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PRIORITY PRESS - The Canadian Immunization Conference (CIC)

Ottawa, Ontario / December 6-8, 2016

Ottawa - Short-term thinking about influenza infection limits the illness to the acute period of illness when in fact, functional decline following hospitalization for influenza can be persistent and life-altering. Among the well, vaccine effectiveness (VE) even in the elderly is quite acceptable but VE declines as the level of frailty increases and it’s in the frail elderly where enhanced immunization strategies are urgently needed. Currently, the MF59 adjuvanted trivalent inactivated vaccine appears to provide more robust immune responses than non-adjuvanted trivalent inactivated vaccines and it remains a viable option for those 65 years of age and older. Results evaluating a high-dose influenza vaccine also suggest it provides incremental protection compared to standard-dose vaccines again among older patients although it is not part of any publically funded program as yet.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Prevention of acute influenza infection in older patients is only part of what protection against infection does and physicians need to be think more broadly about what can happen to the older patient once they acquire the infection and require hospitalized care, speakers here agreed.

“Traditionally, we have this short-term thinking around influenza, that the burden of illness happens when you’re acutely ill along,” Dr. Melissa Andrew, Associate Professor of Medicine and Geriatrics, Dalhousie University, Halifax, told delegates here at the Canadian Immunization Conference.

“But we know from the geriatric literature that older adults can have persistent, functional deficits long past the illness itself and we need to look at preventing persistent functional decline rather than just the morbidity and mortality associated with an acute episode,” she added. “Reducing the burden of influenza-related hospitalization is an important public health goal.”

Nowhere is the risk of developing a serious, “catastrophic” decline in the ability to carry out activities of daily living greater than among the frail. “Frailty comes down to vulnerability and the patient’s ability to overcome insults or not,” Dr. Andrew explained. Frailty is also a much more discerning predictor of outcomes than age per se, she added.

This was highlighted in an analysis of the Canadian Immunization Research Network (CIRN) Serious Outcomes Surveillance (SOS) Network of the 2011 and 2012 influenza season. The SOS Network includes both academic and community hospitals across Canada where all patients 16 years of age and older admitted to hospital for acute respiratory illness are tested for the presence of influenza. Cases are defined as patients who test positive for influenza while controls are patients who are admitted to hospital with an acute respiratory infection but who test negative for the infection.

In Dr. Andrew’s analysis of the 2011 and 2012 influenza season, special attention was paid to frailty (measured by a frailty index) and functional status (measured by the Barthel index) in patients 65 years of age and older. Vaccine effectiveness (VE) was then analyzed on the basis of both frailty and function in 320 laboratory-confirmed influenza cases and 564 influenza-negative controls. In their unadjusted analysis, VE against influenza-related hospitalization due to any strain of influenza was 45%.

Adjusted for many confounding variables, VE was higher at 58% while adjusting for the same variables but without including frailty, VE was similar to the unadjusted level at 43.3%. In contrast, when Dr. Andrew and colleagues included only frailty in the adjusted model, VE increased to 58.7%. “If you are going to consider any one thing in an older population to understand VE better, frailty is your best bet—age does not work in the same way—it has to be a composite measure of vulnerability and health status,” Dr. Andrew said.

The SOS Network analysis also showed that the same group of older, hospitalized patients responded to influenza vaccines either quite well or very poorly depending on their level of frailty. For example, VE reached a “pretty good” level of protection at 77.6% in patients who were not frail on being hospitalized. VE in turn was only about 60% in the frail elderly and among those most frail, VE fell to approximately minus 25%, as Dr. Andrew reported. Furthermore, as she indicated, most patients experience some decline in function when ill but on average, most tend to “bounce back” to approximately the same level of function they had prior to being hospitalized.

