[114] Shingrix: A New Vaccine for Shingles

[114] Shingrix: A New Vaccine for Shingles

Herpes zoster (HZ) or “shingles” occurs when the varicella zoster virus (VZV), lying latent in the sensory ganglia, becomes reactivated. An HZ outbreak typically presents as a vesicular skin eruption most characteristically forming a painful girdle around one side of the thorax. The rash and pain usually resolve over a few weeks. However, about 10% of patients with shingles develop some degree of persistent HZ-related pain (post-herpetic neuralgia or PHN).1

Health Canada approved a two-dose adjuvanted herpes zoster subunit vaccine (Shingrix) in October 2017.

Zostavax, a live attenuated vaccine, was approved 10 years ago. Both vaccines are for the prevention of HZ in people ≥ 50, but neither is approved for prevention of PHN.


More than 90% of Canadian adults have had chicken pox (VZV) infection.2 A major risk factor for developing HZ is increased age, with an incidence of 6 to 8 per thousand people per year at age 60, and 8 to 12 per thousand people per year at age 80.3 About 5% of people with HZ experience recurrence.4 Population-based data in British Columbia reports that the overall HZ incidence increased from 3.2 per thousand in 1997 to 4.5 per thousand in 2012, but the increase in incidence may reflect an increase in reporting.4


We used Cochrane systematic review methods for the literature search, data collection and analysis, and risk of bias assessment. We included randomized controlled trials (RCTs) of Shingrix versus active vaccine, no vaccine or placebo. We sought out and included related unpublished data from registries5,6 and clinical study reports7,8.


Five RCTs (with about 32,000 participants) met our inclusion criteria.9-13 No trials directly compared Shingrix to Zostavax. Three trials included a placebo comparator and were meta-analyzed.9-11 In our pooled analysis, HZ occurred in 0.28% of patients who received the HZ vaccine versus 3.54% for placebo over about 3.5 years. This translates to a Number Needed to Vaccinate (NNV) of about 31 to prevent 1 case of HZ over 3.5 years. The incidence of post-herpetic neuralgia (PHN) declined in RCTs in proportion to the reduction of HZ, but the absolute reduction is much smaller, NNV = 358.9,10 Not all PHN is severe or lasts for years. Of every 10 patients vaccinated, 8 or 9 had an adverse effect, most commonly injection-site pain, myalgia or fatigue lasting up to a few days. There was no difference in serious adverse events in around 4 years of follow-up, or withdrawals due to adverse events.

Two additional studies did not report on clinical efficacy outcomes of interest and reported insufficient information on safety.12,13

Our full systematic review is available on our website.1

Risk of bias of included studies

All included studies were funded by the manufacturer. Other limitations include the use of data carried from last point of patient contact for patient withdrawals, selective reporting of some patient analyses and substantial inconsistency in the magnitude of vaccine effect when pooling study data. Overall, we graded the certainty of evidence as moderate.1


  • Compared to placebo the Shingrix vaccine reduced the incidence of herpes zoster by 3.26 % (NNV = 31) over 3.5 years in all age groups and reduced the incidence of post-herpetic neuralgia by 0.28% (NNV ≈ 350).
  • Compared to placebo Shingrix increased grade 3 systemic reactions (which prevented normal daily activities for about 1-3 days) by 4 to 9% (NNH 11 to 25).
  • The effectiveness (i.e. maintained protection) and safety of Shingrix are still unknown beyond about four years.
  • Discuss the balance of baseline herpes zoster risk, harms, benefits and costs when considering this vaccine.

Shingrix clinical evidence

Indication Prevention of herpes zoster (HZ) or “shingles” in people age 50 or older
Findings from main
clinical studies
  • ZOE-5010, 2015: n = 15,411 immunocompetent, follow-up 3.2 years
  • ZOE-709, 2016: n = 13,900 immunocompetent, follow-up 3.7 years
  • Chlibek 201311, n = 410 immunocompetent, follow-up 12 months
  • Pooled analysis (using total vaccinated cohort) over about 3.5 years:
    • Incidence of HZ:9-11 Shingrix: 0.28% vs placebo 3.54%, ARR 3.26%, NNV = 31; age-based subgroups:
      • Age 50-59: ARR 2.97%
      • Age 60-69: ARR 4.10%
      • Age ≥70: ARR 3.16%
    • Incidence of PHN:9,10 Shingrix: 0.06% vs placebo 0.34%, ARR 0.28%, NNV = 358
    • Incidence of solicited or unsolicited adverse effects in 7 days post-vaccination:9,10
      Shingrix: 83.94% vs placebo 37.39%, ARI 46.55%, NNH = 2
    • Grade 3 systemic reaction (preventing normal activity):
      • ZOE-5010: ARI 8.96%, NNH = 11; ZOE-709: ARI 3.97%, NNH = 25
Special populations
  • Elderly patients included: mean age in ZOE-709 = 76 years; approx. 22% ≥ 80 years
  • Pregnancy/Nursing: no data
  • Immunocompromised: limited data; satisfactory immune response and safety profile in:
    • HIV population: 1 RCT (n = 123)14
    • Renal transplant population: 1 RCT (n = 265)5
    • Hematopoietic stem cell transplant recipients: 2 RCTs (n = 18776 and n = 12115)
  • Those with history of HZ: limited data; 1 non-randomized study (n = 96)16 showed similar immune response and safety to those without previous HZ
  • Those with previous vaccination against HZ with live vaccine: limited data; 1 non-randomized study (n = 430)17 showed similar immune response and adverse effects rate to a matched, non-vaccinated population
Duration of HZ protection Unknown beyond 4 years
Cost Approximately $300 per two-shot series in BC

