Age profile of H1N1 cases sparks discussion of 'original antigenic sin'

May 28, 2010 (CIDRAP News) – A letter and commentary published this week in Emerging Infectious Diseases explore the idea that "original antigenic sin"—the hypothesis that the first influenza A virus a person encounters in childhood strongly influences his or her immune responses to all related flu viruses encountered later—may explain the partial protection that older people have against the pandemic H1N1 flu virus.

As explained in the letter by Amesh A. Adalja and D. A. Henderson of the University of Pittsburgh Medical Center, original antigenic sin (OAS) holds that a person who is exposed to an influenza A virus in childhood will, in later encounters with related flu viruses, mount an immune response primarily directed at the original virus, even when the newly encountered virus is antigenically different. An implication of the theory is that OAS can trigger an ineffective or less effective immune response when a person is exposed to a virus that's related to the original one.

Because H1N1 viruses circulated continually from 1918 until 1957, most people born before 1957 were exposed to them, Adalja and Henderson write. "According to the theory of original sin, these persons may have partial protection from severe disease from infection with the new influenza virus A (H1N1)," they state.

The accompanying commentary, written by three other experts, generally concurs that OAS may account for the protection older people enjoy but says it is unclear whether the phenomenon is a bane or a blessing overall.

Meanwhile, another virology expert told CIDRAP News that there is conflicting evidence on OAS and that it may not be necessary to invoke such a complex idea to explain older people's immunity to the pandemic virus.

Adalja and Henderson cite a number of animal and human studies that seem to support OAS, which was first proposed by Thomas Francis in 1960. For example, a 1994 study showed that a current flu vaccine strain given to people of different ages generated antibodies to the flu virus that had circulated in each age-group's childhood.

However, they also cite one report pointing the other direction, a 2008 study showing that "monoclonal antibodies generated through vaccination were highly specific to the current vaccine strain rather than to influenza strains that had circulated in the past."

But they suggest that the scarcity of pandemic H1N1 cases in people in their 50s and 60s, particularly in Mexico, the United States, and Australia, supports the OAS hypothesis.

As for the practical implications, flu surge planning assumes a high rate of illness in elderly people, but if the H1N1 age pattern continues, healthcare facilities should also prepare to treat more younger people, Adalja and Henderson write.

In addition, to further explore the OAS hypothesis, they suggest doing studies on people born between 1957 and 1968, when H1N1 viruses were not circulating, to assess their antibodies to the 2009 H1N1 virus and any preexisting immunity to the H1N1 subtype.

The accompanying commentary, by David M. Morens of the National Institutes of Health, Donald S. Burke of the University of Pittsburgh Graduate School of Public Health, and Scott B. Halstead of the Uniformed Services University of the Health Sciences, delves into the nuances of the OAS phenomenon.

The genesis of the theory goes back to 1947, when some college students who had participated in a trial of the 1946 seasonal flu vaccine became infected with a new flu virus, later identified as an H1N1 reassortant. Francis found that the students developed low levels of antibodies to the new virus and higher titers to H1N1 viruses they had encountered previously.

Further research suggested to Francis and colleagues that the dominant antigens—the particular hemagglutinin components that trigger immune responses—of first-infecting viruses can be present as secondary antigens on other flu viruses encountered later. Francis concluded that these antigens "somehow reinforced antibody responses to the original strains at the apparent expense of responses to newer strains."

Later studies show that OAS is a general phenomenon that occurs when hosts are sequentially infected with related virus strains, particularly influenza A and flaviviruses, according to Morens and colleagues. The phenomenon seems most pronounced when the sequential viruses are of "intermediate antigenic relatedness" and antigenically complex and when the time interval between infections is long.

Some recent studies have focused attention on OAS as a possible cause of more severe disease or decreased vaccine effectiveness, the commentary notes. In addition, it has been cited as a possible reason for the mysterious Canadian finding that people who received the 2008-09 seasonal flu vaccine seemed to have a greater risk of 2009 H1N1 infection. (That finding has not been duplicated in other countries.)

Another research team, the commentary notes, also ascribed the age profile of pandemic H1N1 to OAS, but proposed that the hemagglutinins of H1N1 viruses evolving after 1943 changed through glycosylation—the addition of sugar molecules around the antigens—which shielded the antigens and enabled the viruses to evade the immune system.

"However, the possibility that the age structure of pandemic H1N1 2009 infection is due simply to single or repeated exposures to different or differentially exposed hemagglutinin epitopes has not been ruled out," Morens and colleagues add.

They suggest that more light could be shed on the subject by comparing antibody levels and the OAS phenomenon in the various age-groups that were exposed to different H1N1 strains, including the 25 million surviving Americans who received the 1976 swine flu vaccine.

Commenting that the pandemic offers an opportunity to deepen our understanding of the complex epidemiology of influenza, they conclude, "Is original antigenic sin really a sin from which our immune systems need to be saved? Or is it an epidemiologic blessing in disguise? We have much more to learn."

Vincent Racaniello, PhD, a virologist and Higgins Profession in microbiology and immunology at Columbia University in New York City, told CIDRAP News there is conflicting evidence on the existence of OAS in humans and that it may not be needed to explain the low incidence of pandemic H1N1 in older people. Racaniello is also the author of Virology Blog.

He said several studies have shown the antigenic similarity of the pandemic H1N1 virus and H1N1 strains that circulated from 1918 until the 1940s. Researchers have found that mice that were immunized with a 1918-like vaccine were protected from a lethal challenge with the 2009 virus and that the 1918 and 2009 H1N1 virus hemagglutinins have similar three-dimensional structures, he said.

"In other words, there are ample data which explain the protection of older individuals from infection with the 2009 H1N1 virus as a consequence of the relatedness of the HA [hemagglutinin] of the virus with those that circulated during and after 1918," Racaniello commented. "There is no reason to invoke original antigenic sin to explain these observations."

He added that it's not clear "why one would invoke OAS instead of simply [immune] memory."

"OAS is of course a form of immune memory in which the memory response is skewed to the original virus, not the antigenically changed one," he said. "But I don’t think anyone has said that older people preferentially make antibodies against the 1918 virus over the 2009 H1N1, when immunized with the current pandemic vaccine."

Adalja AA, Henderson DA. Original antigenic sin and pandemic (H1N1) 2009. (Letter) Emerg Infect Dis 2010 Jun;16(6):1028-9 [Full text]

Morens DM, Burke DS, Halstead SB. The wages of original antigenic sin. (Commentary) Emerg Infect Dis 2010 Jun;16(6):1023-4 [Full text]

See also:

Apr 6 CIDRAP News story "New Canadian studies suggest seasonal flu shot increased H1N1 risk"

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