Zoster (herpes zoster)

What

Herpes zoster, commonly known as shingles, is a reactivation of the varicella-zoster virus (VZV) in a person who has previously had varicella (chickenpox). Herpes zoster commonly presents as a painful, self-limiting vesicular rash in a dermatomal distribution.

Who

Zostavax is recommended for:

• adults aged ≥60 years
• adults aged ≥50 years who are household contacts of a person who is immunocompromised

How

A single dose of Zostavax is recommended.

There is currently no booster recommendation for Zostavax.

Why

The lifetime risk of reactivation of VZV is about 50%. It affects half of people who live to 80 years of age.

See Infographic. Vaccination for healthy ageing.

Zoster vaccines available in Australia

There are two vaccines available in Australia for the prevention of herpes zoster and associated complications – Zostavax and Shingrix. For clinical guidance on the use of Shingrix please refer to the ATAGI clinical statement on the clinical use of Zoster vaccine in Australia.

The Therapeutic Goods Administration website provides product information for each vaccine.

See also Vaccine information and Variations from product information for more details.

Dose and route

The dose of Zostavax is 0.65 mL given by subcutaneous injection.

Co-administration of Zostavax with other vaccines

Adults can receive Zostavax with other inactivated vaccines (such as tetanus-containing vaccines, influenza vaccine¹⁹ and pneumococcal polysaccharide vaccine^20-22), either:

• at the same time, or
• at any time after

If a person needs both Zostavax and another live parenteral vaccine (such as measles-mumps-rubella or yellow fever), they can receive the vaccines either:

• on the same day, or
• at least 4 weeks apart

See also Varicella.

Contraindications to the use of Zostavax

Anaphylaxis to vaccine components

Zostavax is contraindicated in people who have had:

• anaphylaxis after a previous dose of any live varicella-zoster virus (VZV) vaccine
• anaphylaxis after any component of Zostavax vaccine

People who are immunocompromised

In people who are or have recently been immunocompromised due to a medical condition or medical treatment, consider the safety of giving Zostavax on a case-by-case basis. If uncertain about the person’s level of immunocompromise and whether vaccination is safe, do not vaccinate. Seek expert advice from the treating physician or an immunisation specialist. See also Adverse events.

Because Zostavax contains live attenuated VZV, it is contraindicated in people with current or recent severe immunocompromising conditions from either:

• a primary or acquired medical condition, or
• medical treatment

Refer to Table. Recommendations for use of Zostavax in people on immunosuppressive therapy.

This includes people who:

• are receiving high-dose systemic immunosuppressive therapy, such as chemotherapy, radiation therapy or oral corticosteroids (≥20 mg per day of prednisilone equivalent dose)
• are receiving biologic or targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs or tsDMARDs)
• have malignant conditions of the reticuloendothelial system (such as lymphoma, leukaemia or Hodgkin disease, even if they are not receiving active treatment)
• have AIDS or symptomatic HIV infection
• have similar immunocompromising conditions due to a disease or treatment

People who have stopped treatment with high-dose systemic immunosuppressive therapy may receive Zostavax after an appropriate time. See Table. Recommendations for use of Zostavax in people on immunosuppressive therapy and Vaccination for people who are immunocompromised.

In some cases, the level of immunocompromise that absolutely contraindicates live attenuated vaccines can last for 1 year or longer after the previous dose of therapy. This can occur after therapy with biologics such as rituximab, which can have long-term effects on the immune system. Blood tests may be needed before considering vaccination with Zostavax to ensure that immune system has recovered and biologic drug levels are low. If you are uncertain about the level of immunocompromise in any person who has received a biologic therapy, do not give Zostavax or any other live attenuated vaccine. Consult with a medical specialist who can help determine the appropriate interval since last treatment and, in some cases, can assess the person’s immunological recovery.

