INTRODUCTION — Varicella-zoster virus (VZV) infection causes two clinically distinct diseases. Primary infection with VZV results in varicella, also known as chickenpox, characterized by vesicular lesions in different stages of development concentrated on the face and trunk and less so on the extremities. Herpes zoster, also known as shingles, results from reactivation of latent VZV (from the varicella infection) in neurons within the sensory ganglia. Herpes zoster is characterized by a painful, unilateral vesicular eruption that occurs in a restricted dermatomal distribution.
Vaccines are available for prevention of both infections. This topic will address the use of the two vaccines used to prevent herpes zoster. A discussion of the vaccine to prevent varicella (chickenpox) is found elsewhere. (See "Vaccination for the prevention of chickenpox (primary varicella infection)".)
IMPORTANCE OF CELL-MEDIATED IMMUNITY — Varicella-zoster virus (VZV)-specific cell-mediated immune responses play a critical role in controlling VZV latency and limiting the potential for reactivation [1]. A decline in cell-mediated immunity has been documented in older individuals and in patients with lymphoproliferative malignancies, both populations that experience higher rates of herpes zoster (figure 1). These epidemiologic observations are supported by in vitro data that demonstrate reduced VZV-specific T cell frequency in aging patients who are more susceptible to virus activation [2-5]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)
Immunity and risk of reactivation — A decline in VZV-specific cell-mediated immunity is regarded as the major precipitant for VZV reactivation [4]. Approximately 30 to 40 percent of persons over the age of 55 years do not have any detectable VZV-specific T-cell responses by some assay methods [4].
Among those who develop herpes zoster, in vitro data suggest that robust VZV cell-mediated immunity at the onset of rash is correlated with reduced severity of disease and less risk of postherpetic neuralgia [6]. Immunocompromised individuals who lack adequate VZV-specific cellular immune responses are at greater risk for prolonged episodes of reactivation and disseminated disease, which can be fatal [7]. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)
Several observations suggest that a decline in cell-mediated immunity, rather than humoral immunity, is linked directly to reactivated VZV syndromes. As an example, in allogeneic hematopoietic cell transplants, both cell-mediated and humoral immune responses are ablated, and although antibody is replaced with intravenous gamma-globulin (which contains VZV antibody), these patients have very high rates of herpes zoster [8]. In addition, children with hypogammaglobulinemia do not experience severely protracted or fulminant primary varicella infection or increased rates of herpes zoster [9].
Boosting of T-cell-specific immunity to VZV — Cell-mediated immune responses improve with periodic subclinical varicella-zoster virus (VZV) reactivation (endogenous boosting), which may limit virus replication and decrease the risk of developing herpes zoster [4,10]. Environmental boosting of T-cell responses has also been documented among VZV-immune healthy adults who have had household exposures to children with primary varicella, which may also decrease the risk of herpes zoster [4,11-13]. The impact of varicella vaccination on the incidence of herpes zoster is discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of herpes zoster".)
Zoster immunization, with either of the available vaccines, is associated with a boost in VZV-specific T-cell immune responses, which contribute to the vaccine's efficacy in preventing or attenuating disease [6,14-18]. Data demonstrating the efficacy of these vaccines are described below [19,20]. (See 'Available vaccines' below.)
APPROACH TO VACCINATION — Vaccination is indicated to reduce the risk of developing herpes zoster and postherpetic neuralgia in those at increased risk for disease (immunocompetent individuals ≥50 years of age, immunocompromised patients ≥19 years of age at increased risk of herpes zoster) (figure 2 and figure 3) [21]. Vaccination is not indicated for the treatment of these conditions.
This section will review the approach to vaccination in different patient populations. Details regarding the individual vaccines, a nonlive recombinant glycoprotein E vaccine (designated recombinant zoster vaccine [RZV]) and a live attenuated vaccine (designated zoster vaccine live [ZVL]), are found below. (See 'Recombinant zoster vaccine' below and 'Zoster vaccine live' below.)
Immunocompetent persons ≥50 years of age — We suggest zoster vaccination in immunocompetent individuals ≥50 years of age, and we recommend it strongly for older patients (eg, ≥60 years of age). It is not necessary to confirm immunity to varicella-zoster virus (VZV; eg, history of varicella [chickenpox]) prior to vaccination [22]. Most adults born before 1980 have had varicella (eg, 99 percent of those born in the United States), and waning antibodies in previously exposed individuals, particularly older adults, may lead to negative antibody results despite past infection or vaccination. In addition, a self-reported history of shingles is often of questionable reliability [19].
The choice of vaccine (RZV versus ZVL) is often dictated by availability [23]. When both are available, our approach is as follows:
●Preferred approach – We recommend zoster vaccination with RZV for most immunocompetent patients ≥50 years of age. Populations in whom RZV may be contraindicated are discussed below. (See 'Contraindications and precautions' below.)
We prefer RZV to ZVL based on indirect evidence suggesting that it has greater efficacy (table 1). RZV is efficacious in patients with diabetes mellitus or chronic heart, lung, liver, or kidney disease [24]. While RZV and ZVL have not been compared head-to-head, a network meta-analysis suggested that RZV was superior to ZVL in reducing the incidence of herpes zoster [25,26]. RZV also was superior to ZVL in reducing postherpetic neuralgia in patients >60 years of age, but this was most likely a consequence of the marked reduction in herpes zoster [26].
