BETHESDA, MD—The influenza viruses responsible for the pandemics of 1918 and 2009 share a structural detail that makes both susceptible to neutralization by the same antibodies, according to NIAID researchers. A study that appeared online last month in the journal Science Translational Medicine describes the molecular basis for this shared vulnerability, and suggests how it might be exploited to design vaccines matched to future pandemic influenza virus strains.

In one set of experiments, NIAID scientists injected mice with a vaccine made from inactivated 1918 influenza virus. Then they exposed the mice to high levels of 2009 H1N1 virus. All of the vaccinated mice survived. The reverse was also true: Mice vaccinated with inactivated 2009 H1N1 virus and then exposed to 1918 virus also survived exposure. The researchers concluded that vaccination with either pandemic virus caused the mice to produce antibodies capable of neutralizing the other virus.

Ordinarily, antibodies made in response to one year’s seasonal flu strain do not fully react with, or cross-neutralize, seasonal flu strains that come along just a few years later. This is due in part to slight, yearly changes in the amino acid sequence of hemagglutinin (HA), a viral surface protein. The amino acid sequences of the 1918 and 2009 H1N1 influenza viruses in a portion of HA called the globular head differ by about 20%. That difference is on a par with amino acid divergence in the HA head region among seasonal strains, so the researchers reasoned that antibody cross-neutralization in the pandemic viruses must be due to some feature besides simply the degree of amino acid variation.

In a series of experiments and computer modeling studies, Dr Gary Nabel, MD, PhD, and his team at NIAID determined that both pandemic viruses lack a cap of sugar (glycan) molecules at two specific spots on the top of HA’s globular head. Without these sugars, both the 1918 and 2009 pandemic viruses have unfettered access to the receptors that HA uses to enter human cells. This viral advantage quickly diminishes as the immunity provided by neutralizing antibodies arises in people who have been infected (and recovered) or when people are vaccinated.

In contrast to the 1918 and 2009 viruses, when the investigators analyzed the structure of seasonal flu strains that had circulated between 1977 and 2008, they found that 97.8% had at least one glycan molecule covering the HA’s head, while 87.8% of the strains had two glycans. The glycans create a physical barrier over the virus and prevent antibody neutralization.

Researchers engineered mutant pandemic flu viruses by placing sugar molecules on the two critical regions at the top of the globular head. Once covered, antibodies could no longer recognize and neutralize the virus. However, researchers noted, the sugar-capped viruses did perform well as vaccines.

In their last series of experiments, investigators added sugar molecules to a 1918 influenza virus and vaccinated mice with it. The mice produced antibodies able to neutralize the original, sugar-free version of the 1918 virus. Researchers hope that this knowledge can be used to preemptively design vaccines with glycosylated versions of 2009 H1N1 virus. Such a vaccine would protect against the pandemic virus and limit the virus’s chance of acquiring a sugar shield that would allow it to entrench itself as a seasonal variant.

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