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

The development of vaccines has proven to be one of the most important advancements in scientific history. The first vaccine was created by Edward Jenner in 1796 to protect against smallpox¹. Since then, many vaccines have been developed and implemented into immunisation programmes, leading to the near elimination of diseases such as measles and polio¹. Vaccines against herpes zoster have provided tremendous health benefits, reducing the morbidity of herpes zoster in vaccinated individuals². Here we review the developmental history of the varicella and herpes zoster vaccines.

The need for a VZV vaccine

Atypical to most viruses, varicella zoster virus (VZV) causes two clinically distinct diseases. Primary infection results in varicella (‘chickenpox’), and reactivation of latent infection results in herpes zoster (‘shingles’). For many years, varicella was considered a mild disease – too mild to warrant prevention³. However, this view changed in the late 1960s and early 1970s³. Across these two decades, children with leukaemia began to be cured with anticancer drugs, and organ transplantation was made possible with steroid therapy³. Whilst these were undeniably landmark success stories for the medical field, anticancer medicines and steroids caused immunosuppression³. For immunosuppressed or immunocompromised children, varicella can have severe consequences. This became evident when children cured of leukaemia died of varicella - initiating the need for a vaccine³.

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 Japan⁴. The vOka vaccine was created from a wild-type strain of the VZV obtained from a healthy 3-year-old boy with varicella named Oka⁴. A method of serial passaging was used to develop the attenuated vaccine strain⁵. 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 tolerated⁴. The risk of clinical reactions following administration was very low for immunocompetent individuals, but immunocompromised individuals had a higher risk⁴. Though the risk was higher, the reactions were generally mild and resolved spontaneously⁴.

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 2007⁶. 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 varicella⁷.

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 complications⁸.

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 vaccine⁸. 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 vaccine⁹. Hence the modified live, attenuated zoster vaccine (ZVL) contains 14 times more vOka than the varicella vaccine⁸.

The primary endpoint of the SPS, the vaccine efficacy for the burden of illness due to herpes zoster for ZVL was 55.4%⁸. Reported adverse events were generally mild, and there were no clinically meaningful differences in the adverse events reported by the vaccine and placebo groups⁸.

Following the results of the SPS, the ZVL was approved by the US Food and Drug Administration (FDA) in May 2006⁹. However, like other live vaccines, the ZVL is contraindicated in immunocompromised patients because of the theoretical risk of causing serious disease⁹.

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 adjuvant².

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 groups². 

In 2017, RZV was approved by the FDA⁹. Due to the recombinant nature of RZV, this vaccine is not contraindicated in immunocompromised patients¹².

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 US¹³.

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 zoster¹². ZVL is indicated for immunisation in immunocompetent individuals ≥50 years old¹⁶. 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.