In addition, there is less concern for waning immunity over time with RZV compared with ZVL [23]. (See 'Durability of protection' below.)
Although RZV has a higher incidence of side effects that affect everyday activities, this is usually not a reason for choosing ZVL. The side effects seen with RZV typically resolve in one to three days [27-29] and, in most cases, do not prevent individuals from completing the RZV vaccine series. The network meta-analysis comparing RZV and ZVL did not find a difference in serious adverse event rates [26]. A more detailed discussion of the side effects of RZV and ZVL is presented below. (See 'Adverse events' below and 'Adverse events' below.)
●Alternative approach – Vaccination with ZVL is an alternative for immunocompetent patients where RZV is not available. RZV can be administered in the future if it becomes available. (See 'Patients who received zoster vaccine live or varicella vaccine' below.)
ZVL is also an alternative for those who are allergic to any of the components of RZV and in those who are at risk of complications associated with RZV (eg, patients with a history of Guillain-Barré syndrome). (See 'Contraindications and precautions' below.)
ZVL is also reasonable for those who are unlikely to complete the two-dose RZV series; ZVL is given as a single dose. (See 'Administration' below.)
When ZVL is used, specific age recommendations vary by country. As an example, ZVL is licensed for those ≥50 years of age; however, when ZVL was used in the United States, the Advisory Committee on Immunization Practices (ACIP) suggested it be administered to those ≥60 years old. The ACIP used this age cut-off since the long-term protection provided by ZVL is limited [20,23,24,30-33], and there is a lower rate of herpes zoster in persons aged 50 to 59 years compared with those ≥60 years old [24]. Moreover, routine vaccination with ZVL in persons aged 50 to 59 years was not supported in a cost-effectiveness analysis [34]. (See 'Immunity and risk of reactivation' above and 'Zoster vaccine live' below.)
Immunocompromised persons — For immunocompromised patients, the approach to vaccination depends upon the patient's age and underlying condition, type of immunosuppressive therapy, history of prior varicella infection or vaccination, and which herpes zoster vaccine formulations are available. For those initiating immunosuppressive therapy, the approach to vaccination also depends upon when immunosuppression is planned.
Vaccination for immunocompromised patients had previously been approved only for those ≥50 years of age. However, in January 2022, the ACIP extended the recommendation to include RZV for adults ≥19 years of age who are or will become immunocompromised [21]. The US Food and Drug Administration (FDA) and the European Medicines Agency have approved the use of RZV for individuals aged ≥18 years who are at increased risk of herpes zoster due to immunodeficiency or immunosuppression [35,36].
Determining need for vaccination — Vaccination against herpes zoster is indicated for immunocompromised individuals ≥19 years of age who have a history of prior varicella infection or varicella vaccination and are (or will be) at increased risk for herpes zoster.
●Determining risk for herpes zoster – Immunocompromised patients with reduced T-cell-mediated immunity are at increased risk for VZV reactivation. This includes transplant recipients, patients receiving selected immunomodulator therapies, and patients treated with chemotherapy and/or corticosteroids. (See 'Importance of cell-mediated immunity' above and "Epidemiology, clinical manifestations, and diagnosis of herpes zoster", section on 'Risk factors'.)
Some immunocompromised patients may not be at increased for herpes zoster (eg, patients with impaired splenic function). In such patients, the approach to vaccination is generally the same as for immunocompetent adults. (See 'Immunocompetent persons ≥50 years of age' above and "Prevention of infection in patients with impaired splenic function".)
●Determining the timing of vaccination – Vaccination should be administered prior to immunosuppression whenever possible. (See 'Future immunosuppression planned' below.)
When this cannot be done, the approach to vaccination should be individualized, taking into account vaccine efficacy, the patient’s risk for developing herpes zoster, and the potential risks of vaccination. Ideally, vaccination should be administered when the immune response is likely to be most robust (eg, during periods of lower immunosuppression and stable disease) [21]. (See 'Patients with existing immunocompromise' below.)
●Patients without prior VZV infection or vaccination – In immunocompromised persons, it is not necessary to confirm immunity to varicella prior to administering zoster vaccination. The vast majority of patients have had varicella or have been vaccinated against varicella, and serologic testing may not be reliable as antibody titers may have waned.
However, assessing for prior varicella infection (eg, verification of disease, laboratory evidence of immunity) or varicella vaccination can be a routine part of the initial evaluation in some patient groups (eg, transplant recipients).
•In these cases when there is no evidence of immunity, it may be reasonable to administer the varicella vaccine (a live, attenuated vaccine), if immunosuppressive therapy can be delayed.
•By contrast, for those who are already immunocompromised, the approach is less clear since varicella vaccine is generally contraindicated and the efficacy and safety of RZV for preventing primary varicella have not been evaluated. In such patients, when an exposure to varicella or herpes zoster occurs, providers typically administer post-exposure prophylaxis with antiviral therapy or immunoglobulin to reduce the risk of developing varicella since there is the most clinical experience with this approach. However, some experts may also administer RZV prior to any exposure, as it likely elicits partial immunity against varicella and some exposures to varicella may not be recognized.
