Varicella and Herpes Zoster Vaccines

Number: 0115

Policy

1. Aetna considers varicella (chicken pox) vaccine a medically necessary preventive service according to the recommendations of the Centers for Disease Control's (CDC) Advisory Committee on Immunization Practices (ACIP).

2. Aetna considers combination measles, mumps, rubella, and varicella vaccine (MMRV) (ProQuad) a medically necessary preventive service alternative to individual measles, mumps and rubella (MMR) and varicella vaccines for children 12 months to 12 years of age where simultaneous administration of MMR and varicella vaccines is indicated. 

3. Aetna considers varicella primary vaccination medically necessary in HIV-infected, varicella zoster virus negative persons aged greatr than 8 years with CD4 cell counts greater than 200 cells/µL and in HIV-infected children aged 1 to 8 years with CD4 percentages greater than 15 %.

4. Aetna considers zoster vaccine (Zostavax) medically necessary to reduce the risk of herpes zoster (shingles) in members 50 years of age and older if herpes zoster subunit vaccine (Shingrix) is unavailable. Aetna considers repeat (booster) zoster vaccination as experimental and investigational.

5. Aetna considers herpes zoster subunit vaccine (Shingrix) medically necessary for the prevention of herpes zoster and related complications for immunocompetent adults aged 50 years and older, including those who previously received zoster vaccine live (Zostavax).
   
   
6. Aetna considers re-vaccination with Shingrix medically necessary for hemopoietic stem-cell transplant (HSCT) recipients if 24 months have passed since HSCT, the recipient does not have graft-versus-host disease, and is considered immunocompetent.

Aetna considers Shingrix and Zostavax experimental and investigational for treatment of zoster or postherpetic neuralgia (PHN), prevention of primary varicella infection (chickenpox), and for all other indications because its effectiveness for these indications has not been established.

Background

Varicella vaccine (Varivax, Merck & Co., Whitehouse Station, NJ) immunization is recommended for children over 12 months of age who do not have a history of having had varicella (chicken pox).  The Advisory Committee on Immunization Practices (ACIP) recommends that children be immunized with 2 doses of varicella vaccine, with the 1st dose administered between 12 and 15 months of age, and a 2nd dose administered between 4 and 6 years of age.  In addition, the ACIP recommends that other persons who have not been immunized and have no history of varicella receive 2 doses of vaccine.  Children, adolescents and adults who previously received 1 dose of varicella vaccine should receive a 2nd one.

Healthy adolescents past their 13th birthday and adults who have not been immunized and have no history of varicella may also be immunized and require 2 doses of vaccine.  The Centers for Disease Control's (CDC) recommends vaccination of adolescents greater than or equal to 13 years of age and adults at high risk for exposure or transmission.  Groups at high risk include:

• Adolescents and adults living in households with children; and
• International travelersFootnotes^*and
• Non-pregnant women of childbearing age; and
• Persons who live or workFootnotes^* in environments where transmission of chicken pox can occur (e.g., college students, inmates and staff members of correctional institutions, and military personnel); and
• Persons who live or workFootnotes^* in environments where transmission of chicken pox is likely (e.g., teachers of young children, day care employees, and residents and staff members in institutional settings).

Footnotes^*Note: Some Aetna plans exclude coverage of vaccinations for work or for travel.  Please check benefit plan descriptions for details.

Very few people escape childhood without contracting chicken pox.  The recommendation is that all individuals under 21 years of age who do not have a clear history of chicken pox should be assumed to be susceptible and can be immunized.  Adults over 21 who have no history of chicken pox should be tested for immunity and, if they are susceptible, should be immunized.  Five to 10 % of the adult population is probably susceptible; 70 % of 18 year olds have been found to be immune, even if they have no clear history of having had chicken pox.

Children 12 months to 12 years of age should receive a 0.5-ml dose of varicella vaccine administered subcutaneously.  A 2nd dose of varicella vaccine should be given a minimum of 3 months later.  Adolescents and adults 13 years of age and older should receive a 0.5-ml dose administered subcutaneously at an elected date and a 2nd 0.5-ml dose 4 to 8 weeks later.

Varicella vaccine is contraindicated in certain individuals, including persons with an immunodeficient condition or receiving immunosuppressive therapy, persons with active untreated tuberculosis, and women who are pregnant.

