Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

Researchers struggle to make more effective flu vaccines for older people.

Influenza remains a major public health issue around the world, with seasonal influenza accounting for approximately 20,000 deaths in the U.S. per year. Among older individuals who are most susceptible to flu-related disease and mortality, a 2010 Morbidity and Mortality Report (MMWR) found that during seasons when influenza A (H3N2) viruses were prominent death rates were more than double what they were during seasons when influenza A (H1N1) or influenza B viruses predominated.

Additionally, the study confirmed previous findings that approximately 90% of influenza-associated deaths occur among adults aged greater than or equal to 65 years. An estimated annual average of 124 persons aged less than 19 years and 2,385 aged 19–64 years die from influenza-associated respiratory or circulatory causes.

But the older individuals, those most susceptible to flu-related disease and mortality, are among those least likely to respond optimally to vaccination with flu vaccine. This suboptimal response, scientists say, occurs due to a complex deterioration of multiple immune system components, or “immunosenescence.”

Just how the intricate mechanisms involved in immune response to influenza vaccine, and how these responses change with age, have led scientists, they say, to adopt a systems biology approach to understand exactly why the response to vaccination diminishes with age.

Of key importance are efforts to develop vaccines to which the aging immune system can respond, the potential use of adjuvants to enhance less-than-optimal immune responses, and an advanced understanding of the mechanisms behind deteriorating immunity.

Flu Vaccine Less Effective for Older People

Vaccine efficacy against influenza illness in older adults is difficult to measure; to date, there has been only one placebo-controlled trial of influenza vaccine efficacy against laboratory-confirmed illness in older adults. The study estimated protection from influenza illness at approximately 50%, but estimates vary considerably.

An alternative and widely accepted approach is the measurement of influenza-specific antibody titers as a correlate of protection. Titers are traditionally measured using a hemagluttination inhibition (HAI) assay, which quantifies the ability of hemagglutinin (HA)-specific antibodies to block N-acetylneuraminic acid-mediated viral agglutination of red blood cells. Using the set guidelines of this assay, vaccine protection can be assessed based on patient seroconversion (fourfold increase in antibody titers post vaccination) and seroprotection (HAI antibody titers greater than or equal to 1:40 post vaccination).

Quantitative analysis of this data showed that HA-neutralizing antibodies were considerably lower in vaccinated older adults than in younger adults. Data analysis also demonstrated a correlation between health status in older adults and HAI titers, with healthy older adults having statistically significant higher levels of HAI titers than those with chronic diseases.

Apart from inherent changes in the aging immune system that may make immune responses to vaccines less efficient, the type of influenza vaccine used in older individuals may be less effective in eliciting a protective anti-flu response.

According to Ted Ross, Ph.D., program director of vaccines and viral immunity at the Vaccine and Gene Therapy Institute, Port St. Lucie, Florida, current influenza vaccine is made using either a live inactivated version of the influzenza virus administered intranasally, or the killed version of the virus administered via intramuscular injection. “While the intranasal, live attenuated version is more effective,” Dr. Ross says, the live version “can cause disease in older persons; we can’t give it older people—only people up to 49 years old, in the U.S.”

Another key issue, he says, is that “the killed version of the vaccine doesn’t elicit high titer immunity in the elderly, with effective seroconversion occurring in approximately 30 percent of vaccinated elderly individuals, whereas in young people it’s around 80 percent. Unfortunately, those older individuals, even those people are getting vaccinated, don’t actually have any protection!” And he notes, a dead vaccine elicits limited T-cell responses, while live vaccines elicit robust T-cell responses.

With age, people produce fewer naïve T cells, which make them less able to combat new health threats, as well as rendering them less responsive to vaccines. Exceptions do exist—for example, the shingles vaccine that relies on existing memory T cells and has been particularly effective in older people.

No One-Size-Fits-All Vaccine

According to Abbe De Vallejo, Ph.D., associate professor of pediatrics and immunology at the University of Pittsburgh School of Medicine, flu vaccines “need to be targeted, customized to specific populations.” For example, he explained, a population of elderly people living in the community is likely to face different immunologic challenges than a group living in a nursing home. There is no such thing as a one-size-fits-all flu vaccine, he says. Dr. De Vallejo and his team conduct research on mechanisms of lymphocyte senescence, immune remodeling, and health/function outcomes of aging.