More detailed information on post-exposure prophylaxis and the approach to varicella vaccination in immunocompromised patients is presented elsewhere. (See "Post-exposure prophylaxis against varicella-zoster virus infection" and "Vaccination for the prevention of chickenpox (primary varicella infection)" and "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Varicella' and "Immunizations in solid organ transplant candidates and recipients", section on 'Varicella' and "Immunizations in autoimmune inflammatory rheumatic disease in adults", section on 'Live vaccines'.).
Future immunosuppression planned — For patients ≥19 years old who are planning immunosuppressive therapy that puts them at increased risk for herpes zoster, we recommend zoster vaccination prior to immunosuppression. This includes solid organ transplant recipients, patients receiving selected immunomodulator therapies, and patients treated with certain chemotherapy agents. More detailed information on vaccination in specific patient populations is found below and in separate topic reviews. (See 'Patients with cancer' below and 'Transplant recipients' below and 'Patients with other autoimmune conditions' below.)
This recommendation is based in part on evidence that patients who are immunocompromised are at substantial risk of zoster infection, and that immunization of immunocompromised patients with RZV is effective in reducing the incidence of zoster [37]. These data are discussed separately. (See "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'Zoster vaccine'.)
At least two studies have suggested that vaccination prior to transplantation produces a robust serologic immune response [38,39]. Furthermore, vaccination prior to immunosuppression provides an opportunity for patients who cannot receive RZV to get vaccinated with ZVL, which is contraindicated in patients who are immunosuppressed.
●Preferred approach – As with immunocompetent hosts, RZV is preferred, and only RZV is recommended for patients 19 to 49 years of age [35].
RZV requires two doses. Although the typical interval between doses is two to six months, it can be reduced to one to two months if needed. Immunosuppressive therapy should be delayed two weeks after the second dose to allow an optimal immune response to develop.
●Alternative approach – If ZVL is used because of lack of availability or contraindication to RZV, it should be administered ≥4 weeks before the initiation of immunosuppressive therapy [40]. ZVL is only approved for use in those ≥50 years of age.
Patients with existing immunocompromise
Patients receiving low-dose immunosuppressive therapy — If vaccination prior to immunosuppression is not possible, it may be reasonable for those receiving low-level immunosuppression. However, the likelihood of responding to vaccination has not been established in such patients, and the decision to vaccinate depends upon the patient’s risk for developing herpes zoster (age, type of therapy) and the potential risk of vaccination (eg, flare of their underlying condition, risk of adverse reaction from the vaccine).
Examples of low-dose immunosuppressive therapy include [40]:
●Low-dose prednisone (<2 mg/kg: maximum ≤20 mg/day) or equivalent
●Methotrexate (≤0.4 mg/kg/week)
●Azathioprine (≤3 mg/kg/day)
●6-mercaptopurine (≤1.5 mg/kg/day)
As with immunocompetent hosts, RZV is generally preferred [23], and only RZV is approved for individuals 18 to 49 years of age [35,36].
ZVL can be used in patients ≥50 years of age receiving low-level immunosuppression, but disseminated herpes zoster with vaccine-type virus has occurred rarely in such patients who have received ZVL [41].
Patients with HIV — The approach to zoster vaccination in patients with HIV is discussed is a separate topic review. (See "Immunizations in persons with HIV".)
Patients with primary immunodeficiency — The approach to immunization in patients who have primary immunodeficiencies (eg, severe antibody or combined immunodeficiency, leukocyte-adhesion deficiency, and cytotoxic granule defects) is discussed separately. (See "Immunizations in patients with primary immunodeficiency".)
ZVL is contraindicated in these patients since they are at risk for developing disseminated VZV infection with the vaccine strain of the virus [23,24,40,42-45]. (See 'Contraindications and precautions' below.)
Patients with cancer — The approach to zoster vaccination in patients with cancer is discussed separately. (See "Immunizations in adults with cancer" and "Immunizations in hematopoietic cell transplant candidates and recipients".)
RZV appears safe and immunogenic in many patient groups [23,37,43,46-49]. However, data are somewhat limited.
In general, ZVL is contraindicated in patients with leukemia, lymphoma, or other malignancies affecting the bone marrow or lymphatic system, as well as those receiving immunosuppressive therapies such as cytotoxic agents, high doses of corticosteroids (eg, ≥20 mg daily for ≥14 days), and/or certain biologic agents (eg, rituximab). Such patients are at risk for developing disseminated VZV infection with the vaccine strain of the virus [23,24,40,42-45]. (See 'Contraindications and precautions' below.)
ZVL can be administered after completion of immunosuppressive therapy, provided there is no evidence of ongoing immune compromise. The duration depends upon the specific regimen. As an example, patients who have received chemotherapy or radiation for cancer and are in remission should generally wait at least three months before receiving ZVL [50]; however, vaccination should be deferred longer for those receiving other agents, such as rituximab. (See "Immunizations in adults with cancer", section on 'Timing of immunizations'.)