Managing people who are immunocompromised and who inadvertently receive Zostavax

If an immunocompromised person is inadvertently vaccinated with Zostavax:

• promptly assess them
• discuss their appropriate management with an infectious diseases and/or immunisation expert
• notify the relevant state or territory health authority, and the Therapeutic Goods Administration (TGA)

For mechanisms for reporting to the TGA, see Adverse events following immunisation.

It is important to establish the person’s degree of immunocompromise and risk of vaccine-associated adverse effects. Patient management may include:

• pre-emptive or therapeutic use of antiviral medication as soon as possible after inadvertent administration of Zostavax
• clinical investigations, such as laboratory testing for VZV from any rash or other affected sites

Women who are pregnant or breastfeeding

Because Zostavax contains live attenuated VZV, it is contraindicated in pregnant women.

Women should avoid pregnancy for 28 days after vaccination with Zostavax. See also Varicella.

Adults can still receive Zostavax if they have a household contact who is pregnant.

See Table. Vaccines that are contraindicated in pregnancy: live attenuated vaccines in Vaccination for women who are planning pregnancy, pregnant or breastfeeding for more details.

Breastfeeding women can receive Zostavax if they are eligible for vaccination.

Precautions to the use of Zostavax

People with mild to moderate immunocompromising conditions

People ≥50 years of age with mild to moderate immunocompromising conditions may receive Zostavax.

Assess each person individually and, if necessary, seek appropriate specialist advice before vaccinating. See Table. Recommendations for use of Zostavax in people on immunosuppressive therapy and Vaccination for people who are immunocompromised.

For example, people may be suitable to receive Zostavax if they are receiving a single conventional synthetic DMARD in low doses, such as:

• azathioprine ≤3.0 mg per kg per day
• 6-mercaptopurine ≤1.5 mg per kg per day
• methotrexate ≤0.4 mg per kg per week

People who receive these non-biologic DMARDs in combination with low-dose corticosteroids (such as <20 mg per day of prednisolone equivalent) may also be suitable to receive Zostavax and should be individually assessed.^23,24 At these doses, the person is not likely to be severely immunocompromised. However, careful pre-screening and a risk-based assessment are recommended before administering Zostavax. This may include medical specialist consultation or screening for pre-existing antibodies to VZV.

If the person is about to start immunotherapy, a 4-week interval is recommended between receiving Zostavax and starting therapy. If this is not possible, do not give Zostavax, and seek specialist advice.

See Adverse events in people with immunocompromising conditions or on immununosuppressive therapy

Serological confirmation of VZV infection

For some people receiving immunosuppressive therapy, or for those whose pre-vaccination assessment shows an uncertain level of immunocompromise, it may be appropriate to confirm previous VZV infection using serological testing before vaccination with Zostavax. Detection of VZV-specific antibody may help confirm previous VZV infection and therefore immune memory. In someone with a mild level of immunocompromise, pre-existing immunity provides additional reassurance about the safe use of Zostavax in that person. See Serological testing before and after Zostavax.

People with HIV

People ≥50 years of age with asymptomatic HIV infection can receive Zostavax if they are:

• on antiretroviral therapy and
• have a very low or undetectable viral load and
• have a CD4+ count ≥350 per µL

If there is a strong indication to vaccinate, some experts suggest a CD4+ count >200 per µL is safe.⁶

Before vaccinating a person with asymptomatic HIV infection:

• seek expert advice from the treating physician and/or an immunisation specialist (see also People with HIV in Vaccination for people who are immunocompromised)
• check for previous VZV infection using serological testing before vaccination with Zostavax

See Serological testing before and after Zostavax.

People with asymptomatic HIV infection are likely to have a higher relative risk of developing herpes zoster in the future.²⁵ It is possible that both the efficacy and the safety of Zostavax may be lower in these people than in uninfected people.

People who are anticipating to be significantly immunocompromised in the future

Seek specialist advice before administering Zostavax to an immunocompetent person ≥50 years of age whose immune status may change because of an existing illness.⁶ This may include people:

• anticipating solid organ transplantation²⁶
• with solid tumours that will require future chemotherapy or radiation therapy
• with inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease or psoriasis that may need further immunosuppressive medical treatment

These people may have a functioning immune system now, but may be significantly immunocompromised in the future because of their disease or treatment.

