new suggested vaccine strain

[gsgs]

average number of differences in a pair of
H5N1-PB2

year,differences,pairs considered
---------------------------------
1997: 107.8   961
1998: 00.00     1
1999: 15.84    25
2000: 81.96   100
2001: 73.89  1849
2002: 82.86  2401
2003: 63.47  3969
2004: 73.85 20736
2005: 97.28 58081
2006: 78.19 71289
2007: 76.42  6561
2008: 68.73    49

the recent decline is because H5N1 concentrates to 2 or 3 strains
recently and because Indonesian sequences from 2007,2008
are missing. However the diversity inside the same strain is
usually increasing

differences in PB2 between pairs of some proposed vaccine strains:

                                           1   2   3   4   5   6   7   8   9  10  11  12  13  14  15  16 
---------------------------------------------------------------------------------------------------------
  1 >A/HK/156/97(H5N1)                     0 318 312 312 323 296 321 319 321 308 318 294 301 302 321 303 
  2 >A/VNM/1194/04(H5N1)                 318   0  23  60  63 170  62  55  62  22  56 162 163  36  58  27 
  3 >A/VNM/1203/04(H5N1)                 312  23   0  61  62 176  63  56  63  25  57 169 172  35  59  30 
  4 >A/IDN/5/05(H5N1)                    312  60  61   0  72 203  81  74  81  61  76 186 186  35  87  45 
  5 >A/human/Zhejiang/16/06(H5N1)        323  63  62  72   0 195  77  67  77  51  71 187 192  50  72  44 
  6 >A/China/GD01/06(H5N1)               296 170 176 203 195   0 194 186 194 167 189  16  64 172 192 161 
  7 >A/Shenzhen/406H/06(H5N1)            321  62  63  81  77 194   0  48   0  58  49 188 191  56  50  51 
  8 >A/Turkey/15/06(H5N1)                319  55  56  74  67 186  48   0  48  51  12 181 182  52  19  46 
  9 >A/human/China/GD02/06(H5N1)         321  62  63  81  77 194   0  48   0  58  49 188 191  56  50  51 
 10 >A/HK/213/03(H5N1)                   308  22  25  61  51 167  58  51  58   0  52 159 164  26  54  17 
 11 >A/turkey/Turkey/1/05(H5N1)          318  56  57  76  71 189  49  12  49  52   0 183 183  51  17  45 
 12 >A/Jap.white-eye/HK/1038/06(H5N1)    294 162 169 186 187  16 188 181 188 159 183   0  60 164 186 153 
 13 >A/Gs/Guiyang/337/06(H5N1)           301 163 172 186 192  64 191 182 191 164 183  60   0 165 188 158 
 14 >A/Dk/Hunan/795/02(H5N1)             302  36  35  35  50 172  56  52  56  26  51 164 165   0  52  20 
 15 >A/Ck/India/NIV33487/06(H5N1)        321  58  59  87  72 192  50  19  50  54  17 186 188  52   0  47 
 16 >A/Dk/Guangxi/50/2001(H5N1)          303  27  30  45  44 161  51  46  51  17  45 153 158  20  47   0 
---------------------------------------------------------------------------------------------------------
                                           1   2   3   4   5   6   7   8   9  10  11  12  13  14  15  16 

Glaxo's Prepandrix: 23(VNM),60(IDN),56(TRK),63(ZHE),58(IND)
Gx50:               30(VNM),45(IDN),45(TRK),45(ZHE),47(IND)

for HA:

                                 1   2   3   4   5   6   7   8   9  10
-----------------------------------------------------------------------
 1 A/Dk/Guangxi/50/01            0  32  32  43  52  44  59  43  61  47
 2 A/VNM/1194/04                32   0  14  59  66  60  79  59  73  65
 3 A/VNM/1203/04                32  14   0  57  68  58  76  57  75  63
 4 A/Anhui/1/05                 43  59  57   0  62   6  91  16  73  61
 5 A/turkey/Turkey/1/05         52  66  68  62   0  63  96  62  26  66
 6 A/Dk/Laos/3295/06            44  60  58   6  63   0  92  17  74  62
 7 A/Gs/Guiyang/337/06          59  79  76  91  96  92   0  89 104  93
 8 A/Jap.white-eye/HK/1038/06   43  59  57  16  62  17  89   0  75  59
 9 A/Egypt/2321-NAMRU3/2007     61  73  75  73  26  74 104  75   0  74
10 A/IDN/5/05                   47  65  63  61  66  62  93  59  74   0