Transplant recipients — Vaccination with live virus vaccine (ZVL) is not recommended for transplant recipients (hematopoietic and solid organ recipients). Also, in certain transplant recipients, there is a theoretic risk that RZV could lead to rejection of the graft due to the immune response elicited by the adjuvant. Studies to answer these questions are still underway. In the meantime, the decision to vaccinate with RZV and the approach to vaccination must be individualized. This is discussed in detail separately.
●(See "Immunizations in hematopoietic cell transplant candidates and recipients".)
●(See "Immunizations in solid organ transplant candidates and recipients".)
Patients with a history of Guillain-Barré syndrome — We generally avoid administering RZV to patients with a known history of Guillain-Barré syndrome (GBS), given the possible association between RZV and GBS, as described below. (See 'Risk of Guillain-Barré syndrome' below.)
In the post-marketing observational study that assessed risk of RZV and development of GBS [51], the US FDA determined that the study results showed an association of GBS with RZV, but there was insufficient evidence to establish a causal relationship between receipt of RZV and GBS. However, based on these findings, we advise against administering RZV to patients with a prior history of GBS pending additional safety data. If available, ZVL is a reasonable alternative for immunocompetent patients.
Patients with other autoimmune conditions — In patients with autoimmune conditions, such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, and other autoimmune diseases, the decision to vaccinate with RZV needs to be made on a case-by-case basis given the limited data in these populations. Providers must take into consideration the possible risks, such as a flare of the underlying condition due to the immune response elicited by the adjuvant, as well as the efficacy of the vaccine in those receiving immunosuppressive agents.
Limited data suggest RZV appears safe and immunogenic in patients with immune-mediated diseases [52,53]. As an example, in a post-hoc analysis of the ZOE trials described above [27,28], the safety and efficacy of RZV were evaluated in 1934 patients with autoimmune diseases not receiving immunosuppressive therapies [52]. Similar to other participants who received RZV, the overall efficacy against herpes zoster was 90.5 percent, and serious and fatal adverse events were similar to controls. However, until additional data are available, the decision must be individualized. Disease-specific discussions are provided separately; as examples:
●(See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
●(See "Management of moderate to severe ulcerative colitis in adults".)
ZVL is contraindicated in patients receiving immunosuppressive therapies such as corticosteroid therapy with a dose ≥20 mg/day of prednisone or equivalent for ≥14 days, and/or biologic agents such as rituximab, tumor necrosis factor (TNF)-alpha antagonists or blockers, and Janus kinase inhibitors. These patients are at risk for developing disseminated VZV infection with the vaccine strain of the virus [23,24,40,42-45]. (See 'Contraindications and precautions' below.)
ZVL can be administered to those who have completed immunosuppressive therapy after a certain duration, provided there is no evidence of ongoing immune compromise. As an example, among patients receiving immunosuppressive agents such as high-dose corticosteroids or TNF-alpha inhibitors, vaccination should be deferred at least one month after completion of the treatment course. Vaccination may need to be deferred longer for those receiving other agents, such as rituximab. (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
Additional considerations
Patients with prior herpes zoster infection — When herpes zoster vaccination is indicated (eg, immunocompetent individuals ≥50 years of age, immunocompromised patients ≥19 years of age at increased risk of herpes zoster), it should be given regardless of a history of prior herpes zoster infection. (See 'Immunocompetent persons ≥50 years of age' above and 'Immunocompromised persons' above.)
However, the timing of vaccination in a patient with a recent episode of zoster is uncertain. We typically delay vaccination for approximately one year since herpes zoster itself will boost VZV-specific immunity for several years. Guidelines from the United States Centers for Disease Control and Prevention (CDC) do not indicate a specific length of time a patient should wait to get vaccinated after an episode of herpes zoster but do state that RZV should be delayed until the acute stage of the illness is over and symptoms resolve (eg, the rash has gone away) [21,23,54].
Studies have found that ZVL and RZV can be safely administered to immunocompetent patients ≥50 years of age with a prior history of herpes zoster, although the clinical efficacy in this situation has not been established [55-57].
Patients who received zoster vaccine live or varicella vaccine — We suggest that patients who previously received ZVL receive the two-dose series of RZV. RZV can be safely administered to patients who have previously received ZVL [58].
The optimal timing of revaccination is unclear. However, for patients who received ZVL, the ACIP recommends that the first dose of the RZV be given at least eight weeks after ZVL [23].
Revaccination with RZV for patients who received ZVL is warranted given the reduced efficacy of ZVL compared with RZV (particularly in patients ≥70 years of age), as well as waning immunity, which is seen within five to eight years of receiving ZVL. Data supporting these findings are described below. (See 'Efficacy' below.)
The ACIP states that RZV may also be used in patients who received the varicella vaccine since herpes zoster due to the vaccine-strain of virus has been reported [23,24]. However, there are no data on the efficacy of RZV in reducing vaccine-strain herpes zoster.
Household contacts of immunocompromised hosts — The indications for herpes zoster vaccination in household contacts of immunocompromised patients are the same as those for the general population, and RZV is preferred. (See 'Immunocompetent persons ≥50 years of age' above.)
ZVL is not contraindicated in this group, but immunocompromised patients should avoid contact with household contacts who develop skin lesions resulting from ZVL until the lesions clear [40]. Transmission of vaccine virus has not been reported in clinical trials [59]; however, the vaccine package insert mentions the possibility that transmission of vaccine virus to immunocompromised contacts may occur rarely from vaccine recipients who develop a varicella-like rash [60].
