2013

Evolution and control of H5N1: A better understanding of the evolution and diversity of H5N1 flu virus and its host species in endemic areas could inform more efficient vaccination and control strategies
Watanabe Y, Ibrahim MS, Ikuta K.
EMBO Rep. 2013 Feb;14(2):117-22. doi: 10.1038/embor.2012.212. Epub 2013 Jan 11.


A readily readable paper on the state of H5N1 virus infection in poultry with particular attention given to Egypt.

“Unfortunately, it is unlikely that science will ever produce a clear answer as to when, where and how the next pandemic influenza virus will emerge.”

Yet another group of authors coming to the same conclusion.

December 2013

Human infection with avian influenza A H6N1 virus: an epidemiological analysis.
Wei SH, Yang JR, Wu HS, Chang MC, Lin JS, Lin CY, Liu YL, Lo YC, Yang CH, Chuang JH, Lin MC, Chung WC, Liao CH, Lee MS, Huang WT, Chen PJ, Liu MT, Chang FY.
Lancet Respir Med. 2013 Dec;1(10):771-8. doi: 10.1016/S2213-2600(13)70221-2. Epub 2013 Nov 14.

A 20 year old woman with respiratory distress presented to a hospital in Taiwan. An unusual influenza virus subtype was isolated, H6N1 making it the first recorded case. Molecular analysis of the virus identified a G228S mutation in the hemagglutinin (H) surface protein which is generally considered to help hemagglutinin binding to human a2-6 linked sialic acid receptors, although it was not proven here. As a unique clade of H6N1 viruses with a G228S substitution of hemagglutinin have circulated persistently in poultry in Taiwan the case represents another example of a zoonosis, and probably a dead-end infection.

The article concludes with “Our report highlights the continuous need for preparedness for a pandemic of unpredictable and complex avian influenza.” This is an impossible conclusion. Extrapolation from a single point is not possible. Furthermore the “unpredictable and complex nature of avian influenza” has been highlighted before and our ability to predict the next pandemic has been found wanting. 

Nonetheless, it represents an important case report.

October 18, 2013

Gain-of-function research: unproven technique.
Mahmoud A.
Science. 2013 Oct 18;342(6156):310-1. doi: 10.1126/science.342.6156.310-b.

Gain-of-function research: unknown risks.
Rey F, Schwartz O, Wain-Hobson S.
Science. 2013 Oct 18;342(6156):311. doi: 10.1126/science.342.6156.311-a.

Both comment on a H7N9 influenza virus research manifesto that was simultaneously published in both Science and Nature.

Mahmoud says simply that there is nothing in influenza virus gain of function research that will help vaccine makes. This comes form a former President of Merck Vaccines (1999-2005). He is currently Professor, Department of Molecular Biology and the Woodrow Wilson School of Public and International Affairs at Princeton University.

Rey et al., point out that the H7N9 research manifesto is standard virology and that GOF research is not an axiomatic part of virology.

October 11, 2013

Dual use research. Dutch H5N1 ruling raises new questions
Enserink M
Science. 2013 Oct 11;342(6155):178. doi: 10.1126/science.342.6155.178. 

A good discussion of the impact of EU export controls as they pertain to dual use research.

August 7-8, 2013

Avian flu: Gain-of-function experiments on H7N9.
Fouchier RA, Kawaoka Y, Cardona C, Compans RW, Fouchier RA, García-Sastre A, Govorkova EA, Guan Y, Herfst S, Kawaoka Y, Orenstein WA, Peiris JS, Perez DR, Richt JA, Russell C, Schultz-Cherry SL, Smith DJ, Steel J, Tompkins SM, Topham DJ, Treanor JJ, Tripp RA, Webby RJ, Webster RG.
Nature. 2013 Aug 8;500(7461):150-1. doi: 10.1038/500150a.

Gain-of-function experiments on H7N9.
Fouchier RA, Kawaoka Y, Cardona C, Compans RW, Fouchier RA, García-Sastre A, Govorkova EA, Guan Y, Herfst S, Kawaoka Y, Orenstein WA, Peiris JS, Perez DR, Richt JA, Russell C, Schultz-Cherry SL, Smith DJ, Steel J, Tompkins SM, Topham DJ, Treanor JJ, Tripp RA, Webby RJ, Webster RG.
Science. 2013 Aug 7. [Epub ahead of print]

The texts are identical. They outline a research manifesto for human H7N9 influenza A research. As the human outbreak of H7N9 occurred in the spring of 2013 there was great concern as to its future. For comment see October 18, 2013.