The Food and Drug Administration (FDA) has approved a combined attenuated live virus vaccine containing measles, mumps, rubella, and varicella viruses (MMRV) (ProQuad injection, Merck & Co., Whitehouse Station, NJ) for use in children aged 12 months to 12 years.  It is also approved for use in this population if a 2nd dose of measles, mumps, and rubella vaccine is to be administered.

The approval was based on study data showing the immunogenicity, antibody persistence, and safety of the combination vaccine to be similar with that of its previously approved components (measles, mumps, and rubella (MMR) and varicella).  The incidence of adverse events including those most commonly reported (injection site reactions, nasopharyngitis, cough) was similar between the treatment groups.

Herpes zoster (HZ) is the consequence of re-activation of the varicella zoster virus (VZV) that remains latent since primary infection (varicella).  The overall incidence of HZ is about 3 per 1,000 of the population per year increasing to 10 per 1,000 per year by age 80.  Approximately 50 % of persons reaching age 90 years will have had HZ.  In approximately 6 %, a second episode of HZ may occur; usually several decades after the first attack.  The most common complication of HZ is post-herpetic neuralgia (PHN), defined as significant pain or dysaesthesia present 3 months or more following HZ.  More than 5 % of the elderly have PHN at 1 year after acute HZ.  Reduced cell-mediated immunity to HZ occurs with aging, which may be responsible for the increased incidence in the elderly and from other causes such as tumors, human immunodeficiency virus infection as well as immunosuppressant drugs.  Diagnosis of PHN is usually clinical from typical unilateral dermatomal pain and rash.  Prodromal symptoms, pain, itching and malaise, are common (Johnson and Whitton, 2004).

There is reliable evidence that zoster vaccine significantly reduces morbidity from HZ and PHN among older adults.  In a randomized, controlled, multi-center study, Oxman and colleagues (2005) examined if vaccination against VZV would decrease the incidence, severity, or both of HZ and PHN among older adults.  A total of 38,546 adults aged 60 years or older were enrolled in this study.  The vaccine used was a live attenuated Oka/Merck VZV vaccine.  Herpes zoster (shingles) was diagnosed according to clinical and laboratory criteria.  The pain and discomfort associated with HZ were measured repeatedly for 6 months.  The primary end point was the burden of illness due to HZ, a measure affected by the incidence, severity, and duration of the associated pain and discomfort.  The secondary end point was the incidence of PHN.  More than 95 % of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for HZ.  A total of 957 confirmed cases of HZ (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of PHN (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis.  The use of the zoster vaccine reduced the burden of illness due to HZ by 61.1 % (p < 0.001), reduced the incidence of PHN by 66.5 % (p < 0.001), and reduced the incidence of HZ by 51.3 % (p < 0.001).  Reactions at the injection site were more frequent among vaccine recipients but were generally mild.  These researchers concluded that the zoster vaccine significantly reduced morbidity from HZ and PHN among older adults.

In May 2006, the FDA approved Zostavax (Merck & Co., Inc., Whitehouse Station, NJ), a vaccine for use to reduce the risk of HZ in people aged 60 years and older.  Zostavax is administered subcutaneously in one single injection, preferably in the upper arm.  The most common adverse effects in individuals who received Zostavax were redness, pain and tenderness, swelling at the site of injection, itching, as well as headache.

The FDA approved prescribing information indicates that zoster vaccine is not indicated for the treatment of herpes zoster or PHN.  Zoster vaccine is a live attenuated virus vaccine, and the labeling states that zoster vaccine is contraindicated in the following persons:

• Persons with active untreated tuberculosis;
• Persons on immunosuppressive therapy, including high-dose corticosteroids;
• Those with a history of anaphylactic/anaphylactoid reaction to gelatin, neomycin, or any other component of the vaccine;
• Those with a history of primary or acquired immunodeficiency states including leukemia; lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system; or AIDS or other clinical manifestations of infection with human immunodeficiency viruses;
• Women who are or may be pregnant.

Zostavax is a live attenuated virus vaccine and is contraindicated in immunosuppressed persons, including persons with a history of primary or acquired immunodeficiency states including leukemia, lymphomas of any type, or other malignant neoplasms affecting the bone marrow or lymphatic system; with AIDS or other clinical manifestations of infection with human immunodeficiency viruses; and with active untreated tuberculosis.  Zostavax is also contraindicated in persons on immunosuppressive therapy, including high-dose corticosteroids, and in women who are or may be pregnant.