AVAILABLE VACCINES — There are two types of effective zoster vaccines. While these vaccines have not been compared head-to-head, indirect comparisons suggest they may differ in their efficacy as well as the durability of response (table 1). These vaccines are also variably available.
Recombinant zoster vaccine — The recombinant glycoprotein E vaccine (designated recombinant zoster vaccine [RZV]; sold as Shingrix) was approved for use in the United States in October 2017 [61]. RZV contains varicella-zoster virus (VZV) glycoprotein E in combination with an adjuvant (AS01B).
Availability — RZV is available in several countries, including the United States, Canada, Belgium, Germany, Sweden, the Netherlands, and China. Although RZV is licensed in several other countries (eg, Australia, the European Union, Japan, New Zealand, Hong Kong), it may not yet be available because of limited supply.
Efficacy — RZV is effective in reducing the incidence of herpes zoster and postherpetic neuralgia. Two randomized controlled trials (ZOE-50 and ZOE-70) have evaluated the efficacy of RZV. In both trials, participants received the recombinant vaccine or placebo at zero and two months [27,28].
In one trial, 15,411 individuals ≥50 years old were evaluated [27]. During a mean follow-up of approximately three years, RZV reduced the risk of developing herpes zoster by 97.2 percent (95% CI 93.7-99.0); herpes zoster was confirmed in six individuals in the RZV group and 210 individuals in the placebo group. No cases of postherpetic neuralgia were reported in the RZV group compared with 18 cases reported in the placebo group.
In a subsequent trial in 13,900 adults aged 70 years or older who were followed for a mean of 3.7 years [28], the efficacy of RZV in preventing herpes zoster was 90 percent (95% CI 84.2-93.7); herpes zoster developed in 23 patients who received the vaccine versus 223 who received placebo. In addition, the vaccine efficacy against postherpetic neuralgia was 89 percent (95% CI 68.7-97.1).
RZV was immunogenic even in patients who are considered frail or prefrail [62]; such patients are at risk for adverse health outcomes and have been found to have low immune responses to certain vaccines. (See "Frailty".)
Durability of protection — The long-term efficacy of RZV was evaluated in extension studies of the two clinical trials. An interim analysis suggested that immune response as well as efficacy against herpes zoster remained high (84 and 91 percent) through seven years of follow-up [63]. In addition, immune responses (antibody and T-cell immunity) have remained elevated for up to nine years in a limited number of patients with long-term follow-up [32].
Administration — The RZV requires two doses administered intramuscularly for protection. For most patients, the second dose should be administered two to six months after the first [35]. However, for immunocompromised patients who would benefit from an expedited vaccine series (eg, those getting vaccination prior to receiving immunosuppression), the second dose can be delivered one to two months after the first dose. (See 'Future immunosuppression planned' above.)
This schedule should be used for all patients, including those with a history of prior herpes zoster and those who previously received zoster vaccine live (ZVL). The timing of vaccination in these patients is discussed above. (See 'Patients with prior herpes zoster infection' above and 'Patients who received zoster vaccine live or varicella vaccine' above.)
If there is a deviation from the recommended schedule, the Advisory Committee on Immunization Practices (ACIP) provides the following guidance [23]:
●If there is a delay in administering the second dose (ie, more than six months after the first dose), the second dose can be administered at any time; the series does not need to be restarted. However, the efficacy of the vaccine in this setting is unclear.
●If the second dose is received less than four weeks after the first, the second dose should be repeated at least four weeks after the dose given too early [21].
Coadministration with other vaccines — The ACIP advises that recombinant vaccines, such as RZV, can be administered at the same time as other routine vaccines in adults but at different anatomic sites [21,23]. Although data are limited, studies have demonstrated that RZV can be safely administered with several of the commonly used vaccines (eg, diphtheria and acellular pertussis [Tdap] vaccine, the 23-valent pneumococcal polysaccharide vaccine, the quadrivalent influenza vaccine), without affecting the immune response of either vaccine [64-66]. Studies evaluating coadministration of RZV with the quadrivalent adjuvanted inactivated influenza vaccine are in progress. (See "Standard immunizations for nonpregnant adults" and "Standard immunizations for nonpregnant adults", section on 'Immunization schedule for nonpregnant adults' and "COVID-19: Vaccines".)
The ACIP states that the zoster vaccine can also be administered at the same time as the COVID-19 vaccine [21]. However, studies evaluating the safety of administering these vaccines together are ongoing. Pending additional data, clinicians may choose to separate these vaccines (prioritizing the COVID-19 vaccine first), since both are associated with adverse side effects that can limit the ability to participate in routine activities for one to two days. (See "Standard immunizations for nonpregnant adults" and "Standard immunizations for nonpregnant adults", section on 'Immunization schedule for nonpregnant adults' and "COVID-19: Vaccines".)
Adverse events
Common reactions — RZV can cause injection site and systemic reactions [67]. Adverse events are generally less severe after the second dose [68] and are less frequent in persons aged 70 years or older compared to 50 to 69 year olds [69].