However, in this particular sample, approximately 15% of patients left the hospital with persistently lower levels of function—defined as a loss in the ability to carry out two or more activities of daily living—so clearly, VE decrease as the baseline level of frailty increases, as she observed.  “If we can prevent these hospital admissions in the first place, we may be able to make a dent in this persistent functional decline which extends the time horizon over which influenza is a really important infection for older people,” Dr. Andrew concluded.

“[But frailty nonwithstanding], influenza vaccination remains an effective tool for preventing influenza-related hospitalizations in an older adult population and it should continue to be used.”

Enhanced Influenza Protection

Although people 65 years of age and older respond relatively well to standard influenza vaccines, researchers are still looking for ways to enhance protection among the elderly, who remain among the most vulnerable to the ravages of influenza. In a pooled analysis from the same SOS Network, Dr. Shelly McNeil, Professor of Medicine, Dalhousie University, Halifax first looked at VE by influenza season and by vaccine type—all vaccines, the non-adjuvanted trivalent inactive vaccine (TIV) (multiple brands) and the MF59 adjuvanted TIV (FLUAD). Three seasons were included in this analysis: 2011-2012; 2012-2013, and 2013 to 2014.

Overall, VE for each of the three seasons varied from a high of approximately 51% for 2013-2014 and a low of approximately 35% for 2012 to 2013. For those 65 years of age and older, VE estimates were again variable, ranging from a high of 58% in 2011 to 2012 to a low of about 26% in 2012 to 2013. Pooled adjusted VE estimates across the three seasons showed that “all vaccines” had an overall VE of about 42% with slightly lower protection rates in those 65 years of age and older, while non-adjuvanted TIV had an overall VE rate of about 36%, protection rates again being slightly lower in those 65 years of age and older.

In contrast, the adjuvanted TIV had an overall VE rate of approximately 61% and protective rates were identical in recipients 65 years of age and older. “Vaccine effectiveness varies year to year based on many factors including virulence of the circulating strains and mismatch between circulating strains and vaccine strains,” Dr. McNeil observed.

“But we did see a statistically and clinically important benefit of vaccinating adults in the prevention of severe outcomes over three seasons and  increased VE in an older adult population is vital to reducing serious outcomes associated with influenza, including ICU admission, loss of function and death.”

If it is premature to conclude that the adjuvanted TIV definitely offers superior protection against influenza illness in older patients (for whom it is recommended as a vaccine option), a validated model showed that its efficacy is clearly higher in those 65 years of age and older than the non-adjuvanted TIV. Data from three comparative clinical trials were used to estimate the number of influenza cases that the adjuvanted TIV could prevent per 100,000 adults 65 years of age and older on a background influenza incidence of 5%.

The number of incremental cases of influenza prevented using the adjuvanted TIV instead of the non-adjuvanted TIV ranged from a low of 108 cases per 100,000 individuals 65 years of age and older to a high of 236 cases for the same 100,000 population. “This analysis demonstrates the superior immune response provided by FLUAD in a population aged 65 years and older and may be predicted to translate into a higher relative vaccine effectiveness across all three influenza strains: 33% H1N1, 44% H3N2 and 12% B,” lead investigator Van Hung Nguyen, MPH, VHN consulting, Montreal, concluded.

A recent randomized trial again in an elderly population comparing a high-dose influenza vaccine (60 µg per strain) vs standard dose (15 µg per strain) vaccine showed that the high- dose vaccine was associated with an incremental 24% greater protection against laboratory-confirmed influenza compared with a standard-dose vaccine, although the high-dose vaccine is not yet publicly funded.

Summary

It’s no secret that influenza infection remains a major public health challenge, among the most at risk being patients 65 years of age and older. Despite variations in VE across seasons and age groups, the annual flu shot must be regarded as a vital strategy to prevent not only morbidity and mortality associated with acute illness but a longer-term, potentially catastrophic decline in functional status, the frail elderly being most at risk. Currently available strategies to enhance immune protection include the use of either an adjuvanted vaccine system or higher antigen content in the vaccine itself with on-going efforts aimed at boosting immune responses to influenza expected to yield even better results.