2. Adverse events live zoster vaccine (LZV).
| Comparison (studies) | Results |
|
LZV versus placebo (Hata 2016; Levin 2018; Mills 2010; Murray 2011; NCT00886613; Oxman 2005; Vermeulen 2012) |
The following adverse events did not differ significantly between groups receiving LZV or placebo: death (Hata 2016; Murray 2011; Oxman 2005), 1 or more SAE regardless of type of storage of the vaccine (Murray 2011; Oxman 2005), vaccine‐related serious adverse events (Murray 2011; Oxman 2005), hospitalisation (Oxman 2005), hospitalisation related to HZ (Oxman 2005), systemic adverse events (Hata 2016; Mills 2010; NCT00886613; Oxman 2005; Vermeulen 2012), systemic pruritus (Hata 2016; Vermeulen 2012), general malaise (Hata 2016), headache (NCT00886613), varicella‐like rash not at injection site (from day of vaccination to day 42) (NCT00886613; Oxman 2005; Vermeulen 2012), rash unrelated to HZ (from day of vaccination to day 42) (NCT00886613; Oxman 2005), haematoma at inoculation site (Oxman 2005), and adverse events not related to vaccine (Hata 2016). Participants of vaccinated group had a higher incidence of the following: 1 or more adverse events (RR 1.71, 95% CI 1.38 to 2.11; RD 0.23, 95% CI 0.14 to 0.32; NNTH 4.3, 95% CI 3.1 to 7.1) (Analysis 1.3.6) (Hata 2016; Mills 2010; NCT00886613; Oxman 2005; Vermeulen 2012); vaccine‐related adverse events (RR 2.64, 95% CI 1.21 to 5.75; RD 0.26, 95% CI 0.03 to 0.55; NNTH 3.8, 95% CI 1.8 to 33.3) (Analysis 1.3.7) (Hata 2016; NCT00886613; Vermeulen 2012); and vaccine‐related systemic adverse events (RR 1.30, 95% CI 1.07 to 1.58; RD 0.01, 95% CI 0.00 to 0.03; NNTH 100.0 95% CI 33.3 to 100.00) (Analysis 1.3.9) (Mills 2010; NCT00886613; Oxman 2005). The vaccinated group had a higher incidence of adverse events at the injection site (RR 3.73, 95% CI 1.93 to 7.21; RD 0.28, 95% CI 0.15 to 0.41; NNTH 3.6, 95% CI 2.4 to 6.7) (Analysis 1.3.15) (Hata 2016; Mills 2010; Oxman 2005; Vermeulen 2012). Specific injection site adverse events also occurred more frequently in the vaccinated group:
Varicella‐like rash at injection site (up to day 42) also occurred more frequently in the vaccinated group: RR 2.86, 95% CI 1.21 to 6.76, but without a significant RD due to the small number of events (Analysis 1.3.24) (Oxman 2005). The risk of herpes zoster‐like rash up to 42 days postvaccination was lower in the vaccinated group (RR 0.47, 95% CI 0.27 to 0.84) than in the placebo group, but without a significant RD (Analysis 1.3.26) (Oxman 2005). Duration of injection site adverse events Injection site adverse events generally lasted longer in the zoster vaccine group. There were significant differences with respect to the duration of the following local adverse events: erythema MD 2.40 days (95% CI 1.56 to 3.24) (Analysis 1.4.1); pruritus MD 2.40 days (95% CI 1.32 to 3.48) (Analysis 1.4.3); and swelling MD 1.90 days (95% CI 1.35 to 2.45) (Analysis 1.4.4). The duration of pain and haematoma did not differ significantly between the groups: MD 1.00 (95% CI −0.10 to 2.10) (Analysis 1.4.2) and MD −0.50 (95% CI −5.52 to 4.52) (Analysis 1.4.6), respectively. The duration of rash was longer in the placebo group than in the vaccine group: RR −16.60 (95% CI −33.68 to 0.48) (Analysis 1.4.5). |
| High‐potency versus low‐potency zoster vaccine (Tyring 2007) | The comparison of high‐ versus low‐potency zoster vaccine yielded no significant differences between groups for the following adverse events: vaccine‐related adverse events, systemic vaccine‐related adverse events, and vaccine‐related serious adverse events (death). |
