Evidence for off-target effects of live Shingles vaccination against all-cause death and infection-associated hospitalisation in older adults in England: a population-based cohort study

Background: Off-target, heterologous, or non-specific live vaccine effects have been described in paediatric populations. We investigated whether off-target effects are observed in older adults with live shingles (Zostavax) immunisation. Methods: A population-based cohort study was performed using primary- and secondary-care data from the Clinical Practice Research Datalink in England. Vaccine eligible individuals aged 70 years and over who had received pneumococcal immunisation were studied. All-cause death, all-cause hospitalisation, and infection-associated hospitalisation rates were compared between vaccinated and unvaccinated groups using time-to-first-event Cox regression and a time-varying coefficient model, while adjusting for confounding. Findings: Between September 2013 and June 2019 375 048 participants aged 70 years and over were identified, of which 56% had live shingles vaccine exposure. All-cause death rate was 18.9 per 1000 person-years, all-cause hospitalisation rate was 214 per 1000 person-years, and infection-associated hospitalisation rate was 48.4 per 1000 person-years. Live shingles vaccine exposure was associated with a reduction in all-cause death (adjusted hazard ratio 0.68; 95% confidence interval 0.67, 0.70) and infection-associated hospitalisation (adjusted hazard ratio 0.83; 95% confidence interval 0.81, 0.84). Protective vaccine effects were observed for at least five years post-immunisation. No protective vaccine effect was observed against all-cause hospitalisation. Interpretations: Receipt of live shingles vaccine associates with lower mortality and morbidity in older adults in England. The potential for causal linkage should be validated in robust prospective studies, with major implications for national immunisation policies. Funding: No specific funding for this project. KD was supported by an NIHR academic clinical fellowship.