Pandemic, vaccine debate spur ideas to save elders

Antivirals, new vaccines, higher doses

Regardless of the current controversy regarding the efficacy of seasonal influenza vaccination in the elderly, it seems a given that seniors will fare much worse should a pandemic strain arise that eludes an immune response in all ages. But under closer scrutiny, that logic does not hold.

The fate of the elderly in the next flu pandemic will be in part determined by the genetic shuffle and mutation of the virus that eventually emerges, whether it be avian influenza A (H5N1) or another novel virus. Surprisingly, the elderly were relatively unscathed by the legendary 1918 pandemic, which strangely targeted young healthy people. However, the 1957 and 1968 pandemics conformed to more traditional expectations, causing the most mortality in the elderly, infants, and those with underlying health conditions.

"The 1918 pandemic is our current scenario for pandemic planning, but infants and seniors were just not really at risk in that one," says Lone Simonsen, PhD, MS, visiting professor and research director in the department of global health at the George Washington School of Public Health in Washington, DC. "The problem is we don't know what's coming. If it is more like '57 or '68, then the seniors will be the most at risk and they should be the ones protected by vaccination. The pandemic plan has just changed the opinion about the high-risk groups. [The elderly] used to be absolutely on top and now they have pregnant women, infants, and toddlers [above them]."

38 million at high risk

The CDC pandemic plan includes among its groups "at high-risk of severe complications" the approximately 38 million people in the U.S. age 65 years or older. Although, as Simonsen noted, on the plan posted on the HHS web site as this issue were to press, the elderly group was listed only one notch above healthy adults ages 19 to 64, who unless designated by occupation or some other factor would be of lowest priority to receive vaccine. (Available at http://www.pandemicflu.gov/index.html.)

Planners are looking at all possibilities for a flu pandemic and are well aware that various populations could be affected differently dependent on the stain that emerges, says Carolyn Bridges, MD, associate director of science at the Centers for Disease Control and Prevention. "The impact on all age groups is being looked at based on historical data from the previous three pandemics," she says. "In the 1918 pandemic deaths, the number of excess deaths — the number of deaths above expected — was really highest in the less-than-2-years-olds and young adult age groups. The other two pandemics, the excess deaths were really under 4 years old and then 65 and older."

Was it the cytokine storm?

A prevailing theory about the 1918 pandemic — which occurred before a flu vaccine or antibiotics were available — is that it prompted a hyperimmune response, the famously described "cytokine storm." In the ongoing research with the reconstructed 1918 strain, CDC researchers are finding that it replicates deep within mice lungs, prompting a similar immune system hyperreaction. Cytokines are proteins in the immune system that send out messages as part of the body's response to an invading pathogen. A cytokine storm is a term used to describe an extremely powerful cytokine reaction — an overreaction, if you will — that may do more harm than good. That could possibly explain why the 1918 pandemic caused such devastating mortality in young and healthy people who usually survive disease epidemics. Provoking a hyperimmune response — something that would be much less likely in elderly people with weakened immune systems — may be the key to the 1918 strain's legendary virulence.

On the other hand, the elderly would be in serious peril if a pandemic virus essentially mimicked a seasonal strain, which causes the majority of fatal infections in those 65 years and older. But they would not be defenseless. One promising line of research in developing a pandemic vaccine — which experts say could take as much as five months after a pandemic strain emerges — is the use of immune boosters called adjuvants. For example, aluminum salts or "alum" can boost the immune system by prompting immune-system cells to secrete key proteins and enhance B-cell response to the vaccine. "The good news for pandemic vaccine [development] is that they are working with adjuvant vaccines, which is another way to augment protection for seniors," Simonsen says. "There have been several studies showing that with adjuvant flu vaccines, you actually get a better antibody response and a longer duration of it."

Other measures needed

With an effective vaccine not likely to be available during the beginning of a pandemic, community mitigation measures such as shutting down schools and public gatherings may limit transmission and protect the elderly. Another key weapon against pandemic influenza in the elderly would be the use of antiviral drugs such as oseltamivir (Tamiflu®) and zanamivir (Relenza®). These antiviral medications can be used as a prophylaxis to prevent flu or to lessen the severity of illness if administered within a few days of infection. "The goal of the federal government in planning is to have enough antiviral medication to treat 25% of the population with the hope that would decrease complications," Bridges says. "For example, in a nursing home, even if a vaccine was available you might not ee good immune response in that population. Another strategy might be doing very good surveillance in nursing homes, looking for influenza. Then when you find it, you give everyone an antiviral."

Antivirals, herd immunity

In a recent study, a prospectively identified cohort of patients with laboratory-confirmed influenza requiring hospital admission, treatment of adults with oseltamivir was associated with a clinically significant reduction in mortality within 15 days, the authors found.1

"The evidence that it helps seriously ill people with seasonal flu supports the argument that it is likely to be of some benefit in a pandemic," says lead author Allison McGeer, MD, microbiologist and infectious disease consultant at Mount Sinai Hospital in Toronto. "I don't think anyone should be relaxing about pandemic flu or thinking that [antivirals are] going to make a huge difference, but it does give me hope that it could make some difference."

While seniors may not achieve an immune response after vaccination — and thus remain vulnerable to flu infection — antivirals work independently to kill circulating virus. "It acts directly against the virus, so you are not expecting a contribution from the immune system," she says. "When using a vaccine, you are dependent on the host immune system for its function. When you are [using] an antiviral, as long as [the elderly] absorb as well as the next person, there should be no difference between them."

In addition to pandemic discussions, the controversy over the efficacy of the flu vaccine in the elderly has actually invigorated research and discussion, she says. "I think the good thing is that people are talking about better vaccines for the elderly with some of the adjuvant work that is happening with H5N1 vaccines," she says. "People are talking about double doses and different delivery systems to try and get the elderly to respond a little better."

Ongoing studies in administering the elderly a seasonal vaccine with large quantities of antigen are showing some promise, Bridges adds. There are 15 mcg of antigen per dose of inactivated flu vaccine. In one study, researchers have found that elderly volunteers were able to muster 44% to 79% higher levels of antibody after being given high-dose shots that contained 60 mcg of antigen.2 Moreover, the vaccine was well tolerated at all dosage levels. "There have also been a number of studies that have been done over the years looking at the benefit of giving an extra dose during the year to elderly people," Bridges says. "There is general agreement that we need a better vaccine for the elderly — a more immunogenic vaccine. As people age and have high-risk conditions, their immune response is diminished."

Another common sense strategy is vaccinating all health care workers, while promoting herd immunity by immunizing children and family members who may be in contact with the elderly. "There is no doubt that the most cost-effective way to prevent influenza is to extend vaccination programs," McGeer says. "If we actually got 80% of the population vaccinated, including most kids, the herd immunity effect might be big enough that it wouldn't have to worry so much about elderly people."

Benefits of health care worker vaccination in reducing mortality in the elderly have been clearly shown, but it is too early to tell the whether the more recent push to immunize children will translate to benefits for their elders.

"The [push to vaccinate children] was really made because of new and more specific evidence that kids in those young age groups were at high risk of influenza [complications], not to promote herd immunity," Bridges says. "What kind of vaccination rate would you really need to obtain to see indirect benefit for the elderly? I don't know what that is, but I don't think we have seen it yet."

References

  1. McGeer A, Green K, Plevneshi A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis 2007; 45:1,568-1,575.
  2. Keitel WA, Atmar RL, Cate TR, et al. Safety of high doses of influenza vaccine and effect on antibody responses in elderly persons. Arch Intern Med 2006; 166:1,121-1,127.