ACIP Evidence to Recommendations (EtR) Framework: High-Dose and Adjuvanted Influenza Vaccines for Solid Organ Transplant Recipients

Question: Should high-dose inactivated, adjuvanted inactivated, and/or recombinant influenza vaccines be recommended as an option for influenza vaccination of solid organ transplant recipients who are younger than the approved age indication?

Population: Solid organ transplant recipients aged ≥6 months

Interventions: High-dose (HD-IIV) (including use of multiple doses of standard-dose inactivated influenza vaccines[SD-IIVs]), MF59-djuvanted (aIIV), or recombinant (RIV) trivalent or quadrivalent influenza vaccines

Comparisons: Single intramuscular dose of trivalent or quadrivalent unadjuvanted standard dose influenza vaccines

Outcomes:

Benefits:

Medically-attended influenza (Critical)
Influenza-associated hospitalization (Critical)
Laboratory-confirmed influenza—immunogenicity data acceptable (Important)

Harms:

Transplant rejection or graft failure (Critical)
Neuroinflammatory conditions , e.g. GBS, ADEM (Critical)
Other immune-related adverse events, including new onset or exacerbation of an autoimmune condition (Critical)

Background: Solid organ transplant recipients generally require lifelong immunosuppressive medications in order to maintain graft function, and are potentially at increased risk of severe and complicated influenza illness (1, 2). Higher-dose and adjuvanted influenza vaccine strategies have been studied in this population as interventions which might promote a stronger immune response (3-9). The American Society for Transplantation (AST) states that high-dose or boosted influenza vaccine dosing might be preferable post-transplant (10). However, currently available high-dose and adjuvanted inactivated influenza vaccines are approved only for persons aged ≥65 years in the United States (11, 12).

Public Health Importance

Problem
Criteria	Work Group Judgements	Evidence	Additional Information
Is the problem of public health importance?	Yes	An estimated 430,000 solid organ transplant recipients were living in the United States in 2020 (13). In a 5-year cohort of 477 SOT recipients with influenza (2): 21% had lower respiratory tract disease on presentation. 69% were hospitalized. 11% admitted to an intensive care unit. 8% required mechanical ventilation. 3% died (all-causes) within 30 days

Benefits and Harms

Benefits and Harms
Criteria	Work Group Judgements	Evidence	Additional Information
How substantial are the desirable anticipated effects?	Don't Know	Only one study reported influenza-associated hospitalizations, with no difference in risk reported for either HD-IIV or aIIV vs SD-IIV. No studies reported medically-attended influenza illness. There was evidence of better likelihood of seroconversion for both HD-IIV and aIIV vs SD-IIV.	Lesser proportions of WG members indicated “Small” or “Moderate”.
How substantial are the undesirable anticipated effects?	Minimal	No studies reported neuroinflammatory or other immune mediated adverse events, There was no evidence of difference in risk for graft rejection with either HD-IIV or aIIV vs SD-IIV.	Lesser proportions of WG members indicated “Small” and “Don't Know”.
Do desirable effects outweigh undesirable effects?	Favors Intervention		Lesser proportions of WG members indicated “Don't Know”, “Favors Both”, and “Favors Neither”.
What is the overall certainty of the evidence of effects?	Overall GRADE Evidence Certainty: Benefits: Low Harms: Moderate

Values

Values
Criteria	Work Group Judgements	Evidence	Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects?	Probably Yes	No direct evidence was identified reflecting values or preferences for specific influenza vaccine types among SOT recipients. There might be a healthcare provider preference for HD-IIV, evidenced by the recommendations of the American Society for Transplantation (10).	Lesser proportions of WG members indicated"Yes," “Don’t Know” and “Varies”.
Is there important uncertainty about or variability in how much people value the main outcomes?	Probably Not Important Uncertainty or Variability		Lesser proportions of WG members indicated “Probably Important Uncertainty or Variability”, “No Important Uncertainty or Variability”, or “Important Uncertainty or Variability”.

Acceptability

Acceptability
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention acceptable to key stakeholders?	Probably Yes	Acceptability of a recommendation for high-dose vaccine is possibly evidenced by preference expressed by AST for high-dose vaccine (10). Acceptability might be limited among healthcare and public health systems and insurers by need for changes in standing orders, immunization information systems, and electronic medical record platforms	Lesser proportions of WG members indicated “Yes” and “Varies”.

