Update 5. I compared the amino acids in the putative protective antibody binding sites, and tentatively conclude that while there may be a little cross-protection between the vaccine H1N1 and the epidemic H1N1, there’s not likely to be a lot.
Update 4.5: This is getting way past tl;dr territory, so I’m going to show my work in this post but add another post to give just the summary is what I’m doing and concluding
Update 4: Looked at conserved residues to try to validate Gerhard’s epitope prediction. Conserved areas seem consistent with his conclusions
Update 3: Quick comparison of Gerhard’s prediction of antigenic sites, vs. the differences between the vaccine and the epidemic H1N1
Update 2: Added reference and figure from Walter Gerhard’s 1982 analysis of antibody epitopes of H1 hemagglutinin.)
The regular influenza vaccine this year included an H1N1 virus. Will that protect against infection with the new H1N1 strain? (See what I did there? I didn’t say “swine flu.”) (Oops.)
I’ve seen several statements in the media that the vaccine won’t protect, but I haven’t seen any explanation why not. (If anyone knows more about how it was determined that the vaccine wouldn’t give much cross-protection, and who said it, please let me know.) But it wouldn’t be surprising if there wasn’t much cross-protection; two different H1s can be significantly different.
(I’m assuming that most people who are interested in this are at least generally aware of the H and N nomenclature and so on. If not, The Virology Blog has a brief outline of the structure of influenza here, and there are primers on influenza at The Flu Wiki here, here, here, and here.)
My first question was, How similar is this H1N1 to that in the current vaccine? (This isn’t going to definitively answer the question of cross-reactivity, but it can give us some pointer. This year’s vaccine included the following viruses (here’s the WHO page with a link to a PDF with more info):
- an A/Brisbane/59/2007 (H1N1)-like virus;
- an A/Brisbane/10/2007 (H3N2)-like virus;
- a B/Florida/4/2006-like virus.
So what’s the Brisbane H1N1 look like? How close is it to the epidemic H1N1? The answer is, Not very. I ran a quick-and-dirty alignment and phlyogenetic tree of the three vaccine virus HA proteins (not nucleic acids here because we’re interested in what antibodies might see). The vaccine strain is only 79% identical to the present strain, which isn’t terrible but isn’t very good either. (Quick update for context:The H3 hemagglutinin in the vaccine is around 45% identical to the H1; we know there’s almost no cross-reactivity between these types. The HA from the B/Florida/4/2006, a B rather than an A strain and expected to very quite different, is about 30% identical.) The phylogenetic tree shows that the present viruses are, as we already know, tightly clustered and relatively distant from the vaccine H1N1.
I’m not an antibody guy (or, as I keep pointing out, an influenza guy) but I believe there’s something known about where on HA and N the main neutralizing antibody recognition sites are. If I find time through the day (may not happen; I have meetings in the morning, and this afternoon I’m volunteering at my son’s Grade 3 science class) I’ll try to track that down and see if we can predict neutralzing antibody cross-reactivity between the vaccine strain and the epidemic H1N1.
Update 2. Walter Gerhard published a paper in 19821 looking at major binding sites on H1. Here’s the most relevant figure from his paper — later today I’ll look at how this compares to the presence H1N1 virus protein.
Update 3: Gerhard says the most important antibody binding sites on H1 are what he defined as the Sa, Sb, Ca1, Ca2, and Cb sites, with the Sa site being the most important. Here’s the relevant residues. They refer to the PR8 influenza strain, so to see how our H1s compare I will have to dig the sequence of that one up (I have it somewhere already, since I use the hemagglutinin in the lab as a marker quite a bit, but I won’t have time for that for a couple of hours):
|Site name||Amino acids involved (by residue number)|
|Sa||124, 158, 129, 160, 161, 162, 163|
|Sb||152, 155, 188, 189, 192, 194|
|Ca1||165, 169, 178, 203, 236, 270|
|Ca2||136, 139, 141, 220, 221|
|Cb||70, 71, 73, 74, 75, 115|
Update 4: To look at Gerhard’s conclusions from a different viewpoint, I looked at conserved residues within influenza H1s. My reasoning here is that areas in the hemagglutinin that are vulnerable to antibodies will be rapidly selected against, and therefore will be lesat conserved. In other words, the amino acids that are most different from each other, in different flu strains, are most likely to be antibody epitopes. I downloaded a thousand or so H1 protein sequences, and ran a python script to determine amino acid frequency at each position, then plotted it out. Here is frequency (Y axis) vs. position (X axis) for the first third of H1. A completely conserved amino acid will have a frequency of 100, less than that means variable. I’ve boxed the Sa region that Gerhard says is likely the most important antibody target. As you can probably see (click for a larger version), this region is also highly non-conserved — presumably the result of selection at that region to avoid antibody responses. So this is consistent with Gerhard’s conclusion and I’m willing to go with those regions as antibody binding sites.
Update 5. Assuming that those sites are actually the important antigenic sites — and also assuming I didn’t lose track of numbering and forget what I was doing ( this was run in between volunteering at one son’s Grade 3 science class, getting dinner ready, taking son 1 to soccer practice, picking up son 2, picking up son 1 from soccer practice, working on dinner, and, oh yes, doing the work I actually have to do) — the result isn’t completely clear — but my guess would be that the vaccine H1N1 would confer some, but not a lot, of protection against the epidemic H1N1.
Here’s the table showing the vaccine amino acids (“Bris”) vs the epidemic amino acids (“Tex”) in each of the putative protective antibody-binding sites.
