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Application of Virological Risk Assessments: US Department of Health and Human Services (HHS) sponsors clinical trials of a vaccine targeted to a novel A(H3N2)v influenza strain

17 Jan 2012

The US Department of Health and Human Services (HHS) recently announced that it has asked for clinical trials of a vaccine targeted against the novel A(H3N2)v triple reassortment viruses infecting some people in the USA.[1] The United States the Centers for Disease Prevention and Control (CDC) has prepared the virus for vaccine development and made the resulting product available to any interested manufacturer or institution. [2] Following that the US Government has asked two manufacturers (Sanofi Pasteur and Novartis) to produce investigational vaccine lots for undertaking trials.[1] As these are novel influenza viruses their movement within the Global Influenza Surveillance and Response System can be tracked through WHO’s Influenza Virus tracking Mechanism.[3]

A(H3N2)v is the shorthand agreed by the WHO, the Food and Agriculture Organisation (FAO) and the World Organization for Animal Health (OIE) for swine-origin triple reassortant  A(H3N2) viruses that include a segment of M-gene from A(H1N1)pdm09 viruses (the 2009 pandemic influenza virus).[4,5] These viruses have recently infected some people in the US but their main reservoir is thought to be pigs in North America.[4]  Surveillance data on influenza in pigs in North America are scanty and most is known about the distribution of these viruses through  their transmitting over to humans in the USA and then those infections being detected and reported to CDC, which maintains an invaluable repository of guidance and data on these viruses.[6] The viruses are not well adapted to humans hosts and only occasionally result in short chains of human to human transmission.[4] ECDC published two Public Health Developments on the topic, on 28th October 2011 and 25th November 2011 and then covered them as novel infections in a fuller risk assessment published on November 2011.[7] It has to be appreciated that though surveillance of influenza viruses in pigs is weak on both sides of the Atlantic the viruses circulating in pigs seem to be quite different between the two continents. There is no evidence of triple reassortant influenza viruses in general or A(H3N2)v specifically in pigs in Europe as shown by the swine influenza surveillance programmes supported on European Commission Research funding, [ESPNIP 2 and ESPNIP 3].  However while these viruses may not be circulating in the European pigs at present, if they adapted to humans and emerged as a human pandemic strain in the US they would come to Europe quickly. Hence indirectly Europe gains from the United States initiatives in that if the viruses did start to be found in pigs in Europe at least these vaccines will have had initial trials by companies that have influenza vaccine production capacity in Europe.

The ECDC risk assessment mentioned that there is evidence that some people in Europe may have considerable immunity to the viruses because of antigenic similarities with other human viruses. This statement stems  from innovative work undertaken by French researchers in the autumn of 2011.[7] They speedily drew on the virus sequences published in a publicly accessible database (Epiflu) by American colleagues under the GISAID mechanism and then inferred the likely human immunity based on genetic comparisons. They concluded that many older people in Europe would probably have immunity to an A(H3N2)v influenza that adapted to humans. This work was subsequently subjected to peer-review and published in the journal EuroSurveillance.[8]  

ECDC Comment  (17 January 2011)

One of the post-hoc criticisms following the A(H1N1) pandemic was that authorities should have had a novel A(H1) vaccine programme ready. If that had been the case vaccine production might have started immediately in the Spring of 2009, rather than having to go through the time consuming development phase which can take up to six months. This was an unfair criticism since the A(H1N1)pdm09 virus had never been observed before the start of 2009, even in pigs.  However it raised the question over which of a number of animal influenza viruses families and previous human viruses: A(H2), A(H7), A(H9) etc  should go forward through the early stages of vaccine development?  The simplistic answer “all of them” is unrealistic since the early stages of development are all resource intensive in terms of person time and monies. One has to be selective, identifying influenza viruses that deserve to go forward for development of vaccines. This process of prioritisation can be called Virological Risk Assessment

In the Autumn of 2011 international researchers and agencies attended a meeting in Washington DC organised by CDC at which a tentative formalised virological risk assessment procedure was put forward and discussed.  It was proposed to have an internationally standardised approach, based on ten or so parameters from virological, animal and human studies. This information would be used in combination to prioritise which of the many animal influenza circulating viruses are justified to pressing ahead with to selecting a seed strain, developing a vaccine and reagents and undertaking clinical trials. Reports and details are now being worked through from that meeting and should be published in due course. Working along the same lines EFSA made a call for tender in 2011 and has awarded funding to a EU project which will be called Flurisk and this is starting this year. Among other objectives this will undertake work that produces data useful for prioritising viruses for vaccine development.   


  1. CIDRAP Influenza update.  HHS orders novel H3N2 vaccine for clinical trials. January 6th 2011. 
  2. CDC Iowa Reports Novel Influenza Infections in Three Children November 22, 2011
  3. WHO Influenza Virus Traceability Mechanism (IVTM)   
  4. CDC Influenza A(H3N2)v transmission and guidelines – Five states 2011. MMWR January 6, 2012 / 60(51);1741-1744
  5. WHO-FAO-OIE – Joint announcement,  Standardization of terminology for the variant A(H3N2) virus recently infecting humans 23 December 2011
  6. CDC Information on H3N2 variant influenza A viruses
  7. ECDC Risk Assessment 'Swine-origin triple reassortant influenza A(H3N2) viruses in North America', 29 November 2011
  8. Lina B, Bouscambert M, Enouf V, Rousset D, Valette M, van der Werf S. S-OtrH3N2 viruses: use of sequence data for description of the molecular characteristics of the viruses and their relatedness to previously circulating H3N2 human viruses. Euro Surveill. 2011;16(50):pii=20039.
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