Because these people have a high risk of developing zoster in the future, it may be appropriate to vaccinate them at least 1 month before they become immunocompromised.⁶ Seek specialist advice.

Serological confirmation of previous VZV infection is recommended before vaccination with Zostavax. See Table. Recommendations for use of Zostavax vaccine in people on immunosuppressive therapy and Serological testing before and after Zostavax.

Vaccination before or after immunoglobulin or blood product administration

People ≥50 years of age can receive Zostavax at any time before or after receiving immunoglobulin or any antibody-containing blood product. This is because Zostavax is indicated in people who, because of their age, are assumed to have had previous infection with VZV. This means they already have serum antibody levels that are comparable to those found in blood products. See also Vaccination for people who have recently received normal human immunoglobulin and other blood products.

People receiving long-term aspirin or salicylate therapy

People ≥50 years of age receiving long-term salicylate therapy (aspirin) can receive Zostavax. Natural varicella infection and salicylate use has been associated with an increased risk of developing Reye syndrome. There have been no reports of an association between Reye syndrome and varicella vaccination.

People receiving antiviral medicines

Antivirals with anti-VZV activity may interfere with the replication of the Zostavax live attenuated virus. These antivirals include:

• aciclovir
• famciclovir
• valaciclovir

People taking an antiviral medicine should:^6,24

• stop taking it at least 24 hours before vaccination with Zostavax
• start taking it again at least 14 days after vaccination with Zostavax

Contraindications and precautions to the use of Shingrix

Please refer to the ATAGI clinical statement on the clinical use of Zoster vaccine in Australia.

The Shingles Prevention Study was a very large clinical trial on live attenuated zoster vaccine (Zostavax). Together with other smaller studies, it demonstrated that Zostavax is safe and generally well tolerated among adults ≥50 years of age.^1,8

Zostavax is contraindicated in people who are severely immunocompromised. It is important to monitor for a disseminated (non-localised) varicella-zoster virus (VZV)-like rash as a potential adverse event after Zostavax administration in these people. VZV-like rash after Zostavax administration has also very rarely been reported to occur in people who are immunocompetent or on low-dose immunosuppressive therapy. See Adverse events in people with immunocompromising conditions or on immunosuppressive therapy.

Injection site reactions

Injection site reactions occurred in 48% of clinical trial participants who received Zostavax, regardless of their history of herpes zoster, compared with 17% of participants who received placebo. These reactions included:^8-27

• erythema
• pain
• swelling
• itching at the injection site

Mild to moderate adverse events, particularly injection site reactions, were more common in vaccine recipients aged 50–59 years than in those aged ≥60 years.^8,27

Varicella-like rashes at the injection site were rare. 0.1% of vaccine recipients developed a rash, and this was more common than in placebo recipients.¹

Varicella-like rashes that were not localised to the injection site were also rare. This occurred in vaccine and placebo recipients at the same incidence (0.1%).¹

Clinical trials for Zostavax analysed rashes in the vaccine (and placebo) recipients for the presence of VZV using PCR. Most rashes, in both groups, were due to wild-type virus. Only 2 participants in 1 early trial reported rashes due to the Oka VZV vaccine strain. See also Vaccine information.

Post-marketing studies of Zostavax in the United States found a 2-fold increased risk in the 1st week after vaccination for events coded as ‘allergic reactions’. However, on more detailed review, most of these were injection site reactions.²⁸

Systemic symptoms

Fever of >38.3°C was not more common in Zostavax recipients than placebo recipients, and occurred in <0.1% of clinical trial participants overall.¹

Systemic symptoms occurred in Zostavax recipients (6.3%) more commonly than in placebo recipients (4.9%). The most common systemic symptoms reported were headache⁸ and fatigue.¹

Post-marketing surveillance of Zostavax in the United States in a cohort of almost 200,000 adults found that vaccination did not increase the risk of adverse events such as cerebrovascular events or encephalitis.²⁸ 

Very rarely, a non-localised VZV-like rash occurs around 2–4 weeks after vaccination with Zostavax.²⁹ This type of rash may be due to the Oka vaccine VZV strain. Always advise people who have received Zostavax to:

• seek immediate medical attention if they develop a generalised VZV-like rash 
• inform their medical practitioner that they have recently received Zostavax.

