The Bug Has Left the Barn

Cary Grant His Girl Friday 2Hildy Johnson: [speaking to Walter on the phone] Did you hear that? That’s the story I just wrote. Yes, yes, I know we had a bargain. I just said I’d write it, I didn’t say I wouldn’t tear it up! It’s all in little pieces now, Walter, and I hope to do the same for you some day!
[hangs up emphatically]
Hildy Johnson: [to the other reporters] And that, my friends, is my farewell to the newspaper game.
–Charles Lederer, Ben Hecht and Charles MacArthur, His Girl Friday (1940)

On Thursday the local paper here published two articles the editors could never connect in a million years, even if it had occurred to them to do so. Think trying to stick together two powerful magnets of the same polarity.

The first—big headline on the front page, “FLU OUTBREAK RIVALS DEADLY 2009 PANDEMIC”—described a record 123 Minnesota children testing positive for flu at Children’s Hospitals and Clinics, higher than the highest week during the 2009 outbreak.

The local outbreak appears part and parcel of a three-prong national attack: aggressive A/H3N2 and type B influenzas, a norovirus, and the worst whopping cough outbreak in sixty years.

If it’s a workaday influenza season, one wonders why the outbreak is earlier and nastier than usual. Michael Oleson hypothesizes Hurricane Sandy may be in part responsible for this year’s early entrance,

The virus was being amplified in the shelter populations, and response teams were coming in from all over the country to help those in need. They, too, would have been exposed to the virus in the shelter settings and could have played the role of a vector in bringing the virus to airports, where they could have spread it still further, and also back to their communities of origin.

But influenza dynamics are a complicated dance of the prevalent virus, other circulating strains, and the changing immune profile in the populations the virus targets, the geography of which we will address below. There are in addition stochastic elements to each of these inputs, including ongoing neutral evolution.

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Ignorance, however, is as much a means of power as knowledge. Now that I’ve had my eye on a number of these outbreaks, human and otherwise, it’s clear each is accompanied by a comorbidity of official defensiveness, in which the institutions responsible for reacting to the outbreak claim, whatever happens, all is going according to plan.

Vaccines, for instance, are central to the influenza narrative. As we discussed previously, vaccination is effective in principle, bears no responsibility for autism, and is no government plot. But since the flu vaccine market went private, in conjugation with its lapse in Keynesian subsidies, development, production and delivery have been regularly slowed and interrupted.

The vaccine substrate is incubated in stacks of chicken eggs, technology that originated in the 1940s. Imagine it the medical equivalent of walking around in a fedora and channeling Cary Grant on a candlestick phone, “Now, Rosalind, we need another shipment.” Production takes months, meaning health officials must choose the right seed strains at the start of the flu season.

Ever the contrarian, Recombinomics’ Henry Niman claims, contra media and government reports, that this year’s flu vaccine isn’t a good match. Niman identifies two ‘low reactors’ prevalent–flus outside vaccine protection. Substrain A/Hawaii/29/2012 appears to have undergone a change from leucine to serine at hemagglutinin position 157 (L157S). For 40% of samples by the end of November, A/Iowa/14/2012 appears to have undertaken a Fujian-like T128A, removing a glycosylation site.

In other words, hardly a surprise, influenza continues to evolve even after the vaccine strains are selected.

That hasn’t stopped public health officials from spinning such delays are a good thing. During the H1N1 (2009) pandemic, CDC Director Thomas R. Frieden, confounding the issue of the failure to deliver vaccine with anti-vax hysteria, framed that year’s vaccine delay in terms of safety,

Clearly the vaccine production technologies need to continue to improve. We’re still using eggs. We’re still using technologies that have been around for a long time. We did not cut any corners in terms of vaccine safety. All of the safeguards are being used. We’re using the same production methods, the same factories, the same companies, the same safeguards to make a vaccine that’s been used for hundreds of millions of doses with an excellent safety record.

But even should our Rosalind make a good match and–big picture–new technologies sped up production, there’s increasing evidence flu vaccines aren’t as effective as once thought. Mike Osterholm’s CIDRAP conducted a meta-analysis across the biomedical literature and concluded the vaccine works on average 59% in adults 18-64 years old, with weaker coverage for children and the elderly. This year’s vaccine efficiency is clocking in at 62%, within the 50-70% range of the past 20 years. Which is better than nothing, but not the panacea PR campaigns—“get your flu shot”—routinely presume.

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The worst caveat may be found in what isn’t said.

The second of the articles, in the business section, reported Minnetonka-based Cargill, the largest privately owned company in the world, scored, on $35.2 billion in revenue, a fourfold increase in its earnings from the year previously, raking in $409 million this quarter alone.

Four of Cargill’s five divisions produced new profits. Its crop and processing unit, including grain, sugar, soybean and cotton, provided the biggest boost. Its ethanol holdings, tackily folded into its food ingredient unit, suffered a decline, but profits in other sectors there, including its global meat business—turkeys to chickens to pigs—covered some of the deficit.

Cargill’s agricultural services division also saw profit increases, in part by way of its animal feed business. The financial services and risk management division, with which Cargill covers its bets in the commodity markets and maneuvers farmers into production rachets, also posted greater profits.

The company’s future looks bright too. Cargill presently has $2.4 billion invested in capital projects under construction in thirteen countries around the world.