I’ve highlighted differences in pink, identities in green. You can see that of the five antibody-binding sites, four are really very different, while one is quite similar. Even in that one, the single difference, from Ser to Pro, is a drastic change that would probably significantly reduce antibody binding. So most antibodies wouldn’t bind well to the new H1N1. However, the most similar region (“Sa”) is the one that Gerhard flagged as the most important for antibody binding, so I’m leaning to the concept that there probably will be a little bit of cross-protection, but not a lot.
The phylogenetic tree includes three of the present H1N1 strain, plus the three components of this year’s vaccine (click for a larger version):
Here’s the alignment, the A/Texas/05/2009(H1N1) isolate from the present outbreak and the A/Brisbane/59/2007(H1N1) from the vaccine (let’s see if I can make the fonts work out properly so I don’t have to paste in an image here; you may need to play with your browser window to stop the lines from wraping and let them line up .. yeah, that’s ugly, but it’s the best I can do for now):
A/Texas/05/2009(H1N1) vs. A/Brisbane/59/2007(H1N1) Identities = 449/566 (79%), Positives = 497/566 (87%), Gaps = 1/566 (0%) Texas 1 MKAILVVLLYTFATANADTLCIGYHANNSTDTVDTVLEKNVTVTHSVNLLEDKHNGKLCK 60 MK L+VLL TF ADT+CIGYHANNSTDTVDTVLEKNVTVTHSVNLLE+ HNGKLC Brisb 1 MKVKLLVLLCTFTATYADTICIGYHANNSTDTVDTVLEKNVTVTHSVNLLENSHNGKLCL 60 Texas 61 LRGVAPLHLGKCNIAGWILGNPECESLSTASSWSYIVETSSSDNGTCYPGDFIDYEELRE 120 L+G+APL LG C++AGWILGNPECE L + SWSYIVE + +NGTCYPG F DYEELRE Brisb 61 LKGIAPLQLGNCSVAGWILGNPECELLISKESWSYIVEKPNPENGTCYPGHFADYEELRE 120 Texas 121 QLSSVSSFERFEIFPKTSSWPNHDSNKGVTAACPHAGAKSFYKNLIWLVKKGNSYPKLSK 180 QLSSVSSFERFEIFPK SSWPNH + GV+A+C H G SFY+NL+WL K YP LSK Brisb 121 QLSSVSSFERFEIFPKESSWPNH-TVTGVSASCSHNGESSFYRNLLWLTGKNGLYPNLSK 179 Texas 181 SYINDKGKEVLVLWGIHHPSTSADQQSLYQNADAYVFVGSSRYSKKFKPEIAIRPKVRDQ 240 SY N+K KEVLVLWG+HHP DQ++LY +AYV V SS YS+KF PEIA RPKVRDQ Brisb 180 SYANNKEKEVLVLWGVHHPPNIGDQKALYHTENAYVSVVSSHYSRKFTPEIAKRPKVRDQ 239 Texas 241 EGRMNYYWTLVEPGDKITFEATGNLVVPRYAFAMERNAGSGIIISDTPVHDCNTTCQTPK 300 EGR+NYYWTL+EPGD I FEA GNL+ PRYAFA+ R GSGII S+ P+ C+ CQTP+ Brisb 240 EGRINYYWTLLEPGDTIIFEANGNLIAPRYAFALSRGFGSGIINSNAPMDKCDAKCQTPQ 299 Texas 301 GAINTSLPFQNIHPITIGKCPKYVKSTKLRLATGLRNVPSIQSRGLFGAIAGFIEGGWTG 360 GAIN+SLPFQN+HP+TIG+CPKYV+S KLR+ TGLRN+PSIQSRGLFGAIAGFIEGGWTG Brisb 300 GAINSSLPFQNVHPVTIGECPKYVRSAKLRMVTGLRNIPSIQSRGLFGAIAGFIEGGWTG 359 Texas 361 MVDGWYGYHHQNEQGSGYAADLKSTQNAIDEITNKVNSVIEKMNTQFTAVGKEFNHLEKR 420 MVDGWYGYHHQNEQGSGYAAD KSTQNAI+ ITNKVNSVIEKMNTQFTAVGKEFN LE+R Brisb 360 MVDGWYGYHHQNEQGSGYAADQKSTQNAINGITNKVNSVIEKMNTQFTAVGKEFNKLERR 419 Texas 421 IENLNKKVDDGFLDIWTYNAELLVLLENERTLDYHDSNVKNLYEKVRSQLKNNAKEIGNG 480 +ENLNKKVDDGF+DIWTYNAELLVLLENERTLD+HDSNVKNLYEKV+SQLKNNAKEIGNG Brisb 420 MENLNKKVDDGFIDIWTYNAELLVLLENERTLDFHDSNVKNLYEKVKSQLKNNAKEIGNG 479 Texas 481 CFEFYHKCDNTCMESVKNGTYDYPKYSEEAKLNREEIDGVKLESTRIYQILAIYSTVASS 540 CFEFYHKC++ CMESVKNGTYDYPKYSEE+KLNRE+IDGVKLES +YQILAIYSTVASS Brisb 480 CFEFYHKCNDECMESVKNGTYDYPKYSEESKLNREKIDGVKLESMGVYQILAIYSTVASS 539 Texas 541 LVLVVSLGAISFWMCSNGSLQCRICI 566 LVL+VSLGAISFWMCSNGSLQCRICI Brisb 540 LVLLVSLGAISFWMCSNGSLQCRICI 565