Resource Use

Resource Use
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention a reasonable and efficient allocation of resources?	Probably Yes	HD-IIV3 and aIIV3 are more costly (2023-24: $73-77) than unadjuvanted influenza vaccines (2023-24: $21-34) (14).	Lesser proportions of WG members indicated “Don’t Know” and “Yes”. No economic analysis was performed for this review given: Relatively small size of population (estimated approximately 430,000 as of 2020) (13); Insufficient data concerning relative effectiveness of influenza vaccines in SOT populations; Insufficient data indicating extent to which use of these vaccines is already occurring among off-label age group SOT recipients.

Equity

Equity
Criteria	Work Group Judgements	Evidence	Additional Information
What would be the impact on health equity?	Probably increased	No direct evidence was identified. A WG member noted other potential barriers for SOT recipients: SOT recipients face barriers to receiving newer influenza vaccines as they are usually excluded from clinical trials, and there are few data for this population Transplant programs with greater financial resources might be able to purchase vaccines for their patients, whereas those less well-resourced might not	Lesser proportions of WG members indicated “Probably Reduced”, “Don’t Know”, "Increased", or “Probably No Impact”. While no literature was found specific to use of enhanced influenza vaccines among transplant recipients, among Medicare beneficiaries aged ≥65 years in a single-season (2015-16), Black, Asian, and Hispanic persons were 26% to 32% less likely to receive HD-IIV3 than White persons.

Feasibility

Feasibility
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention feasible to implement?	Probably Yes	No direct evidence was identified. A new recommendation might improve access, if HD-IIV and aIIV are more likely to be covered by insurance. The vaccines of interest are already readily available in office and retail settings. Use of these vaccines in a new age group might require changes in standing orders, Electronic Medical Record programming, and immunization information systems.	A lesser proportion of WG members indicated “yes”.

Balance of Consequences:

The majority of the Work Group members responded that desirable consequences probably outweigh undesirable consequences in most settings. A smaller proportion responded that there is insufficient evidence, that desirable consequences clearly outweigh undesirable consequences in most settings, or that the evidence is closely balanced or uncertain.

Work Group Judgement of Sufficiency of Information:

The Work Group feels there is sufficient evidence to move forward with a recommendation.

ACIP Recommendation:

ACIP recommends high-dose inactivated (HD-IIV3) and adjuvanted inactivated (aIIV3) influenza vaccines as acceptable options for influenza vaccination of solid organ transplant recipients aged 18 through 64 years who are receiving immunosuppressive medication regimens, without a preference over other age-appropriate IIV3s or RIV3.

References

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.
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.
Mombelli M, Neofytos D, Huynh-Do U, Sanchez-Cespedes J, Stampf S, Golshayan D, et al. Immunogenicity of High-Dose Versus MF59-Adjuvanted Versus Standard Influenza Vaccine in Solid Organ Transplant Recipients: The Swiss/Spanish Trial in Solid Organ Transplantation on Prevention of Influenza (STOP-FLU Trial). Clin Infect Dis. 2024 Jan 25;78(1):48-56.
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.
Natori Y, Shiotsuka M, Slomovic J, Hoschler K, Ferreira V, Ashton P, et al. A Double-Blind, Randomized Trial of High-Dose vs Standard-Dose Influenza Vaccine in Adult Solid-Organ Transplant Recipients. Clin Infect Dis. 2018 May 17;66(11):1698-704.
Kumar D, Campbell P, Hoschler K, Hidalgo L, Al-Dabbagh M, Wilson L, Humar A. Randomized Controlled Trial of Adjuvanted Versus Nonadjuvanted Influenza Vaccine in Kidney Transplant Recipients. Transplantation. 2016 Mar;100(3):662-9.
Magnani G, Falchetti E, Pollini G, Reggiani LB, Grigioni F, Coccolo F, et al. Safety and efficacy of two types of influenza vaccination in heart transplant recipients: a prospective randomised controlled study. J Heart Lung Transplant. 2005 May;24(5):588-92.
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.
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.
Danziger-Isakov L, Kumar D, et al. 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.
Fluzone High-Dose [Package Insert]. Swiftwater, PA: Sanofi Pasteur; 2024.
Fluad [Package Insert]. Holly Springs, NC: Seqirus; 2024.
Organ Procurment and Transplantation Network/Scientific Registry of Transplant Reicipients (OPTN/SRTR). 2020 Annual Data Report.
Centers for Medicare and Medicaid Services. Influenza vaccine pricing, 2023-24.

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