a cohort of individuals who had received the HZ vaccine a decade previously was reimmunized. This resulted in higher VZV-CMI levels than obtained in age-matched first-time vaccinees. Thus, the decline could be reversed, and was even additive to the residual VZV-CMI from the initial vaccination [17]. This booster effect was demonstrable at 1 year after boosting, and partially maintained at 3 years after boosting [18].

Long-term Vaccine Safety

A recent 10-year review of vaccine safety by Willis et al [19] reported 23556 adverse events reports of which 93% were not serious. Five cases of Zoster vaccine, live attenuated (ZVL) herpes zoster, 4 in immunocompromised patients and rare cases of disseminated HZ and 1 death, were included. There are 2 other case reports of fatal disseminated HZ from ZVL, all in immunocompromised patients, emphasizing the importance of adhering to guidelines on administration of ZVL to severely immunocompromised patients.

INVESTIGATIONAL VACCINES

Heat-Inactivated VZV Zoster Vaccine

The current zoster vaccine is contraindicated for use in immunocompromised individuals, which is a population especially in need of protection against HZ. Research began >20 years ago on a heat-inactivated, non-live formulation of the live Oka strain of VZV, using a lower initial titer than in the live HZ vaccine. Studies in hematopoietic cell transplant recipients demonstrated immunogenicity and efficacy, using a regimen that included a dose before transplantation and 3 additional monthly doses thereafter [20, 21]. This inactivated vaccine was also immunogenic in patients with solid and hematologic tumors receiving chemotherapy and in patients with human immunodeficiency virus (HIV) (CD4 count < 200 cells/µL), but not in allogeneic stem cell transplant recipients [22]. A phase 3 trial in a similar mixed population of immunocompromised patients, using a 4-dose schedule and γ-irradiated VZV, demonstrated 64% efficacy against HZ, 74% efficacy against HZ complications, and 84% efficacy against PHN [23]. There are no data on the persistence of this effect. It is unclear how this vaccine will be used, given the requirement for 4 doses and the alternative non-live vaccine discussed below. However, it does not contain an adjuvant, is well tolerated, and might have value as a precursor to a live vaccine or to boost other vaccines that might be used in immunocompromised patients.

RECOMBINANT SUBUNIT HERPES ZOSTER VACCINE (HZ/SU)

A subunit vaccine (HZ/su) consisting of recombinant VZV glycoprotein E (gE) and the AS01B adjuvant system was developed by GlaxoSmithKline Vaccines (Wavre, Belgium). In this type of vaccine the antigen directs the immune response against the specific pathogen and the adjuvant determines the type of immune response and enhances it. Such an approach has been investigated for numerous pathogens, including herpes simplex virus and malaria [24–26], with partial success.

VZV gE is the most abundant glycoprotein on VZV-infected cells and is also a major target for VZV-specific antibody and T cells [27–29]. The gene was truncated to 546 amino acids by inserting a stop codon before the transmembrane sequence to provide a soluble secreted molecule, which reacted with monoclonal and polyclonal antibodies to the native protein. It also had a similar pattern and extent of glycosylation to the native molecule and induced virus-neutralizing antibodies in vitro (and also in vivo in clinical trials [30]). AS01B consists of the Toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPL), and the saponin QS21 (a purified extract from the tree Quillaja saponaria), both contained within liposomes. ASO1B was combined with gE because of its ability to stimulate both strong CD4⁺ T-cell and antibody responses in animal models [31, 32].

In phase 1/2 clinical trials, combinations and concentrations of the antigen and adjuvant were tested in adults ≥50 years of age. Addition of the adjuvant components produced higher gE-specific CD4⁺ T-cell and antibody responses than recombinant gE alone, especially in older subjects ≥70 years of age (Figure 1). Administration of a second dose of gE/AS01B 2 months later resulted in markedly greater VZV-specific CD4⁺ T-cell frequencies and antibody levels, leading to a 2-dose schedule for phase 3 trials. The strong immune responses to HZ/su have remained above baseline levels for at least 9 years [33–37].

Two randomized, blinded, placebo-controlled phase 3 trials of HZ/su were conducted concurrently in 18 countries (in North America, Europe, Asia-Australia, and Latin America) to determine the safety and efficacy against HZ and PHN in adults ≥50 years of age (Zoster Efficacy Study in Adults ≥50 Years of Age [ZOE-50; NCT01165177] and Zoster Efficacy Study in Adults ≥70 Years of Age [ZOE-70; NCT01165229]) [38, 39]. In ZOE-50, subjects were stratified into decades 50–59, 60–69, and ≥70 years of age and in ZOE-70 into 70–79 and ≥80 years of age. Both trials determined efficacy for prevention of HZ, vaccine safety and reactogenicity, compared to placebo, in the overall study populations, and in each age group by decade. The ZOE-70 trial was designed to better define efficacy against HZ in people ≥70 years of age and against PHN, which is more common in this group [38, 39].

