The 2009 H1N1 pandemic, better known as the season of swine flu, was not like other flu seasons of recent vintage. A typical seasonal strain of influenza is most deadly at the extremities of age, with the highest mortality rates in the very young and very old. One of the reasons why experts were concerned about the 2009 flu was that it went off-script, killing mostly people in their twenties and thirties. Influenza researchers speculated on why the normally vulnerable elderly appeared to have the advantage against this particular pandemic. But it wasn’t until a recent study by University of Chicago and Stanford scientists looking at the failure of flu vaccines in older adults that the source of this advantage revealed itself.
In a typical season, senior citizens are among the priority groups for receiving the flu vaccine, due to their increased risk of severe symptoms. Yet the success rate of the standard influenza vaccine is reduced in those above 65 years of age, falling from 90 percent efficacy to as low as 17 percent. Most have attributed this decline to a general principle called “immunosenescence,” the weakening of a person’s immune system as they grow older. Since vaccines work by stimulating the production of antibodies against an inactivated flu strain to protect against the real virus, is the deficiency in the aged a matter of antibody quantity, quality, or both?
A multi-institutional team led by co-first authors Meghan Sullivan of UChicago and Sanae Sasaki of Stanford developed a new assay to test this question for a recent article in The Journal of Clinical Investigation. Two groups of volunteers – one aged 18-30, one aged 70-100 – received the seasonal flu vaccine in the winter of 2007-08, and researchers took blood samples from them seven days later, when vaccine-induced antibody production is at its peak. Scientists could then measure the number of antibody-secreting cells, called plasmablasts, and antibodies circulating in the blood of the volunteers. They could also run experiments testing how well those immune defenses bind different strains of influenza, the first step in fighting off a virus.
Their first experiments replicated the clinical data – even in a test tube, younger volunteers (or at least their antibodies) are much more likely to respond to the influenza strains included in the vaccine than samples from older subjects. Subsequent experiments revealed that the immune systems of elderly subjects were at a numerical disadvantage, with significantly fewer plasmablasts observed in serum compared to the samples from their younger counterparts.
“It had been appreciated before that there are fewer immune cells in older people, but this is the first time showing that fewer antibody secreting cells are raised in response to vaccination,” said Sullivan, a graduate student in the laboratory of Patrick Wilson (and a contributor to ScienceLife).
But surprisingly, that was where the immune deficits in older patients started and ended. Though there were fewer plasmablasts in older subjects, each produced the same number of antibodies as those of the young. What’s more, when the antibodies from young and old were compared for their ability to bind the viral strains targeted by the vaccine, they were nearly identical. So the failure rate of vaccines in elderly can be explained by the lower quantity of antibody “factories,” rather than a defect in the quality of the antibodies themselves.
“We would think that antibody activity would be decreased in older people, but in fact the ability to bind is basically identical,” Sullivan said. “The antibody secreting cells are the weak point; elderly people are just not making enough.”
Amid the media storm surrounding the rapid spread of swine flu in 2009, the research team used the same samples to test another idea. One theory for why senior citizens were protected against that particular H1N1 strain was that they may have been exposed to a similar influenza that circulated before 1950. With their blood samples, the researchers could compare how the antibodies of their old and young subjects responded to the 2009 H1N1, which neither group had been vaccinated against two years prior. In this competition, the senior citizens were the surprise winners – antibodies from older subjects (especially those older than 78) were more responsive to the H1N1 virus than those from younger volunteers.
The result suggests something off an immune system trade-off in the elderly. Though they may have a harder time producing sufficient antibodies to fight off the flu, the antibodies they do produce are able to attack a more diverse range of influenza strains.
“It definitely raises some interesting ideas about how immune memory works,” Sullivan said. “Someone who is 90 years old will naturally have more memories than a 20 years old does, and the same holds true for immune memory. There could be a huge reservoir of memory cells to draw on in the aged that you might not have in the young, and the seasonal vaccine could boost their prior immune responses.”
If the reduced immune response to the vaccine in the elderly could be improved, this deeper immune memory could be better put to use. A stronger vaccine may help stimulate more antibody secreting cells in older recipients (or younger people with immune system deficiencies), or another agent, an adjuvant, might be added to the vaccine to help activate their defenses. In a commentary accompanying the JCI paper, authors Bonnie Blomberg and Daniela Frasca suggest that the plasmablast assay could be used as a biomarker of a vaccine’s success – by measuring their numbers in a patient seven days after vaccination, physicians can decide whether a stronger dose is needed.
“The development of accurate biomarkers will help determine in which patients altered/enhanced vaccines should be used and beckons us to generate not only better adjuvants but also to screen for pharmaceutical and/or lifestyle changes that can improve vaccine responses to ensure effective disease prevention,” they write.
Sasaki, S., Sullivan, M., Narvaez, C., Holmes, T., Furman, D., Zheng, N., Nishtala, M., Wrammert, J., Smith, K., James, J., Dekker, C., Davis, M., Wilson, P., Greenberg, H., & He, X. (2011). Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies Journal of Clinical Investigation, 121 (8), 3109-3119 DOI: 10.1172/JCI57834
Blomberg, B., & Frasca, D. (2011). Quantity, not quality, of antibody response decreased in the elderly Journal of Clinical Investigation, 121 (8), 2981-2983 DOI: 10.1172/JCI58406