Episode 328: Time to roll out vaccination against varicella/zoster?
As you probably know, there is an ongoing controversy about vaccination against the virus that causes chickenpox (windpokken) as a primary disease and shingles (zona) . Whereas vaccination against varicella using a live-attenuated OKA strain is recommended for all young children to prevent chickenpox in a number of countries (e.g. the US and Germany), many other countries (including Belgium) are having a more “conservative” approach and only advised it in an “at risk” populations. More recently, however, a recombinant adjuvanted glycoprotein vaccine (Shingrix) was developed and is now increasingly used to prevent reactivation (shingles) in older subjects.
In this episode, I will first remind you about the pathogenesis and burden of varicella-zoster and then critically discuss vaccination strategies.
Par 1 Introduction on pathogenesis and clinic of chickenpox and shingles
Ep 328-1: Anne Gershon NATURE REVIEWS | DISEASE PRIMERS 2015 Varicella-zoster infection.
Different phases of varicella zoster virus infection
Primary infection with varicella zoster virus (VZV) in susceptible individuals causes varicella, which usually is harmless in healthy children whose immune system controls the infection. VZV establishes latency in ganglionic neurons, and reactivation of viral replication and spread of the virus to the skin innervated by these neurons causes zoster. Increasing age and compromised immune function are risk factors for complications of VZV infections. However, some of these complications, such as postherpetic neuralgia, can also occur without these predisposing factors.
Latent and lytic infection.
a | Lytic infection with varicella zoster virus (VZV) starts with attachment, fusion and uncoating of the virion. The virus capsid is then transported to the cell nucleus, where the viral DNA becomes circular. The full set of viral proteins, including immediate early (IE), early (E) and late (L) proteins, are expressed and enter the nucleus. New virions then bud in a two-step process. This full cycle of viral replication leads to substantial cell damage and eventually lysis; the acidic environmental in the endosome damages the virus particles and reduces their infectiousness. The micrograph shows VZV infection of guinea pig enteric neurons showing lytic infection. Isolated neurons were cultured in vitro and infected with cell-free VZV to induce infection. The cultures were fixed and immunostained with antibodies against VZV ORF29p (red) and glycoprotein E (green). The neurons were analysed 48 h after infection with cell-associated virus; after lytic infection, neurons die with 48–72 h. The neuron is filled with cytoplasmic glycoprotein E immunoreactivity and the immunoreactivity of ORF29p has almost entirely translocated to the nucleus (arrow).
b | The exact mechanisms of latent infection are unclear but viral replication is thought to stop at the circular DNA stage and no or only limited protein expression occurs. Furthermore, no viral proteins are found in the nucleus. Latent infection causes no easily observable changes of cell morphology (see micrograph). The micrograph shows VZV infection of guinea pig enteric neurons showing latent infection47. Isolated neurons were cultured in vitro and infected with cell-free VZV to induce infection. The cultures were fixed and immunostained with antibodies against VZV ORF29p (red) and glycoprotein E (green). The neurons were analysed 2 weeks after infection with cell-free VZV; after latent infection, neurons survive in vitro for as long as cultures can be maintained. Note that ORF29p immunoreactivity is confined to the cytoplasm; there is no nuclear immunoreactivity (arrow). TGN, trans-Golgi network
Natural history and pathogenesis of zoster.
The classic model of zoster pathogenesis first described by Hope-Simpson20 links viral replication and clinical disease with the levels of cell-mediated immunity (CMI). In primary infection, no immunity to varicella zoster virus (VZV) exists and infection becomes apparent as varicella. CMI then controls replication, and reactivation of the virus remains subclinical and asymptomatic (‘contained reversions’). Exogenous contact with VZV can boost CMI; nevertheless, CMI levels decrease over time and when they fall below a critical level, zoster can develop
Varicella in the infant
Severe varicella in an 11‑month-old infant who, during the incubation period, had received dexamethasone as part of therapy for pneumococcal meningitis. Pictured on day 5 of the rash, when he was still systemically unwell and acquiring new lesions. The infant made a full recovery with intravenous acyclovir therapy
CONGENITAL VARICELLA Compared to congenital CMV
Complications of herpes zoster
Antiviral treatment in VZV disease.