If the person has suspected disseminated VZV infection:

• conduct appropriate diagnostic testing
• start empirical antiviral treatment
• consult with an infectious diseases specialist 
• stop immunosuppressive therapy, if relevant 
• notify the relevant state or territory health authority, and the Therapeutic Goods Administration (TGA) - see Reporting AEFIs

Adverse events in people with immunocompromising conditions or on immunosuppressive therapy

Zostavax is contraindicated in severely immunocompromised people. Administering Zostavax to people with severe immunocompromise can result in disseminated disease from the Oka vaccine virus. Without an adequate immune response, the vaccine virus can replicate unchecked.^30,31 2 people with chronic lymphocytic leukaemia who were given Zostavax died from disseminated Oka vaccine virus disease.^15,30,31 They were not receiving immunosuppressive treatment when they were vaccinated. Another person, who at the time of vaccination was taking prednisolone and had also recently been taking checkpoint inhibitors, died a few weeks after receiving Zostavax.³³

People on multiple medications associated with low level immunosuppression may also be at risk. In Australia, 1 person died from infection with the Oka VZV vaccine strain 3 weeks after receiving Zostavax. The person was taking long-term hydroxychloroquine and low-dose prednisolone (5 mg per day).³²

The TGA and the Australian Technical Advisory Group on Immunisation (ATAGI) continue to monitor global evidence on the safety of Zostavax. To date, there have been no other reports of a fatal outcome from vaccine-related VZV infection in people who were either mildly immunocompromised or not known to be immunocompromised.

Varicella-zoster virus (VZV) is a DNA virus of the Herpesviridae family.

Pathogenesis

Primary infection with VZV is known as varicella or chickenpox.³³ After primary infection, the virus resides in the sensory ganglia.³³

Herpes zoster, or shingles, occurs when latent VZV reactivates. This could be due, in part, to a decline in cellular immunity to the virus.³⁴ Virus-specific cellular immunity most commonly declines with ageing or with immunocompromising medical conditions or immunosuppressive treatment.

Transmission

VZV spreads through direct contact with fluid from the rash blisters caused by herpes zoster. This can cause primary varicella in exposed susceptible people.⁶

Most cases present with a unilateral vesicular rash in a dermatomal distribution.

80% of cases have a prodromal phase 48–72 hours before the rash appears.³⁴ Associated symptoms may include:^35,36

• headache
• photophobia
• malaise
• itching, tingling or severe pain in the affected dermatome

In most people, herpes zoster is an acute and self-limiting disease. The rash usually lasts 10–15 days.^33,37 However, complications can occur, especially with increasing age.

PHN and other complications

Post-herpetic neuralgia (PHN) is the most frequent debilitating complication of herpes zoster. PHN is a neuropathic pain syndrome that persists or develops after the dermatomal rash has healed.

PHN is most commonly defined as the persistence of pain for longer than 3 months after the onset of the rash. But definitions can vary by the period of persistent pain.^38,39

Other complications depend on the site of reactivation, and may include:⁴⁰

• ophthalmic disease, such as keratitis and chorioretinitis
• neurological complications, such as meningoencephalitis and myelitis
• secondary bacterial skin infection
• scarring
• pneumonia

Rarely, some people may develop disseminated herpes zoster. This is characterised by widespread vesicular rash, and visceral, central nervous system and pulmonary involvement. Disseminated disease is more common in people who are immunocompromised, and may be fatal.³⁶

Some people may also experience dermatomal pain without a rash. This is known as zoster siné herpéte.

Treating herpes zoster

Antiviral therapy can reduce the severity and duration of herpes zoster if therapy starts within 3 days of onset.

