Vaccines for preventing herpes zoster in older adults

Background Herpes zoster, commonly known as shingles, is a neurocutaneous disease caused by the reactivation of the virus that causes varicella (chickenpox). After resolution of the varicella episode, the virus can remain latent in the sensitive dorsal ganglia of the spine. Years later, with declining immunity, the varicella zostervirus (VZV) can reactivate and cause herpes zoster, an extremely painful condition that can last many weeks or months and significantly compromise the quality of life of the affected person. The natural process of aging is associated with a reduction in cellular immunity, and this predisposes older people to herpes zoster. Vaccination with an attenuated form of the VZV activates specific T-cell production avoiding viral reactivation. The USA Food and Drug Administration has approved a herpes zoster vaccine with an attenuated active virus, live zoster vaccine (LZV), for clinical use amongst older adults, which has been tested in large populations. A new adjuvanted recombinant VZV subunit zoster vaccine, recombinant zoster vaccine (RZV), has also been approved. It consists of recombinant VZV glycoprotein E and a liposome-based AS01B adjuvant system. This is an update of a Cochrane Review last updated in 2016. Objectives To evaluate the effectiveness and safety of vaccination for preventing herpes zoster in older adults. Search methods For this 2019 update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, January 2019), MEDLINE (1948 to January 2019), Embase (2010 to January 2019), CINAHL (1981 to January 2019), LILACS (1982 to January 2019), WHO ICTRP (on 31 January 2019) and Clinical Trials.gov (on 31 January 2019). Selection criteria We included randomised controlled trials (RCTs) or quasi-RCTs comparing zoster vaccine (any dose and potency) versus any other type of intervention (e.g. varicella vaccine, antiviral medication), placebo, or no intervention (no vaccine). Outcomes were incidence of herpes zoster, adverse events (death, serious adverse events, systemic reactions, or local reaction occurring at any time after vaccination), and dropouts. Data collection and analysis We used standard methodological procedures expected by Cochrane. Main results We included 11 new studies involving 18,615 participants in this update. The review now includes a total of 24 studies involving 88,531 participants. Only three studies assessed the incidence of herpes zoster in groups that received vaccines versus placebo. Most studies were conducted in high-income countries in Europe and North America and included healthy Caucasians (understood to be white participants) aged 60 years or over with no immunosuppressive comorbidities. Two studies were conducted in Japan. Fifteen studies used LZV. Nine studies tested an RZV. The overall quality of the evidence was moderate. Most data for the primary outcome (incidence of herpes zoster) and secondary outcomes (adverse events and dropouts) came from studies that had a low risk of bias and included a large number of participants. The incidence of herpes zoster at up to three years follow-up was lower in participants who received the LZV (one dose subcutaneously) than in those who received placebo (risk ratio (RR) 0.49,95% confidence interval (CI) 0.43 to 0.56; risk difference (RD) 2%; number needed to treat for an additional beneficial outcome (NNTB) 50; moderate-quality evidence) in the largest study, which included 38,546 participants. There were no differences between the vaccinated and placebo groups for serious adverse events (RR 1.08, 95% Cl 0.95 to 1.21) or deaths (RR 1.01, 95% Cl 0.92 to 1.11; moderate-quality evidence). The vaccinated group had a higher incidence of one or more adverse events (RR 1.71,95% Cl 1.38 to 2.11; RD 23%; number needed to treat for an additional harmful outcome (NNTH) 4.3) and injection site adverse events (RR 3.73, 95% Cl 1.93 to 7.21; RD 28%; NNTH 3.6) of mild to moderate intensity (moderate-quality evidence). These data came from four studies with 6980 participants aged 60 years or over. Two studies (29,311 participants for safety evaluation and 22,022 participants for efficacy evaluation) compared RZV (two doses intramuscularly, two months apart) versus placebo. Participants who received the new vaccine had a lower incidence of herpes zoster at 3.2 years follow-up (RR 0.08, 95% Cl 0.03 to 0.23; RD 3%; NNTB 33; moderate-quality evidence). There were no differences between the vaccinated and placebo groups in incidence of serious adverse events (RR 0.97, 95% Cl 0.91 to 1.03) or deaths (RR 0.94, 95% Cl 0.84 to 1.04; moderate-quality evidence). The vaccinated group had a higher incidence of adverse events, any systemic symptom (RR 2.23,95% Cl 2.12 to 2.34; RD 33%; NNTH 3.0), and any local symptom (RR 6.89, 95% Cl 6.37 to 7.45; RD 67%; NNTH 1.5). Although most participants reported that there symptoms were of mild to moderate intensity, the risk of dropouts (participants not returning for the second dose, two months after the first dose) was higher in the vaccine group than in the placebo group (RR 1.25, 95% Cl 1.13 to 1.39; RD 1%; NNTH 100, moderate-quality evidence). Only one study reported funding from a non-commercial source (a university research foundation). All of the other included studies received funding from pharmaceutical companies. We did not conduct subgroup and sensitivity analyses Authors' conclusions LZV and RZV are effective in preventing herpes zoster disease for up to three years (the main studies did not follow participants for more than three years). To date, there are no data to recommend revaccination after receiving the basic schedule for each type of vaccine. Both vaccines produce systemic and injection site adverse events of mild to moderate intensity. PLAIN LANGUAGE SUMMARY Vaccines for preventing shingles in older adults Review question We evaluated the effectiveness and safety of vaccines to prevent shingles in healthy older people. Background Varicella zoster virus causes chickenpox and can remain inactive in nerve cells for many years. The virus can reactivate, travel through the nerve to the skin, and produce blisters along the nerve path. This condition is called shingles (herpes zoster), and mostly affects people with low immunity, such as older people. Before blisters appear, symptoms may include itching, numbness, tingling, or local pain. Shingles causes nerve inflammation and severe pain that can affect quality of life. The incidence rate of herpes zoster ranges from 2.08 cases to 6.20 cases per 1000 person-years (i.e. the number of new cases per population at risk, in a given time period). This number is increasing, due in part to people living longer. This is an update of a Cochrane Review last updated in 2016. Search date 31 January 2019. Study characteristics We included 11 new studies involving 18,615 participants in this update; the review now includes evidence from 24 studies involving 88,531 participants. Most studies were conducted in high-income countries in Europe and North America, whilst two studies were conducted in Japan. Study participants were healthy adults aged 60 years or over with no difficulty fighting infection, most of whom were Caucasian (understood to be white) women. Follow-up ranged from 28 days to 7 years. All primary study reports were published in English. Key results One large, high-quality study including 38,546 participants aged 60 years or over compared LZV versus fake (placebo) vaccines (one dose administered as a subcutaneous (given under the skin) injection) and found that the active vaccine can prevent shingles for up to three years. The adverse effects of the vaccine were mostly mild to moderate, for systemic symptoms as well as for injection site reactions. RZV is a new vaccine that contains a small part of the varicella zoster virus plus adjuvant. An adjuvant is a substance that enhances the response of the body against a stimulus (bacteria, viruses, and substances that appear foreign and harmful) to defend itself. This vaccine requires a total of two intramuscular doses, given two to six months apart. Two studies (29,311 participants for safety evaluation and 22,022 participants for efficacy evaluation) compared RZV versus placebo and reported that people who received the RZV had fewer episodes of herpes zoster but more systemic symptoms and injection site reactions. Most participants reported that these adverse effects were of mild to moderate intensity. It is important to note that the number of participants who did not receive the second dose was higher in the vaccine group than in the placebo group. Quality of the evidence We assessed the overall quality of evidence as moderate because the studies included many participants.