What substance was used in control group for shingrix trials

1. What the registrational trials actually used as the control: placebo in ZOE-50/70

The large, pivotal ZOE‑50 and ZOE‑70 phase 3 trials were explicitly run as randomized, observer‑blind, placebo‑controlled studies: subjects were randomized to receive two intramuscular injections of HZ/su (SHINGRIX) or placebo given two months apart, and the modified total vaccinated cohorts compared vaccine versus placebo outcomes ^{[1] [2] [3]}. Regulatory summaries, the product label, and peer‑reviewed reports all characterize these phase 3 trials as having placebo control arms used to calculate the >90% efficacy estimates reported in licensing documents ^{[6] [3] [7]}.

2. The nuance: adjuvant‑only comparators in earlier trials and regulator discussions

Not all clinical work used a simple saline placebo; the vaccine includes a proprietary adjuvant system, and early phase development and FDA review documents note comparisons against adjuvant‑only formulations to dissect the contribution of antigen versus adjuvant to immune responses and reactogenicity. The FDA clinical review explicitly discusses that an adjuvant (rather than another undefined comparator) was considered for control in Phase 2 dose‑finding evaluations, reflecting typical developer practice to test antigen+adjuvant versus adjuvant alone in early immunogenicity studies ^[4]. Those adjuvant‑only arms are used to understand mechanism and safety profiles, but they are distinct from the placebo arms used in the pivotal efficacy trials ^{[4] [1]}.

3. Why long‑term follow‑up didn’t have a contemporary unvaccinated control

After the randomized trials completed, placebo recipients were offered SHINGRIX vaccination, so the long‑term follow‑up (ZOE‑LTFU) could not retain an unvaccinated placebo group; investigators therefore used a historical control constructed from the original ZOE‑50/70 placebo data to estimate long‑term vaccine efficacy ^{[5] [2]}. Company and investigator documents explicitly warn about limitations of such historical controls and cite FDA guidance on choice of control groups when contemporary unvaccinated cohorts are not available ^[5].

4. Why this matters: interpreting efficacy and safety signals

Using a true placebo control in the phase 3 trials gives clear randomized efficacy comparisons and underpins the high efficacy figures quoted in regulatory and peer‑reviewed sources ^{[3] [8]}. However, adjuvant‑only comparators in early phases help parse reactogenicity and immunologic drivers, and reliance on historical placebo data for long‑term efficacy introduces methodologic caveats — openly acknowledged in GSK materials and the LTFU reporting ^{[2] [5]}. Regulatory product information and the FDA package insert aggregate safety data from the placebo‑controlled studies when reporting adverse event frequencies, reflecting the central role of those randomized placebo arms in the evidence base ^{[6] [8]}.

5. Bottom line for readers and investigators

The direct answer is that the registrational ZOE‑50 and ZOE‑70 trials used placebo control arms for efficacy and safety comparisons; earlier phase work sometimes used adjuvant‑only comparators for mechanistic purposes, and long‑term follow‑up analyses used historical placebo data because the original placebo recipients were subsequently vaccinated ^{[1] [4] [5]}. Where the literature or regulatory files discuss adjuvant‑only arms, that refers to different, earlier study objectives and does not contradict that the pivotal efficacy trials were placebo‑controlled ^{[4] [3]}.