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Influenza Vaccine Update - Episode II, Adults are People Too

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Grant Paulsen, MD
Cincinnati Children's Hospital Medical Center
Cincinnati, OH, USA

Very little in life is ever simple or clear-cut; that is doubly true when discussing vaccines and transplant patients. Upon further review, there may be benefit to discussing some of the specific options available for influenza vaccination in adults.

The FDA currently has 21 different influenza vaccines licensed for distribution in the US [1]. That's a bit much to keep up with, even for an Infectious Disease physician, not to mention someone that doesn't spend all of their waking hours trying to keep track of the differences in flu vaccine between manufacturers. The goal here is to focus on a few key points and try to simplify that list of twenty-one vaccines a bit.

First, for our purposes, we can quietly set aside discussion of the live attenuated influenza vaccines, which takes us down to 19. We can also remove the monovalent vaccines and those in the National Stockpile, as their clinical niche is fairly small. That leaves us with twelve. Nine of the remaining are trivalent vaccines and three are quadrivalent inactivated influenza vaccines (IIV). The quadrivalent vaccines add an additional strain of influenza B, without interfering with the response to the other three antigens/strains [2].

Of the nine remaining trivalent vaccines, one is high dose (see below), one is an adjuvant containing vaccine (see below, again), two are intended for those with true anaphylaxis to egg protein (cell culture-based and recombinant) and the rest are standard dose preparations. There are no recommendations stating a preference for vaccine formulation or individual vaccine as long as the vaccine is licensed for the appropriate group. A detailed table is available from the CDC at: http://www.cdc.gov/flu/protect/vaccine/vaccines.htm.

The high dose (HD) influenza vaccine contains four times the amount of hemagglutinin as the standard-dose (SD). A randomized trial comparing high dose to standard dose in 31,989 adults, 65 years or older, found significantly higher responses and better protection with the high-dose vaccine [3]. Supplementary analysis demonstrated similar efficacy for those with at least one high-risk condition, including immune compromising conditions [4]. Studies in adult stem cell transplant recipients [5] and pediatric solid organ transplant patients [6] are encouraging with some increased responsiveness to the HD vaccine in these populations. Both studies did report an increase in local reactions in the HD versus the SD groups.

The first US seasonal flu vaccine containing an adjuvant (aIIV), under the brand name Fluad® (Novartis), was approved by the FDA on Nov 24, 2015 for persons 65 years of age and older [7]. This vaccine was first approved in Italy in 1997 and is now approved in 39 countries. In a multicenter trial of 7,082 participants age 65 and older, the aIIV was found to be non-inferior to the comparator (non-adjuvant IIV), elicited significantly higher antibody responses at day 22, but did not meet criteria for superiority [8]. Of note, patients with impaired/altered immune function were excluded from this trial.

The adjuvant (MF59®) is an oil-in-water emulsion of squalene oil that appears to enhance the immune response to antigens [9]. As discussed previously, there have been concerns regarding development of HLA alloantibodies and rejection following the 2009 adjuvanted pandemic (H1N1) flu vaccine [10-13]. The adjuvant used in those reports was the AS03® adjuvant with tocopherol, polysorbate 80 and squalene; different in that MF59® does not contain tocopherol. A randomized trial in 60 adult kidney transplant (KT) recipients reported similar overall immunogenicity, with significantly greater seroconversion in those 18 to 64 years old, and no increase in HLA alloantibodies in those who received the MF59® adjuvanted vaccine [14]. An earlier prospective study of 58 heart transplant patients, 21 given MF59® adjuvanted flu vaccine versus non-adjuvanted IIV reported equivalent effect and no increased risk of acute myocardial rejection [15] . Additional studies of MF59®, largely in renal transplant patients have also reported no increased risk of rejection/graft dysfunction [16-18].

