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Are Immune Complexes Responsible for Severe Cases of 2009 H1N1 Influenza?

By Amesh A. Adalja, MD, December 17, 2010

Many hypotheses have been advanced to explain the severe pathology seen in some cases during the 2009 H1N1 pandemic, among them: cytokine storms, enhanced viral replication, and genetic changes in the virus. A paper by Monsalvo and colleagues just published in Nature Medicine suggests that the presence of immune complexes may in fact be responsible.

The Role of Cross Reactive Antibodies

The 2009 pandemic strain of H1N1was antigenically distinct from the seasonal H1N1 strains that had been circulating since 1977. It was more similar to H1N1 strains in circulation from 1918 through 1957. After the H2N2 pandemic of 1957, H1N1 viruses disappeared until 1977. Given the length of time that H1N1 viruses were circulating globally, it was expected that the population would possess antibodies that would cross react to a greater or lesser extent to the novel 2009 H1N1 virus.

As the 2009 virus was genetically and antigenically much closer to older influenza viruses, antibodies of individuals who were exposed only to recent seasonal H1N1 viruses would be less avid than those of the older generation (ie, those exposed to H1N1 viruses between 1918 and 1957). Avid antibodies would be expected to protect an individual from infection; less avid antibodies may not provide protection, and may actually promote the creation of potentially harmful immune complexes. The researchers examined the possible role of immune complexes comprising less avid antibodies in the pathogenesis of severe 2009 H1N1 disease.

Precedents with RSV and Measles

In other diseases, less avid antibodies have been shown to trigger the deposition of immune complexes, causing a complement-mediated inflammatory process that results in severe disease. Prior work by members of the same research team has shown that this phenomenon was active in severe cases of RSV that followed administration of an RSV vaccine and also in cases of atypical measles following measles vaccination. In both examples, the antibodies generated by the vaccines were not avid enough to prevent infection and, instead, precipitated the formation of immune complexes.

Antibody Avidity, Immune Complexes, and Complement

The research team compared the antibody avidity to 2009 H1N1 of middle aged and elderly adults and found that the antibodies present in middle aged subjects were less avid to the 2009 H1N1 virus. Because of prior associations of less avid antibodies with enhanced disease, the researchers looked for evidence of immune complex disease.  Immune complexes are harmful through activation of the complement pathway; therefore, lung specimens from fatal cases were examined for the presence of a complement breakdown product (C4d). C4d was found in abundance in the lungs of fatal cases of 2009 H1N1 but was not detected in prior fatal cases of seasonal strains of influenza. Immune complexes were also detected in the respiratory secretions of 2009 H1N1 patients, and patients admitted to ICUs had higher levels of immune complexes than did those who were admitted to regular nursing floors. Patients with more severe symptoms demonstrated lower complement levels (C3) than moderately ill patients, indicating higher levels of activation of the complement system.

Using archived samples of lung from the 1957 H2N2 influenza A pandemic, the research team demonstrated the presence of complement (C4d) in fatal cases from this prior pandemic strain.

Greater Understanding to Inform Planning

The study provides evidence that some severe cases of influenza during the 2009 H1N1 and 1957 H2N2 pandemics might have been related to antibodies with diminished avidity and pathology induced by immune complexes. This mechanism likely depends on prior exposure to somewhat similar but antigenically distinct strains. Other severe cases of influenza may depend on different mechanisms of pathogenicity. The majority of deaths from the 1918 influenza pandemic have been attributed to secondary bacterial pneumonia, while the majority of deaths from the H5N1 virus have been attributed to characteristics of the virus that enhance its replication. As understanding of the host-pathogen relationship in humans grows, so will understanding of the nature of pandemic influenza, which will, in turn, inform pandemic planning.


Monsalvo AC, Batalle JP, Lopez MR, et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nature Med 2010. Accessed December 10, 2010.