Comparing trivalent and quadrivalent seasonal influenza vaccine efficacy in persons 60 years of age and older: A systematic review and network meta-analysis

ABSTRACT Objectives To compare the efficacy of influenza vaccines of any valency for adults 60 years and older. Methods Design Systematic review with network meta-analysis (NMA) Information sources MEDLINE, EMBASE, JBI Evidence-Based Practice (EBP) Database, PsycINFO, and Cochrane Evidence Based Medicine database from inception to June 20, 2022. Eligibility criteria Randomized controlled trials (RCTs) including older adults (≥60 years old) receiving an influenza vaccine licensed in Canada or the United States (versus placebo, no vaccine, or any other licensed vaccine), at any dose. Outcome measures Primary outcomes: Laboratory-confirmed influenza (LCI) and influenza-like illness (ILI). Secondary outcomes: number of vascular adverse events, hospitalization for acute respiratory infection (ARI) and ILI, inpatient hospitalization, emergency room (ER) visit for ILI, outpatient visit, and mortality, among others. Data extraction, risk of bias (ROB), and certainty of evidence assessment Two reviewers screened, abstracted, and appraised articles (Cochrane ROB 2 tool) independently. We assessed certainty of findings using CINeMA and GRADE approaches. Data synthesis We performed random-effects meta-analysis and NMA, and estimated odds ratios (ORs) for dichotomous outcomes and incidence rate ratios (IRRs) for count outcomes along with corresponding 95% confidence intervals (95%CI) and prediction intervals. Results We included 41 RCTs and 15 companion reports comprising eight vaccine types and 206,032 participants. Vaccines prevented LCI compared with placebo, with high-dose trivalent (IIV3-HD) (NMA, nine RCTs, 52,202 participants, OR 0.23, 95%CI [0.11 to 0.51], low certainty of evidence) and RIV (OR 0.25, 95%CI [0.08 to 0.73], low certainty of evidence) among the most efficacious vaccines. Standard dose trivalent inactivated influenza vaccine (IIV3-SD) prevented ILI compared with placebo, but the result was imprecise (meta-analysis, two RCTs, 854 participants, OR 0.39, 95%CI [0.15 to 1.02], low certainty of evidence). Any high dose (HD) prevented ILI compared with placebo (NMA, nine RCTs, 65,658 participants, OR 0.38, 95%CI [0.15 to 0.93]). Adjuvanted quadrivalent inactivated influenza vaccine (IIV4-Adj) was associated with the least vascular adverse events (NMA: eight RCTs, 57,677 participants, IRR 0.18, 95%CI [0.07 to 0.43], very low certainty of evidence). RIV on all-cause mortality was comparable to placebo (NMA: 20 RCTs, 140,577 participants, OR 1.01, 95%CI [0.23 to 4.49], low certainty of evidence). Conclusions This systematic review demonstrated high efficacy associated with IIV3-HD and RIV vaccines in protecting elderly persons against LCI, and RIV vaccine minimizing all-cause mortality when compared with other vaccines. However, differences in efficacy between these vaccines remain uncertain with very low to moderate certainty of evidence. Funding Canadian Institutes of Health Research Drug Safety and Effectiveness Network (No. DMC – 166263) Systematic review registration PROSPERO CRD42020177357 SUMMARY BOX What is already known on this topic Seasonal influenza vaccination of older adults (≥60 years old) is an important societal, cost-effective means of reducing morbidity and mortality. A multitude of licensed seasonal influenza vaccines for older adults are available in a variety of formulations (such as IIV3, IIV4; prepared in standard and high doses; with and without an adjuvant) relying on production methods including those based on embryonated chicken eggs, or mammalian cell cultures and comprising seasonally selected viral strains or recombinant constructs. Lack of high-quality analysis of randomized control trial (RCT) data pertaining to influenza vaccine production and composition poses challenges for public health clinicians and policy makers who are tasked with making evidence-based decisions regarding recommendations about choosing optimally efficacious and safe influenza vaccines for older adults. What this study adds This systematic review and network meta-analysis of RCT data found that recombinant influenza vaccines (RIV) are among the most effective (lowest odds of laboratory-confirmed influenza [LCI]) and safest (lowest odds of all-cause mortality) of any licensed influenza vaccine type administered to older adults. How this study might affect research, practice or policy Our review points to a potential safety concern regarding increased odds of all-cause mortality associated with older adults receiving adjuvanted influenza vaccines (IIV3-adj and IIV4-adj).