●Injection site reactions – The most common side effect after RZV administration is pain at the injection site in 78 percent of subjects in the two trials [27,28]. Reactions that prevented normal, everyday activities (pain, redness, and swelling) occurred in 9.4 percent of vaccine recipients.
●Systemic reactions – The most common systemic effects in the trials were myalgia (44.7 percent), fatigue (44.5 percent), headache (37.7 percent), shivering (26.8 percent), fever (20.5 percent), and gastrointestinal symptoms (17.3 percent). Systemic effects that prevented normal, everyday activities were reported by 10.8 percent of vaccine recipients versus 2.4 percent in those who received placebo [23].
In the clinical trials of RZV, combined local and systemic reactions that prevented everyday activities were more common among those who received RZV compared with placebo (16.5 versus 3.1 percent) [23,27,28]. Most of these reactions lasted one to three days, and their frequency and severity rarely resulted in refusal of the second vaccine dose. There were no significant differences in the percentage of participants who experienced serious adverse events, immune-mediated diseases, or death in the vaccine and placebo groups. In a study of 401 adults who received RZV, physical functioning and quality-of-life measures were generally not affected after the first dose of RZV [70]. Similar findings were seen after administration of the second dose [71]. However, in these studies, participants with severe (Grade 3) reactions did have a temporary decline in physical function for the first two days after the first or second dose of RZV was administered.
The safety of this vaccine was further evaluated in a postlicensure surveillance study that was conducted over an eight-month period and included 4381 adverse event reports [69]. There was a low rate of serious adverse events (eg, hospitalization, life-threatening illness), which was consistent with findings in prelicensure clinical trials. The types of adverse events (eg, fever, injection site reactions, chills, headache, fatigue) were also similar to the early clinical trials, and there were very few complications suggesting immune-mediated diseases. In this study, 65 percent of the adverse events were reported in females. In addition, individuals aged 50 to 69 years were more likely to experience systemic signs and symptoms compared with those ≥70 years, who were most likely to report local symptoms (eg, injection site erythema and pain).
When counseling patients about the potential adverse reactions associated with RZV, it is useful to tell patients that about one in six persons have reactions that prevent them from doing normal activities, but that they usually resolve within one two days, and it’s useful to avoid strenuous activities for a few days after vaccination [23]. Providers can find additional informational resources through the United States Centers for Disease Control and Prevention (CDC) [72].
Risk of Guillain-Barré syndrome — There may be an association with RZV and Guillain-Barré syndrome (GBS) [51,73]. In a post-marketing observational study using Medicare claims data that identified 3,729,863 vaccinations with RZV, there was an increased risk of GBS in adults aged ≥65 years during the 42 days following vaccination, with an estimated three excess cases of GBS per million doses administered [51]. In secondary analyses, there was estimated excess of six cases of GBS per million doses of RZV during the 42 days following the first dose of RZV, but no increased risk of GBS was observed following the second dose. The risk of GBS in patients 50 to 65 years of age was not evaluated. A more detailed discussion of GBS is presented elsewhere. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Vaccinations'.)
Contraindications and precautions — RZV should not be given to patients with a known allergy to the components of the vaccine.
There are also potential risks of using RZV in select populations:
●Transplant recipients (see 'Transplant recipients' above)
●Those with autoimmune conditions (see 'Patients with other autoimmune conditions' above)
●Those with a history of GBS (see 'Patients with a history of Guillain-Barré syndrome' above)
RZV should be avoided during pregnancy since it has not been studied in persons who are pregnant. However, the ACIP states clinicians can consider RZV vaccination without regard to breastfeeding status when RZV is indicated since recombinant vaccines such as RZV pose no known risk to mothers who are breastfeeding or to their infants [21].
Zoster vaccine live — A live attenuated vaccine (designated zoster vaccine live [ZVL]; sold as Zostavax), ZVL contains 18,700 (at expiry) to 60,000 plaque-forming units of VZV, considerably more than the approximately 1350 plaque-forming units found in the Oka/Merck vaccine for prevention of varicella. (See "Vaccination for the prevention of chickenpox (primary varicella infection)".)
Availability — As of July 2020, ZVL is no longer sold in the United States [74]. However, it continues to be used in many other countries.
Efficacy — ZVL is effective in reducing the incidence of herpes zoster and postherpetic neuralgia.
The Shingles Prevention Study (SPS) was a placebo-controlled clinical trial that evaluated ZVL in 38,546 adults 60 years of age or older [75]. At three years, ZVL reduced the incidence of herpes zoster by 51 percent compared with placebo (1.6 versus 3.3 percent). Vaccine efficacy was significantly greater in individuals aged 60 to 69 years compared with those ≥70 years (63.9 versus 37.6 percent). The incidence of postherpetic neuralgia was reduced by 67 percent in the vaccine group (0.46 versus 1.38 cases per 1000 person-years). Unlike the incidence of herpes zoster, the benefit appeared greater in patients ≥70 years of age. A 2016 systematic review and meta-analysis confirmed the benefits observed in the earlier definitive SPS study and calculated that 50 people need to be vaccinated to protect one person from herpes zoster [76].
