Older Adults over age 65

Because of the vulnerability of older adults to severe influenza illness, hospitalization, and death, efficacy and effectiveness of influenza vaccines in this population is an area of active research (see Immunogenicity, Efficacy, and Effectiveness of Influenza Vaccines: HD-IIV3, aIIV3, and RIV4 for Older Adults in the Background Document). Recent comparative studies of vaccine efficacy/effectiveness against laboratory-confirmed influenza outcomes among older adults have focused on HD-IIV3 (Fluzone High-Dose) (57–60), RIV4 (Flublok Quadrivalent) (61), and aIIV3 (Fluad) (62) (see Table in Background Document; https://www.cdc.gov/flu/professionals/acip/2019-2020/acip-table.htm). These studies have evaluated each of these three vaccines compared with standard-dose, unadjuvanted IIV. To date, HD-IIV3 has been the most extensively studied in this regard, and evidence has accumulated for its superior efficacy and effectiveness compared with SD-IIV3 in this population. Data from studies comparing the efficacy or effectiveness of HD-IIV3, aIIV3, and RIV4 directly with one another against laboratory-confirmed influenza outcomes among older adults are limited, which prevents recommending one of these three vaccines over another for this population. In comparative safety studies, some injection site and systemic reactions were observed more frequently in older persons vaccinated with HD-IIV3 and aIIV3 compared with unadjuvanted SD-IIV3 (63,64).

Fluzone High-Dose (HD-IIV3) met prespecified criteria for superior efficacy against laboratory-confirmed influenza compared with that of Fluzone SD-IIV3 in a randomized trial conducted over two seasons (2011–12 and 2012–13) among 31,989 persons aged ≥65 years and might provide better protection than SD-IIV3 for this age group (58,65,66). For the primary outcome (prevention of laboratory-confirmed influenza caused by any viral type or subtype and associated with protocol-defined influenza-like illness [ILI]), relative efficacy of Fluzone HD-IIV3 compared with Fluzone SD-IIV3 was 24.2% (95% confidence interval [CI]: 9.7%–36.5%). These findings are further supported by results from retrospective studies of Centers for Medicare and Medicaid Services (CMS) and Veterans Administration data, as well as a cluster-randomized trial of HD-IIV3 compared with SD-IIV among older adults in nursing homes (67–71). A meta-analysis reported that HD-IIV3 provided better protection than SD-IIV3 against ILI (relative VE = 19.5%; 95% CI: 8.6%–29.0%); all-cause hospitalizations (relative VE = 9.1%; 95% CI: 2.4–15.3); and hospitalizations due to influenza (relative VE = 17.8%; 95% CI: 8.1–26.5), pneumonia (relative VE = 24.3%; 95% CI: 13.9–33.4), and cardiorespiratory events (relative VE = 18.2%; 95% CI: 6.8–28.1) (72).

In an exploratory analysis of data from a single-season (2014–15) randomized trial conducted among 8,604 adults aged ≥50 years, Flublok Quadrivalent (RIV4) was more efficacious than SD-IIV4 (61,73); however, no claim of superiority was approved for the package insert (73). For the primary outcome (protocol-defined ILI, caused by any influenza virus type or subtype, confirmed by reverse transcription polymerase chain reaction), the relative VE of RIV4 compared with SD-IIV4 was 30% (95% CI: 10–47). When restricted to persons aged ≥65 years, the relative VE of RIV4 was 17% (95% CI: −20%–43%).

No data are available concerning efficacy of aIIV3 compared with nonadjuvanted IIV3 against laboratory-confirmed influenza outcomes from a randomized trial in older adults. Fluad (aIIV3) was more effective against laboratory-confirmed influenza than unadjuvanted SD-IIV3 among adults aged ≥65 years (N = 227, 165 of whom received aIIV3 and 62 SD-IIV3) in an analysis from a small single-season (2011–12) observational study (62). The relative effectiveness of aIIV3 compared with unadjuvanted SD-IIV3 was 63% (95% CI: 4–86). Fluad was associated with reduced risk for hospitalization for pneumonia and influenza diagnoses (74) and pneumonia, cerebrovascular, or cardiovascular diagnoses relative to unadjuvanted IIV3 in retrospective studies of medical record data (75).