The draft of this Therapeutics Letter was submitted for review to 130 experts and primary care physicians in order to correct any inaccuracies and to ensure that the information is concise and relevant to clinicians.

The Therapeutics Initiative is funded by the BC Ministry of Health through a grant to the University of BC. The Therapeutics Initiative provides evidence-based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.
ISSN 2369-8691 (Online) <||> ISSN 2369-8683 (Print)



  1. Therapeutics Initiative. Systematic review report: Efficacy and safety of adjuvanted herpes zoster subunit vaccine. October 2018. https://ti.ubc.ca/shingrix
  2. Canadian Immunization Guide, Public Health Agency of Canada. Herpes zoster (shingles) vaccine. 2014. https://www.canada.ca/en/public-health/services/publications/healthy-living/canadian-immunization-guide-part-4-active-vaccines/page-8-herpes-zoster-(shingles)-vaccine.html
  3. Kawai K, Gebremeskel BG,  Acosta CJ. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open 2014;4:e004833. DOI: 10.1136/bmjopen-2014-004833
  4. Marra F, Chong M, Najafzadeh M. Increasing incidence associated with herpes zoster infection in British Columbia, Canada. BMC Infectious Diseases. 2016;16(1):589. DOI: 10.1186/s12879-016-1898-z
  5. ClinicalTrials.gov. Immunogenicity and safety of GlaxoSmithKline (GSK) Biologicals’ herpes zoster subunit (HZ/su) vaccine in adults 18 years of age or older with renal transplant. (updated Aug 2018) https://clinicaltrials.gov/ct2/show/NCT02058589
  6. ClinicalTrials.gov. Study to evaluate efficacy, safety, and immunogenicity of GlaxoSmithKline (GSK) Biologicals’ herpes zoster vaccine GSK1437173A. (updated Jan 2018) https://clinicaltrials.gov/ct2/show/NCT01610414
  7. GlaxoSmithKline Biologicals, SA. Clinical Study Report for Study 113077 (ZOSTER-022). GSK Clinical Study Register. https://www.gsk-clinicalstudyregister.com/files2/gsk-113077-clinical-study-report-redact.pdf
  8. GlaxoSmithKline Biologicals, SA. Clinical Study Report for Study 110390 (ZOSTER-006). GSK Clinical Study Register. https://www.gsk-clinicalstudyregister.com/files2/gsk-110390-clinical-study-report-redact.pdf
  9. Cunningham AL, Lal H, Kovac M, et al. Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med. 2016;375(11):1019-32. DOI: 10.1056/NEJMoa1603800
  10. Lal H, Cunningham AL,  Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med. 2015;372(22):2087-96. DOI: 10.1056/NEJMoa1501184
  11. Chlibek R, Bayas JM, Collins H, et al. Safety and immunogenicity of an ASO1-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults ≥50 years of age. J Infect Dis. 2013;208(12):953-61. DOI: 10.1093/infdis/jit365
  12. Leroux-Roels I, Leroux-Roels G, Clement F, et al. A phase 1/2 clinical trial evaluating safety and immunogenicity of a varicella zoster glycoprotein E subunit vaccine candidate in young and older adults. J Infect Dis. 2012;206(8):1280-90. DOI: 10.1093/infdis/jis497
  13. Chlibek R, Smetana J, Pauksens K, et al. Safety and immunogenicity of three different formulations of an adjuvanted varicella-zoster virus subunit candidate vaccine in older adults: A phase II, randomized controlled study. Vaccine. 2014;32(15):1745-53. DOI: 10.1016/j.vaccine.2014.01.019
  14. Berkowitz EM, Moyle G, Stellbrink HJ, et al. Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: A phase 1/2a randomized, placebo-controlled study. J Infect Dis 2015;211(8):1279-87. DOI: 10.1093/infdis/jiu606
  15. Stadtmauer EA, Sullivan KM, Marty FM, et al. A phase 1/2 study of an adjuvanted varicella-zoster virus subunit vaccine in autologous hematopoietic cell transplant recipients. Blood. 2014;124(19):2921-9. DOI: 10.1182/blood-2014-04-573048
  16. Godeaux O, Kovac M, Shu D, et al. Immunogenicity and safety of an adjuvanted herpes zoster subunit candidate vaccine in adults ≥ 50 years of age with a prior history of herpes zoster: A phase III, non-randomized, open-label clinical trial. Hum Vaccin Immunother. 2017;13(5):1051-58. DOI: 10.1080/21645515.2016.1265715
  17. Grupping K, Campora L, Douha M, et al. Immunogenicity and safety of the HZ/su adjuvanted herpes zoster subunit vaccine in adults previously vaccinated with a live attenuated herpes zoster vaccine. J Infect Dis. 2017;216(11):1343-51. DOI: 10.1093/infdis/jix482
  • Caroline Murphy
    Posted at 05:39h, 16 October Reply