Vaccine Efficacy Against the Incidence of Herpes Zoster

In ZOE-50, 15411 evaluable participants randomly received either HZ/su or placebo and were followed for a mean of 3.2 years. HZ was confirmed by polymerase chain reaction (PCR) of lesion swabs for VZV DNA (90%) or by expert clinical adjudication committee if a PCR-based decision could not be made. The modified vaccinated cohort received both doses of vaccine or placebo and did not develop HZ within 1 month after the second dose. In this cohort 6 subjects in the vaccine group and 210 in the placebo group developed confirmed HZ. The incidence was 0.3 vs 9.1 per 1000 person-years, respectively. The vaccine efficacy against HZ was 97.2% (95% confidence interval [CI], 93.7%–99.0%; P < .001) for the overall study population and was similar in the 3 age groups (95% CI, 96.6%–97.9%; P < .001 for each) and in different regions of the world [38, 39]. In ZOE-70, during a mean follow-up of 3.7 years, 13900 evaluable participants of average age 75.6 years received HZ/su or placebo. In the modified vaccinated cohort, 23 vaccine recipients and 223 placebo recipients developed HZ. Vaccine efficacy was 89.8% (95% CI, 84.2%–93.7%; P < .001), and was similar in those 70–79 years of age (90.0%) and ≥80 years of age (89.1%; P < .001) (Figure 2). Pooled data from the 2 trials showed a vaccine efficacy of 91.3% in subjects ≥70 years of age. The absence of an age effect on efficacy contrasts favorably with the live attenuated vaccine discussed above.

HZ/su Efficacy Against PHN

Combined data from the phase 3 trials showed 4 cases of PHN (among 29 with HZ) in vaccine recipients and 46 cases (among 433 with HZ) in the placebo recipients. The respective incidences were 0.1 and 0.9 cases with PHN per 1000 person-years and the vaccine efficacy against PHN was 91.2%. No cases of PHN in subjects <70 years of age were observed. Notably, the incidence of PHN in cases of HZ was similar in the HZ/su and placebo recipients, indicating that HZ/su prevents PHN mainly through preventing HZ. Definition of additional attenuation of disease in vaccine recipients was limited by the low number of breakthrough HZ cases (Figure 3). In contrast, the live vaccine exerted an additional effect against PHN (66.5% efficacy) beyond preventing HZ (51% efficacy) in people ≥60 years of age, with an even greater difference in subjects ≥70 years of age (Table 1) [9, 39]. In a recent cohort study this was confirmed up to age 80 for >6 years [40]. This similar efficacy of HZ/su on the incidence of HZ and PHN in younger and older adults is important because the incidence and severity of HZ increases markedly with age in unvaccinated people

HZ/su Safety, Reactogenicity, and Tolerability

There was much more reactogenicity to HZ/su than placebo in both ZOE-50 and ZOE-70. The most frequent reactions were pain at the injection site and generalized myalgia and fatigue [33, 36, 41]. For systemic reactions, the overall incidence in vaccine vs placebo recipients was 53%–66.1% vs 25.1%–29.5%, respectively. Grade 3 systemic reactions (defined as preventing everyday activities) were reported in 6.0%–11.4% of vaccine recipients and in 2.0%–2.4% of placebo recipients, respectively. Injection site reactions occurred in 74.1%–81.5% of vaccine recipients vs 9.9%–11.9% of placebo recipients. Grade 3 injection site reactions (defined as those impairing everyday activities) were reported in 8.5%–9.5% of HZ/su recipients vs 0.2%–0.4% of placebo recipients. However, these reactions were generally transient, with a median duration of 1–2 days for systemic reactions and 2–3 days for injection site reactions. Systemic or injection site reactions were not worse with the second dose and were less frequent in those ≥80 years of age. In addition, vaccine reactogenicity did not prevent 95% subjects from receiving a second vaccine dose [38, 39]. In the phase 2 HZ/su trials, the adjuvant made the major contribution to injection-site and systemic reactions [1, 33, 36]. Proven HZ in the previous 5 years did not adversely influence safety or immunogenicity of HZ/su [42]. There was no increased risk of new immune-mediated diseases or exacerbations of old ones (a potential concern for new adjuvants like AS01B) detected in HZ/su compared with placebo recipients [43, 44]. There were also no differences in serious adverse events and death between the 2 groups.