a | Antiviral treatment of varicella is indicated in immunocompromised individuals, neonates, patients with chronic skin or lung diseases and in individuals aged >13 years. Patients receive oral acyclovir (ACV), valaciclovir (VACV) or famciclovir (FCV; not approved by the FDA for use in children) unless they are clinically ill or at high risk (most immunocompromised patients are considered to be at high risk, except those who receive long-term, effective immunoglobulin replacement therapy or those who received only mildly immunosuppressive drugs a long time ago). Ill and high risk patients receive intravenous (IV) ACV or foscarnet if the infection is caused by ACV-resistant VZV. Intravenous treatment always needs careful consideration of kidney function.
b | The treatment of zoster follows a similar algorithm; here compromised immunity, illness, severe rash, involvement of eyes or face, and other complications are indications for antiviral treatment. In addition to ACV, VACV and FCV, brivudin (BVDU; not approved by the FDA) might be used. Patients who develop varicella or zoster in hospital will generally receive antiviral therapy as part of an infection control strategy. PO, per os (oral administration).
Various remaining questions
Par 2 Burden of disease
Ep 328-2: ECDC 2015 Burden of varicella in Europe
Most varicella cases in general practice fully recover but 2‒6% develop complications: skin and soft tissue superinfections, followed by neurological and pulmonary complications.
Risk of severe varicella is RELATIVELY higher in immunocompromised infants and adults, BUT IN ABSOLUTE NUMBERS most complications, hospitalizations and deaths due to varicella occur in children who are immunologically healthy with no underlying medical conditions.
Incidence of varicella primary infection
- 52‒78% of the incident cases occur in children (< 6 years) and 89‒ 95.9% before adolescence (i.e. before 12 years )
- Incidence of hospitalization for varicella = 2-6/100,000, but highest in babies under 1 year: 20-170/100,000
- Incidence of primary varicella during pregnancy = 40-60 per 100,000:
- 10-20 % of varicella pneumonia in the infected mother
- About 1 % congenital varicella if infection in the first 20 weeks.
- Generalized neonatal varicella with up to 20 % mortality if acute maternal varicella in the days around delivery
Varicella complication (focusing on hospitalized cases)
- Skin and soft tissue superinfections in 8-59% of all hospitalized cases
- Neurological complications (meningo-encephalitis or cerebellar ataxia): in 4-60 % of hospitalized
- Respiratory (pneumonia, otitis media): 3-22 % of hospitalized
- Other complications: gastrointestinal, hepatic and haematological
- Long term sequelae (severe cutaneous scarring, ataxia/coordination disorders, epilepsy or cerebral nerve paralyses): 8.7 %
- Mortality: Case fatality rates 0.01% to 5.4% among hospitalised cases.
- Persons over 15 years of age have a greater risk of dying than children aged 1-4 years.
- Most of those who died of varicella were reported to have been previously healthy individuals.
With regard to herpes zoster reactivation:
Infection from primary varicella usually confers lifetime immunity,
BUT life-time risk of HZ reactivation is 28% for England and Wales
more usual in immunocompromised patients and patients over 50 years, and is unusual in children
Ep 328-3: Superior Health Council 2022 Herpes Zoster (HZ)
Complications of HZ in 10-15 %
- Herpes zoster ophthalmicus:
- Prodromen: unilateral burning pain, allodynia, and headache along the ophthalmic (V1) branch of the trigeminal nerve.
- Then an erythematous, vesicular rash subsequently erupts, lasting up to 10 day
- 50 % of untreated develop significant ptosis secondary to edema, resulting in inability to close the eyelid and dry eye. Red eye, excessive tearing, eye pain, blurred vision, photophobia, and decreased visual acuity are common complaints.
