Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Higher-Dose and Adjuvanted Influenza Vaccines for Solid Organ Transplant Recipients

Background: The number of solid organ transplants (SOTs) performed each year in the United States has increased steadily over the last two decades, from 25,475 in 2003 to 46,630 in 2023.  The most commonly transplanted organs are kidney (59% in 2023), followed by liver (23%), heart (10%), lung (6%), and dual kidney/pancreas (2%) (1).  The majority of transplants are performed among adults ages 18 through 64 years (72% in 2023), with a lesser proportion in adults aged ≥65 years (24%) and children aged <18 years (4%) (1). SOT recipients generally require lifelong immunosuppressive medications to maintain viability of the grafted organ. This population has been shown in some studies to be at potentially increased risk of severe and complicated influenza illness (2, 3).

SOT recipients aged ≥6 months are recommended to receive routine annual influenza vaccination with an age-appropriate inactivated or recombinant vaccine (4).  Given their potential increased susceptibility to severe influenza, higher antigen dose vaccination strategies and adjuvanted influenza vaccines have been studied in this population.  Moreover, the American Society for Transplantation (ATS) has stated that either high-dose or booster influenza vaccination strategies might be preferable for this population (5).  However, high-dose influenza vaccine and adjuvanted influenza vaccine are approved in the United States only for persons aged ≥65 years; administration to persons aged <65 years might not be covered by insurance.

The purpose of this review was to determine whether there is adequate evidence to support a recommendation that higher dose and adjuvanted influenza vaccines are acceptable options for influenza vaccination of solid organ transplant recipients who are younger than the approved age for these vaccines.

Methods

A systematic literature search was conducted to identify and review published literature relevant to the efficacy, effectiveness and safety of HD-IIV, aIIV, and RIV, and other increased antigen dose strategies (e.g., double doses of standard -dose vaccine administered simultaneously) compared with unadjuvanted SD-IIVs and with one another among immunocompromised persons. Literature search strategies are summarized in Appendix 2. Following screening of literature for eligibility, papers describing data for solid organ transplant populations were identified.  Randomized and observational studies (traditional and test-negative case-control, retrospective and prospective cohort designs) were included.  Case reports and case series were excluded. Risk of bias was assessed with the Cochrane Risk of Bias version 2 tool for randomized studies (6) and the tool proposed by Murad et al. for nonrandomized studies without comparison groups (7).  Meta-analyses were performed using R (8).  Given the small number of available studies for each comparison, meta-analyses were performed using a fixed-effects (or common effects) model.  Risk ratios were calculated using the Mantel-Haenzel exact method; if both arms had zero events, the study was excluded from the meta-analysis model. GRADE tables were compiled using GRADEPro (9).

Table 1: Policy Question and PICO

Table 2: Outcomes and Rankings

Table 3: Summary of Studies Reporting Outcomes of Interest

Table 3b: Summary of Studies Reporting Medically-Attended Influenza Illness (Critical)
No studies reported this outcome.

Table 3e: Summary of Studies Reporting Neuroinflammatory Adverse Events (Critical)
No studies reported this outcome.

Table 3f: Summary of Studies Reporting Other Immune-Mediated Adverse Events (Critical)
No studies reported this outcome.

Table 4 GRADE Summary of Findings Tables

Table 5: Summary of Evidence for Outcomes of Interest

Appendix 1. Studies Included in the Review of Evidence

Appendix 2. Databases and strategies used for systematic review

References

1. Health Resources and Services Administration (HRSA) Organ Procurement and Transplant Network (OPTN). National Data. Available at:https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/. Acceswsed June 10, 2024. .
2. Mombelli M, Kampouri E, Manuel O. Influenza in solid organ transplant recipients: epidemiology, management, and outcomes. Expert Rev Anti Infect Ther. 2020 Feb;18(2):103-12.
3. Kumar D, Ferreira VH, Blumberg E, Silveira F, Cordero E, Perez-Romero P, et al. A 5-Year Prospective Multicenter Evaluation of Influenza Infection in Transplant Recipients. Clin Infect Dis. 2018 Oct 15;67(9):1322-9.
4. Grohskopf LA, Blanton LH, Ferdinands JM, Chung JR, Broder KR, Talbot HK. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices – United States, 2023-24 Influenza Season. MMWR Recomm Rep. 2023;72(2):1-25.
5. Danziger-Isakov L, Kumar D, Practice AICo. Vaccination of solid organ transplant candidates and recipients: Guidelines from the American society of transplantation infectious diseases community of practice. Clin Transplant. 2019 Sep;33(9):e13563.
6. Sterne JAC, Savovic J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug 28;366:l4898.
7. Murad MH, Sultan S, Haffar S, Bazerbachi F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med. 2018 Apr;23(2):60-3.
8. R Core Team (2023). _R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. <https://www.R-project.org/>.
9. GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University and Evidence Prime, 2024. Available from gradepro.org.
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11. Mombelli M, Rettby N, Perreau M, Pascual M, Pantaleo G, Manuel O. Immunogenicity and safety of double versus standard dose of the seasonal influenza vaccine in solid-organ transplant recipients: A randomized controlled trial. Vaccine. 2018 Oct 1;36(41):6163-9.
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14. Pollok M, Geiger H, Floege J, Paschke R, Abendroth D, Bienzle U, et al. Increased immunogenicity with an MF59-adjuvanted influenza vaccine (FLUAD(R)) compared with a conventional subunit vaccine (Agrippal(R)) in renal transplant recipients. International Congress Series. 2004;1263:453-6.
15. Odongo FCA, Braga PE, Palacios R, Miraglia JL, Sartori AMC, Ibrahim KY, et al. An Open-label Randomized Controlled Parallel-group Pilot Study Comparing the Immunogenicity of a Standard-, Double-, and Booster-dose Regimens of the 2014 Seasonal Trivalent Inactivated Influenza Vaccine in Kidney Transplant Recipients. Transplantation. 2022 Jan 1;106(1):210-20.
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