    Thanks for this. this will be a great tool when talking with patients about this vaccine.
    Given the significant difference in cost between Shingrix and Zostavax, have you previously done a letter on Zostavax? So the 2 vaccines could be compared in a way?

    • Alan Cassels @ TI
      Posted at 14:55h, 01 November Reply

      Sorry, we haven’t critically examined the Zostavax vaccine. I believe that there hasn’t been a head-to-head trial done of these two vaccines so it’s difficult to draw definitive lessons on their comparative effectiveness.
      Thank you for the feedback
      Cheers, Alan Cassels

  • Cameron Ross
    Posted at 18:41h, 16 October Reply

    Thanks for doing this although a bit late to the party given the hype of the last year. Fortunately I had a sharp keen resident who critically appraised the data and gave me similar info 10 months ago . It’s so great to work with bright young minds.😀

    • Alan Cassels @ TI
      Posted at 14:50h, 01 November Reply

      Thank you for your feedback,
      Cheers, Alan Cassels
      Communications Director, Therapeutics Initiative

  • David Patrick
    Posted at 15:24h, 31 October Reply

    Hi TI Group. I like these updates and your usual methods are good. However, we might put some thought into whether we treat vaccines (that work through an anamnestic response), the same as other drugs, which are gone when they are gone. In this review, you did the conservative thing and calculated NNV and absolute risk reduction only on the observed 3 or 4 years of follow up. Now we KNOW we cannot claim lifelong protection but we also know that:
    1) Strong early anamnestic responses generally correlate with longer duration of protection
    2) Protection wanes gradually – so complete censorship at 3-4 years is unrealistic
    3) The epidemiology of shingles is such that the absolute risk of both disease and PHN escalates dramatically over the decades of our senior years

    My concern is that the strict time frame paints an unrealistically nihilistic picture for vaccine mediated reduction of absolute risk.

    Solution? We certainly cannot assume duration of protection, but most work on vaccines will employ mathematical models involving various rates of waning of immunity, but also in this case, increasing absolute risk of disease. Such models for the less immunogenic initial zoster vaccine offerings gave more realistic estimates of cost and benefit.

    I have no relationship with the manufacturer of this product and I generally like your methods. But I think we should open a conversation about how best to estimate the benefits for a vaccine that is intended to effect disease incidence over 3 decades, not 3 years.

    My best to you.

    • Jesse
      Posted at 16:41h, 18 November Reply

      I was thinking the same thing Patrick. The vaccine has benefits more than 3.5 years. So multiply those NNV and NNH by 3..or even 10. That’s more realistic.

  • David Patrick
    Posted at 15:33h, 31 October Reply

    Thanks, TI! I generally love your methods but have a few issues:
    1) Vaccines are not drugs and anamnestic response means we cannot censor their impact at one time point
    2) Strong immune responses predict longer ones most of the time and immunity wanes gradually. It is biologically not plausible that it disappears at year 4.
    3) Shingles epidemiology ramps UP with increasing age so that the absolute risk of shingles and PHN gets much higher with age. What we care about is a 3 decade, not a 3 year risk period.
    4) Normally, we address these factors by modeling various assumptions around waning immunity, not by assuming an end to benefit at 3 or 4 years.
    All in, your rigorous and conservative approach is correct over 3 years, but is probably nihilistic about the longer term spectrum of absolute risk reduction. We should start a conversation on best methods for considering longer term impacts of new vaccines. (I have no links to the manufacturer). With my very high regards.