Zostavax (zoster vaccine) is given as a single 0.65 mL dose by subcutaneous injection (not intramuscularly). Studies are ongoing to assess the duration of protection from a single dose of zoster vaccine and the need, if any, for booster doses. Zostavax (zoster vaccine) is stored frozen and requires reconstitution prior to administration. The product should be reconstituted immediately upon removal from the freezer. The diluent should be stored separately at room temperature or in the refrigerator. The reconstituted vaccine should be discarded if it is not used within 30 minutes; the reconstituted vaccine should not be frozen.

Wutzler (2010) stated that although the efficacy of zoster vaccine against HZ declined with advancing age of the vaccinees, subjects older than 70 years also benefited from vaccination because the burden of illness was considerably reduced.  The protective effect of zoster vaccine persists for at least 7 years post-vaccination.  The author stated that the need for, or timing of, re-vaccination has not yet been determined.  Zostavax has been well-tolerated.  It can be concomitantly administered with inactivated influenza vaccine at separate sites.  The author stated that zoster and pneumococcal vaccines should not be given concomitantly.

According to the CDC (2011), zoster vaccine is administered subcutaneously as a single dose.  The vaccine should not be injected intra-muscularly.  However, it is not necessary to repeat vaccination if the shingles vaccine is administered intra-muscularly.  Studies are ongoing to assess the duration of protection from 1 dose of zoster vaccine and the need, if any, for booster doses.

The ACIP currently recommends Zostavax for all adults aged 60 years and older with no contraindications and for adults older than 80 years with chronic illnesses (Splete, 2011). No changes were made to the current recommendation of herpes zoster vaccination for adults aged 60 years and older, the CDC's ACIP reported.  The FDA licensed Zostavax for use in adults aged 50 to 59 years in March 2011.  However, the working group did not currently propose changes to the current ACIP recommendations.  Data from studies conducted by Merck have shown vaccine efficacy in the 50 to 59 age group, but there is insufficient evidence regarding the duration of vaccine protection when it is given well before the peak age for zoster incidence.  The working group observed that it might be inappropriate to expand recommendations while the vaccine remains in short supply, and the incidence could increase if limited supply is used at time of low incidence.  The ACIP published updated their recommendations for shingles vaccine in August 2014 and maintained their current recommendation for shingles vaccine for persons age 60 years and older (Hale, et al., 2014).

Guidelines for preventing infections in hematopoietic cell transplant (HCT) recipients by the Center for International Blood & Marrow Transplant Research, National Marrow Donor Program, European Group for Blood and Marrow Transplantation, American Society for Blood and Marrow Transplantation, Canadian Blood and Marrow Transplant Group, Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, Association of Medical Microbiology and Infectious Disease, and the CDC (Ljungman et al, 2009) indicated that zoster vaccine (Zostavax, live) should not be given to HCT recipients.

The British Society for Haematology’s guidelines on “The diagnosis, investigation and management of chronic lymphocytic leukaemia” (Oscier et al, 2012) states that “live vaccines such as polio, herpes zoster, and yellow fever should be avoided”.

Zhang et al (2012) stated that methotrexate (MTX) has become the foundation disease-modifying anti-rheumatic drug (DMARD) for rheumatoid arthritis (RA).  However, concern exists regarding its possible association with infectious complications including VZV and HZ.  Furthermore, no consensus exists regarding pre-MTX VZV screening or the use of VZV vaccine.  These researchers undertook systematic literature review (SLR) investigating the relationship between the use of MTX in patients with RA and VZV and HZ infection.  Additionally, the European Centre for Disease Prevention and Control, HPA, the CDC, Rheumatology societies and WHO web sites and publications were consulted.  A total of 35 studies fulfilled the inclusion criteria comprising 29 observational studies and 6 case reports.  The case reports and 13 observation studies considered the association between MTX and HZ.  Three of the observational studies reported a positive association although in 5 cases, patients were concurrently treated with prednisolone.  Five studies concluded that there was no association between HZ and MTX.  Three studies comparing the infection rates of MTX with other RA therapies found that MTX did not result in higher HZ infection rates.  Three studies examining the association between HZ and MTX treatment duration failed to show a link.  The authors concluded that no evidence exists to support an association between MTX and VZV infection in RA patients and the data regarding the role of MTX in HZ development is conflicting.  The role of pre-MTX VZV screening is controversial and, as it may delay initiation of RA treatment, these investigators suggested against VZV screening in this context.

