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Saturday, January 15, 2022

Where are the Variant Specific Boosters?

 by  Alex Tabarrok in 

I wasn’t shocked at the failures of the CDC and the FDA. I am shocked that our government still can’t get its act together in the third year of the pandemic. Consider how lucky, yes lucky, we have been. Here’s Eric Topol:

…the original vaccines were targeted to the Wuhan ancestral strain’s spike protein from 2019. The spike protein, no less the rest of the original SARS-CoV-2 structure, is almost unrecognizable now in the form of the Omicron strain (see antigenic drift from prior post). While there’s naturally been much focus on the extraordinary number of mutations in the receptor binding domain and the rest of the spike protein, over 50 mutations are spread out throughout Omicron, making the prior major variants of concern (Alpha, Beta, Gamma, Delta) lightweights with respect to changes in structure that are not just linear or uni-dimensional. Each mutation can interact with others (epistasis); any mutation or combination of mutations has the potential to change the 3D structure of the virus. In this sense, Omicron is an overwhelming reboot of the ancestral strain.

Omicron is very different from the Wuhan ancestral strain and it’s only a matter of luck that the vaccines continue to work and that Omicron is likely less severe than Delta. Don’t tell me that viruses evolve to be less severe over time–that isn’t correct in theory or practice. The most one might say is that a very deadly virus may be difficult to transmit but that only closes off a small part of the evolutionary design-space. There is plenty of room for transmission and lethality to both increase. So the vaccines continue to work well. We got lucky. But for how long will our luck last? Do we really have to wait for a more transmissible, more deadly, more vaccine escaping variant before we act?

Where are the variant-specific boosters? The FDA has said they would approve them quickly, without new efficacy trials so I don’t think the problem is primarily regulatory. Why not catch-up to the virus and maybe even get a jump ahead with pan-coronavirus vaccines?

More generally, in our February 2021 paper in Science my co-authors and I argued that we were still leaving trillion dollar bills on the sidewalk by not investing in more vaccine capacity. I am sorry to say that we were right. Why the failure to invest more broadly?

Mostly I blame American lethargy. After 9/11 the country was angry and united and we had troops in Afghanistan within a matter of weeks and we had taken over the country in a matter of months. For better or worse, we acted quickly and with resolve. Yet, when the virus was killing at 9/11 levels every day the public never reached the same level of anger or resolve. Even now Congress has spent trillions on unemployment insurance, business protection, money for schools and stimulus but has not passed the American Pandemic Preparedness Plan, a pretty decent, mostly science-based investment plan.

80,000 hours ranks research and investment against Global Catastrophic Biologic Risk (GCBR) as among the most pressing and yet tractable problems to work on and yet they estimate that quality-adjusted only about a billion dollars is being spent on these risks. Moreover, COVID doesn’t even count as a GCBR, i.e. 80000 hours at least recognizes that things could be much worse.

I understand that future people don’t vote but even so I expected a little bit more foresight.

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"Pfizer CEO Albert Bourla said Monday that his pharmaceutical company is planning to have a vaccine targeting the Omicron variant ready in March.

Bourla made the announcement in an appearance on CNBC’s “Squawk Box,” where he said “this vaccine will be ready in March.”

“We [are] already starting manufacturing some of these quantities at risk,” Bourla added. “The hope is that we will achieve something that will have way, way better protection particularly against infections, because the protection against the hospitalizations and the severe disease — it is reasonable right now, with the current vaccines as long as you are having let’s say the third dose.”

According to CNBC, Bourla said the vaccine will also target other COVID-19 variants. In the interview, he did not clarify if he thinks a fourth COVID-19 vaccine is necessary."

Omicron first reported to WHO on 24 November 2021. As of Jan. 11, vaccine manufacture has already started. Talk about lethargy. Almost as if someone keeps lazily playing the same tune over and over again.

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Alex overstates the case, but I think it is true that the government has largely dropped the ball on pushing for improved vaccines.

