a-t 2016; 47: 118

... clinical efficacy benefits still not proven

Is there now new, better evidence of the benefit of flu vaccination with FLUAD?

T. BAUER (Specialist in General Medicine)
D-79540 Lörrach
Conflict of interests: none

The trivalent adjuvanted flu vaccine FLUAD has been on the market in this country for 16 years (a-t 2000; 31: 75). The vaccine is approved for persons aged 65 years and older only, in whom it is supposed to be more strongly immunogenic in comparison to conventional non-adjuvanted vaccines (VAXIGRIP, etc.) (1). In several randomised studies in this age group, immunisation with FLUAD did indeed induce significantly higher antibody titres against at least two of the three virus strains contained in the vaccine in comparison to conventional flu vaccines (e.g. 2, 3).

However, there is still insufficient evidence regarding whether the adjuvanted vaccine really does provide older individuals with better protection against viral influenza and its complications (4), as is frequently claimed. Such statements are based solely on data from observational studies (cf. a-t 2007; 38: 48) (1, 5, 6), but because of the high risk of bias with such studies they do not admit of conclusions regarding the clinical superiority of FLUAD.

A study performed in 7082 subjects for the approval in the USA (7), by far the largest published randomised study of FLUAD to date, does not indicate any clinical benefits for the adjuvanted vaccine. Within a year following immunisation of the patients (mean age 72 years), the occurrence of flu-like illnesses was no less frequent with FLUAD than with a conventional flu vaccine (9.2% versus 9.0%; risk ratio [RR] 1.02; 95% confidence interval [CI] 0.87-1.19). There was also no difference in unplanned visits to the doctor or hospital admissions due to influenza, pneumonia, cardiac or pulmonary disease (7.9% vs. 8.3%; RR 0.95; 95% CI 0.81-1.12), exacerbation of pre-existing chronic illnesses* (4.2% vs. 3.8%; RR 1.35; 95% CI 0.80-2.26) or mortality (1.5% vs. 1.3%; RR 1.13; 95% CI 0.76-1.68) (7, 8). However, it is maintained that the study was insufficiently powered for these clinical, secondarily recorded endpoints. Although FLUAD was not immunologically inferior to the non-adjuvanted vaccine in this study, it did not meet the criteria for superiority. At the same time, as in other studies, vaccine reactions occurred more frequently with the adjuvanted vaccine than with the conventional vaccine. Within the first week following vaccination, local pain (25% vs. 12%) and hardening (21% vs. 11%) were more common with FLUAD; the systemic reactions muscle pain (15% vs. 9%) and fatigue (13% vs. 9%) were also reported more frequently (7).

In the USA, the vendor Novartis does not make any superiority claims for FLUAD. In a further study of clinical benefit required in connection with US approval, the adjuvanted vaccine will therefore be compared not with a conventional flu vaccine but rather with a tetanus-diphtheria vaccine (Td-PUR, etc.), in the sense of an 'impure placebo' (8).

    (R = randomised clinical trial)
  1 Seqirus: SPC FLUAD, as at July 2016
R 2 DE DONATO, S. et al.: Vaccine 1999; 17: 3094-101
R 3 SEO, Y.B. et al.: Clin. Vaccine Immunol. 2014; 21:: 989-96
  4 Ärzte Zeitung, 12. Sept. 2016
  5 VAN BUYNDER, P.G. et al.: Vaccine 2013; 31: 6122-8
  6 MANNINO, S. et al.: Am. J. Epidemiol. 2012; 176: 527-33
R 7 FREY, S.E. et al.: Vaccine 2014; 32: 5027-34
  8 FDA: Clinical Review FLUAD, Nov. 2015; http://www.fda.gov/downloads/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/UCM478096.pdf
  * Defined as unscheduled physician visits or hospitalisations for chronic congestive heart failure, chronic obstructive pulmonary disease, asthma, hepatic disease, renal disease, neurologic/neuromuscular or metabolic disease.

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