Glaxo's Prepandrix: 14(VNM),65(IDN),66(TRK),59(ANH)
Gx50:               32(VNM),47(IDN),52(TRK),43(ANH)


I ask WHO to test antigenicity of 
A/Dk/Guangxi/50/2001(H5N1) as a vaccine-candidate in ferrets
and compare it with the other H5N1-vaccine candidates 
and to publish the results !

 

[HenryN]

Re: new suggested vaccine strain

Why would WHO want to go backwards and use a 2001 isolate? By definition, each isolate that originated with A/Dk/Guangxi/50/2001 would have the early set of polymorphisms plus more.

 

[gsgs]

Re: new suggested vaccine strain

imagine the viruses as points on an expanding sphere.
The distance between two random points on the sphere(2008) is larger
than the distance from one random point to the center=sphere(2001).

 

[HenryN]

Re: new suggested vaccine strain

imagine the viruses as points on an expanding sphere.
The distance between two random points on the sphere(2008) is larger
than the distance from one random point to the center=sphere(2001).

Virus evolves AWAY from earlier strains. The older the strain, the less in common with current strains.

 

[Sally Furniss]

Re: new suggested vaccine strain

Evolution is the cumulative changes that occur over time within a population. Two strains cannot move in diametrically opposite directions if evolutionary pressures are the same for each strain.

 

[gsgs]

Re: new suggested vaccine strain

I think, flu almost does.
At least on the nucleotide level.

When one strain infects two hosts and both variations
survive, then their difference after time t is almost
the same as the difference between a virus and its descendents
after time 2*t

I haven't examined yet, how well it works on the protein-level
where the selection-constraints are larger, as you wrote.

 

[AlaskaDenise]

Re: new suggested vaccine strain

gs:

Your proposals seem to be based on the assumption that influenza acts according to predictable mathematical models, with little or no non-mathematical criteria. Papers I've read that include statements to effect that even the best experts don't understand all the logic behind its activity. Could you supply sources showing that influenza activity is determined by predictable mathematical principles.

.

 

[Oracle]

Re: new suggested vaccine strain

Antigenic Cartography_ Visualizing Viral Evolution for Influenza Vaccine Design.
http://en.oreilly.com/et2008/public/schedule/detail/2408 (pdf is ~10MB), presentation zip file

See also:
http://antigenic-cartography.org/
http://radar.oreilly.com/2008/05/antigenic-cartography-flu-maps.html

Mankind has been fighting influenza for thousands of years. The 1918 pandemic killed 50-100 million people. Today, influenza kills roughly half a million people each year. Because the virus evolves, it is necessary for vaccines to track its evolution closely in order to remain effective.

Antigenic Cartography is a new computational method that allows a unique visualization of viral evolution. First published in 2004, the technique is now used to aid the WHO in recommending the composition of human influenza vaccines. It is also being applied to the design of pandemic influenza vaccines and to the study of a variety of other infectious diseases.

The rise of Antigenic Cartography is a remarkable story of how recent immunological theory, mathematics, and computer science have combined with decades of virological and medical research and diligent data collection to produce an entirely new tool with immediate practical impact.

 

[AlaskaDenise]

Re: new suggested vaccine strain

Thanks. (off to do some reading)

The "immunological theory" may still be the variable in the equation.

.

 

[gsgs]

Re: new suggested vaccine strain

not "predictable". Just statistically it's more likely to fit to next year's strains
when it's close to this year's strains .
But for H5N1 we have several strains while current strategy is to take one
monovalent vaccine and hoping for cross-protection should another strain
go pandemic.
USA actually stockpiles different prepandemic H5N1-vaccines targeting different strains.

