InfluenzaThe 1918 influenza pandemic that killed between 20 million and 100 million people world-wide was unusual in a lot of ways. One of the most extraordinary things about it was not just the high mortality rate, but the mortality pattern. Normally influenza kills the very old and the very young; but the 1918 flu killed young adults as well — people in the prime of life, who normally are highly resistant to death from influenza. The famous graph below1 (click for a larger version) shows this; the dashed line is mortality vs. age for “normal” influenza outbreaks (the “U-shaped curve”), and the solid line shows mortality vs. age for the 1918 flu (a “W-shaped curve”).

Influenza mortality by age, 1918

There are two ways to look at the W-shaped curve. You can either ask, Why did the young adults die? Or you can ask, Why did the older adults NOT die? In other words, was there something that protected the older adults that the younger ones didn’t have?

One explanation (and I can’t find the original paper to give credit) is that somewhere around 1870-ish (that is, 45 or 50 years before 1918) some other influenza strain infected the population, and gave a little bit of cross-protection against the 1918 strain. People alive in 1870 were exposed to this (hypothetical) strain of virus, developed immunity, and fifty years later were protected against the 1918 strain.2 Of course, supporting this idea is the recent paper3 that received a fair bit of attention, showing that survivors of the 1918 pandemic still have specific immune responses to that virus, 90 years later — so certainly immunity could last fifty years.

Dali, The Persistence of MemoryOne of the problems with influenza vaccination, of course, is that the virus changes. New strains arise and mutate, and the vaccines have to match the major circulating virus pretty well. Antibodies against one major strain of influenza don’t do a good job against a shifted strain. We see this is the paper I just mentioned — hardly anyone younger than 90 responded to the 1918 flu, even though they had been exposed to influenza viruses (of different types) every year for up to 80 years.

It would be nice if there was a vaccine that gave resistance to many strains of influenza, and we didn’t have to develop new vaccines ad hoc each year, based on imperfect guesses as to which viruses will circulate six months in the future. What’s more, we don’t really have good vaccine strains for novel influenza strains — like, say, whichever strain of avian influenza eventually succeeds in making the jump to humans.

Our present vaccines against flu are designed to raise protective antibodies. Antibodies in general target the outside of the viruses, which are intrinsically variable; hence the need to customize the vaccine strain with the circulating strain. Cytotoxic T lymphocytes, on the other hand, at least have the potential to target internal components of the viruses, which may have different constraints and therefore not be able to change as much. Could these CTL be more cross-reactive than antibodies?

It turns out that, yes, CTL are quite cross-reactive. A paper from Tao Dong’s and Sarah Rowland-Jones’ lab4 looked at anti-influenza T cells from normal volunteers (who had, of course, been exposed to the usual influenza A strains that sweep around the world each year).

Memory CD4+ and CD8+ T cells isolated from the majority of participants exhibited human influenza-specific responses and showed cross-recognition of at least one H5N1 internal protein.

The bad news is that these cross-reactive T cells are not very effective even against conventional influenza strains. Most of us are walking around with cross-reactive T cells, yet we still need antibody (such as from the vaccine) to actually be resistant to infection with one of the cross-reactive viruses. The good news is that the T cells aren’t entirely useless. It’s been shown several times that they do offer some protection, and in fact may be one reason that healthy adults are relatively resistant to influenza (the U-shaped curve above) — the very young would not have been previously exposed so wouldn’t have any cross-reactive T cells, while the very old often have defects in T cell responses. As Peter Doherty notes in his accompanying commentary:

The argument is that if seasonal influenza infection does promote cross-reactive T cell responses, then why do so many people get sick every one or two years? The counter-argument is, of course, that the majority of individuals may be protected from more serious disease by their T cell response.5

If the T cells that are normally present are partially protective, could they be cranked up to offer more protection? For example, what if vaccines (as well as triggering antibody responses) also tried to boost these cross-reactive memory responses? Potentially, this could lead to people who have long-term resistance to many influenza viruses, avoiding the need for annual re-vaccination, as well as having immunity to new influenza viruses that aren’t otherwise covered by the vaccinations; such as avian influenza.

Most influenza vaccines used today are killed (inactivated) vaccines, which are not very good at inducing CTL responses. However, cold adapted live attenuated influenza vaccines (LAIVs) are also used in some cases, and these should act as boosters for CTL:

… it would be worth evaluating the extent of cross-protection against H5N1 potentially conferred by currently available seasonal human LAIVs. Memory T cell populations boosted by these vaccines may in theory cross-react and provide partial protection against H5N1 by targeting highly conserved internal virus proteins. … The aim of such T cell-based approaches would be to provide broader partial protection against overwhelming infection and help lower morbidity and mortality rather than to provide complete protection against establishment of infection. This would be a highly relevant and perhaps more realistic public health goal in a pandemic situation.4


  1. taken from Taubenberger JK, Morens DM. 1918 influenza: the mother of all pandemics. Emerg Infect Dis. 2006 Jan. http://www.cdc.gov/ncidod/EID/vol12no01/05-0979.htm[]
  2. There were influenza pandemics in 1830-33; 1889-1890; and 1900; as well as epidemics in some other years. That was long before influenza virus was identified, and we have no idea what those strains were.[]
  3. Yu X, Tsibane T, McGraw PA, House FS, Keefer CJ, Hicar MD, Tumpey TM, Pappas C, Perrone LA, Martinez O et al. (2008) Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors. Nature[]
  4. Laurel Yong-Hwa Lee, Do Lien Anh Ha, Cameron Simmons, Menno D. de Jong, Nguyen Van Vinh Chau, Reto Schumacher, Yan Chun Peng, Andrew J. McMichael, Jeremy J. Farrar, Geoffrey L. Smith, Alain R.M. Townsend, Brigitte A. Askonas, Sarah Rowland-Jones, Tao Dong (2008). Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals Journal of Clinical Investigation DOI: 10.1172/JCI32460[][]
  5. Doherty PC, Kelso A (2008) Toward a broadly protective influenza vaccine. J Clin Invest doi:10.1172/JCI37232. []