    • Alan Cassels @ TI
      Posted at 15:03h, 01 November Reply

      David, thank you for your thoughtful comments in this post and the other one.
      As you see we are able to only report on how long the vaccine has been studied. As you indicate it’s likely the immunity lasts longer (and that’s what most people are going to care about) but we didn’t have the space to weigh into modelling around waning immunity. We don’t want to be nihilistic and agree with you that considering the long term impacts of new vaccines needs a global conversation.
      This is our first therapeutic newsletter dealing with a vaccine so appreciate any comments to improve future newsletters dealing with evidence of vaccine effectiveness and safety.
      All the Best, Alan Cassels
      Communications Director, Therapeutics Initiative

      • David Patrick
        Posted at 15:35h, 01 November Reply

        Thanks, Alan. I’ll figure out who can best contribute to a methods discussion on modeling vaccine impacts. Keep up the good work. My best, David Patrick. PS. Sorry for posting twice! Thought I lost the first one.

  • David Wolfson
    Posted at 18:20h, 06 November Reply

    It is interesting how reporting of numbers can create an illusion of efficacy or lack thereof. You say that “Compared to placebo the Shingrix vaccine reduced the incidence of herpes zoster by 3.26%.” This figure – derived by subtracting the 0.28% incidence of HZ in the vaccinated group from the 3.54% incidence in the unvaccinated group – sounds like a relatively small reduction. Yet if you divide 0.28% by 3.54% it yields a relative risk of 0.07%. This translates into a vaccine efficacy of 1 – 0.07, or 93%, meaning those who were vaccinated were 93% less likely to develop HZ than were those who did not receive the vaccine. Viewed from this statistical angle, all of the sudden Shingrix efficacy appears to be much more robust!

    • Jessica Otte
      Posted at 13:46h, 08 April Reply

      It sure is interesting. And, that is how marketing works! The benefits of most drugs are put in relative terms – making them sound far more effective than placebo – but it is a matter of perspective. If the baseline chance of getting something is very very low, then the absolute benefit of a drug will also be very very low.

      Here’s a (simple) video demonstrating Absolute vs Relative risk https://www.youtube.com/watch?v=ew_5eTcm7bk

      It’s important for patients to know what their baseline risk is for a disease, and how that baseline risk can be altered by medications. Often the effect of drugs is not quite as dramatic as we would like!

  • Patsy Anne Bickerstaff
    Posted at 06:15h, 11 November Reply

    The side effects do not list increased blood pressure, dizziness and difficulty with balance. I had the 1st injection two days ago, and while I am now able to lift my arm above shoulder height, and the extreme pain from shoulder to wrist has subsided considerably, my blood pressure is still elevated (despite being on blood-pressure medication) and I am still unsure about my balance. The fatigue and weakness persist, also. I found out only after the injection that the immunity is neither 100% reliable, nor permanent. And the probability of not contracting shingles without any vaccine is at least 67%, I am considering not taking the second injection. What would happen to me if I don’t take it? Also, I was diagnosed with MS at age 65 (first episode at 57, misdiagnosed) at my second (and, apparently last) major exacerbation, so my immune system is, or was, probably hyperactive anyway. I’m nearly 79 now. Does this make a difference?

    • Dr Jessica Otte @ TI
      Posted at 13:58h, 08 April Reply

      Hi Patsy Ann:

      Sorry to reply so late in the game. Hopefully you recovered and were feeling better before too long!

      In our reading, the vaccine was not tested on people with multiple sclerosis. In fact, most drugs are not tested on the ‘real world’ population. Also, in the trials that we looked at, they didn’t look at the data of the people who only received one injection. In our analysis we tried to include some of the people that were removed from the study due to issues like this (only getting one dose of vaccine, or developing shingles after the first vaccine).

      The science “guess” would be that with one dose, you may have some partial or short-acting reduction in risk of developing shingles, but since it has not been studied we really cannot say.

      You are right, even if one doesn’t get the vaccine, a person may never develop shingles. The choice to try to reduce the risk of developing shingles is yours – it may or may not be worth the harms. From our understanding of the research, it seems clear that we should warn patients about the sore arm or ill feelings which may prevent them from doing their usual activities for a few days, so that they might consider this in their decision. As more ‘real world’ evidence accumulates, hopefully we’ll have a better sense of the side effects, harms, and benefits to expect for real people like you.

  • Maureen McGuire
    Posted at 14:12h, 19 July Reply

    My physician and rheumatologist recommend I receive the Shingles vaccine.
    I have with interest the research regarding effectiveness and side effects. Regardless, I am hoping to avoid getting Shingles.
    Our carrier Blue Cross does not cover either vaccine. I question the ethics of drug companies profiting from a substantial senior population signing up for this vaccine. In addition, many seniors will not benefit due to a lack of funds.
    Should seniors not be advocating for compensation ?
    Maureen McGuire

    • Alan Cassels @ TI
      Posted at 15:58h, 23 July Reply

      Maureen, We can’t say whether seniors should be advocating for compensation, though if your insurer chooses not to cover the vaccine I’d suggest it is likely an issue you could take up with them. You do understand from our letter that the level of effectiveness of the Shingles vaccine is probably much less than people expect.
      cheers, Alan Cassels, Communications Director

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