|
Refrigerated versus frozen zoster vaccine (Gilderman 2008) |
There were no significant differences between the refrigerated versus the frozen zoster vaccine for the following adverse events: 1 or more adverse events, vaccine‐related adverse events, systemic adverse events, systemic vaccine‐related adverse events, serious adverse events, vaccine‐related serious adverse events or death. However, there were more injection site adverse events in the group receiving frozen vaccines (RR 0.77, 95% CI 0.60 to 0.98). |
|
2 doses versus a single dose of LZV and 2 doses given at different intervals (Vesikari 2013) |
Zoster vaccine 1‐month schedule versus zoster vaccine 3‐month schedule There was no statistical difference between participants who received the doses of zoster vaccine 2 months apart compared to those receiving them 3 months apart: SAE (RR 0.95, 0.14 to 6.70); withdrawal due to AE (RR 2.86, 95% CI 0.12 to 69.80); AE (RR 1.10, 95% CI 0.91 to 1.31); vaccine‐related AE (RR 1.00, 95% CI 0.81 to 1.24); systemic AE (RR 1.34, 95% CI 0.90 to 2.00); vaccine‐related systemic AE (RR 1.27, 95% CI 0.45 to 3.60); rash of interest non‐injection site rashes (RR 0.95, 95% CI 0.06 to 15.14); varicella/varicella‐like rash (RR 0.95, 95% CI 0.06 to 15.14); injection site reaction (RR 0.99, 95% CI 0.80 to 1.23); solicited injection site reaction (RR 1.00, 95% CI 0.81 to 1.25); unsolicited injection site reaction (RR 0.41, 95% CI 0.11 to 1.56); erythema injection site (RR 1.01, 95% CI 0.80 to 1.27); pain injection site (RR 0.84, 95% CI 0.57 to 1.25); swelling injection site (RR 1.05, 95% CI 0.75 to 1.47). No participants from either group reported the following AEs: vaccine‐related SAE; vaccine‐related withdrawal due to AE; non‐serious vaccine‐related withdrawal due to AE; and herpes zoster/zoster‐like rash. Zoster vaccine 1‐month schedule versus zoster vaccine single dose Only participants with systemic AE: there were significant differences in favour of the 2 doses 1 month apart, with a higher incidence in the single‐dose group: RR 0.74, 95% CI 0.56 to 0.97; RD −0.07, 95% CI −0.13 to −0.01; NNTH 14.3, 95% CI 7.6 to 100. There was no statistical difference for most adverse events: SAE (RR 0.72, 95% CI 0.16 to 3.30); withdrawal due to AE (RR 0.36, 95% CI 0.05 to 2.82); vaccine‐related withdrawal due to AE (RR 0.21, 95% CI 0.01 to 3.74); non‐serious vaccine‐related withdrawal due to AE (RR 0.21, 95% CI 0.01 to 3.74); AE (RR 0.92, 95% CI 0.80 to 1.05); vaccine‐related AE (RR 0.91, 95% CI 0.77 to 1.08); vaccine‐related systemic AE (RR 0.54, 95% CI 0.26 to 1.12); rash of interest non‐injection site rashes (RR 1.61, 95% CI 0.15 to 17.72); varicella/varicella‐like rash (RR 9.66, 95% CI 0.39 to 236.25); herpes zoster/zoster‐like rash (RR 0.64, 95% CI 0.03 to 13.36); injection site reaction (RR 0.93, 95% CI 0.78 to 1.10); solicited injection site reaction (RR 0.94, 95% CI 0.79 to 1.11); unsolicited injection site reaction (RR 0.35, 95% CI 0.11 to 1.13); injection site erythema (RR 0.98, 95% CI 0.81 to 1.17); injection site pain (RR 0.74, 95% CI 0.54 to 1.01); injection site swelling (RR 1.08, 95% CI 0.82 to 1.41). There were no participants with vaccine‐related SAE in either group. Zoster vaccine 3‐month schedule versus zoster vaccine single dose Participants in the single‐dose group had a higher incidence of the following AEs in comparison to the group that received 2 doses, 3 months apart: AE (RR 0.84, 95% CI 0.72 to 0.97; RD −0.09; 95% CI −0.17 to −0.02; NNTH 11.1, 95% CI 5.9 to 50); systemic AE (RR 0.55, 95% CI 0.39 to 0.76; RD −0.13, 95% CI −0.18 to −0.07; NNTH 7.6, 95% CI 5.6 to 14.3); vaccine‐related systemic AE (RR 0.42, 95% CI 0.18 to 0.98; RD −0.04, 95% CI −0.06 to −0.01; NNTH 25.0, 95% CI 16.6 to 100). There were no significant differences between groups for the following adverse events: SAE (RR 0.75, 95% CI 0.16 to 3.46); withdrawal due to AE (RR 0.18, 95% CI 0.01 to 3.04); vaccine‐related withdrawal due to AE (RR 0.23, 95% CI 0.01 to 3.93); non‐serious vaccine‐related withdrawal due to AE (RR 0.23, 95% CI 0.01 to 3.93); vaccine‐related AE (RR 0.91, 95% CI 0.77 to 1.08); rash of interest non‐injection site rashes (RR 1.69, 95% CI 0.15 to 18.60); varicella/varicella‐like rash (RR 10.14, 95% CI 0.41 to 247.92); herpes zoster/zoster‐like rash (RR 0.68, 95% CI 0.03 to 14.02); injection site reaction (RR 0.93, 95% CI 0.79 to 1.11); solicited injection site reaction (RR 0.93, 95% CI 0.78 to 1.11); unsolicited injection site reaction (RR 0.85, 95% CI 0.38 to 1.91); injection site erythema (RR 0.97, 95% CI 0.80 to 1.17); injection site pain (RR 0.87, 95% CI 0.65 to 1.17); injection site swelling (RR 1.03, 95% CI 0.77 to 1.36). There were no participants with vaccine‐related SAE in either group. |
| LZV AMP versus LZV (NCT01505647) | There were no significant differences between LZV AMP versus LZV for the following adverse events: participants with 1 or more adverse events; injection site adverse events; injection site erythema; injection site pain; injection site pruritus; and injection site swelling. It is important to note that there was a significant difference for participants with 1 or more serious adverse events (RR 0.25, 95% CI 0.08 to 0.82; RD −0.04, 95% CI −0.07 to −0.00; NNTH 25.0, and no RD favourable to LZV). There were no deaths in this study. |
| Heat‐treated LZV versus LZV or placebo (NCT00886613) |
Heat LZV versus LZV There was no SAE in this comparison. There were no significant differences between groups for the following adverse events: 1 or more AE, 1 or more vaccine‐related AE, 1 or more systemic AE, 1 or more vaccine‐related systemic AE, headache, injection site erythema, and injection site pruritus. On the other hand, for 1 or more injection site AE (RR 0.40, 95% CI 0.23 to 0.70; RD −0.40, 95% CI −0.60 to −0.20; NNTH 2.5, 95% CI 1.17 to 5.0); vaccine‐related 1 or more injection site AE (RR 0.48, 95% CI 0.27 to 0.85; RD −0.30, 95% CI −0.50 to −0.09; NNTH 3.3, 95% CI 2 to 11.1); injection site induration (RR 0.36, 95% CI 0.16 to 0.82; RD −0.26, 95% CI −0.45 to −0.08; NNTH 3.8, 95% CI 2.2 to 12.5); injection site pain (RR 0.18, 95% CI 0.07 to 0.48; RD −0.44, 95% CI −0.62 to −0.26; NNTH 2.3, 95% CI 1.6 to 3.8). All significant differences were favourable to heat LZV. Heat LZV versus placebo There was no SAE in this comparison. There was no significant difference between heat LZV and placebo for all adverse events reported. |
|
LZV IM route versus LZV SC route (Diez‐Domingo 2015) |
The participants who received SC vaccines had a significantly higher incidence of the following adverse events:
There were no significant differences between groups for the following adverse events: all systemic adverse events: RR 1.03, 95% CI 0.70 to 1.51; vaccine‐related systemic AE: RR 0.93, 95% CI 0.44 to 1.98; headache considered as vaccine‐related by the investigator: RR 0.75, 95% CI 0.17 to 3.32; unsolicited injection site reaction: RR 0.65, 95% CI 0.29 to 1.45; severe injection site erythema (> 10 cm): RR 0.67, 95% CI 0.11 to 3.96; severe injection site pain (inability to work or perform usual activity): RR 1.01, 95% CI 0.14 to 7.06; severe injection site swelling (> 10 cm): RR 0.25, 95% CI 0.03 to 2.23. |