A post-licensure observational study of ZVL, including more than 75,000 vaccinated patients, provides further support for its efficacy [77]. In an adjusted analysis, vaccination was associated with a significantly reduced risk of herpes zoster (hazard ratio [HR] 0.45; 95% CI 0.42-0.48). This risk reduction occurred in all age strata (60 to >80 years of age) and among individuals with chronic diseases (eg, diabetes, liver disease, coronary artery disease). The risk of ophthalmic herpes zoster and hospitalization was also reduced by approximately two-thirds. An even larger effectiveness trial confirmed these findings for herpes zoster and postherpetic neuralgia [78].
The efficacy of vaccination among patients 50 to 59 years of age was evaluated in the Zostavax Efficacy and Safety Trial (ZEST). In this trial, 22,439 patients aged 50 to 59 years from the United States and Europe were randomly assigned to vaccine or placebo and followed for a mean of 15 months for the development of herpes zoster [79]. The vaccine efficacy for preventing herpes zoster was 70 percent (95% CI 54.1-80.6); zoster vaccine reduced the incidence of herpes zoster from 99 cases in the placebo group (6.6 per 1000 person-years) to 30 cases in the vaccine group (2 per 1000 person-years).
Durability of protection — An immunology substudy of 1395 patients demonstrated increases in VZV-specific antibody and cell-mediated immunity at six weeks after vaccination compared with placebo [14]. These increases persisted during the three years of follow-up, although the magnitude of T-cell responses declined over time.
Protection appears unchanged through year 5 [33]; however, it wanes significantly after about eight years (from approximately 50 percent to 20 to 30 percent) [33,78,80-83]. In one study, there was no benefit from ZVL in reducing herpes zoster after year 8, although prevention of postherpetic neuralgia was partially preserved [81].
Administration — ZVL is administered as a one-time subcutaneous injection.
Coadministration with other vaccines — ZVL may be administered at the same visit as other vaccines. However, other live vaccines (eg, measles, mumps, and rubella) should be separated by at least 28 days if they are not given on the same day.
There have been concerns that coadministration of pneumococcal polysaccharide vaccine (PPSV23) may reduce the immunogenicity of ZVL [84-86]. Although the manufacturer states that clinicians should consider administering these two vaccines at least four weeks apart, the CDC recommends that they be administered at the same visit to eligible patients [87,88]. This approach avoids barriers to receiving indicated vaccines. This is supported by an observational study that did not find a difference in the rate of herpes zoster among those who received both vaccines concurrently compared with those who received them four weeks apart [89]. (See "Pneumococcal vaccination in adults".)
Adverse events — ZVL is generally well tolerated, and systemic side effects such as myalgia, fatigue, headache, shivering, and fever are rare [90-92].
●Injection site reactions – The most common side effect after ZVL administration is pain at the injection site. In a randomized trial, injection site pain was reported in 48 and 16 percent of vaccine and placebo recipients, respectively; the median duration was three days [91]. For most patients, the erythema, swelling, and pain were described as mild.
●Acute retinal necrosis – Six cases of optic neuritis, acute retinal necrosis, uveitis, or keratitis following vaccination with ZVL have been reported; the patients developed loss of vision from six days to two months following vaccination, respectively [93]. Most were over 75 years of age and one was immunocompromised, having undergone renal transplantation. VZV was detected from the vitreous or aqueous fluid by polymerase chain reaction in two patients. Only one of these was identified as the Oka strain of VZV (the viral strain used in both the varicella and zoster vaccines). This was in the vitreous aspirate and core vitrectomy specimen of the immunosuppressed patient who developed retinitis approximately one month after receiving the varicella vaccine [94].
●Vaccine-associated zoster – Vaccine-associated VZV can establish latency, and there was a single case report of an immunocompetent patient who developed localized herpes zoster infection with the vaccine strain of virus nine months after vaccination with ZVL [95]. In the large efficacy studies of ZVL described above, patients who developed herpes zoster had infection with wild-type virus. (See 'Efficacy' above.)
Contraindications and precautions — Contraindications to the administration of ZVL include:
●Allergy – Patients with anaphylactic reactions to gelatin or neomycin [90]. (See "Allergic reactions to vaccines".)
●Immunocompromise – ZVL is contraindicated in populations who are at high risk for developing disseminated VZV infection with the vaccine strain of the virus. This includes:
•Patients who have primary immunodeficiencies (eg, severe antibody or combined immunodeficiency, leukocyte-adhesion deficiency, and cytotoxic granule defects), or acquired immunodeficiencies (eg, leukemia, lymphoma, or other malignancies affecting the bone marrow or lymphatic system).
•Solid organ and hematopoietic cell transplant patients.
•Patients with HIV and a CD4 count <200 cells/microL.
•Patients receiving immunosuppressive therapies, such as cytotoxic agents, corticosteroid therapy with a dose ≥20 mg/day of prednisone or equivalent for ≥14 days, and/or biologic agents such as rituximab, tumor necrosis factor (TNF)-alpha antagonists or blockers, and Janus kinase inhibitors.
•Pregnancy – ZVL should not be administered to pregnant women; however, this scenario is unlikely since it is not indicated for women of childbearing age. (See "Immunizations during pregnancy", section on 'Immunizations to avoid during pregnancy'.)