Guthridge et al (2013) noted that patients with systemic lupus erythematosus (SLE) are at increased risk of HZ.  Although Zostavax has been approved by the FDA, its use in immunocompromised individuals remains controversial because it is a live-attenuated virus vaccine.  In a pilot study, these researchers examined the immunogenicity of Zostavax in patients with SLE.  A total of 10 patients with SLE and 10 control subjects aged 50 years or older participated in this open-label vaccination study.  All were sero-positive for VZV.  Patients with SLE were excluded for SLE Disease Activity Index (SLEDAI) greater than 4, or use of mycophenolate mofetil, cyclophosphamide, biologics, or greater than 10 mg prednisone daily.  Follow-up visits occurred at 2, 6, and 12 weeks.  Clinical outcomes included the development of adverse events, particularly HZ or vesicular lesions, and SLE flare.  Immunogenicity was assessed with VZV-specific interferon-gamma-producing enzyme-linked immunospot (ELISPOT) assays and with antibody concentrations.  All subjects were women.  Patients with SLE were slightly older than controls (60.5 versus 55.3 years, p < 0.05).  Median baseline SLEDAI was 0 (range of 0 to 2) for patients with SLE.  No episodes of HZ, vesicular rash, serious adverse events, or SLE flares occurred.  Three injection site reactions occurred in each group: mild erythema or tenderness.  The proportion of subjects with a greater than 50 % increase in ELISPOT results following vaccination was comparable between both groups, although absolute SLE responses were lower than controls.  Antibody titers increased only among controls following vaccination (p < 0.05).  The authors concluded that HZ vaccination yielded a measurable immune response in this cohort of patients with mild SLE taking mild-moderate immunosuppressive medications; no herpetiform lesions or SLE flares were seen in this small cohort of patients.  This was a pilot study testing the immunogenicity of Zostavax in SLE patients; the clinical value of Zostavax in these patients needs to be further-evaluated in well-designed studies.

Son et al (2010) assessed the effectiveness of varicella virus in clinically stable HIV-infected children.  The investigators assessed its effectiveness by reviewing the medical records of closely monitored HIV-infected children, including those receiving highly active antiretroviral therapy (HAART) between 1989 and 2007, noting both varicella immunization and development of varicella or herpes zoster. Effectiveness was calculated by subtracting from 1 the rate ratios for the incidence rates of varicella or herpes zoster in vaccinated versus unvaccinated children. The results showed the effectiveness of the vaccine was 82% (95% confidence interval [CI], 24%-99%; P = .01) against varicella and was 100% (95% CI, 67%-100%; P < .001) against herpes zoster. The authors further noted that when the analysis was controlled for receipt of HAART, vaccination remained highly protective against herpes zoster.

Taweesith et al (2011) stated that the live attenuated varicella vaccine is recommended for HIV-infected children who are not severely immunosuppressed.  The authors conducted a study aimed to assess the immunogenicity and safety of varicella vaccination among HIV-infected children who had severe immunosuppression before receiving antiretroviral therapy.  A total of 60 HIV-infected children with no history of chickenpox or herpes zoster infection with CD4 T lymphocyte counts ≥ 15 % or ≥ 200 cell/mm were enrolled and administered two doses of varicella vaccine, the first at the time of enrollment and the second at 3 months.  The analysis showed a median (interquartile range) of age, CD4 nadir, and current CD4 percentage were 11.2 (8.5 to 12.8) years, 9.5 % (3 to 14), and 28 % (22 to 32), respectively and that 57 children (95 %) received anti-retroviral therapy for a median of 27 months.  The results showed that among 34 children (57 %) who were VZV sero-negative at baseline, 11.8 % (95 % CI: 3.3 % to 27.5 %) and 79.4 % (95 % CI: 62.1 % to 91.3 %) were VZV seroconverted after first and second dose of vaccine, respectively.  Children who had VZV sero-conversion were found to be more likely to have HIV RNA less than 1.7 copies/mL (92.6 % versus 71.4 %, p = 0.18) and among 26 children who were sero-positive at baseline, the geometric mean titers were increased from 56.7 to 107.9 and 134.6 unit/mL, respectively.  Local and systemic reactions of grade 1 and 2 were reported in 13 % and 4 % of children, respectively.  There was a trend toward better response among children with younger age, high CD4, and viral suppression. Thus, the authors concluded that administration of the 2 doses of varicella vaccine resulted in high sero-conversion rates without serious adverse reactions.  Varicella vaccination for HIV-infected children should be encouraged.

