More Is Better: High-Dose Flu Vaccine Helps Protect Seniors

AS SURELY AS the sun comes up every morning, every year we can count on the winter-spring epidemic of seasonal influenza, with a heavy toll in flu-related illness and deaths. As the inevitable result of immunosenescence — declining natural immunity over time — persons aged 65 years and older are at the greatest risk, accounting for an estimated 50 percent to 70 percent of all flu-related hospitalizations and 80 percent to 90 percent of flu-related deaths each year in the U.S.^1,2

Unfortunately, this declining immune responsiveness to flu virus exposure also severely limits the protective benefit of conventional seasonal influenza vaccines in the older age demographic that most needs it. Even as successful public health campaigns have more than doubled the flu vaccination rate for seniors since 1990, overall hospital admission and death rates in that age cohort did not decline over the ensuing two decades, even after accounting for shifting age demographics and year-to-year variation in vaccine effectiveness against each season’s dominant new flu strain.³

Approved in December 2009, Sanofi Pasteur’s Fluzone High-Dose (HD) represents the first seasonal flu vaccine specifically designed to be more immunogenic and, in theory, more effective in preventing influenza-like illness (ILI) and its serious complications. In the same 0.5 mL dose for intramuscular injection, Fluzone HD packs 60 mcg of each of the three hemagglutinin viral surface antigens — four times the 15 mcg present in standard-dose (SD) flu vaccines. Immunogenicity studies have shown that HD vaccine elicits substantially higher hemagglutinin inhibition (HI) titers than SD vaccine. In the largest of these studies, the mean post-vaccination antibody titers elicited by HD vaccine against the A/H1N1, A/H3N2 and B flu strains were 70 percent, 80 percent and 30 percent higher, respectively, than the mean titer elicited by the SD vaccine.^4,5

But does the increased immunogenicity of HD vaccine translate into reduced rates of influenza or its serious complications in this particular age cohort? Results of two recent large-scale clinical studies have affirmed that, in fact, it does.

High-Dose Vaccine Cuts Flu and Related Hospitalization Risk

The New England Journal of Medicine study. Sponsored by Sanofi Pasteur, a two-year prospective trial involving 126 research centers in the U.S. and Canada randomized nearly 32,000 participants to receive SD (Fluzone) and HD (Fluzone HD) vaccine during the 2011-2012 and 2012-2013 influenza seasons.⁶ Consistent with earlier studies, HI titers were again significantly higher for all three strains — A/H1NI, A/H3N2 and B — in the group vaccinated with the HD product. For both A strains across both seasons, geometric mean titers favored HD vaccine by a ratio of between 1.8 and 2.0; for the B strain, that ratio averaged 1.5, but was still highly significant. There was also a significant difference in the seroprotection rate, again favoring the HD vaccine.

A total of 529 participants met the primary endpoint, defined as laboratory-confirmed ILI: 228 in the HD group and 301 in the SD group; the HD vaccine was 24.2 percent more effective (95% confidence interval [CI], 9.7% to 36.5%). In other words, about one-quarter of all breakthrough influenza illnesses could be prevented if HD vaccine were used instead of SD vaccine. While the confidence intervals were wide, study participants with ILI who received HD flu vaccine had a lower relative risk (RR) of pneumonia (RR, 0.66; 95% CI, 0.51-0.81*) and hospitalizations (RR, 0.70; 95% CI, 0.54-0.91*) compared with those in the SD group who contracted ILI.

Assuming an absolute efficacy of 50 percent for the SD vaccine suggested by previous studies, the absolute efficacy of HD vaccine would be estimated at 62 percent — a level of protection similar to that seen with SD vaccines in younger adults.⁷ For flu seasons where there is a relatively good match between flu strains selected for the vaccine and those that later become epidemic, the HD vaccine is likely to be even more protective: compared with SD vaccine used in this study, the HD vaccine was 51.1 percent more effective in preventing modified CDC-defined, culture-confirmed influenza disease caused by strains antigenically similar to the strains contained in the vaccine.

Also reassuring was the finding that the HD flu vaccine was efficacious in preventing ILI both in the 2011-2012 season, marked by low influenza activity and a moderate-to-good match between the vaccine and circulating strains, and in the 2012-2013 season, marked by high influenza activity and a relatively poor match between predominant circulating strains and the egg-propagated vaccines used in this study.