- Ramsay Hunt syndrome: peripheral facial palsy and HZ in the external ear, tympanic membrane with our without tinnitus, vertigo or deafness
- Post-herpectic neuropathy (PNH) (Ep 328-5) = lancinating/burning pain in a unilateral dermatomal pattern:
- General: 10 % after 1 month, decreases to 5 % after 3 months and 3 % after 1 year
- Much higher in elderly: up to 6à % after 60 Years of age
- Other complications include Bell's palsy ("idiopathic" facial paresis), non-cranial nerve zoster-paresis, focal neurological deficits (granulomatous angiitis), myelitis, aseptic meningitis, meningoencephalitis and Guillain-Barré syndrome)
- In immune compromised subjects (untreated HIV, immune-suppressive drugs, cancer, chemotherapy…): visceral dissemination through viraemia, resulting in pneumonia, hepatitis, encephalitis, and disseminated intravascular coagulopathy. Associated with mortality of 5-15 %
Risk factors for Hepers Zoster
Hospital admissions for Zoster by age in Belgium
- Gender and race: women > men and whites > blacks
- Immune suppression: advanced age, HIV, haematological malignancies, inflammatory diseases (lupus, rheumatoid arthritisn Crohn, MS)
- Relation Zoster and Varicella epidemics? Clearly, it is the same virus, but varicella (VZV) is the primary acute infection (mainly in children) while zoster (HZ) is the reactivation (usually in adults)
- Exposure to varicella can reduce the risk of HZ through exogenous boosting of VZV-immunity.
- HZ does not induce varicella-epidemics, because too little virus is reactivated for infection.
Summary of risk factors: (from Ep 238-4)
Acute HZO (herpes zoster)
PHN (post herpetic neuralgia)
≥50 years old
Involvement of frontal nerve fibers of V1
≥50 years old
≥30 days of pain
≥50 years old
Extent and severity of rash
Reduced corneal and cutaneous sensation
Abbreviations: HTN, hypertension; HZO, herpes zoster ophthalmicus; PHN, postherpetic neuralgia.
Par 3 Live attenuated vaccine = derived from OKA strain
Ep 328-6: Takahasi JID 2018
Oka strain of varicella-zoster virus = isolated from vesicles of a healthy 3-year old with with typical varicella.
The virus was passaged 11 times in human embryonic lung fibroblasts at 34 °C and 12 times in guinea pig embryo fibroblasts (GPEFs) at 37°C.
→ safe and effective for healthy and immunocompromised children.
Is NOT followed by latent infection and therefore should prevent herpes zoster reactivation.
Ep 328-2: ECDC report p.18:
The vaccine offered definite protection when given within three days of exposure.
Safe in immunosuppressed subjects, if acceptable lymphocyte counts and in remission after chemotherapy
Protection in healthy children:
- Against confirmed varicella: 65 % after 1 dose and 95 % after 2 doses
- Against severe varicella: 100 % after 1 or 2 doses
Correlate of protection:
- 5 gpELISA when using a glycoprotein based enzyme linked immunosorbent assay (gpELISA),
- 50mIU/ml was set as the threshold for whole-cell ELISA assay to calculate response rates
Breakthrough varicella (BV) = mild
- Both monovalent and combined varicella (with measles-mumps-rubella) = very efficacious
- Higher efficacy against severe varicella than against less severe varicella.
- A two-dose vaccination regimen results in higher vaccine efficacy than a single-dose
- Second dose six to twelve weeks after the first dose
- There is a continuous relationship between antibody titre and the probability of breakthrough varicella even though a protective antibody titre has not been defined.
Gaps and uncertainties include
- the duration of immunity,
- the risk of complications in BV cases many years after vaccination,
- long-term effects of varicella vaccination further than 14 years (e.g. maternal antibody levels in newborns from varicella-vaccinated mothers)
Varicella vaccination recommendation in Europe= very heterogeneous
- Only six countries universally recommend varicella vaccination for children at national level and two countries at regional level.
- Sixteen countries recommend nationwide vaccination for susceptible teenagers and/or risk groups only.
Ep 328-7: Belgian Superior Health Council 2017 (A = Dutch; B = French , no English version)
“The High Council is convinced of the advantage of 2 dose vaccination but does not recommend to generalize it”
Reasons for doubt ?
- Fear that an insufficient degree of vaccination would be reach to significantly reduce the circulation of wild virus
- Uncertainty about the duration of protection: primo infection later in life tends to be worse
- Uncertainty about the effect of varicella vaccination on the incidence of zoster.