Immunogenicity of HZ/su

An immunologic correlate of HZ protection has not been defined. Cell-mediated immunity, both CD4⁺ and CD8⁺ T-cell responses, are important in preventing VZV reactivation (and recovery from VZV disease) [42, 43]. Although the protective role of humoral responses is less clear [13, 27, 45, 46], a 4-fold rise in VZV-specific antibody titers measured by glycoprotein-based enzyme-linked immunosorbent assay was a good correlate of protection for the live-attenuated HZ vaccine [12, 25]. In ZOE-50 and ZOE-70, a ≥4-fold increase in anti-gE antibody concentration occurred in 97.8% of HZ/su recipients compared with 2.0% of placebo recipients, regardless of age. In the HZ/su recipients at 1 month after dose 2, the geometric mean concentration of anti-gE antibodies was 39.4-fold above baseline, and at 36 months was 8.7-fold above baseline. In the placebo group antibody concentrations remained at or below baseline. gE-specific CMI responses, measured as the frequency of CD4⁺ T cells expressing ≥2 (of 4) activation markers (CD4²⁺) after stimulation with gE peptides, were observed in 93.3% of HZ/su recipients and not in placebo recipients. The CD4²⁺ frequencies peaked at 1 month post–dose 2, with an overall median frequency of gE-specific CD4²⁺ that was 20.5-fold above baseline in HZ/su recipients and below the baseline in placebo recipients. The median frequency of CD4²⁺ T cells was somewhat lower at 1 month post–dose 2 in those ≥70 years of age compared to those 50–59 years of age. These frequencies subsequently declined in all age groups, but remained above baseline at 36 months, including in subjects ≥70 years of age. Furthermore, there was a progressive loss of CD4⁺ T cells expressing 1 or 2 markers, which resulted in the proportion of CD4⁺ T cells expressing all 4 markers increasing over 36 months in all age groups [30]. However, determining an immunological correlate of protection was not possible because of the few cases of HZ in vaccine recipients and the small number of subjects tested in the immunologic substudy.

The most important immunologic principle emerging from the phase 1/2 and 3 trial data is that a single viral protein combined with an appropriate adjuvant combination provided strong protection against HZ in both older and immunocompromised populations, with persistence for many years. This is probably because VZV gE is an excellent immune target that elicits both neutralizing antibody and CD4⁺ T-cell responses, and because of boosting of VZV-specific memory immune responses by AS01B [31, 47]. In the phase 1–2 studies, gE adjuvanted with AS01B elicited much higher gE-specific CD4⁺ T-cell and humoral immune responses than gE alone, especially in those ≥70 years of age [31, 32, 41]. These results suggest that HZ/su can circumvent immunosenescence to provide protection against HZ [1, 41, 48]. Therefore, subunit approaches employing one or a few target antigens combined with appropriate adjuvants could lead to successful prophylactic or therapeutic vaccines for other diseases of the elderly.

Mechanism of Action of AS01B in HZ/su

MPL in both the AS04 and AS01B adjuvant combinations stimulates TLR4 on antigen-presenting cells. The mechanism of QS21 in AS01B is not fully defined, especially in humans. However, in mice QS21 stimulates inflammasomes in macrophages of lymph nodes draining the muscle injection site, with a subsequent increase in the number of activated resident lymph node dendritic cells and those derived from immigrating blood monocytes. These dendritic cells present the gE antigen to T cells [49]. HZ follows reactivation of an existing latent infection and may be an easier target than primary immunization [25, 49].

IMMUNIZATION OF IMMUNOCOMPROMISED PATIENTS

The severity and incidence of HZ is increased in immunocompromised patients in proportion to the degree of immunosuppression. In particular, patients receiving allogeneic or autologous hematopoietic stem cell transplantation (HSCT) experience an incidence of HZ of 15%–30% in their first year, and have an increased risk of visceral dissemination [50]. Although the introduction of antiretroviral therapy has decreased the risk of HZ in HIV-infected people from 10- to 20-fold higher than the age-matched population, it is still approximately 2- to 3-fold higher, especially in people with CD4 counts <200 cells/μL. Complications of HZ, including recurrent episodes, are still approximately 3-fold higher in HIV-infected people than the age-matched population [51]. HZ/su may fill this unmet medical need in severely immunocompromised individuals [35], provided that its efficacy is proven in such settings. Phase 1/2 trials of the safety and immunogenicity of HZ/su in autologous HSCT recipients and patients with HIV have been published [50, 51]. In the trial of HSCT for Hodgkin disease, non-Hodgkin lymphoma, multiple myeloma, or acute myeloid leukemia, HZ/su was immunogenic for at least 1 year [50]. In HIV-infected patients, strong anti-gE antibody and gE-specific CD4⁺ T-cell responses persisted until the end of the 18-month study, whether vaccinees had low or normal CD4 counts or were antiretroviral therapy experienced or naive [51]. In these trials, reactogenicity was similar to that in immunocompetent patients and there were no vaccination-related severe adverse effects. In the HIV trial there was no effect on CD4 count or HIV viral loads. Much research is still needed in immunocompromised patients. A phase 2 study has been completed in renal transplant recipients and there is a ongoing phase 3 efficacy study of HZ/su in autologous stem cell transplant recipients. Phase 1/2 trials are also in progress in other immunocompromised conditions, such as other solid organ transplantation and hematologic malignancies.