Pfizer has developed this on their own because other countries are asking for it. Not us, though--not only are we not prioritizing it, Fauci has announced that we don't need an Omicron specific vaccine (even while acknowledging in the same comments that existing vaccines are less effective).

Optimizing the vaccines should have been a huge priority--not only optimizing for new variants, but also testing different doses, spacing between doses, mixing vaccine types, etc. Instead, we hoped to just coast along on initial success. That didn't work very well.

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Was it Pfizer that developed the updated vaccine or BioNtech?

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Both, probably?

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Libertarians said we had herd immunity two years ago. Why do libertarians want a vaccine now? Once a vaccine is available, libertarians don’t want everyone to get vaccinated.

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"Libertarians said we had herd immunity two years ago."

No one was saying we had herd immunity in early 2020. Your comment is nonsensical.

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I don't think that's quite true. CK's comment is obviously nutball and nonsensical, yes, but there were plenty of people thinking we were at or near herd immunicty in first-half 2020 on this site. They were obviously crazy and grasping at straws, but they were definitely around.

Remember all those people saying asymptomatic infections were 10x symptomatic ones, so we were at or near herd immunity very early on? I don't remember them being libertarian to any extent - fringe, yes, but not libertarian in particular.

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Go back through Tylers posts. For a while he was citing someone (mathematician?) who based upon data somewhere thought we might reach herd immunity in a few months. IIRC I think that person even suggested herd immunity at 30%-40%.

Steve

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Continue this thread →

There were people making claims about durable herd immunity in 2020 after initial COVID waves that receded with perhaps 15% to 25% of the population in given areas infected. Some focused on the idea of highly effective cross-immunity in most of the population from exposure to other viruses, such as the 4 coronaviruses that cause some common colds.

In hindsight, a key problem seems to be that people implicitly accepted the simple epidemiological SIR models that predicted high rates of spread until reaching durable herd immunity unless drastic containment measures were imposed. It's now clear that's not a good model for SARS-CoV-2, most likely due to seasonality and/or the highly heterogeneous nature of contacts in populations. (Tyler has previously linked to Philippe Lemoine at CSPI arguing for the second point.)

My view now is that this should have been foreseen at the time by people with domain expertise (i.e., infectious disease epidemiologists) based on (1) pre-COVID knowledge about seasonality of respiratory viruses and (2) the multiple waves associated with prior respiratory virus pandemics (such as flu pandemics).

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Some of the COVID skeptic crowd was claiming herd immunity as early as May 2020 or so. Maybe we can be generous and say that's nearly two years.

Still a nonsensical comment, it groups people with very different views.

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Since you can gst covid multiple times, even if we get to herd immunity this time, that won't save us next time.

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Furthermore, I disagree with Topol's assumption that Tabarrok repeats:

Omicron is very different from the Wuhan ancestral strain and it’s only a matter of luck that the vaccines continue to work and that Omicron is likely less severe than Delta.

SARS-1 and SARS-CoV-2 are ACE2 specific viruses. It is not a matter of luck that the vaccines continue to work, it is the constraints that limit how this class of virus can evolve. The human immune system uses a multilayered approach to protection; we need to learn to use our multilayered public health tools more effectively. My intuition is that an Omicron specific booster, even if available weeks ago, would make little measurable difference to blunt the current wave compared to the Wuhan/OG vaccine unless you could suddenly convince the immune-naive to get vaccinated with it. I could be convinced otherwise with a data model.

We are dancing around the key truth of Omicron: the antibody escaping properties have changed the game in a novel new way. Our classic SIR model has to be forked into an unchanged Severe-SIR and a fully reset mild-SIR and evolve our mitigation tools for the mild-Omicron-SIR realities. We are quickly approaching the peak of the Omicron wave, only the tools at hand matter. There will be time later for a proper postmortem.