| LZV intradermal route versus LZV SC route (Beals 2016) |
Full‐dose intradermal versus full‐dose subcutaneous There were significant differences in favour of LZV SC for 2 AEs: 1 or more injection site AEs (RR 1.53, 95% CI 1.12 to 2.09; RD 0.27, 95% CI 0.08 to 0.47; NNTH 3.7, 95% CI 2.1 to 12.5) and erythema (RR 2.49, 95% CI 1.59 to 3.89; RD 0.46, 95% CI 0.27 to 0.65; NNTH 2.2, 95% CI 1.5 to 3.7). There were no significant differences between groups for the following adverse events: pain, swelling, induration, pruritus, haematoma or anaesthesia or rash. 1/3 dose intradermal versus full‐dose subcutaneous There were significant differences in favour of full‐dose LZV SC for the following AEs: erythema (RR 1.95, 95% CI 1.20 to 3.18; RD 0.29, 95% CI 0.09 to 0.50; NNTH 3.4, 95% CI 2.0 to 11.1) and induration (RR 3.57, 95% CI 1.38 to 9.23; RD 0.25, 95% CI 0.07 to 0.42; NNTH 4.0, 95% CI 2.4 to 14.3). There was no significant difference between groups for the other adverse events. 1/10 dose intradermal versus full‐dose subcutaneous There was no significant difference between groups for any adverse events. 1/27 dose intradermal versus full‐dose subcutaneous Erythema (RR 1.72, 95% CI 1.03 to 2.88; RD 0.22, 95% CI 0.01 to 0.43; NNTH 4.5, 95% CI 2.30 to 100.0) and induration (RR 3.06, 95% CI 1.14 to 8.17; RD 0.20, 95% CI 0.03 to 0.37; NNTH 5.0, 95% CI 2.7.0 to 3.3). There was no significant difference between groups for the other adverse events. Full‐dose intradermal versus 1/3 dose subcutaneous There was a difference between the groups favourable to the subcutaneous 1/3 dose group, which had a significantly lower incidence of the following AEs:1 or more injection site adverse events (RR 3.86, 95% CI 1.95 to 7.63; RD 0.59, 95% CI 0.40 to 0.77; NNTH 1.7, 95% CI 1.3 to 2.5); erythema (RR 5.20, 95% CI 2.27 to 11.93; RD 0.62, 95% CI 0.43 to 0.80; NNTH 1.6, 95% CI 1.2 to 2.3); and induration (RR 6.00, 95% CI 1.45 to 24.81; RD 0.29, 95% CI 0.12 to 0.47; NNTH 3.4, 95% CI 2.1 to 8.3). There was no significant difference between groups for the other adverse events. 1/3 dose intradermal versus 1/3 dose subcutaneous There was no significant difference between groups for all adverse events reported. 1/10 dose intradermal versus 1/3 dose subcutaneous There were significant differences in favour of 1/3 dose SC for the following AEs: 1 or more injection site adverse events (RR 2.71, 95% CI 1.32 to 5.60; RD 0.35, 95% CI 0.14 to 0.57; NNTH 2.9, 95% CI 1.8 to 7.1); erythema (RR 3.20, 95% CI 1.32 to 7.75; RD 0.32, 95% CI 0.12 to 0.53; NNTH 3.1, 95% CI 1.9 to 8.3); and induration (RR 5.50, 95% CI 1.32 to 22.98; RD 0.26, 95% CI 0.09 to 0.44; NNTH 3.8, 95% CI 2.3 to 11.1). There was no significant difference between groups for the other adverse events. 1/27 dose intradermal versus 1/3 dose subcutaneous There were significant differences in favour of 1/3 dose SC for the following AEs: 1 or more injection site adverse events (RR 2.71, 95% CI 1.32 to 5.60; RD 0.35, 95% CI 0.14 to 0.57; NNTH 2.9, 95% CI 1.8 to 7.1); erythema (RR 3.60, 95% CI 1.51 to 8.59; RD 0.38, 95% CI 0.18 to 0.59; NNTH 2.6, 95% CI 1.7 to 5.6); and induration (RR 5.00, 95% CI 1.18 to 21.14; RD 0.24, 95% CI 0.06 to 0.41; NNTH 4.2, 95% CI 2.4 to 16.7). There was no significant difference between groups for the other adverse events. |
