Sequencing everything, everywhere will boost our biodefenses

COVID variant tracking is having its moment. It’s the hot new topic we all need to have an opinion on. It comes up in the pre- and post-meeting banter on my day-to-day Zoom calls. It’s the peg for the latest round of How worried should you be about… news articles. It’s getting Cabinet-level attention, and a $1.75 billion earmark in the new COVID relief bill.

On the one hand, this is simple stuff. SARS-CoV-2 mutates constantly. It’s hard to know whether it is becoming more or less deadly. We won’t know for years how durable our diagnostics and vaccines are. The only way to build our understanding is with genomic epidemiology, a close tracking of the virus’s genome around the world and over time.

That’s why CDC is shifting $200 million to support additional variant tracking. It’s why lawmakers put money for sequencing into the COVID bill. It’s why the United Kingdom implemented nationwide COVID sequencing way back in April, 2020.

So we’re going to buy a lot more sequencers, and run them more often. Is there anything to see here, aside from being a great example of government becoming biotech’s biggest customer?

Disease sequencing is bigger than COVID-19

The accepted surveillance target is 5% of cases. As I write this, the US is recording tens of thousands of new COVID-19 cases per day. This implies that we should be sequencing tens of thousands of SARS infections a month. We have to sequence a lot of COVID-19 cases, but only because we’ve already lost control.

The bigger question is what else we should be sequencing.

Narrow but big idea: sequence more of every disease. Why not sequence 5% of flu cases (which escapes its vaccine annually), and HIV (which continually develops drug resistance)?

Big but obvious idea: let’s track the genomes of emerging diseases too. Our goal is to intercept new diseases before they become endemic. Ideally, we want to identify and suppress diseases before they get here. Sequencing is used to identify diseases when they are new. It also reveals targets for vaccines. It provides a diagnostic backstop against diseases that mutate so rapidly that traditional diagnostics are unreliable. It can track wildlife diseases at high risk of zoonotic spillover to humans.

The point is, if we’re going to start investing billions into infectious disease surveillance, we might as well set up to catch the next biothreat while we’re looking for new outbreaks of the old one.

Sequencing, near and far

Think of diseases as invading enemies, which we can categorize by how deeply penetrate our defenses. At one extreme, we have the endemic diseases: SARS-2, influenza, HIV. At the other extreme, we have the diseases that don’t yet transmit among humans, like avian flu. In the middle are those that broke out but were contained (SARS-1, MERS); those that we have failed to eradicate but which remain at a distance (Ebola, Lassa); and vector-borne diseases, which tend to be climate-specific (Dengue, Zika).

The analytic tools we need depend on how far a disease has penetrated our population.

This framing makes it easier to envision the tools we might need. For endemic disease, we need a network of massive, centralized sequencing facilities. For emerging threats, we need portable solutions that can travel into the field, into villages and farms and jungles and open-air markets.

The right surveillance tools and methods will depend on which disease we’re tracking. In many cases, a 5% sampling rule won’t work, nor will mailing in positive cases to reference labs. A few examples:

  • For SARS-2 (and flu, HIV, etc.) we want to sequence known positives to track vaccine and diagnostic escape
  • For avian flu, we want to screen farms for infections—likely with pooled testing—then sequence both animal samples and the farm workers to look for zoonotic transmission
  • In regions with Ebola (and Lassa, Marburg, etc.), we want to sequence known positives, and perhaps a sampling of any patient with a fever, because so many of the regional diseases have overlapping symptoms
  • For Dengue and Zika, we want to collect and test mosquitos, and screen individuals traveling between regions of similar climate (say, between Brazil and Florida), referring any hits for sequencing

With few notable exceptions, the tools we need already exist. BARDA and NIH could fast-track development of the missing pieces.

The main challenge isn’t technological, scientific, or medical. Setting up true infectious disease surveillance is a massive geopolitical project that will never end. We can’t sequence samples in populations without health infrastructure. We can’t sequence samples in countries that won’t let us in. We can’t sequence samples from animals when the companies that own the farms block access. Tracking disease will require as much diplomacy as epidemiology.

The COVID relief bill will be a good first step toward standing up infectious disease surveillance. But let’s not fool ourselves into thinking it’s anything more than just the first step.