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This is just another way of saying that severity matters, and that cases shouldn't be a metric we should use to impose public health tyranny.

But that was all true during Delta. And is true during Omicron. And will be true with future waves.

Arguably it was true the entire time if you think the unvaccinated IFR wasn't worth the response it was given. Most especially since children had the worse restrictions and the least risk (still ongoing).

So again...this is a spiritual problem. The effective work is getting decision makers to accept risk. Praying for a technological fix to their culture of fear is going to be constantly trumped by biology.

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That is NOT what I'm saying. I'm saying that when the number of people susceptible to mild/transmissible disease suddenly jumps from 20% of the population to 80% then you need to pivot.

I am, and have always been, geared towards problem solving; Omicron represents a significantly new problem. Work the problem. Exorcise your own animal spirits before mocking the spiritual menageries inhabiting others.

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Vaccine immunity from infection wore off pretty fast over time even with the ancestral strain. I've never considered near universal boosters of a vaccine with such high side affects every six months to be a reasonable outcome. The variants simply accelerate how quickly the anti-body immunity to infection wanes from say six months to three months.

I doubt we can approve, produce, and distribute new variant specific vaccines fast enough to stop each wave of infections. We can't even get boosters of the original strain distributed in the middle of the omicron wave. People are waiting weeks for an appointment.

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What VAE rate do have data for? I mean Sabin polio outright reverts and gives a miniscule fraction of kids vaccine associated polio. So I would dearly love to see your quantified numbers for "such high side effects".

Covid is a time where we got unlucky. The initial R0 on the first strain and the apparent duration of immunity (at that point solely from natural immunity) looked like they might be enough lead to eradication. Most zoonotic diseases end up going down that path.

But things changed. R0 has gone up with subsequent infections. Cross reactivity from other coronavirus antibodies has been muted. Vaccination uptake has been lower than we needed for reaching herd immunity via vaccination for even less virulent strains (e.g. with R0 of 2 you need 75% of the population to be immune to cut transmission chains).

Omicron is estimated to be something like 7 or 8 so we will need well over 90% of the population to be immune. The US is not remotely close to hitting that number and will not be close absent political/tribal/social changes. The mutation rate has been higher than we expected and the lethality in immunocompromised patients has been lower than expected (so the virus lives longer in one patient creating far more variants).

Will we need annual boosters to achieve some herd immunity goals? Possibly yes, and possibly no. We did not even calculate out an optimal timeline for administering initial doses, we just threw some darts at the wall because we had to pick something for the clinical trial. Maybe optimal dosing will be 5 doses spread over 5 years. Maybe it will be once every 5-10 years.

Or maybe these vaccines are not the best option (after all it took something like 30 attempts to get a functional polio vaccine) and we might find something that targets a more conserved set of viral epitopes.

Is Covid going endemic? Certainly looks that way. Do the vaccines help? Yes, they reduce the duration and severity of illness on average. Could we have better vaccines? Undoubtedly.

But is getting vaccinated more dangerous than a naive infection? Not for any cohort from which I have ever seen data.

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The maximum SARS-CoV-2 antibody levels and rate of contraction (i.e. waning) seem to be inline with typical immune behavior. Delta was the first variant that resulted in infectious breakthrough disease. Alpha and Beta re-infections/breakthrough tended to be asymptomatic and did not result in onward transmission. The degree of Delta re-infection/breakthrough with onward transmission was minor now that we've seen what a true antibody escaping variant is capable of.

Once again, I don't think that the vaccine reactogenicity you experienced was typical. The influenza virus and vaccine have very different characteristics than SARS-CoV-2 and the mRNA/adenovirus-vectored vaccines. Trevor Bedford is a great source for this topic.

Paul Offitt says vaccines must be 1. Produced, 2. Distributed, and 3. Administered (i.e. injected into arms). The peak vaccination rate in the U.S. reached about 1% of the population per day in April and it is significantly below that now. You can reach your entire population in 100 days at a 1% rate so it is a good heuristic to have at hand. Sure used to complain about the poor execution of the U.S. vaccination campaign; I think he has abandoned hope rather than changed his mind.

