Concentrations, Number of Doses, and Formulations of Aluminium Adjuvants in Vaccines: A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Randomized Clinical Trials

Abstract

Aluminium adjuvants are commonly used in vaccines to boost the effects of vaccination. Here, we assessed the benefits and harms of different aluminium adjuvants vs. other aluminium adjuvants or vs. the same aluminium adjuvant at other concentrations, administered a different number of doses, or at different particle sizes used in vaccines or vaccine excipients. We conducted a systematic review with meta-analysis and Trial Sequential Analysis to assess the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). We obtained data from major medical databases until 20 January 2023 and included 10 randomized clinical trials of healthy volunteers. The comparisons assessed higher vs. lower aluminium adjuvant concentrations; higher vs. lower number of doses of aluminium adjuvant; and aluminium phosphate adjuvant vs. aluminium hydroxide adjuvant. For all three comparisons, meta-analyses showed no evidence of a difference on all-cause mortality, serious adverse events, and adverse events considered non-serious. The certainty of evidence was low to very low. None of the included trials reported on quality of life or proportion of participants who developed the disease being vaccinated against. The benefits and harms of different types of aluminium adjuvants, different aluminium concentrations, different number of doses, or different particle sizes, therefore, remain uncertain.

Keywords: aluminium adjuvants; aluminium hydroxide; aluminium phosphate; evidence; meta-analysis; randomized clinical trials; systematic review; trial sequential analysis; vaccines.

Figure 1

Meta-analysis of the effect of higher vs. lower concentration of aluminium adjuvant on the proportion of participants with one or more serious adverse events [34,38,39].

Figure 2

Meta-analysis of the effect of higher vs. lower concentrations of aluminium adjuvant on the proportion of participants with one or more adverse events not considered serious [31,33,34,38,39].

Figure 3

Trial Sequential Analysis of the effect of higher vs. lower concentrations of aluminium adjuvant on the proportion of participants with one or more adverse events not considered serious. We used an alpha of 3.3%, a power of 90%, control event proportion of 86.8%, diversity of 30.4%, and RRR of 20%. The relative risk was 1.01 with a TSA adjusted CI of 0.92 to 1.12.