However, the question remains: what made the second wave of the Spanish influenza in the fall of 1918 so lethal? And why were healthy young adults affected so disproportionately? Genetic studies from the resurrected 1918 influenza virus are starting to answer these questions.

Most influenza outbreaks show a mortality curve that is U-shaped, with most victims being either the very young, or very old. The 1918 influenza was unique; its curve is W-shaped, with a high incidence of mortality at the mean of 28 years old. Both younger and older victims had less mortality than was expected for this outbreak as well. It is now suspected that prior contact with earlier influenza strains either strengthened or weakened the immune system of the population at the time, depending on which strain they were exposed to earlier in life.

Influenza attacks the immune system of its host through the hemagglutinin (HA) and neuraminidase (NA) antigens that protrude from its surface. There are 15 different HA shapes and nine NA; this is where virus subtypes get their name H1N1, H5N1, etc. These foreign antigens cause a response in the immune system, which sends defenses to fight off the intruders. Dendritic cells engulf invading antigens and "read" them, then travel to the spleen and lymph nodes, where other white cells "learn" that the new antigens are invaders. They in turn produce killer cells and antibodies to go fight the infection. Enzymes are also released, killing targets, raising body temperatures, and communicating with white blood cells to send them where they are needed. Body aches, a familiar symptom of the flu, are caused by the bone marrow churning out thousands of white blood cells to defeat the invading virus. After an illness, some of these white blood cells "remember" these specific antigens and the person's immune system will recognize and kill the virus off in short order should it invade again. For many diseases, this is enough to render the person immune to the antigen and to the microorganisms that cause it.

Influenza, however, has antigens that mutate very quickly, and the immune system has a difficult time keeping up. This is called "antigen drift.” Antigen drift is the reason a new vaccine is for seasonal flu is required each year; epidemiologists have to guess which strain with which mutations is likely to be the one circulating that year. When the antigens shift, the body no longer recognizes them as invaders, and few people will have immunity to the new virus. In this way a disease can quickly explode in an unprotected population.

A second factor in the virulence of influenza, particularly for young adult victims, was the virus' ability to trigger a "cytokine storm," an immune system overreaction in which cytokines activate immune cells to fight the infection. The immune cells then signal more cytokines to active yet more cells. In some diseases, this can start an unending feedback loop where more and more cells are sent to fight the infection and they in turn signal more cells to come. Because young people have more robust immune systems, they disproportionately suffered from this complication. Cytokine storms caused viral pneumonia, severe Adult Respiratory Distress Syndrome (ARDS), organ failure, and heliotrope cyanosis, in which the patient turned blue due to lack of oxygen in the bloodstream. It could also render the patient vulnerable to opportunistic diseases such as bacterial pneumonia.

A third factor may have been prior exposure to influenza viruses. An H1N8 virus was most likely circulating in the population before 1889, and then after 1900. Individuals who were born before 1889 or after 1900 would have had some immunity against the new H1N1 strain that developed in 1918. In 1889, however, a pandemic of H3N8 influenza broke out. People who were 25-28 years old in 1918 and were born when this virus was circulating would have had immunity to H3 strains, but would have no immunity against H1. This may have been because they were not exposed to the earlier H1 strains, or because exposure to the H3 antibodies during the 1889 pandemic left their immune systems no longer able to recognize the H1 strains and effectively combat them. The high mortality rate described by the "W" shaped distribution supports this theory.