Every nation should revisit their maximum vaccination rate, it is a key bang-for-the-buck metric with room for improvement.

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I agree, I thought it was odd that Topol, who no doubt knows more about this stuff than me, considers something like this "luck." Vaccines don't continue to work based on luck or on a whim. Very odd.

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Totally agree. Not to mention the military's pan-coronavirus vaccine. The bureaucracies may have been slow to react and evolve but big things are happening, have happened.

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Pfizer is manufacturing the vaccines "at risk" so the point that the feds aren't putting in enough money is valid.

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I like how everyone's a virologist now.

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You almost need to be your own virologist because the public presentation of real virology has been infected with politics.

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Any libertarian qualifies as a virologist, especially libertarians with an interest in economics.

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Alex has rather consistently been ahead of the curve on COVID. Rather unlike a supposed ideological compatriot of his like Jeffrey Tucker.

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Since everyone is a virologist, many may answer my (serious) question: do we know a species of animals (vertebrates I would prefer, and if possible mammals) who has ever become extinct because of a virus or bacterial infection?

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Not sure about viruses specifically, but there have been instances where parasites have been introduced to a new host species which resulted in extinction. Here's an example I found:

Co-evolved hosts and parasites have adaptations that allow hosts to defend themselves and parasites to escape host defences. Co-evolutionary adaptations can lead to stable population dynamics of both the host and the parasite (Schmid-Hempel 2011). In contrast, naïve host populations may not have had time to evolve effective defences against introduced parasites. Under this scenario, parasites can cause host populations to quickly decline and even go extinct locally (Lyles & Dobson 1993; Mutze, Cooke & Alexander 1998; Atkinson & LaPointe 2009).
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Island populations of hosts are particularly at risk from introduced species of parasites, due to limited habitat size and a lack of genetic diversity (Paulay 1994; Blackburn et al. 2004; Steadman 2006; Pimm et al. 2014). For example, the extinction of half of Hawaii's endemic honeycreeper species has been attributed, in part, to the introduction of avian malaria and avian pox (Warner 1968; van Riper et al. 1986; Atkinson et al. 2000; van Riper, van Riper & Hansen 2002).

https://besjournals.onlinelibrary.wiley.com/doi/10.1111/1365-2664.12575

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No reason to be picky when talking about transmissible conditions, especially as the germ theory of disease has yet to reach its second century.

Tasmanian Devils - Devil facial tumour disease (DFTD) is an aggressive non-viral clonally transmissible cancer which affects Tasmanian devils, a marsupial native to Australia. DFTD was first described in 1996. In the subsequent decade the disease ravaged Tasmania's wild devils. Affected high-density populations suffered up to 100% mortality in 12–18 months. Between 1996 and 2015, DFTD wiped out 95% of affected populations.

Bats - White-nose syndrome (WNS) is a fungal disease in North American bats which has resulted in the dramatic decrease of the bat population in the United States and Canada, reportedly killing millions as of 2018. The condition is named for a distinctive fungal growth around the muzzles and on the wings of hibernating bats. It was first identified from a February 2006 photo taken in a cave located in Schoharie County, New York. The syndrome has rapidly spread since then, however. In early 2018, it was identified in 33 U.S. states and seven Canadian provinces; plus the fungus, albeit sans syndrome, had been found in three additional states. Most cases are in the eastern half of both countries, but in March 2016, it was confirmed in a little brown bat in Washington state. In 2019, evidence of the fungus was detected in California for the first time, although no affected bats were found.

The disease is caused by the fungus Pseudogymnoascus destructans, which colonizes the bat's skin. No obvious treatment or means of preventing transmission is known, and some species have declined >90% within five years of the disease reaching a site.

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