Research Contradicts Other Recent Findings

By Brenda L. Mooney

PHILADELPHIA — As the latest influenza season finally abates, a new VA study raises questions about how effective the high-dose vaccine really is for the 65 or older cohort.

Beginning at 65, people generally are offered two flu vaccine options: either the standard vaccine or a high-dose version designed to better activate the immune system, which weakens with age.

Darren Linkin, MD,  and Diane Richardson, PhD, both based at the Philadelphia VAMCr, studied whether the high-dose flu vaccine is really more effective than the standard dose for older.people. Photo by Tommy Leonardi

Darren Linkin, MD, and Diane Richardson, PhD, both based at the Philadelphia VAMCr, studied whether the high-dose flu vaccine is really more effective than the standard dose for older people. Photo by Tommy Leonardi

A number of studies, including one published in March, have found that the high-dose vaccine provides superior protection. The new study led by researchers from the Philadelphia VAMC, however, found increased value only for the “oldest old,” those 85 or older.

The national Centers for Disease Control and Prevention (CDC) and its Advisory Committee on Immunization Practices have not expressed a preference for any flu vaccine indicated for people 65 and older but only recommend flu vaccination as the first and most important step in protecting against the flu.

That VA study, published online in the journal Clinical Infectious Diseases, included more than 165,000 VA patients — 25,000 of them receiving the high-dose vaccine and the rest getting a standard vaccine — during the 2010-2011 flu season. Researchers tracked rates of hospitalization and deaths.1

Results indicate that the rate of hospitalization for influenza or pneumonia was 0.3% in both groups in the influenza season.

“After accounting for patient characteristics in propensity-adjusted analyses, the risk of hospitalization for influenza or pneumonia was not significantly lower among patients receiving HD vaccine vs. those receiving SD vaccine (risk ratio, 0.98; 95% confidence interval, 0.68-1.40),” the authors write. “In the subgroup of patients ≥85 years of age, receiving HD (compared with SD) vaccine was associated with lower rates of hospitalization for influenza or pneumonia.”

“The main overall outcome was that we didn’t find a difference between the groups,” said study co-author Darren Linkin, MD, of the CDC Prevention Epicenter Program. “But in a secondary analysis, there appeared to be a strong effect for those 85 and older.”

“Sixty-five and older sounds like one homogenous group, but it could be that the oldest of the old may respond differently,” explained Linkin, who also is an infectious disease specialist, the hospital epidemiologist at the Philadelphia VAMC and an assistant professor in the Perelman School of Medicine at the University of Pennsylvania.

Lead author Diane Richardson, PhD, co-director of the Biostatistics and Informatics Core in VA’s Center for Health Equity Research and Promotion in Philadelphia, said the study was conducted because “older adults have reduced immunity. So a natural question is whether the specific age bracket within the older population makes a difference. That’s what we wanted to find out.”

Flu Season Severe

That is an especially important issue in the wake of the 2014-2015 season, when influenza activity started early and had a relatively long duration. Influenza-like illness (ILI) exceeded baseline the week ending Nov. 22 and remained elevated for 20 consecutive weeks, making the season slightly longer than average. During most flu seasons over the past 13 years, influenza-like illness has been at or above baseline for 13 weeks, on average, with a range of one week to 19 weeks, according to the Centers for Disease Control and Prevention (CDC).

The season also was especially severe for people 65 and older, the CDC said. In fact, this season recorded the highest hospitalization rates among the older age group since record-keeping began in 2005.

People 65 and older accounted for more than 60% of all reported hospitalizations, and, from Sept. 28 through April 18, an estimated 313.8 per 100,000 people in the age group were hospitalized from flu. The next-highest recorded hospitalization rate in this age group (182.3 per 100,000) occurred during the 2012-2013 season.

The VA researchers’ findings that use of the more expensive high-dose vaccine accrued no benefit except in the oldest segment of recipients veers from other recent research, although the authors said the particular flu seasons studies could explain some of the variation.

More Effective in Medicare Recipients

A Food and Drug Administration-funded study published in March by The Lancet found that the high-dose vaccine was 22% more effective at preventing flu-related hospital admissions for Medicare patients during the 2012-2013 flu season. It looked at 2.5 million U.S. adults, and the authors left little room for doubt in reporting their results.

“Our retrospective cohort study in U.S. Medicare beneficiaries shows that, in people 65 years of age and older, high-dose inactivated influenza vaccine was significantly more effective than standard-dose vaccine in prevention of influenza-related medical encounters,” they write. “Additionally, the large population in our study enabled us to show, for the first time, a significant reduction in influenza-related hospital admissions in high-dose compared to standard-dose vaccine recipients, an outcome not shown in randomized studies. These results provide important new information to be considered by policy makers recommending influenza vaccinations for elderly people.”

Last year, a randomized controlled trial published in the New England Journal of Medicine study and involving Sanofi Pasteur, manufacturer of the high-dose vaccine, also found that flu shot provided better protection against lab-confirmed flu illness than did the standard vaccine. The two-year trial, which indicated the high-dose vaccine triggered stronger immune responses, included nearly 32,000 participants and lasted from 2011 to 2013.

Because of the conflicting results with their study, the VA team is anxious for more research.

“It would be good to have larger VA studies looking across multiple years,” suggested Richardson, whose group examined only one season. She notes a multi-year effort would help control for variations from one flu season to another, such as the quality of the match between circulating viruses and the vaccine strains.

The VA patient population studied was almost all male and tended to have more chronic disease than the groups in the other studies, the authors pointed out.

Linkin suggested that, for individual older patients, given the data from studies so far, it’s not unreasonable to go for the high dose. The difference in side-effect risk is very minimal, he noted, and significant data suggests the higher dose is, in fact, more effective.

From an institutional and public health perspective, however, a lot of questions remain unanswered about whether the pricier high-dose flu vaccine is beneficial, said Linkin, who added, “In terms of looking at these more-serious outcomes among older Americans, more research would be helpful.”

1 Richardson DM, Medvedeva EL, Roberts CB, Linkin DR; Centers for Disease Control and Prevention Epicenter Program. Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccination in Community-Dwelling Veterans. Clin Infect Dis. 2015 Mar 31. pii: civ261. [Epub ahead of print] PubMed PMID: 25829001.

2 Izurieta HS, Thadani N, Shay DK, Lu Y, et. al. Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Lancet Infect Dis. 2015 Mar;15(3):293-300. doi: 10.1016/S1473-3099(14)71087-4. Epub 2015 Feb 9. Erratum in: Lancet Infect Dis. 2015 Mar;15(3):263. PubMed PMID: 25672568.

3 DiazGranados CA, Dunning AJ, Kimmel M, Kirby D, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 2014 Aug 14;371(7):635-45. doi: 10.1056/NEJMoa1315727. PubMed PMID: 25119609.