Additional data concerning these vaccines from studies examining immunogenicity and non–laboratory-confirmed influenza outcomes are discussed in the Background Document. ACIP will continue to review data on the efficacy and effectiveness of these vaccines as more information emerges. No preference is expressed for any one vaccine type. Vaccination should not be delayed if a specific product is not readily available. For persons aged ≥65 years, any age-appropriate IIV formulation (standard dose or high dose, trivalent or quadrivalent, unadjuvanted or adjuvanted) or RIV4 are acceptable options.(CDC)

Timing of Vaccination

Balancing considerations regarding the unpredictability of timing of onset of the influenza season and concerns that vaccine-induced immunity might wane over the course of a season, it is recommended that vaccination should be offered by the end of October. Children aged 6 months through 8 years who require 2 doses (see Children Aged 6 Months Through 8 Years) should receive their first dose as soon as possible after the vaccine becomes available to allow the second dose (which must be administered ≥4 weeks later) to be received by the end of October. For those requiring only 1 dose for the season, early vaccination (i.e., in July and August) is likely to be associated with suboptimal immunity before the end of the influenza season, particularly among older adults. Community vaccination programs should balance maximizing likelihood of persistence of vaccine-induced protection through the season with avoiding missed opportunities to vaccinate or vaccinating after onset of influenza circulation occurs. Efforts should be structured to optimize vaccination coverage before influenza activity in the community begins. No recommendation is made for revaccination later in the season of persons who have already been fully vaccinated (i.e., providing a booster dose). Vaccination should continue to be offered as long as influenza viruses are circulating and unexpired vaccine is available. To avoid missed opportunities for vaccination, providers should offer vaccination during routine health care visits and hospitalizations.

Optimally, vaccination should occur before onset of influenza activity in the community. However, because timing of the onset, peak, and decline of influenza activity varies, the ideal time to start vaccinating cannot be predicted each season. Moreover, more than one outbreak might occur in a given community in a single year. In the United States, localized outbreaks that indicate the start of seasonal influenza activity can occur as early as October. However, in 75% of 36 influenza seasons from 1982–83 through 2017–18, peak influenza activity (which often is close to the midpoint of influenza activity for the season) has not occurred until January or later, and in 58% of seasons, the peak was in February or later (16). Activity most commonly peaked in February in 15 (42%) of these seasons (16).

Several observational studies (17–25) and a post hoc analysis from a randomized controlled trial (26) have reported decreases in vaccine effectiveness (VE) within a single influenza season, with increasing time postvaccination. Waning effects have not been observed consistently across age groups, virus subtypes, and seasons, and observed decreases in protection could be at least in part attributable to bias, unmeasured confounding, or the late-season emergence of antigenic drift variants that are less well-matched to the vaccine strains. Some studies suggest this occurs to a greater degree with influenza A(H3N2) viruses than with influenza A(H1N1) or influenza B viruses (22,24). This effect also might vary with recipient age; in some studies, waning was more pronounced among older adults (17,19) and younger children (19). Rates of decline in VE have also varied. A multiseason (2011–12 through 2014–15) analysis from the U.S. Influenza Vaccine Effectiveness (U.S. Flu VE) Network found that VE decreased by approximately 7% per month for influenza A(H3N2) and influenza B and 6%–11% per month for influenza A(H1N1)pdm09 (21). VE remained greater than zero for at least 5 to 6 months after vaccination. An analysis of the 2010–11 through 2013–14 seasons noted protection estimates ranging from 54% to 67% during days 0 through 180 postvaccination; estimated VE was not statistically significant during the period between days 181 and 365 (20). A third multiseason analysis (2010–11 through 2014–15) conducted in Europe noted a decline in VE to 0% at 111 days postvaccination for influenza A(H3N2) viruses. VE against influenza B viruses decreased more slowly, and VE against influenza A(H1N1) viruses remained roughly stable at 50%–55% through the influenza season (24).

Variable data concerning presence and rate of waning immunity after influenza vaccination, coupled with the unpredictable timing of the influenza season each year, prevent determination of an optimal time to vaccinate. Programmatic issues are also a consideration; although delaying vaccination might result in greater immunity later in the season, deferral also might result in missed opportunities to vaccinate, as well as difficulties in vaccinating a population within a more constrained time period. The potential contributions of these factors among persons aged ≥65 years have been assessed using a simulated mathematical model examining various scenarios of vaccination timing, timing of onset of the influenza season, rate of waning, and vaccine effectiveness (27). In this model, assuming a historical average timing of onset of the influenza season, delaying vaccination until October resulted in more hospitalizations if >11% of persons aged ≥65 years who would have been vaccinated in August or September failed to get vaccinated. However, these predictions varied considerably with assumed timing of season onset, rate of waning immunity, and vaccine effectiveness.

Vaccination efforts should continue throughout the season because the duration of the influenza season varies, and influenza activity might not occur in certain communities until February or March. Providers should offer influenza vaccine routinely, and organized vaccination campaigns should continue throughout the influenza season, including after influenza activity has begun in the community. Although vaccination by the end of October is recommended, vaccine administered in December or later, even if influenza activity has already begun, might be beneficial in the majority of influenza seasons.