Precautions to administration of ZVL include receipt of acyclovir, famciclovir, or valacyclovir 24 hours before vaccination and for 14 days after vaccination, as these antiviral agents may interfere with the vaccine [24].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Varicella-zoster virus".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Vaccines for adults (The Basics)" and "Patient education: What you should know about vaccines (The Basics)" and "Patient education: Shingles (The Basics)")
●Beyond the Basics topic (see "Patient education: Shingles (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Pathogenesis of herpes zoster – Herpes zoster (shingles) results from reactivation of varicella-zoster virus (VZV) infection latent in sensory ganglia and is characterized by a painful, unilateral vesicular eruption in a dermatomal distribution. A decline in VZV-specific cell-mediated immunity, which occurs in immune-compromised and older individuals, is regarded as the major precipitant for VZV reactivation. (See 'Importance of cell-mediated immunity' above.)
●Role of vaccination – Herpes zoster vaccination decreases the risk of developing herpes zoster and postherpetic neuralgia. It is not necessary to determine whether patients have a history of prior varicella (chickenpox) or herpes zoster or to check antibodies prior to vaccination. (See 'Approach to vaccination' above.)
●Approach to vaccination – There are two types of herpes zoster vaccines, a non-live recombinant glycoprotein E vaccine (designated recombinant zoster vaccine [RZV]) and a live attenuated virus vaccine (designated zoster vaccine live [ZVL]). ZVL is no longer available in the United States; however, ZVL continues to be used in many other countries where RZV is not widely available. (See 'Available vaccines' above and 'Recombinant zoster vaccine' above and 'Zoster vaccine live' above.)
The approach to vaccination depends upon the patient population:
•Immunocompetent patients ≥50 years of age – For immunocompetent patients ≥60 years of age, we recommend zoster vaccination to prevent herpes zoster (Grade 1A). We also suggest zoster vaccination for such individuals who are 50 years of age or older (Grade 2A). (See 'Immunocompetent persons ≥50 years of age' above.)
When both vaccines are available, we recommend RZV rather than ZVL for most patients (Grade 1B). RZV provides greater protection against herpes zoster and postherpetic neuralgia. In addition, there is less concern for waning immunity. Although there is an increased risk of mild to moderate side effects with RZV compared with ZVL (eg, fever, injection site reactions, chills, headache, fatigue), there is no difference in serious adverse events. (See 'Approach to vaccination' above.)
•Immunocompromised adults
-Future immunosuppression planned – For adults ≥19 years of age who are planning to receive immunosuppressive therapy with an agent that puts them at increased risk for herpes zoster (eg, solid organ transplant recipients, certain patients with cancer or autoimmune conditions), we recommend zoster vaccination prior to immunosuppression (Grade 1B).
As with immunocompetent hosts, RZV is preferred, and only RZV is approved for patients aged 19 to 49 years. If ZVL is used because of availability or contraindication to RZV, it should be administered ≥4 weeks before the initiation of immunosuppressive therapy. (See 'Future immunosuppression planned' above.)
-Other immunocompromised patients – Zoster vaccination is reasonable for certain patients receiving immunosuppressive therapy and those who have a primary or secondary immunodeficiency. However, data are limited, and the decision to vaccinate must balance the potential efficacy of the vaccine, the risk of developing zoster (eg, age, type of immunosuppressive therapy), and the risks of vaccination (eg, ZVL is contraindicated in most immunocompromised patients). This is discussed in detail above and in separate topic reviews. (See 'Patients receiving low-dose immunosuppressive therapy' above and "Immunizations in adults with cancer" and "Immunizations in hematopoietic cell transplant candidates and recipients" and "Immunizations in solid organ transplant candidates and recipients" and "Immunizations in persons with HIV" and "Immunizations in patients with primary immunodeficiency" and "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
●Additional considerations for patients who meet criteria for herpes zoster vaccination
•Patients with prior herpes zoster – When vaccination is indicated (eg, immunocompetent individuals ≥50 years of age), it should be given regardless of a prior history of zoster infection. However, we typically delay vaccination for approximately one year after infection since herpes zoster itself will boost VZV-specific immunity. (See 'Patients with prior herpes zoster infection' above.)
•Persons who received ZVL – For those who received ZVL, we suggest vaccination with RZV when available (Grade 2C). RZV is warranted given the reduced efficacy of ZVL compared with RZV, as well as waning immunity. The two-dose RZV series should be initiated at least eight weeks after ZVL. (See 'Patients who received zoster vaccine live or varicella vaccine' above.)
●Contraindications and precautions
•RZV – For RZV, hypersensitivity to the vaccine components is the only contraindication. The safety of RZV is still being evaluated in transplant recipients and patients with autoimmune conditions, and the benefits of using RZV must be weighed against the potential risks due to the immune response elicited by the adjuvant (eg, rejection of the graft or a flare of the underlying condition). We generally avoid RZV in patients with a known history of Guillain-Barré Syndrome (GBS) given a possible association between the two. (See 'Contraindications and precautions' above and 'Patients with other autoimmune conditions' above and 'Patients with a history of Guillain-Barré syndrome' above.)
•ZVL – ZVL is contraindicated in most immunocompromised patients. It is also contraindicated in pregnant women and in patients with anaphylactic reactions to gelatin or neomycin. (See 'Contraindications and precautions' above.)
