Pandemic Influenza A (H1N1)

Since the first reports in April 2009 of human infection by a novel influenza A (H1N1) virus, genetically related to swine influenza viruses, the majority of reported illness has been in younger people aged less than 30 years presenting with mild symptoms.

It is striking in countries with robust epidemiological surveillance that the elderly population has showed only low levels of illness. However, approximately 2 per cent of patients have developed more severe illness and deaths have been associated with the infection, mainly among adults aged 30 to 50 years, many having underlying medical conditions.

The sustained spread of the virus outside North America, particularly in southern hemisphere countries, such as Australia and Chile, led the WHO to raise its influenza pandemic alert from phase 5 to 6 on 11th June and declare that the virus was causing a pandemic. The virus spread throughout the world over the summer and autumn months of 2009 and by the beginning of 2010 activity was declining in most parts of the world. As of the spring of 2010 virus circulation was detected predominantly in West Africa and South East Asia. In total over 213 countries or overseas territories have reported laboratory-confirmed pandemic A(H1N1) infection and globally a total in excess of 160 000 deaths have been associated with pandemic A(H1N1) with approximately 10% of these being laboratory confirmed.

The pandemic H1N1 virus is related to swine influenza A (H1N1) viruses recently circulating in pigs in North America and Europe/Asia. Its genetic makeup is a mixture of genes from viruses circulating in the two geographical regions and comprises six genes, including the haemagglutinin, similar to those of the American 'triple reassortant' swine viruses and two genes encoding the neuraminidase and matrix proteins, similar to those of Eurasian swine viruses. This virus was not previously detected in animal or human populations. Subsequently outbreaks in pig herds in Canada in May and in Argentina in June have been reported; however the sources of the infections have yet to be established.

Of the two classes of anti-influenza drugs, the viruses are sensitive to the neuraminidase inhibitors oseltamivir and zanamivir, but resistant to the M2 inhibitors amantadine and rimantadine. A few sporadic detections of oseltamivir-resistant pandemic H1N1 viruses, 267 as of March 2010, have been reported mainly from countries in which Tamiflu has been used as a prophylactic medicine or for treatment. All resistant viruses carry the H275Y amino acid substitution in their neuraminidase. There have been only a few episodes in which transmission of the resistant virus has been suspected. Nucleotide sequence analysis of the HA genes shows that viruses resistant to Tamiflu do not cluster in phylogenetic trees but represent sporadic development of resistance. No resistance to zanamivir has yet been reported.

The Worldwide Influenza Centre has received more than 1700 clinical specimens and virus isolates from some 50 countries for identification and analyses of the pandemic A(H1N1) virus. Full genome sequencing of a selection of the viruses has shown that they are similar to viruses isolated in other parts of the world and no reassortment with other human or animal viruses has been detected.

There have been few common amino acid substitutions in the HA or NA - many of the viruses which possess the substitutions V106I and N148D in NA also have the substitution S203T in HA. Haemagglutination inhibition (HI) assays using post-infection ferret antisera have also shown that recent isolates continue to be antigenically similar to the prototype virus A/California/4/2009 and the vaccine virus A/California/7/2009. Changes at positions 154 to 156 of the HA have been observed to reduce reactivity with reference sera but the decreased antigenic reactivity seem likely to be associated with virus isolation and propagation in a particular cell line rather than representing circulating antigenic variants.

Amino acid substitution at residue 222 of the HA has been observed in a significant number of cases; substitutions D222E and D222G being the most common. The D222E substitution has been observed in viruses from around the world and has very little affect on antigenicity. Viruses carrying the D222G substitution have been isolated from many individuals with severe infection but this substitution has not been observed in all severe cases and is not always associated with severe outcomes of infection.

The viruses analysed around the world have shown a high level of genetic conservation, as illustrated in phylogenetic trees of the HA gene and the NA gene. The HA tree also illustrates that oseltamivir resistant viruses do not cluster phylogenetically, whilst in the NA tree clustering of the resistant viruses can be observed but this phylogenetic clustering is driven by the mutation in the NA gene responsible for the resistant phenotype.

Other Influenza A virus sub-types

Following the pandemics of 1957 (H2N2) and 1968 (H3N2) the new pandemic virus replaced the previously circulating virus (H1N1 in 1957 and H2N2 in 1968). It is striking that the vast majority of viruses sent to the Collaborating Centre have been the pandemic A (H1N1) 2009 virus with very few seasonal H1N1 viruses being received. H3N2 viruses have also been received in smaller numbers, but H3N2 activity has been seen in several countries. It is too early to say whether the pandemic H1N1 virus will replace either the older seasonal H1N1 viruses and/or the H3N2 viruses.

Acknowledgements

We acknowledge the efforts of the many scientists who have deposited sequence data to the GISAID Epiflu and GenBank databases, from which sequences of recent viruses were obtained for these analyses.