Mullane et al (2013) conducted a randomized, double-blind, placebo-controlled, multi-center study on the safety and immunogenicity of heat-treated zoster vaccine (ZVHT).  Four doses of ZVHT or placebo were administered approximately 30 days apart to adults with either solid tumor malignancy (STM); hematologic malignancy (HM); human immunodeficiency virus (HIV) with CD4(+) < 200; autologous hematopoietic stem-cell transplant (HCT) or allogeneic-HCT recipients.  The results indicated that no safety signals were found in any group.  The investigators also found that IFN-gamma ELISPOT geometric mean fold rises (GMFR) after dose 4 in STM, HM, HIV, and autologous-HCT patients were 3.00 (p < 0.0001), 2.23 (p = 0.004), 1.76 (p = 0.026), and 9.01 (p = NA), respectively.  Similarly, antibody GMFR were 2.35 (p < 0.0001), 1.28 (p = 0.003), 1.37 (p = 0.017), and 0.90 (p = NA), respectively.  Thus, the authors concluded that ZVHT was generally safe and immunogenic through 28 days post-dose 4 in adults with STM, HM, and HIV and that autologous-HCT but not allogeneic-HCT patients had a rise in T-cell response. Antibody responses were not increased in either HCT population.

Aberg et al (2014) reported on the 2013 update on primary care guidelines for management of HIV infected persons by the HIV Medicine Association of the Infectious Diseases Society of America.  New information based on literature published from 2009 to 2013 was incorporated into this updated version of the guidelines.  The recommendations stated that varicella primary vaccination may be considered in HIV-infected, varicella zoster virus seronegative persons aged > 8 years with CD4 cell counts > 200 cells / microliter and in HIV-infected children aged 1 to 8 years with CD4 cell percentages > 15% due to moderate quality evidence in the peer-reviewed literature.

A 2014 UpToDate report on immunizations in HIV-infected patients reported results of a trial of 295 HIV-infected individuals with CD4 cell counts ≥ 200 cells/microL and virologic suppression on antiretroviral therapy who received varicella zoster vaccine.  Individuals with CD4 cell counts > 350 cells / microL had the highest post-vaccination zoster antibody level, but there were high rates of injection site reactions in the zoster group (42 versus 12.4 % in the placebo group).  The UpToDate report concluded that although these data are promising, further research is needed to determine which HIV-infected individuals at what age should receive the zoster vaccine.  However, the authors noted that it is reasonable to vaccinate those with CD4 counts > 200 cels/microL if they are aged 60 years or older.  The UpToDate report also states that “zoster vaccine is specifically not recommended for HIV-infected patients with a CD4 cell count < 200 cells/microL” (HIbberd, 2014).

The live attenuated virus vaccine Zostavax has been FDA approved for prevention of herpes zoster (shingles) inn individuals 50 years of age and older.  The FDA package insert further notes that Zostavax is not indicated for the treatment of zoster or postherpetic neuralgia, nor is it indicated for prevention of primary varicella infection (Chickenpox) (FDA, 2006).

In a clinical study, Levin and colleagues (2016) noted that herpes zoster vaccine (ZV) was administered as a 2nd dose to 200 participants greater than or equal to 70 years of age who had received a dose of ZV greater than or equal to 10 years previously.  Varicella zoster virus (VZV) antibody titers (measured by a VZV glycoprotein-based enzyme-linked immunosorbent assay [gpELISA]) and levels of interferon γ (IFN-γ) and interleukin 2 (IL-2; markers of VZV-specific cell-mediated immunity [CMI], measured by means of ELISPOT analysis) in individuals aged greater than or equal to 70 years who received a booster dose of ZV were compared to responses of 100 participants aged 50 to 59 years, 100 aged 60 to 69 years, and 200 aged greater than or equal to 70 years who received their 1st dose of ZV.  The study was powered to demonstrate non-inferiority of the VZV antibody response at 6 weeks in the booster-dose group, compared with the age-matched 1st-dose group.  Antibody responses were similar at baseline and after vaccination across all age and treatment groups.  Both baseline and post-vaccination VZV-specific CMI were lower in the older age groups.  Peak gpELISA titers and their fold rise from baseline generally correlated with higher baseline and post-vaccination VZV-specific CMI; IFN-γ and IL-2 results for subjects greater than or equal to 70 years old were significantly higher at baseline and after vaccination in the booster-dose group, compared with the 1st-dose group, indicating that a residual effect of ZV on VZV-specific CMI persisted for greater than or equal to 10 years and was enhanced by the booster dose.  The authors concluded that these findings supported further investigation of ZV administration in early versus later age and of booster doses for elderly individuals at an appropriate interval after initial immunization against HZ.