Nevertheless a formal recommendation to vaccinate ( 2 doses with 4-6 weeks interval) the following groups:
- Non-immune health care workers
- Other non-immune persons in contact with immune-compromised patients or young children
- Non-immune women who want to become pregnant: administration minimum 1 month before pregnancy
Like any live-attenuated vaccine, it is formally contra-indicated for:
- Patients with suppression of cellular immunity
- Pregnant women
In conclusion, while ECDC and the Belgian Superior Council are convinced about the efficacy of the OKA vaccine, there is a clear hesitance to roll it out with the same vigor as applied for other “childhood” vaccines.
The US is more convinced as the vaccine has been highly recommended and rolled out since 1995.
Several studies in healthy children, but also in children who survived hematological malignancies showed that the vaccine was very safe and very efficient, with protection against varicella of over 90 %.
Gershon A. Live attenuated varicella vaccine. Efficacy for children with leukemia in remission. JAMA 252, 355–362 (1984).
Kutter B Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Paediatric Infectious Diseases Journal 23(2):p 132-137, February 2004.
Ep 328-8: CDC 2019: Varicella (chickenpox) for health care workers
Par 4 Recombinant protein vaccine (Shingrix) to prevent Herpes zoster and post-herpes neuralgia
Ep 328-9 : EMA Approval Document
Summary of phase 3 trial:
- ZOE-50 Total Vaccinated Cohort (TVC) adults ≥ 50 years at least 1 dose of Shingrix (N=7 695) or placebo (N=7 710).
- ZOE-70 (Zoster-022): TVC of 13 900 adults ≥ 70 years at least 1 dose of Shingrix (N=6 950) or placebo (N=6 950).
- Zoster-002: TVC of 1 846 autologous hematopoietic stem cell transplants (aHSCT) recipients at least 1 dose of either Shingrix (N=922) or placebo (N=924)
- Zoster-039: TVC of 562 subjects with hematologic malignancies at least 1 dose of either Shingrix (N=283) or placebo (N=279). F
Table 2: Efficacy against Herpes Zoster
Table 3: Efficacy against Post-herpes neuropathy (PNH)
Both humoral and cellular immunity are strongly enhanced.
Ep 328-10: Gagliardi Cochrane Review 2016 Vaccines for preventing herpes zoster in older adults
In this meta-analysis, the recombinant vaccine Shingrix seems more effective than the attenuated Oka vaccine.
Ep 328-3: Based in the above studies, the Belgian Superior Council has formally advised in facor of Shingrix for elderly and immunocompromised subjects in August 2022
The SHC recommends vaccination against Herpes Zoster with a non-live adjuvanted recombinant HZ subunit vaccine (2 dose regimen) for:
- Immunocompetent adults aged ≥ 60 years.
- Immunocompromised patients, including those under immunosuppressive therapy aged ≥ 16 years and also patients under treatment with anti-JAK therapy.
My preliminary summary (on a topic out of my comfort zone)
- Herpes varicella and zoster are not just annoying childhood respectively elderly diseases. VZV can be have very debilitating and dangerous complications occur, even in immunocompetent subjects.
- In a non-vaccinated population, it is likely that re-exposure to varicella may boost cellular immunity and prevent reactivation of the latent infection (i.e. prevent zoster) to some extent, but this “natural immunity” is clearly not sufficient, it wanes with age and with weakening immunity.
- Despite hesitancy in Europe, there is no convincing evidence that early vaccination (with attenuated Oka) could enhance susceptibility to zoster later in life, but, admittedly, this theoretical possibility had not yet been completely excluded.
- On the other hand, there is now a lot of evidence that Oka primo-vaccination in children can prevent the severe consequences of varicella and that vaccination in elderly and in immunocompromised individuals with Oka is also at least partly protective against zoster.
- The adjuvanted recombinant vaccine Shingrix seems to have superior efficacy against zoster and post-herpetic neuropathy, both in elderly and immune compromised subjects.
There are still a lot of unknowns with regard to the pathogenesis of VZV and with regard to long-term protection after vaccination, but I see no serious objection to include Oka systematically in the childhood vaccination scheme.
I could not find papers on the use of Shingrix in children, but I would certainly favor a trial to compare Oka and Shingrix, as the latter is a more powerful and conceptually more safe vaccine.
Future trials on the frequency of booster vaccination in adults are certainly also needed, with the ultimate goad to reduce all VZV-related pathology to a minimum.
Looking forward to your opinion.
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