1918 Again? – Part 1

For the past week or so, there have been a series of press reports discussing the remarkable similarity between the 1918 H1N1 virus (Spanish flu) and the 2009 pandemic H1N1 virus. Sometimes press reports do a good job summarising scientific papers. This is not one of those times.

To be fair to the reporters covering this work, this is a complex story that does not lend itself to quick newspaper articles. Several features of this story complicate its telling. First, there are *two* scientific papers on this subject by different groups of investigators who use different methodologies. Second, there are at least two “perspectives” on these papers written by commentators on the work. Finally, there have been a variety of interviews with some of the authors of the studies. The end result is that the actual results of the studies have been thoroughly mixed with speculation by the authors, by commentators and by reporters. No wonder, then, that it is difficult to discern what we actually know for sure about the similarities between these two viruses and how they came to be.

Let us first focus on what the studies have established. The first study, from Terrence Tumpey’s laboratory at the CDC and Gary Nabel’s laboratory at the NIAID, looked at the the ability of vaccines against various flu viruses to protect mice against a usually lethal dose of pandemic 2009 H1N1 virus. All 8 mice given phosphate buffered saline (a negative control) instead of vaccine died when inoculated with a high dose of pandemic 2009 H1N1 virus. All 8 mice vaccinated with A/Panama/2007/1999 (H3N2) also died when inoculated with pandemic 2009 H1N1 virus. 1 out of 8 mice vaccinated with A/New Caledonia/20/1999 (H1N1) and 2 out of 8 mice vaccinated with A/Brisbane/59/2007 (H1N1) survived after being infected with pandemic 2009 H1N1.  All 8 mice immunised with A/Mexico/4108/2009 survived infection with this virus. Thus, the recent H3N2 vaccine offered no demonstrable protection, while the two recent H1N1 viruses offered poor protection against pandemic 2009 virus. Vaccination against the pandemic 2009 virus provided complete protection against it. So far, no surprises. However, when the investigators immunized the mice with A/South Carolina/1/1918 (H1N1), they discovered that all 8 mice survived what should have been a lethal dose of pandemic 2009 pandemic H1N1. To summarise, vaccination against recent H3N2 and H1N1 flu viruses provided little or no protection against pandemic 2009 H1N1, but vaccine against a virus from 90 years ago offered full and complete protection. This is surprising, to say the least.

The authors of this vaccine study did additional studies to determine what the 1918 and and 2009 H1N1 viruses had in common. These experiments led the scientists to focus on one viral gene – hemagglutinin (HA). The protein from this gene is involved in helping the virus to bind to the host cell. This protein is also a favored target of the host immune system. Both sequence analysis and experiments provide some support for the idea that the 1918 and 2009 pandemic flu viruses lack glycosylation sites present in many other flu viruses. Glyans are sugars which can attach to glycosylation sites on HA proteins. The authors *speculated* that pandemic strains of flu acquire glycosylation sites to evade immune recognition by hosts, over time. A note added in proof, essentially a late-breaking discovery, reported the presence of mutations that would add  a glycosylation site to the HA gene of four new strains, A/Beijing/SE2649/2009, A/Russia/178/2009, A/Russia/180/2009 and A/Salekhard/01/2009. Although the authors present this information without comment, the implication is that “escape mutants”, viral strains that will prove resistant to vaccines or previous exposure to the virus, may already be emerging in China and Russia.

More tomorrow.

Reference

Wei et al. (2010) Cross -Neutralization of 1918 and 2009 Influenza Viruses: Role of Glycans in Viral Evolution and Vaccine Design. Science Translational Medicine.

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