Lal and associates (2015) stated that in previous phase I and phase II clinical trials involving older adults, a subunit vaccine containing varicella-zoster virus glycoprotein E and the AS01B adjuvant system (called HZ/su) had a clinically acceptable safety profile and elicited a robust immune response.  These researchers performed a randomized, placebo-controlled, phase III clinical trial in 18 countries to examine the safety and effectiveness of HZ/su in older adults (greater than or equal to 50 years of age), stratified according to age group (50 to 59, 60 to 69, and greater than or equal to 70 years).  Participants received 2 intramuscular doses of the vaccine or placebo 2 months apart.  The primary objective was to evaluate the effectiveness of the vaccine, as compared with placebo, in reducing the risk of HZ in older adults.  A total of 15,411 participants who could be evaluated received either the vaccine (7,698 participants) or placebo (7,713 participants).  During a mean follow-up of 3.2 years, HZ was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (incidence rate, 0.3 versus 9.1 per 1,000 person-years) in the modified vaccinated cohort.  Overall vaccine effectiveness against HZ was 97.2 % (95 % CI: 93.7 to 99.0; p < 0.001).  Vaccine effectiveness was between 96.6 % and 97.9 % for all age groups.  Solicited reports of injection-site and systemic reactions within 7 days after vaccination were more frequent in the vaccine group.  There were solicited or unsolicited reports of grade 3 symptoms in 17.0 % of vaccine recipients and 3.2 % of placebo recipients.  The proportions of participants who had serious adverse events (AEs) or potential immune-mediated diseases or who died were similar in the 2 groups.  The authors concluded that the HZ/su vaccine significantly reduced the risk of HZ in adults who were 50 years of age or older; and vaccine effectiveness in adults who were 70 years of age or older was similar to that in the other 2 age groups.

Cunningham and colleagues (2016) noted that a trial involving adults 50 years of age or older (ZOE-50) showed that the HZ subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01B adjuvant system was associated with a risk of herpes zoster that was 97.2 % lower than that associated with placebo.  A 2nd trial was performed concurrently at the same sites and examined the safety and effectiveness of HZ/su in adults 70 years of age or older (ZOE-70).  This randomized, placebo-controlled, phase III clinical trial was conducted in 18 countries and involved adults 70 years of age or older.  Participants received 2 doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart.  Vaccine effectiveness against HZ and PHN was assessed in subjects from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50.  In ZOE-70, 13,900 participants who could be evaluated (mean age of 75.6 years) received either HZ/su (6,950 participants) or placebo (6,950 participants).  During a mean follow-up period of 3.7 years, HZ occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 versus 9.2 per 1,000 person-years).  Vaccine effectiveness against HZ was 89.8 % (95 % CI: 84.2 to 93.7; p < 0.001) and was similar in participants 70 to 79 years of age (90.0 %) and participants 80 years of age or older (89.1 %).  In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine effectiveness against HZ was 91.3 % (95 % CI: 86.8 to 94.5; p < 0.001), and vaccine effectiveness against PHN was 88.8 % (95 % CI: 68.7 to 97.1; p < 0.001).  Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0 % versus 29.5 %).  Serious AEs, potential immune-mediated diseases, and deaths occurred with similar frequencies in the 2 study groups.  The authors concluded that HZ/su was found to reduce the risks of HZ and PHN among adults 70 years of age or older.

