Infectious Disease · Medical Literature
Effect of high-dose versus standard-dose influenza vaccines on hospitalisation outcomes and mortality in older adults: a systematic review and meta-analysis.
Abstract
The comparative efficacy and safety of high-dose inactivated influenza vaccine (HD-IIV) versus standard-dose inactivated influenza vaccine (SD-IIV) in adults 65 years or older remain uncertain. Hence, we aimed to compare the effects of HD-IIV versus those of SD-IIV for hospitalisation and mortality outcomes in this population by synthesising evidence from randomised controlled trials (RCTs). In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Global Health, and ClinicalTrials.gov from inception to Sept 3, 2025, for randomised trials comparing HD-IIV (60 μg of haemagglutinin per strain) with SD-IIV (15 μg of haemagglutinin per strain) in adults aged 65 years or older. We excluded trials of adjuvanted or recombinant vaccines and those conducted during the 2009-10 H1N1 pandemic because the antigenic profile differed from seasonal strains. Pairs of reviewers independently screened studies and extracted aggregate data from eligible reports. Prespecified primary outcomes were hospitalisation for influenza or pneumonia, hospitalisation for influenza, hospitalisation for pneumonia, hospitalisation for laboratory-confirmed influenza, hospitalisation for cardiorespiratory disease, all-cause hospitalisation, and all-cause mortality; serious adverse events (SAEs) were the secondary outcome. We did random-effects meta-analyses and used risk ratio (RR) estimates and baseline risks to calculate absolute risk differences (ie, the difference in absolute number of events per 10 000 vaccinated individuals between SD-IIV and HD-IIV groups) for each outcome. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool, and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation framework. The protocol was registered with the OSF Registry. A total of 1422 records were identified. After screening 813 titles and abstracts, from which 84 full texts were assessed for eligibility, 14 unique RCTs with 581 845 participants were eligible and included in the analyses. Of the 49 outcome results assessed, 32 were rated as low risk of bias and 17 as having some concerns. Compared with SD-IIV, HD-IIV reduced hospitalisation for influenza (RR 0·61 [95% CI 0·50-0·74]; I2=0%; absolute risk difference -4 events per 10 000 vaccinated individuals [95% CI -5 to -3]; high certainty), hospitalisation for laboratory-confirmed influenza (RR 0·68 [0·58-0·80]; I2=0%; absolute risk difference -4 events per 10 000 vaccinated individuals [-5 to -3]; high certainty), hospitalisation for cardiorespiratory disease (RR 0·92 [0·86-0·98]; I2=5·9%; absolute risk difference -15 events per 10 000 vaccinated individuals [-26 to -4]; high certainty), and all-cause hospitalisation (RR 0·97 [0·95-0·99]; I2=8·7%; absolute risk difference -29 events per 10 000 vaccinated individuals [-48 to -10]; high certainty). There was probably little or no difference between the effects of HD-IIV and SD-IIV on all-cause mortality (RR 0·98 [0·92-1·05]; I2=0·0%; absolute risk difference -1 event per 10 000 vaccinated individuals [-4 to 3]; moderate certainty). Compared with SD-IIV, HD-IIV might have little or no effect on hospitalisation for influenza or pneumonia (RR 0·83 [0·66-1·03]; I2=71·3%; absolute risk difference -7 events per 10 000 vaccinated individuals [-14 to 1]; low certainty), hospitalisation for pneumonia (RR 0·85 [0·66-1·08]; I2=72·0%; absolute risk difference -9 events per 10 000 vaccinated individuals [-21 to 5]; low certainty), or SAEs (RR 0·97 [0·93-1·01]; I2=16·4%; absolute risk difference -18 events per 10 000 vaccinated individuals [-41 to 6]; low certainty). HD-IIV could be considered as a strategy to reduce hospitalisation burden in adults 65 years or older; however, the evidence does not support routine preferential use across all older adults irrespective of context. Absolute benefits were modest on average, and the value of HD-IIV is likely to depend on baseline risk, health-care context, and implementation considerations. National Natural Science Foundation of China Youth Science Fund and Shandong Provincial Natural Science Foundation Youth Science Fund.
Clinical relevance
Older adults (≥65 years) bear a disproportionate burden of influenza-related hospitalisation and mortality, yet the optimal inactivated influenza vaccine formulation for this population has remained uncertain. This high-certainty systematic review and meta-analysis of 14 RCTs enrolling 581,845 participants directly compares high-dose (HD-IIV, 60 µg haemagglutinin/strain) versus standard-dose (SD-IIV, 15 µg haemagglutinin/strain) inactivated influenza vaccines on clinically meaningful endpoints. The findings arrive at a moment when many national immunisation programmes are reconsidering preferential vaccine recommendations for older adults, making this evidence immediately actionable for infectious disease specialists, geriatricians, and public health policymakers.
Key findings
1. HD-IIV significantly reduced hospitalisation for influenza compared with SD-IIV (RR 0.61 [95% CI 0.50–0.74]; I²=0%; absolute risk difference [ARD] −4 events per 10,000 vaccinated; high certainty), representing a 39% relative risk reduction. 2. HD-IIV significantly reduced hospitalisation for laboratory-confirmed influenza (RR 0.68 [95% CI 0.58–0.80]; I²=0%; ARD −4 events per 10,000 vaccinated; high certainty), a 32% relative risk reduction with no heterogeneity. 3. HD-IIV significantly reduced hospitalisation for cardiorespiratory disease (RR 0.92 [95% CI 0.86–0.98]; I²=5.9%; ARD −15 events per 10,000 vaccinated [95% CI −26 to −4]; high certainty). 4. HD-IIV significantly reduced all-cause hospitalisation (RR 0.97 [95% CI 0.95–0.99]; I²=8.7%; ARD −29 events per 10,000 vaccinated [95% CI −48 to −10]; high certainty), the largest absolute benefit observed across all outcomes. 5. There was probably little or no difference in all-cause mortality between HD-IIV and SD-IIV (RR 0.98 [95% CI 0.92–1.05]; I²=0%; ARD −1 event per 10,000 vaccinated [95% CI −4 to 3]; moderate certainty). 6. HD-IIV showed little or no effect on combined hospitalisation for influenza or pneumonia (RR 0.83 [95% CI 0.66–1.03]; I²=71.3%; ARD −7 events per 10,000; low certainty), hospitalisation for pneumonia alone (RR 0.85 [95% CI 0.66–1.08]; I²=72.0%; ARD −9 events per 10,000; low certainty), or serious adverse events (RR 0.97 [95% CI 0.93–1.01]; I²=16.4%; ARD −18 events per 10,000; low certainty), with high heterogeneity and wide confidence intervals precluding firm conclusions for these endpoints.
Practice implications
Clinicians should consider preferentially offering HD-IIV (60 µg haemagglutinin/strain) over SD-IIV to adults aged ≥65 years who are at elevated baseline risk of influenza-related cardiorespiratory hospitalisation — such as those with chronic cardiopulmonary disease, immunosenescence, or frequent healthcare utilisation — where even modest absolute risk reductions (ARD −15 to −29 events per 10,000 vaccinated) translate into meaningful population-level benefit. Routine blanket preferential use of HD-IIV across all older adults irrespective of context is not supported by the current evidence, as absolute benefits are modest on average and the marginal benefit is likely modulated by individual baseline risk, local influenza strain characteristics, and health system capacity. The absence of a significant mortality benefit and the low-certainty evidence for pneumonia outcomes underscore the importance of complementary strategies — including pneumococcal vaccination, antiviral prophylaxis protocols, and early treatment pathways — alongside optimised influenza vaccine formulation selection.