The focus on the influenza outbreak in the first article is in effect the view from the far end of the influenza assembly line. By dint of an ironclad hold on media and government, there will be no discussion of the new flu ecosystem at the front end.

As we have repeatedly discussed (here, here and here to start), Cargill, and a dwindling number of consolidating rivals, are helping produce new influenza recombinants one new global pig and poultry megalopolis at a time. Waterfowl, livestock and human influenzas are trading genomic segments at extraordinary rates, spatial extents and ecosocial lengths.

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While we are discussing human influenza, we might ask how, where and when does it spread and evolve? A number of phylogeographies have been recently constructed.

Derek Smith’s group showed a punctuated antigenicity in seasonal H3N2 every three to eight years from 1968 to 2002. That is, H3N2 makes a sudden lurch in its phenotypic evolution.  The group updated its antigenic cartography for 2002-2007, using over 13,000 new flu samples. The second analysis showed an average change of 2.13 antigenic units per year—over the threshold at which a fourfold difference in hemagglutinin inhibition assay titer signals an update to the influenza vaccine is probably required.

Despite differences in antigenicity within and between regions of the world, shifts in antigenicity appear globally consistent, indicating H3N2 evolution panmictic. In other words, H3N2 strains do not appear geographically subdivided across seasons and do not locally evolve away from each other. Instead, the steady antigenic accumulation suggests a new strain—often seeded by the most divergent of last season’s strains —annually emerges somewhere before spreading worldwide.

Smith’s group also dated H3N2 from countries across the world, identifying leading and trailing regions for each year’s outbreak. H3N2 routinely emerged six to nine months earlier in East and Southeast Asia than in other regions of the world (Figure 2a here). Ten percent of the 13,000 samples was genetically typed, a representative sample with the same distribution in time and space (their Figure 2b). While, as long hypothesized, China led some years’ epidemics, the surprise here is that other countries in East and Southeast Asia, and even from other regions, led other years.

None of the inter-epidemic strains genotypically typed from Australia, New Zealand, North America and Japan proved more related to the previous year’s local strains. That is, again, seasonal influenza did not persist locally from season to season, although sparse sampling during off-seasons could miss such transients, including low-pathogenic and subclinical infections. A more global phylogeny showed the same (Figure 2c): each local epidemic is externally seeded and strains do not persist year to year.

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So what is the mechanism by which seasonal influenza survives from year-to-year? Because all countries the Smith group tested, in Southeast Asia included, undertook peaks and troughs in infection dynamics, the team hypothesized no single country acts as the source. However, the team viewed the explanation seasonal influenza annually spreads out from the tropics to temperate zones as too broad a conclusion.

They proposed instead that influenza circulates in overlapping waves of boom-and-busts across Southeast Asian countries during the off-season. As all SE Asian strains in their large sample were descendent from other SE Asian strains, the region suffered no reseeding from elsewhere and so, QED, appears H3N2’s source. Each new H3 strain goes extinct when it reaches the end of the global travel network in South America.

Eddie Holmes’s group offered additional support for the model. The team constructed hemagglutinin, neuraminidase, and M1/2 phylogenies using 492 H3N2 isolates from New York State, USA, 692 from New Zealand and Australia, and 281 from Hong Kong collected 1997-2007 to identify the geographic source of an adamantane-resistant phenotype S31N/M2. The team found the resistance independently emerged eleven times, but the majority of circulating cases arose from a reassortant first found in Hong Kong in 2003. The reassortant circulated locally 2003-2005 before spreading globally.

On the other hand, we may be speaking of seasonal influenza alone, human strains recycling one year to the next. Once one emerges out of wildlife or livestock, human influenzas may be entrained into this particular geography. But as H1N1 (2009) taught us, first emergence may occur anywhere (or anywhere there exists the right agroecological interface).

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I expect it will be a long time before I address an outbreak of human influenza again other than in passing. While an understandable visceral reaction, getting worried at this point in the process is a bit bass-ackwards. The bug, whatever its point of origin, has long left the barn, quite literally.

Although human influenzas do traffic back into livestock, all the pertinent structural causes are upstream, where agricultural intensification and deforestation select for the next recombinant, a topic quietly deleted off the epidemiological radar, one flashing alert after another.

I increasingly find discussing seasonal influenza like talking to a child, although, frankly, children, despite their tantrums and “gimmes,” are able to grasp and assimilate the notion of a shared future.

Many an adult, on the other hand, whatever his or her vantage, is freighted with Conradian expediency. My rent/budget/well-being has nothing to do with yours, buddy. In the company towns of the world, freedom of the press is bought and sold. Voracious accumulation is somehow now a means of helping the poor. Even communism, if in name alone, can be pursued as another bourgeois indulgence.

So, let me correct myself, discussing flu is like talking to an adult. And when it comes to existential threats, the contradictions and multitudes Walt Whitman celebrated, oft-woven here from petty ambition and myopic self-interest, mean ready solutions are to be regularly placed out beyond our reach as a matter of principle.

Now that a nasty flu has arrived, however, gimme my perfect prophylaxis–a promise the system can’t keep–as if H1N1 (2009), H1N2, H3N2v, H5N1, H5N2, H6, H7N1, H7N3, H7N7, and H9N2 never happened.

I tell you, it’s true, Rosalind. I read it in the paper.

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