He and his colleagues have found that with aging, individuals lose the required reserve of T cells needed to mount an effective immune response. At least, he says, flu vaccines should be highly selective for either memory T cells or for the residual naive T cells, the latter relatively rare in older people, as throughout life the naive T-cell stores become depleted.

However, his team has also found that there are novel T cell populations, particularly among highly functioning community-dwelling elders, that express new receptors, which in laboratory experiments were found to impart new ways of triggering T-cell function. His team is now working to examine how to exploit such novel T cells to enhance immune function in old age. Dr. De Vallejo stated, “A shift in research paradigm may be needed to examine unique features of the aged immune system, which would require a shift beyond the usual young-versus-old comparison.” He advocates that studying different kinds of elderly populations would be key to innovations in vaccine and other immune interventions for them.

Other Options

And researchers are investigating ways to develop other vaccines that are adjusted for the changes that happen in an older person’s immune system.

Last September, Dr. Ross received a $2 million subaward grant from the National Institute of Allergy and Infectious Diseases (NIAID), NIH to study immune and genetic responses to influenza during aging.

“This study will give us answers that will help us understand the difference between how people of different age groups respond to seasonal flu vaccine,” said Dr. Ross. His research team will focus the reactions in young children, adults, and the elderly to influenza infection so an improved, more protective flu vaccine can be developed for all age groups.

Other institutions receiving grants included the University of Pittsburgh, Mount Sinai School of Medicine-New York, and University Health Network-Toronto.

One approach to improving the immune response to vaccines in the elderly involved the use of a higher vaccine dose, an approach approved by the FDA in this population. “There are some reports that this caused a higher rate of seroconversion, about 50 percent,” Dr. Ross said. “But, as we have put this into practice, it doesn’t look like the high dose was much more effective for the elderly—still only between thirty and fifty percent. We want to get to eighty percent.”

“The other thing one can do,” he continued, “is to use adjuvants with the vaccine that cause a local inflammatory response, but these can cause a more severe reaction in an elderly person than a young person, as well as reduce compliance. Thus far the FDA has not approved the use of an adjuvant, although some that are currently approved in Europe are undergoing evaluation in the U.S.”

Dr. Ross is developing unique vaccines and testing them with these adjuvants, and attempting to develop a universal vaccine that can anticipate every potential strain that may occur as the flu changes.

Dr. Ross says in developing new vaccines his lab attempts to deal with viral antigenic diversity by using computer modeling to identify widening diversity among epitopes.

“We look at the phylogenetic information to examine consensus sequences that represent different eras of time, and we believe that we have captured the most significant epitopes that have appeared using bioinformatics analyses,” he explains. “Then we engineer those epitopes into a single flu hemmaglutinin molecule. Therefore, we can build a single molecule that contains all of the epitopes of flu over history. This vaccine can recognize epitopes over time and we hope this will continue into the future. Right now we would be happy with five to 10 years of immunity to avoid annual reformulation.

“What’s nice about the way we generate our vaccine is that you can put it into any platform a company is using, for example virus-like particles (VLPs), live attenuated, or any platform a company has.”

Dr. Ross has previously used this method to produce a vaccine against the H5N1 virus, commonly known as the bird flu. The vaccine, well tolerated in preclinical trials, successfully protects against known strains of bird flu. Dr. Ross and his VGTI Florida colleagues are applying similar strategies to fight other serious viruses such as West Nile Virus, dengue, and HIV Type 1 (HIV-1).

But even as researchers work to come up with a more protective flu vaccine for the elderly, a 2010 review published by the Cochrane Collaboration—an independent, nonprofit organization that promotes evidence-based medicine—concluded that “until such time as the role of vaccines for preventing influenza in the elderly is clarified, more comprehensive and effective strategies for the control of acute respiratory infections should be implemented.”

Patricia Fitzpatrick Dimond, Ph.D. ([email protected]), is technical editor at Genetic Engineering & Biotechnology News.

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