From chickenpox to shingles: The developmental history of herpes zoster vaccines

The first varicella vaccine

The first and only live, attenuated varicella vaccine, known as vOka, was developed in 1974 in the laboratory of Professor Michiaki Takahashi in Japan.⁴ The vOka vaccine was created from a wild-type strain of the VZV obtained from a healthy 3-year-old boy with varicella named Oka.⁴ A method of serial passaging was used to develop the attenuated vaccine strain.⁵ The wild-type virus was passaged 11 times in human embryonic lung fibroblasts, 12 times in guinea pig fibroblasts, and then several times in human diploid (WI-38 and MRC-5) cells.^4,5

In clinical trials, the varicella vaccine effectively prevented disease in both immunocompetent and immunocompromised children and was very well tolerated.⁴ The risk of clinical reactions following administration was very low for immunocompetent individuals, but immunocompromised individuals had a higher risk.⁴ Though the risk was higher, the reactions were generally mild and resolved spontaneously.⁴

The varicella vaccine was subsequently approved in the United States in 1995 and recommended as part of a routine 2-dose childhood vaccination schedule in 2007.⁶ A 2016 meta-analysis of 42 studies reported that one dose of the varicella vaccine had an efficacy of 81% for preventing all varicella and 98% for preventing moderate and severe varicella.⁷

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The first herpes zoster vaccine

Herpes zoster can be complicated by chronic pain (postherpetic neuralgia) and other neurological, ocular, visceral and gastrointestinal disorders, which occur in around 50% of older individuals.^6,8 After the varicella vaccine was developed, it was hypothesised that immunisation of older persons with a latent VZV infection could boost their cell-mediated immunity and protect them against herpes zoster and its complications.⁸

This hypothesis was investigated in the 1998 to 2004 Shingles Prevention Study (SPS) – a double-blind trial that involved 38,546 adults ≥60 years old receiving either a placebo or a modified vOka zoster vaccine.⁸ Since herpes zoster occurs in individuals with latent VZV infection and pre-existing immunity, it was theorised that a herpes zoster vaccine would have to generate a more potent immune response than the varicella vaccine.⁹ Hence the modified live, attenuated zoster vaccine (ZVL) contains 14 times more vOka than the varicella vaccine.⁸ 

The primary endpoint of the SPS, the vaccine efficacy for the burden of illness due to herpes zoster for ZVL was 55.4%.⁸Reported adverse events were generally mild, and there were no clinically meaningful differences in the adverse events reported by the vaccine and placebo groups.⁸ 

Following the results of the SPS, the ZVL was approved by the US Food and Drug Administration (FDA) in May 2006.⁹However, like other live vaccines, the ZVL is contraindicated in immunocompromised patients because of the theoretical risk of causing serious disease.⁹

A recombinant herpes zoster vaccine

Shortly after the live zoster vaccine was approved for clinical use, a recombinant herpes zoster vaccine (RZV) was developed, containing VZV glycoprotein E as the antigen and formulated with an AS01_B adjuvant.²

In two randomised controlled Phase III trials (n=15,411 and n=13,900), the vaccine efficacy of RZV for preventing herpes zoster was 97% for adults ≥50 years old (n=15,411) and 91% for adults ≥70 years old.^2,10,11 The RZV was generally well tolerated, with similar rates of serious adverse events across the placebo and vaccine groups.² 

In 2017, RZV was approved by the FDA.⁹ Due to the recombinant nature of RZV, this vaccine is not contraindicated in immunocompromised patients.¹²

Recommendations for herpes zoster vaccination

The US Centers for Disease Control and Prevention recommends using RZV over ZVL for the prevention of herpes zoster and its related complications.^13,14 The RZV is recommended for adults ≥50 and immunodeficient or immunosuppressed adults aged ≥19 years old, irrespective of prior receipt of the varicella vaccine or ZVL.^13,14 As of November 2020, the ZVL is no longer available for use in the US.¹³