Antiviral therapy may also reduce the risk of developing PHN.^41-45 However, PHN can be difficult to treat and may persist for years.⁴⁶

Herpes zoster occurs most commonly in people who:

• are of older age — particularly >50 years
• are immunocompromised
• had varicella in the 1st year of life

The lifetime risk of reactivation of varicella-zoster virus is about 50%. It affects half of people who live to 80 years.^33,47-49

Second attacks of herpes zoster occur in approximately 5% of immunocompetent people, but are more common in people who are immunocompromised.^11,12,34,37

In a large clinical trial of Zostavax in the United States (the Shingles Prevention Study), active surveillance in the unimmunised (placebo) participants estimated the herpes zoster incidence at 1112 cases per 100,000 person-years in people ≥60 years of age.¹

Herpes zoster in Australia

In Australia, there are about 560 cases of herpes zoster per 100,000 population per year in all age groups.⁵⁰

In comparison, there are about 1174 cases per 100,000 population in people aged ≥50 years.⁵⁰ Herpes zoster incidence increases with age, from an estimated rate of 630 per 100,000 population in people aged 50–59 years, to 1531 per 100,000 population in people aged 70–79 years.⁵⁰

Herpes zoster in people who are immunocompromised

People who are immunocompromised have an increased risk of herpes zoster compared with non-immunocompromised people. Rates of herpes zoster are up to 15 times higher in people who are immunocompromised due to HIV. In the 1st year after haematopoietic stem cell transplantation, up to 30% of patients may develop herpes zoster.^25,37

Rate of complications from herpes zoster

Overall, 13–26% of patients with herpes zoster develop complications. Complications occur more often in older people and people who are immunocompromised.^51,52

Post-herpetic neuralgia (PHN) is the most common complication of herpes zoster, but it occurs very infrequently in children and young adults. PHN occurs in approximately 1 in 5 herpes zoster cases in people aged >80 years, compared with approximately 1 in 10 cases in people aged 50–59 years.^4,5,9 The population-based incidence of PHN is 3 times higher in people 70–79 years of age (235 per 100,000) than in people 50–59 years of age (73 per 100,000).⁴

Zostavax is a live attenuated vaccine formulated from the same varicella-zoster virus (VZV) strain (Oka) as the registered varicella (chickenpox) vaccine Varivax. But Zostavax has higher potency (on average, at least 14 times greater) than Varivax. The higher viral titre in Zostavax is needed to boost the immune response in adults who usually remain seropositive to VZV after primary infection, but have declining cellular immunity as they get older.⁵³

Zostavax is used to prevent herpes zoster in people >50 years of age. It is important to note that:

• registered varicella vaccines should not be used to prevent herpes zoster in older people
• Zostavax is not indicated for use in younger people who have not been previously immunised or infected with VZV
• Zostavax is not indicated for use for therapeutic benefit during an acute herpes zoster episode, nor to treat post-herpetic neuralgia (PHN)

It is important to review a person’s medical history and medication use before vaccination. Zostavax is contraindicated in people who are immunocompromised. See Contraindications and precautions.

Vaccine formulation

In Australia, a refrigerated form of Zostavax is registered based on comparable immunogenicity and safety to the frozen vaccine formulation that was used in the Shingles Prevention Study.⁵⁴

Zostavax is also registered for use in people 50–59 years of age based on a study that demonstrated similar immunogenicity in this age group compared with those ≥60 years of age.²⁷ Zostavax has since been shown to reduce the incidence of herpes zoster in people 50–59 years of age.⁸

Efficacy studies

The Shingles Prevention Study was a single large, randomised, double-blind, placebo-controlled efficacy study of the frozen formulation of Zostavax. The study included 38,546 adults aged ≥60 years. Zostavax significantly reduced the likelihood of developing both herpes zoster and PHN.¹ Over a median of more than 3 years follow-up, Zostavax vaccination of people aged ≥60 years reduced the:¹