|
LZV versus pneumo‐23 vaccine (Berger 1998) |
1 study compared 3 different concentrations of plaque‐forming units (pfu) of live attenuated VZV and reported the following adverse events: 3200 pfu VZV/dose versus pneumo‐23 There was a lower incidence of 1 or more injection site reactions in the group vaccinated with the 3200 pfu/dose zoster vaccine (RR 0.61, 95% CI 0.41 to 0.91) as well as pain at the injection site (RR 0.49, 95% CI 0.30 to 0.81). There were no significant differences between the 3200 pfu/dose zoster vaccine and the pneumo‐23 vaccine for the following local adverse events: induration (≥ 2 cm diameter injection site), probably vaccine‐related injection site pain, redness (≥ 2 cm diameter injection site), pruritus or vesicles (no patients had vesicles in the 3200 pfu/dose zoster vaccine nor the pneumo‐23 groups). 8500 pfu VZV/dose versus pneumo‐23 There was a lower incidence of 1 or more injection site reaction in the group vaccinated with the 8500 pfu/dose zoster vaccine (RR 0.63, 95% CI 0.43 to 0.93). There were no significant differences for the following injection site adverse events between participants who received the 8500 pfu/dose VZV vaccine and those who received the pneumo‐23 vaccine: induration (≥ 2 cm diameter injection site), pain (injection site), probably vaccine‐related injection site pain, redness, pruritus and vesicles. 41,650 pfu VZV/dose VZV versus pneumo‐23 Participants receiving the 41,650 pfu/dose zoster vaccine had significantly lower rates of one or more injection site reaction (RR 0.41, 95% CI 0.24 to 0.68) and pain at injection site (RR 0.43, 95% CI 0.25 to 0.74) than those receiving the pneumo‐23 vaccine. There were no significant differences between the groups for the following injection site adverse events: induration (≥ 2 cm diameter injection site), probably vaccine‐related injection site pain, redness (≥ 2 cm diameter injection site), pruritus and vesicles (no patients had vesicles in the 41,650 pfu/dose zoster vaccine nor the pneumo‐23 vaccine groups). |
| LZV + IIV4 concomitant administration versus LZV + IIV4 sequential administration (Levin 2018) | There were no significant differences between groups for the following: death, serious adverse events, one or more adverse events, non injection‐site adverse events, non injection site vaccine‐related AE, injection‐site adverse events. There were no vaccine‐related adverse events. |
AE: adverse event or adverse experiences AMP: Alternative Manufacturing Process CI: confidence interval Elderly or older adults: aged ≥ 60 years old Frozen: −15 °C or colder gE: recombinant subunit VZV composed of glycoprotein E gE/saline: unadjuvanted gE Heat LZV: heat‐treated LZV HZ: herpes zoster ID: identification IIV4: inactivated quadrivalent influenza vaccines IM: intramuscular ISRs: injection site adverse reactions ITT: intention‐to‐treat LZV or ZV: live zoster vaccine (live attenuated Oka varicella zoster virus vaccine) MD: mean difference NNTB: number needed to treat for an additional beneficial outcome NNTH: number needed to treat for an additional harmful outcome pfu: plaque‐forming units pIMDs: potential immune‐mediated diseases pneumo‐23 vaccine: 23–valent pneumococcal polysaccharide vaccine RD: risk difference Refrigerated: 2 °C to 8 °C RR: risk ratio SAEs: serious adverse events SC: subcutaneously or subcutaneous VZV: varicella zoster virus