In Europe, the RZV and ZVL are indicated for the prevention herpes zoster and post-herpetic neuralgia.^12,15 RZV is indicated for the prevention of herpes zoster and post-herpetic neuralgia in adults ≥50 years old and adults aged ≥19 years old at increased risk of herpes zoster.¹² ZVL is indicated for immunisation in immunocompetent individuals ≥50 years old.¹⁶ Individual European countries have varying recommendations regarding the use of ZVL versus RZV, however, the majority state a preference for RZV due to the higher efficacy, longer duration of protection and greater cost-effectiveness of RSV versus ZVL.^15,16

References

1. Hajj Hussein I, Chams N, Chams S, El Sayegh S, Badran R, Raad M, et al. Vaccines Through Centuries: Major Cornerstones of Global Health. Front Pub Health. 2015;3:269.
2. Cunningham AL, Heineman T. Vaccine profile of herpes zoster (HZ/su) subunit vaccine. Expert Rev Vaccines. 2017;16(7):661–670.
3. Gershon AA, Gershon MD, Shapiro ED. Live Attenuated Varicella Vaccine: Prevention of Varicella and of Zoster. Journal of Infectious Diseases. 2021;224:S387–S397.
4. Takahashi M. 25 Years’ Experience With the Biken Oka Strain Varicella Vaccine A Clinical Overview. Paediatr Drugs. 2001;3(4):285–292.
5. Takahashi M, Asano Y, Kamiya H, Baba K, Ozaki T, Otsuka T, et al. Development of varicella vaccine. Journal of Infectious Diseases. 2008;197:S41–S44.
6. Gershon AA, Breuer J, Cohen JI, Cohrs RJ, Gershon MD, Gilden D, et al. Varicella zoster virus infection. Nat Rev Dis Primers. 2015;1:15016.
7. Marin M, Marti M, Kambhampati A, Jeram SM, Seward JF. Global Varicella Vaccine Effectiveness: A Meta-analysis. Review Article Pediatrics. 2016;137(3):e20153741.
8. Oxman M, Levin M, Johnson G, Schmader K, Straus S, Gelb L, et al. A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults. N Engl J Med. 2005;352:2271–2284.
9. Harbecke R, Cohen JI, Oxman MN. Herpes Zoster Vaccines. Journal of Infectious Diseases. 2021;224:S429–S442.
10. Cunningham AL, Lal H, Kovac M, Chlibek R, Hwang S-J, Díez-Domingo J, et al. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older. New England Journal of Medicine. 2016;375(11):1019–1032.
11. Lal H, Cunningham AL, Godeaux O, Chlibek R, Diez-Domingo J, Hwang S-J, et al. Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults. New England Journal of Medicine. 2015;372(22):2087–2096.
12. Shingrix Summary of Product Characteristics. 2018 https://www.ema.europa.eu/en/documents/product-information/shingrix-epar-product-information_en.pdf. Accessed 13 April 2023.
13. Anderson TC, Masters NB, Guo A, Shepersky L, Leidner AJ, Lee GM, et al. Use of Recombinant Zoster Vaccine in Immunocompromised Adults Aged ≥19 Years: Recommendations of the Advisory Committee on Immunization Practices-United States, 2022. Morbidity and Mortality Weekly Report. 2022;71(3):80–84.
14. Dooling KL, Guo A, Patel M, Lee GM, Moore K, Belongia EA, et al. Recommendations of the Advisory Committee on Immunization Practices for Use of Herpes Zoster Vaccines. Morbidity and Mortality Weekly Report. 2018;67(3):103–108.
15. Zostavax Summary of Product Characteristics. 2016. https://www.ema.europa.eu/en/documents/product-information/zostavax-epar-product-information_en.pdf. Accessed 13 April 2023.
16. Parikh R, Widenmaier R, Lecrenier N. A practitioner’s guide to the recombinant zoster vaccine: review of national vaccination recommendations. Expert Review of Vaccines. 2021;20(9):1065–1075.