In a Cochrane review, Gagliardi  and co-workers (2016) evaluated the safety and effectiveness of vaccination for preventing HZ in older adults.  For this 2015 update, these investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 9), Medline (1948 to the 3rd week of October 2015), Embase (2010 to October 2015), CINAHL (1981 to October 2015) and LILACS (1982 to October 2015).  Randomized controlled trials (RCTs) or quasi-RCTs comparing zoster vaccine with placebo or no vaccine, to prevent HZ in older adults (mean age greater than 60 years).  Two review authors independently collected and analyzed data using a data extraction form.  They also performed “Risk of bias” assessment.  These researchers identified 13 studies involving 69,916 participants.  The largest study included 38,546 participants.  All studies were conducted in high-income countries and included only healthy Caucasian individuals greater than or equal to 60 years of age without immunosuppressive co-morbidities.  A total of 10 studies used live attenuated varicella zoster virus (VZV) vaccines; 3 studies tested a new type of vaccine not yet available for clinical use.  These researchers judged 5 of the included studies to be at low risk of bias.  The incidence of HZ, at up to 3 years of follow-up, was lower in participants who received the vaccine than in those who received a placebo: risk ratio (RR) 0.49; 95 % CI: 0.43 to 0.56, risk difference (RD) 2 %, number needed to treat to benefit (NNTB) 50; GRADE: moderate quality evidence.  The vaccinated group had a higher incidence of mild-to-moderate intensity AEs.  These date came from 1 large study that included 38,546 people aged 60 years or older.  A study including 8,122 participants compared the new vaccine (not yet available) to the placebo; the group that received the new vaccine had a lower incidence of HZ at 3.2 years of follow-up: RR 0.04, 95 % CI: 0.02 to 0.10, RD 3 %, NNTB 33; GRADE: moderate quality evidence.  The vaccinated group had a higher incidence of AEs; but most them were of mild-to-moderate intensity.  The authors concluded that HZ vaccine is effective in preventing HZ disease and this protection can last 3 years.  In general, zoster vaccine is well-tolerated; it produces few systemic AEs and injection site AEs of mild-to-moderate intensity. There are studies of a new vaccine (with a VZV glycoproteic fraction plus adjuvant), which is currently not yet available for clinical use.

Shingrix

Shingrix is a non-live, recombinant subunit vaccine that combines an antigen, glycoprotein E, and an adjuvant system, AS01B, intended to generate a strong and long-lasting immune response. The Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention (CDC, 2017) recommended the use of the new Shingrix vaccine (GlaxoSmithKline) over the existing Zostavax vaccine (Merck) for the prevention of shingles in immunocompetent adults 50 years of age and older. The Advisory Committee on Immunization Practices (ACIP) also recommended that adults who previously received Zostavax be given Shingrix. The previous ACIP recommendation applied to adults 60 years of age and older.

The FDA approved Shingrix (zoster vaccine recombinant, adjuvanted) on October 20, 2017 for the prevention of herpes zoster (shingles) in adults aged 50 years and older. The approval was based on a comprehensive phase 3 clinical trial program involving 38,000 adults to evaluate the vaccine's efficacy, safety, and immunogenicity.

In a pooled analysis of these studies, Shingrix demonstrated efficacy against shingles greater than 90% across all age groups, as well as sustained efficacy over a follow-up period of four years. By preventing shingles, Shingrix also reduced the overall incidence of post-herpetic neuralgia (PHN), 

The Prescribing Information for Shingrix states that it is not indicated for the prevention of primary varicella infection (chickenpox). It is contraindicated in persons with a history of severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or after a previous dose of Shingrix.

Shingrix is available as suspension for injection supplied as a single-dose vial of lyophilized varicella. Two doses (0.5 mL each) administered intramuscularly according to the following schedule: First dose at Month 0 followed by a second dose administered anytime between 2 and 6 months later (GSK, 2017).