Using the Guangxi/50 strain would presumably give better crossprotection
to more strains. It's closer to a universal /2008(H5N1)-vaccine with Qinghai,
Indonesia,Vietnam/Thailand,Fujian strains also many others in China.
The downside is, that no current strain is targeted directly,
so it will never fit "really good".
It's worth testing. I (or someone else...) should also maybe examine the
protein-sequences of the antigenic sites directly or the epitopes directly

 

[Oracle]

Re: new suggested vaccine strain

Bioinformatics models for predicting antigenic variants of influenza A/H3N2 virus. Bioinformatics 2008 24(4):505-512. Contact: hsiung{at}nhri.org.tw

Abstract
Motivation: Continual and accumulated mutations in hemagglutinin (HA) protein of influenza A virus generate novel antigenic strains that cause annual epidemics.

Results: We propose a model by incorporating scoring and regression methods to predict antigenic variants. Based on collected sequences of influenza A/H3N2 viruses isolated between 1971 and 2002, our model can be used to accurately predict the antigenic variants in 1999?2004 (agreement rate = 91.67%). Twenty amino acid positions identified in our model contribute significantly to antigenic difference and are potential immunodominant positions.

 

[AlaskaDenise]

Re: new suggested vaccine strain

from: http://antigenic-cartography.org/cam/ac.html

Antigenic cartography has subsequently become an established method in the WHO influenza vaccine strain selection process.

Is the cause of the 2007/2008 influenza vaccine due to bad data or a less-than-perfect antigenic mapping?

...the WHO global influenza surveillance network is the most extensive for any pathogen and provides close to a real-time picture of the global evolution of influenza virus...

It's great that they can provide such an up-to-date picture. How much of an impact is made by countries unable or unwilling to track outbreaks & accurately test influenza?

.

 

[Oracle]

Re: new suggested vaccine strain

At *most*, vaccines that are highly efficient as viral deterrent will provide 70% curb on vaccinated population outbreaks. For many reasons, vaccination may not provide adequate protection within treated individuals who are quite susceptible to infection. With that figure in mind, typical efficiency, year to year, is between 55-65% and in a poor match year, is below 50%.

We have a couple of threads on POF that discuss recent influenza viral strain evolution and serial decisions on trivalent vaccine composition recommendations by the CDC that may possibly have affected both vaccine efficacy and emergence of anti-viral resistance polymorphisms.

Combination of technical difficulties with vaccine production, including contamination and slow growth (H3N2) of new strains, and a willingness to go with the status quo (previously used strains) because data suggested that they were still a good match, are likely reasons for poor match (there are others).

Your question on the effects of failure to test, monitor and report seasonal influenza morbidity and mortality among the population is a good one.

The obvious problem lies in failure of multiple developing nations within regions to provide this information for *any* endemic/epidemic illness that periodically occurs, and it's particularly dangerous for emerging infectious diseases, because you can't properly assess and study infection dynamics common to regions, in order to treat and prevent specific illness in the South Pacific, Eastern and Central Asia, Eastern and Central Europe, Africa and South America.

More than a dozen heavy-hitting infectious diseases have been rolling towards full blown pandemic status, some with alarming new symptoms that dramatically increase mortality, within the past few decades.

Even more alarmingly, we are seeing re-emergence of formerly vaccine-eradicated infectious childhood diseases in developed nations, for several reasons, the most obvious is which that they are reintroduced by (1) parental vaccine risk fears and resistance to vaccination for their children and (2) poorly controlled disease in dirt-poor developing nations that have significant population efflux driven by stark poverty, drought and malnutrition, government corruption, mass starvation, and chronic ethnic/political strife.

Where monetary resources are stretched to provide basic municipal services for clean water and adequate sanitation in urban areas (never mind rural), there is very little left in the public money pot to monitor and report for diseases that are "down on the list" for causing mass morbidity, as these regions attempt to deal with not many emerging infectious disease threats to humans and animals.