• incidence of herpes zoster by 51.3%
• incidence of PHN by 66.5%
• burden of illness associated with herpes zoster by 61.1%

Zostavax was better at reducing herpes zoster in people aged 60–69 years (64% efficacy) than in those aged 70–79 years (41% efficacy). However, efficacy against PHN was similar in both age groups.¹ Efficacy against herpes zoster in the ≥80 years age group was lower (18% and not statistically different to placebo). However, there were fewer participants of this age in the study.⁶

In people who developed herpes zoster despite vaccination with Zostavax, the pain associated with the episode was less severe.⁵⁵

Another randomised controlled study in >22,000 people aged 50–59 years showed that the incidence of herpes zoster was lower over an average follow-up period of 1.3 years (range 0–2 years). The vaccine efficacy for preventing herpes zoster was 69.8%.⁸ In these clinical trials, many participants received antiviral and pain medicines for their herpes zoster. This suggests that the effect of Zostavax was in addition to any benefit from medical therapy.^1,8

Duration of immunity

A single dose of Zostavax appears to lose efficacy over time. One short-term follow-on study of Shingles Prevention Study participants showed a decline in vaccine efficacy. However, estimates remained statistically significant for up to 5 years after vaccination, with uncertain efficacy beyond that.^2,56

A longer-term study of Shingles Prevention Study participants suggested that Zostavax significantly protected against herpes zoster for up to 8 years after vaccination. However, the study’s methods limit confidence in this result.³

One large observational study investigated vaccine effectiveness among community-dwelling adults aged ≥60 years. Vaccine effectiveness decreased with each year of follow-up (from 69% in the 1st year to 4% in the 8th year).⁵⁷

Co-administration with other vaccines

In one study, participants received Zostavax at the same time as inactivated influenza vaccine, in different syringes and at different injection sites. Immunogenicity and safety were comparable to giving the vaccines at different times.¹⁹

In another study, participants received Zostavax at the same time as 23vPPV (23-valent pneumococcal polysaccharide vaccine; Pneumovax 23). Co-administration had no effect on the immunogenicity of 23vPPV. However, the immunogenicity of Zostavax (indicated by VZV antibody levels) may be lower than if the 2 vaccines were given 4 weeks apart.⁵⁸

However, VZV antibody levels do not directly correlate with clinical protection. Also, a large observational study from the United States reported that co-administration of Zostavax and 23vPPV did not affect the effectiveness of Zostavax against herpes zoster.^20-22

Use in people with a history of herpes zoster

People with a history of herpes zoster were excluded from the Shingles Prevention Study (see Vaccine information), so there are no data on vaccine efficacy in this group.

One small clinical trial studied the safety and immunogenicity of Zostavax in people with a history of herpes zoster. Zostavax was well tolerated and immunogenic.⁵⁹

Transport according to National vaccine storage guidelines: Strive for 5.⁶⁰ Store at +2°C to +8°C. Do not freeze. Protect from light.

Zostavax must be reconstituted. Add the entire contents of the diluent container to the vial and shake until the powder completely dissolves. Reconstitute immediately after taking the vaccine out of the refrigerator. Use the reconstituted vaccine within 30 minutes.

Herpes zoster is a notifiable disease in most states and territories in Australia.

State and territory public health authorities can provide advice about the public health management of herpes zoster, including management of cases and their contacts.

Co-administration with influenza vaccine and 23vPPV

The product information for Zostavax states that the vaccine can be given concurrently with inactivated influenza vaccine but not with 23-valent pneumococcal polysaccharide vaccine (23vPPV).

The Australian Technical Advisory Group on Immunisation (ATAGI) recommends that Zostavax may be given concurrently with other vaccines, including 23vPPV.

Administration in people with HIV

The product information for Zostavax states that the safety and efficacy of Zostavax have not been established in adults with known HIV infection with or without evidence of immunosuppression.

ATAGI recommends that Zostavax may be given to people who have HIV but are not immunocompromised, after confirming pre-existing immunity to varicella-zoster virus.

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