August 2013

Considerations regarding appropriate sample size for conducting ferret transmission experiments.
Belser JA, Maines TR, Katz JM, Tumpey TM.
Future Microbiol. 2013 Aug;8(8):961-5. doi: 10.2217/fmb.13.64.

This article addresses the concerns raised by Nishiuria et al. (2013).
PLoS ONE 8(1): e55358. doi:10.1371/journal.pone.0055358

“We agree with these authors that the generally small sample size inherent in conducting ferret transmission research limits some statistical power, and concur that an n = 3 when comparing two groups, in the absence of other supporting data, is often not sufficient to demonstrate significant or meaningful differences in two-sample comparisons.”

“We agree with the premise of the study conducted by Nishiura et al. that sample size is one of many important determinants in achieving an experimental design that yields accurate, repeatable and meaningful results. As differences in experimental protocols, equipment and reagents between laboratories limit our ability to directly compare differences in virus transmissibility between published studies, it is critical for individual studies to contain sufficient data (including but not limited to the number of animals utilized) to reach scientifically sound conclusions. However, by using fewer ferrets to test one particular virus or condition, this allows researchers to perform a greater total number of experiments in a given study. As a result, generalizations can be drawn between fundamental virological properties (such as virus subtypes, or viruses that exhibit antiviral sensitivity versus resistance) with greater confidence that the results are not inadvertently biased due to unintended strain-specific differences or other variances.”

We learn that is it very difficult to “compare differences in virus transmissibility between published studies”. By using fewer animals per experiment “generalizations can be drawn between fundamental virological properties (such as virus subtypes, or viruses that exhibit antiviral sensitivity versus resistance)”. This is far from the initial promises of GOF influenza research agenda.

July 1, 2013

Deadly H7N9 influenza virus: a pandemic in the making or a warning lesson?
Robert A Lamb
Am J Respir Crit Care Med. 2013 Jul 1;188(1):1-2. doi: 10.1164/rccm.201305-0914ED.

This is a clear editorial providing a short description of the mutations encoded by the H7N9 viruses infecting humans. It closes with “it cannot be predicted whether avian/human H7N9 influenza viruses will remain a zoonosis in China or become a global pandemic with dire consequences.”

This is in keeping with other papers discussing the great difficulty in predicting influenza pandemics. Bob Lamb has published more than 140 papers on influenza and its viruses.

June 21, 2013

H5N1 hybrid viruses bearing 2009/H1N1 virus genes transmit in guinea pigs by respiratory droplet.
Zhang Y1, Zhang Q, Kong H, Jiang Y, Gao Y, Deng G, Shi J, Tian G, Liu L, Liu J, Guan Y, Bu Z, Chen H.

Science. 2013 Jun 21;340(6139):1459-63. doi: 10.1126/science.1229455. Epub 2013 May 2.

Comment to be posted.

Sample size considerations for one-to-one animal transmission studies of the influenza A viruses. 
Nishiura H, Yen H-L, Cowling BJ (2013) 
PLoS ONE 8(1): e55358. doi:10.1371/journal.pone.0055358

A very detailed scientific analysis of the number of ferrets needed to generate statistically significant results. 

“The most important caveat in the present study in relation to the common practice is that n = 3 is not enough to show a significant difference as well as Ro>1 for one-sample comparison while it can demonstrate Ro>0. Moreover, comparing a group with n = 3 against a reference group with the same sample size does not allow researchers to demonstrate any significant difference in the transmissibility between two sample groups. If two samples have to be compared, n = 4 would be regarded as minimum, and moreover, k = n for n = 4 and k = n or k= n-1 for n = 5, respectively, would have to be required along with the absence of infected pairs in the control group.”

More prosaically, this says that in an influenza A virus transmission experiment the use of three pairs of ferrets (infected donor and uninfected receiver animal, n = 3) is enough to demonstrate transmission (Ro>0) but not to know whether the virus would spread (Ro>1). If a GOF flu virus is to be compared to a another, say a human influenza virus, a minimum of four pairs of ferrets (n = 4) with all four receiver ferrets becoming infected (k = 4, and hence k = n), would be necessary. If five ferrets were used (n = 5) then a significant result would be obtained if 4 of 5 receiver ferrets were infected (k = n-1 for n = 5).

As n=2 or 3 in the Fouchier and Kawaoka experiments little can be deduced except to say that the viruses were transmitted. Nothing can be said about their potential to spread. In short the conclusions are qualitative.

January 3, 2013

Safety survey reveals lab risks
Van Noorden R.
Nature. 2013 Jan 3;493(7430):9-10. doi: 10.1038/493009a.

The study, which was partly financed by Nature, shows that scientists are overconfident and systematically underestimate risk. This is why scientists need help form outside in assessing risk.