The 2012-2013 Medicare cohort study.While the U.S.-Canadian prospective randomized trial enrolling 32,000 participants represents the gold standard for evaluating safety and efficacy in reducing ILI, that study was not powered to characterize efficacy against serious outcomes, importantly including influenza-related hospital admissions. Aware of this limitation, the U.S. Centers for Disease Control and Prevention (CDC) and U.S. Food and Drug Administration (FDA) collaborated to answer this question by exploiting the massive Medicare insurance claims database, analyzing data from more than 2.5 million Medicare beneficiaries who received either the SD or HD flu vaccines between Aug. 1, 2012, and Jan. 31, 2013.

Of the 12.5 million Medicare beneficiaries aged 65 years and older who were vaccinated during the 2012-2013 flu season, a cohort of 2,545,275 were identified who received their vaccine at 24,501 pharmacies that offered both SD and HD flu vaccine options. Overall, 929,730 and 1,615,545 beneficiaries received the HD and SD vaccines, respectively. The two groups were similar in age and underlying comorbidity patterns. Probable influenza infection was defined by the use of a rapid flu diagnostic test followed by treatment with the antiviral agent oseltamivir (Tamiflu).

The HD vaccine was 22 percent more effective than the SD vaccine both for prevention of probable influenza infections and for prevention of influenza-related hospital inpatient admissions or emergency department visits. The HD vaccine was more effective in all age cohorts: 65-74 years, 75-84 years and 85 years and older. The benefit in reduction of probable flu infection risk — 36 percent — was even more pronounced in persons aged 85 years and older, whose natural immune responsiveness to influenza virus and other invasive pathogens is most seriously compromised.

High-Dose Flu Vaccine: Well Worth the Cost

No other medical intervention is quite analogous to influenza vaccination: a universally recommended preventive treatment that confers protective immunity for some, fails to protect others from developing the illness and its complications, and whose protective benefit fluctuates from one year to the next based on the degree of match with circulating strains and the virulence of those circulating strains. But even with its limitations, influenza vaccination represents one of the most cost-effective treatment modalities available to the older adult population.⁸

Which brings the next logical question to mind: What is the incremental health benefit of HD flu vaccine on a population basis? At about $20 more per dose than standard trivalent flu vaccine, is this product cost-effective? Researchers at the University of Pittsburgh, University of Toronto and Sanofi Pasteur developed a model to answer these questions, applying U.S. influenza health outcome data from the 32,000-subject prospective randomized referenced earlier, together with the average of U.S. influenza epidemiological experience during the 10 flu seasons from 1999-2000 through 2008-2009.

Their findings are striking. Administered entirely in place of SD vaccine, the HD flu vaccine would be expected to avert 195,958 cases of influenza, 22,567 influenza-related hospitalizations and 5,423 influenza-related deaths in U.S. seniors. The HD vaccine generates 29,023 more qualityadjusted life years (QALYs), at an incremental cost effectiveness ratio (ICER) of just $5,299 per QALY.** This compares very favorably to the ICERs for other Medicare-covered senior immunization programs, such as herpes zoster vaccine ($27,000 to $112,000/QALY) and pneumococcal conjugate vaccine ($62,000/QALY).

Proven Effectiveness, More Demand

Sanofi Pasteur reports that utilization of its Fluzone HD vaccine continues to increase year over year. During the 2014-2015 season, more than one in three immunized persons 65 years of age and older received Fluzone HD, up from just one in five over the first three flu seasons it was available. For this 2015-2016 flu season, propelled by findings from The New England Journal of Medicine and CDC-FDA studies, the company projects that it will be the vaccine of choice for over 50 percent of immunized seniors.

While Fluzone HD is currently the most effective available seasonal flu vaccine for U.S. adults aged 65 years and older, it will soon have new competition. A license application for Novartis’ Fluad, an adjuvanted influenza vaccine in wide use outside the U.S. for adults aged 65 years and older, has been submitted to FDA for review. If approved, the first doses of Fluad could be distributed in the U.S. before the end of the 2015-2016 flu season.

Assuming Fluad becomes available, a new Medicare claims-based study may ultimately shed light on its efficacy compared with Fluzone HD. Meanwhile, the vaccines industry never rests on its laurels. There remains a very serious unaddressed risk of contracting influenza and its complications in older adults. We can expect still better flu vaccines designed to further drive down those risks in the not-too-distant future.

** Restricting the analysis to a third-party payer perspective (to only include costs to the healthcare system), the ICER increases to $10,350 per QALY.

LUKE NOLL, FFF Enterprises’ director of vaccine product sales, contributed to the preparation of this article.