In summary, despite the somewhat confusing array of available influenza vaccines, vaccination is still recommended for all organ transplant recipients. There are no indications that the high dose vaccine is unsafe for organ transplant recipients, and it may provide increased protection in those 65 years and older. The adjuvanted influenza vaccine shows promise and the available data are encouraging, for this recently FDA approved flu vaccine. For North America, the 2015-16 influenza season is not yet over, and it is not too late to vaccinate against the flu. In addition, based on CDC reports to date, this year's vaccine appears to be a very good match with the circulating strains. ■

Disclosure Statement: The author has no conflicts of interest to disclose.


  1. FDA. Complete List of Vaccines Licensed for Immunization and Distribution in the US. 12/03/2015]; Available from: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm.
  2. Kieninger, D., et al., Immunogenicity, reactogenicity and safety of an inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine: a phase III, randomized trial in adults aged >/=18 years. BMC Infect Dis, 2013. 13: p. 343.
  3. DiazGranados, C.A., et al., Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med, 2014. 371(7): p. 635-45.
  4. DiazGranados, C.A., et al., Efficacy and immunogenicity of high-dose influenza vaccine in older adults by age, comorbidities, and frailty. Vaccine, 2015. 33(36): p. 4565-71.
  5. Halasa, N.B., et al., Randomized, Double Blind, Study of the safety and Immunogenicity of Standard-Dose Trivalent Inactivated Influenza Vaccine versus High-Dose Trivalent Inactivated Influenza Vaccine in Adult Hematopoietic Stem Cell Transplant Patients. Biol Blood Marrow Transplant, 2015.
  6. GiaQuinta, S., et al., Randomized, double-blind comparison of standard-dose vs. high-dose trivalent inactivated influenza vaccine in pediatric solid organ transplant patients. Pediatr Transplant, 2015. 19(2): p. 219-28.
  7. FDA. FDA approves first seasonal influenza vaccine containing an adjuvant. 2015 [cited 2015 Nov 24]; News Release]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm474295.htm.
  8. Frey, S.E., et al., Comparison of the safety and immunogenicity of an MF59(R)-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Vaccine, 2014. 32(39): p. 5027-34.
  9. Banzhoff, A., et al., MF59-adjuvanted vaccines for seasonal and pandemic influenza prophylaxis. Influenza Other Respir Viruses, 2008. 2(6): p. 243-9.
  10. Brakemeier, S., et al., Immune response to an adjuvanted influenza A H1N1 vaccine (Pandemrix((R))) in renal transplant recipients. Nephrol Dial Transplant, 2012. 27(1): p. 423-8.
  11. Fairhead, T., et al., Poor seroprotection but allosensitization after adjuvanted pandemic influenza H1N1 vaccine in kidney transplant recipients. Transpl Infect Dis, 2012. 14(6): p. 575-83.
  12. Katerinis, I., et al., De novo anti-HLA antibody after pandemic H1N1 and seasonal influenza immunization in kidney transplant recipients. Am J Transplant, 2011. 11(8): p. 1727-33.
  13. Schaffer, S.A., et al., Impact of adjuvanted H1N1 vaccine on cell-mediated rejection in heart transplant recipients. Am J Transplant, 2011. 11(12): p. 2751-4.
  14. Kumar, D., et al., Randomized Controlled Trial of Adjuvanted Versus Nonadjuvanted Influenza Vaccine in Kidney Transplant Recipients. Transplantation, 2015.
  15. Magnani, G., 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. 24(5): p. 588-92.
  16. Esposito, S., et al., An open-label, randomized clinical trial assessing immunogenicity, safety and tolerability of pandemic influenza A/H1N1 MF59-adjuvanted vaccine administered sequentially or simultaneously with seasonal virosomal-adjuvanted influenza vaccine to paediatric kidney transplant recipients. Nephrol Dial Transplant, 2011. 26(6): p. 2018-24.
  17. Fernandez-Ruiz, M., et al., Impact of squalene-based adjuvanted influenza vaccination on graft outcome in kidney transplant recipients. Transpl Infect Dis, 2015. 17(2): p. 314-21.
  18. Gabardi, S., et al., Atovaquone versus trimethoprim-sulfamethoxazole as Pneumocystis jirovecii pneumonia prophylaxis following renal transplantation. Clin Transplant, 2012. 26(3): p. E184-90.

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