Hector S. Izurieta, MD, MPH, PhD, on Flu Vaccine Strategies

Each year, influenza sends an estimated half a million people in the U.S. to the hospital and is associated with 12,000 to 56,000 deaths, mostly in those 65 years of age and older. Studies comparing the efficacy of vaccines for primary flu prevention show that in most seasons, the cell-cultured high-dose influenza vaccine has had moderately higher relative vaccine effectiveness (RVE) compared with standard-dose egg-based vaccines. But during recent influenza seasons, especially those dominated by A(H3N2) viruses, overall influenza vaccine effectiveness has been low, particularly in the elderly.

A new retrospective cohort study, published online in The Journal of Infectious Diseases, analyzes the RVE of the U.S.-licensed influenza vaccines given to more than 12.5 million Medicare beneficiaries between August 5, 2018 and January 31, 2019. Results show that the egg-based adjuvanted and high-dose vaccines were slightly more effective than the egg-based quadrivalent vaccines, with a RVE of 7.7% and 4.9%, respectively -- a finding consistent with previous research. The authors also found no significant difference in the RVE of the cell-cultured quadrivalent vaccines versus the RVE of egg-based quadrivalent vaccines.

The lead study author, Hector S. Izurieta, MD, MPH, PhD, of the FDA's Center for Biologics Evaluation and Research, discussed the results and their significance in greater detail.

During the 2018-2019 flu season in the U.S., how many influenza vaccines were available for the elderly and how were they different?

Izurieta: There were 6 influenza vaccines. Two were not manufactured in eggs, which included a cell-cultured standard-dose quadrivalent vaccine produced in mammalian cells and a recombinant quadrivalent vaccine produced in insect cells. The other 4 were egg-manufactured and included high-dose trivalent, standard dose quadrivalent, standard dose trivalent, and standard-dose adjuvanted trivalent vaccine.

In the 2018-2019 season, the trivalent vaccines contained antigens from subtype A(H1N1), A(H3N2), and a single type B Victoria lineage strain. The quadrivalent vaccine contained antigens from the same strains as well as an additional type B Yamagata lineage strain. The standard dose vaccines were formulated to contain 15 mcg of hemagglutinin per strain, whereas the high-dose and recombinant vaccines contain 60 mcg/strain and 45 mcg/strain, respectively.

What did your analysis show in terms of the number of Medicare beneficiaries who received each of these vaccines?

Izurieta: Of the 12,777,214 beneficiaries who were eligible for the study, the majority -- 62% -- received the high-dose trivalent, 16% got the standard-dose adjuvanted, 11% received the standard-dose quadrivalent, 6% received the cell-cultured quadrivalent, and 2% each received the standard-dose trivalent and recombinant vaccine.

What factors led to the low RVE of influenza vaccines in the 2018-2019 flu season?

Izurieta: The 2018-2019 season was dominated initially by A(H1N1)pdm09 viruses and subsequently by A(H3N2) clade 3C.3a viruses from February 2019 onwards. Because of a mismatch between the dominant circulating A(H3N2) viruses and vaccine virus, the absolute vaccine effectiveness against influenza A(H3N2) viruses for all ages combined was low, compared to the effectiveness against influenza A(H1N1) (9% vs 44%, respectively). Moreover, the seed virus used to produce the A(H1N1)pdm09 antigens for the cell-cultured vaccine was egg-grown, whereas the seed viruses for the A(H3N2) and B antigens were cell grown.

In addition, although the vaccines from all manufacturers comply with the lower HA [hemagglutinin] limit when specifying vaccine potency, there could be differences in the actual HA amount between vaccines.

What should primary care physicians tell older patients about the relative effectiveness of the different types of flu vaccine?

Izurieta: High-dose versus standard-dose relative vaccine effectiveness varies by influenza season. It is difficult to predict RVE since it can be affected by many factors such as the circulating virus strain antigenic similarity of vaccine strain and circulating strain, and characteristics such as the age or health conditions of the person being vaccinated.

Based on our multi-season RVE studies, we found that the high-dose vaccine was at least as effective as standard-dose vaccine in preventing influenza-related hospitalization for people 65 years and older in all seasons and was more effective in some seasons.

What else should readers take away from your research?

Izurieta: Collaborations between the FDA and the Centers for Medicare and Medicaid Services have shown the value of using real world evidence, derived from analysis of real world data, to better understand the potential benefits and risks of FDA regulated products in the U.S. population.

This is the fourth season in which we have provided seasonal RVE estimates for influenza vaccines used among the elderly, and we plan to continue conducting rapid response RVE analyses for each season going forward. For the first time, cell-cultured seeds for all candidate vaccine viruses was available for the 2019-2020 season, so cell-cultured vaccine manufacturers had the opportunity to use seed viruses that have not undergone any egg passage for all antigens in their vaccines. This should further inform our 2019-2020 RVE evaluations and help us to better understand and put in context our 2017-2018 finding of a higher RVE for cell-cultured vaccines.

You can read the study abstract here.