FUTURE QUESTIONS

Direct efficacy comparisons between the live and recombinant vaccines are unlikely. Comparative studies will be limited to immunogenicity and reactogenicity. A relevant trial is just now being analyzed.

• How long does the protection of HZ/su last? The immunogenicity studies on phase 1/2 trials are promising, showing persistence of VZV-specific CD4⁺ T-cell immunity for 9 years, well beyond the 3.2 years and 3.7 years of follow-up for ZOE-50 and ZOE-70, respectively. In contrast, the live attenuated vaccine showed diminishing vaccine effectiveness against HZ after 4–8 years, although effectiveness against PHN was longer [11, 40].

• Can HZ/su be used as a booster in previous recipients of the live vaccine? In some countries, a significant proportion of the susceptible population will have been immunized with live zoster vaccine when HZ/su becomes available. A booster dose of a HZ vaccine, as early as 5 years after a first dose, has been proposed. A recently reported study of HZ/su in previous live zoster vaccine recipients showed similar safety and immunogenicity to unimmunized subjects [52].

• Can the excellent efficacy of HZ/su in people ≥70 years of age be exploited for other vaccines, such as for influenza and pneumococcus? Could the AS01B adjuvant or other similar combinations circumvent immunosenescence with respect to these other vaccines?

  • Will HZ/su be efficacious in severely immunocompromised patients for whom the live vaccine is contraindicated? Data from a phase 3 trial addressing this will soon be available. Although the live-attenuated zoster vaccine is contraindicated in severely immunocompromising conditions [53], in less immunocompromising conditions, such as autoimmune diseases treated with biologic modifiers, this vaccine may be tolerated, but the safety and efficacy need further testing [54].

  • What is the efficacy of HZ/su with a single dose? Is there any setting where the second dose should be omitted? Postmarketing surveillance of HZ/su is important to detect rare safety signals, especially occurrence or recurrence of autoimmune diseases, beyond the >30000 subjects who have received HZ/su in trials and the >70000 who have received ASO1B in trials of other vaccines, including the licensed malaria vaccine.

• Is coadministration of HZ/su with other “adult” vaccines, such as Tdap and pneumococcal conjugate vaccines, safe as for influenza [55]? Phase 2 trials to answer this are in progress or complete.

CONCLUSIONS

The live attenuated vaccine (Zostavax) was important for the prevention of HZ and for understanding the interaction of immunosenescence with immunization. Future investigation of the mechanisms of attenuation of disease and PHN by Zostavax, beyond its effect on incidence of HZ, will provide important information. The recombinant HZ/su is highly efficacious in preventing HZ and PHN in all age groups, even those ≥80 years of age. Almost all subjects responded to HZ/su vaccination with robust antibody and CD4⁺ T-cell responses, including vaccinees ≥70 years of age. Immune responses remained substantially above baseline up to 9 years after vaccination, which may translate into prolonged efficacy. The adjuvant combination is critical for the efficacy and durability of this response.

Notes

Supplement sponsorship. This work is part of a supplement sponsored by the Royal Society of Medicine (Royal Charter number RC000525) funded through unrestricted educational grants from Merck, Sanofi Pasteur MSD, The Research Foundation for Microbial Diseases of Osaka University, Seqirus and GlaxoSmithKline.

Potential conflicts of interest. A. L. C. has consulted on vaccines for Merck, BioCSL/Sequirus, and GlaxoSmithKline, and his institution has received resulting honoraria. M. J. L. received fees for serving on advisory boards from Merck and GSK, grant support from Merck and GSK, and royalties from a patent related to a zoster vaccine held with Merck. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Presented in part: 15th National Immunisation Conference, Public Health Association of Australia, Brisbane, 7–9 June 2016; IDWeek, New Orleans, Louisiana, 26–30 October 2016; International Herpesvirus Workshop, Madison, Wisconsin, 23–27 July 2016; World Congress of Geriatrics and Gerontology, Kaohsiung, Taiwan, 18–20 November 2016; and Congress of the Japan Association of Infectious Diseases, Tokyo, 8 April 2017.

References

Author notes