Lal and colleagues (2018) noted that in phase-III clinical  trials, 2 doses of a HZ subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01B Adjuvant System) administered 2-months apart in older adults (greater than or equal to 50 and greater than or equal to 70 years) demonstrated greater than 90 % efficacy in preventing HZ and had a clinically acceptable safety profile.  In a phase-III, open-label, clinical trial, these investigators reported immunogenicity, reactogenicity and safety following administration of 2 HZ/su doses at intervals longer than 2 months.  This trial was conducted in the U.S. and Estonia; a total of 354 adults greater than or equal to 50 years were randomized 1:1:1 to receive 2 HZ/su doses 2, 6, or 12 months apart; gE-specific humoral immune responses were evaluated at pre-vaccination, 1 and 12 months post-dose 2.  Co-primary objectives were to compare immune responses to HZ/su 1 month post-dose 2 when given 6-months or 12-months apart to those administered 2-months apart.  For each participant, safety information was collected from dose 1 to 12 months post-dose 2; 346 participants completed the study and 343 were included in the according-to-protocol cohort for immunogenicity.  One month post-dose 2, vaccine response rates were 96.5 % (97.5 % CI: 90.4 to 99.2) and 94.5 % (97.5 % CI: 87.6 to 98.3) for the 0, 6- and 0, 12-month schedules, respectively; both schedules meeting the pre-defined criterion.  Non-inferiority of anti-gE geometric mean concentrations was demonstrated for HZ/su administered on 0, 6-month compared to a 0, 2-month schedule; however, HZ/su administered on a 0, 12-month schedule did not meet the non-inferiority criterion.  Injection site pain was the most commonly reported solicited AE; 26 participants each reported at least 1 serious AE; none was assessed as related to vaccination.  The authors concluded that immune responses to HZ/su administered at 0, 6-month were non-inferior to those elicited by a 0, 2-month schedule; HZ/su exhibited a clinically acceptable safety profile for all dosing intervals.

Weinberg and associates (2018) stated that live attenuated (ZV) and recombinant adjuvanted (HZ/su) zoster vaccines differ with respect to efficacy, effect of age, and persistence of protection.  In a randomized, double-blind, placebo-controlled trial, these investigators compared cell-mediated immunity (CMI responses to ZV and HZ/su.  Participants in this study were stratified by age (50 to 59, and 70 to 85 years) and by HZ vaccination status (received ZV greater than or equal to 5 years before entry or not).  Varicella zoster virus (VZV)- and gE-specific CMI were analyzed by interleukin 2 (IL-2) and interferon gamma (IFN-γ) FluoroSpot and flow cytometry at study days 0, 30, 90, and 365.  Responses to ZV peaked on day 30 and to HZ/su (administered in 2 doses separated by 60 days) peaked on day 90.  Age and vaccination status did not affect peak responses, but higher baseline CMI correlated with higher peak responses.  HZ/su generated significantly higher VZV-specific IL-2+ and gE-specific IL-2+, IFN-γ+, and IL-2+/IFN-γ+ peak and 1-year baseline-adjusted responses compared with ZV.  VZV-specific IFN-γ+ and IL-2+/IFN-γ+ did not differ between vaccines.  HZ/su generated higher memory and effector-memory CD4+ peak responses and ZV generated higher effector CD4+ responses .  The authors concluded that the higher IL-2 and other memory responses generated by HZ/su compared with ZV may contribute to its superior efficacy.

Re-Vaccination with Shingrix is for Hemopoietic Stem-Cell Transplant (HSCT) Recipients

The Centers for Disease Control (CDC, 2018) notes that “A hematopoietic cell transplant (HCT) results in immunosuppression because of the hematopoietic ablative therapy administered before the transplant, drugs used to prevent or treat graft-versus-host disease, and, in some cases, from the underlying disease process necessitating transplantation.  HCT involves ablation of the bone marrow followed by reimplantation of the person’s own stem cells or stem cells from a donor.  Antibody titers to vaccine-preventable diseases (e.g., tetanus, poliovirus, measles, mumps, rubella, and encapsulated bacteria) decrease 1 to 4 years after autologous or allogeneic HCT if the recipient is not revaccinated.  HCT recipients of all ages are at increased risk for certain vaccine-preventable diseases, including diseases caused by encapsulated bacteria (i.e., pneumococcal, meningococcal, and Hib infections).  As a result, HCT recipients who received vaccines prior to their HCT should be revaccinated routinely after HCT, regardless of the source of the transplanted stem cells.  Vaccination or revaccination doses of pneumococcal vaccines, DTaP vaccine, Hib vaccine, hepatitis A vaccine, hepatitis B vaccine, meningococcal vaccines, IPV, inactivated influenza vaccines, and human papillomavirus (HPV) vaccines (for individuals aged 9-26 years) are recommended after HCT.  Varicella, zoster, and MMR vaccines may be administered after HCT if 24 months have passed since HCT, the patient does NOT have graft-vs-host disease, and is considered immunocompetent”.

The above policy is based on the following references: