Gold Standard Gain-of-Function

As long as we're on the topic of "dangerous gain-of-function research," let's talk about the NIH's signature "Next-Generation Universal Vaccine Platform"

I wrote a piece recently about gain-of-function research of concern (GOFROC), expressing my concerns that combining poorly crafted, ideologically motivated policy with overzealous, politically-driven regulation would severely hinder biomedical research. As usual, I failed to persuade the anti-vax lab leak community of luminaries on social media, who advised me in no uncertain terms that GOFROC has no benefits and saved no lives, and that I am a shit-for-brains lying fraud. A “journalist” from The Daily Caller’s Ministry of Truth took issue with me citing a commentary from the Journal of Virology written by more than 100 of my colleagues about tangible benefits that have resulted from gain-of-function research in virology. How dare I support my opinion with evidence?!

Needless to say, a lot of people were unconvinced that GOFROC can be beneficial so I thought I would use a different example of a time when it has directly benefitted the American people. Thanks to the innovative scientific acumen of the genius vaccinologists at the NIH, we should look no further than the new universal vaccine platform that NIH rolled out in early May: Generation Gold Standard.

Generation Gold Standard, which NIH Principal Deputy Director Matthew Memoli awarded to his long-time collaborator, Acting NIAID Director Jeffrey Taubenberger, to the tune of half a billion dollars without apparent scientific review, is the direct result of GOFROC.

The ancient secrets of influenza immunization

Generation Gold Standard, according to HHS Secretary Robert F. Kennedy, Jr., is “grounded in gold standard science and transparency, and subjected to the highest standards of safety and efficacy testing.” NIH Director Jay Bhattacharya added that “Generation Gold Standard is a paradigm shift.” I’m not sure what paradigm is shifting, exactly, since Generation Gold Standard is the technological equivalent of riding the rails on a coal-powered steam engine in terms of its innovativeness and novelty. It is a quadrivalent whole-virus inactivated vaccine, which is such ancient technology I’m surprised there aren’t hieroglyphs on Egyptian stele showing the surgeons of antiquity immunizing their peers with this platform.

In 1931, a pathologist at Vanderbilt named Ernest Goodpasture discovered that he could grow up a ton of flu in embryonated (recently fertilized) chicken eggs. It doesn’t seem like a big deal now, but at the time, people barely understood what viruses were, much less how to grow them. Cell culture hadn’t been invented yet. People knew by then that viruses were not cells themselves (on the basis that viruses could pass through porcelain filters that cells could not based on their size), but that they required cells to grow. Unfortunately, people couldn’t reliably grow cells, so viruses had to be grown by infecting animals with them. This was really impractical, so when Goodpasture figured out he could get high titer flu out of an egg, it was a real virological breakthrough.

Immunization hottie Jonas Salk took a break from saving the world’s children from polio to make the first whole virus inactivated flu vaccines 85 years ago and save people from flu, as well

By the 1940s, superstar vaccinologists like Jonas Salk and Macfarlane Burnet were using this technique to make the first experimental flu vaccines. They grew up a large stock of influenza virus in eggs and inactivated it with chemicals and then injected this inactivated virus. Because chemical inactivation leaves the virions (virus particles) intact but non-infectious, the immune system will respond to them based on recognizing their “antigens, or the exposed proteins HA and NA on the surface of the virus. Eventually, people realized that people would need routinely updated flu shots, so they started making these vaccines with multiple subtypes of influenza, and eventually began selecting viruses based on what was circulating in the human population. Some manufacturers started making flu vaccines in cultured cells rather than eggs. They also started using different, more modern adjuvants (vaccine additives that amplify immune responses). However, the basic technology for inactivated flu vaccination remains largely unchanged. Generation Gold Standard is like blue jeans or knee-high boots: timeless style that works in most circumstances, but is not at the cutting edge of modernity or high fashion.

According to Bhattacharya, Generation Gold Standard is “traditional vaccine technology brought into the 21st century.” But in reality, it’s just traditional vaccine technology. Extremely traditional, in fact, since now most modern inactivated flu vaccines use a “split virion” formulation (where the inactivated virus particles are sonicated to break them up into smaller pieces) rather than “whole virus” (where the inactivated virus particles are left intact). Whole virus vaccines typically have more side effects and are less immunogenic than split virion formulations, which is why they are used less frequently these days. But in MAHA logic, what’s tired is now wired. Generation Gold Standard is no longer the vaccine platform of choice for the Greatest Generation, but an innovative paradigm shift.

The Gold Standard for GOFROC

When Generation Gold Standard was announced, I looked up the background information on it and it was pretty scant. Generation Gold Standard is a quadrivalent (contains 4 viruses) whole virus vaccine inactivated by a chemical called beta-propiolactone (BPL). To make this vaccine, they grew up 4 low pathogenicity avian influenza viruses (H1N9, H3N8, H5N1, and H7N3). They used a wide mixture of subtypes (HxNx) to maximize the number of antigens this vaccine will elicit immunity against, since the H (hemagglutinin/HA) and N (neuraminidase/NA) correspond to proteins on the surface of the virus particle that are the targets for immunization. Having broad coverage of multiple subtypes will theoretically elicit immune responses to all of them, which is why Kennedy and Bhattacharya claim that this is a “universal” vaccine platform. “Universal” is relative at best here since this vaccine will only trigger immunity against H1, H3, H5, and H7 and N1, N3, N8, and N9 subtypes, and probably only a subset of viruses within those subtypes since there is still a lot of within-subtype variability. Also, inactivated vaccines don’t work as well as other more advanced vaccine platforms.

Though only a handful of papers exist describing this vaccine, they certainly attracted my notice. I started with this one, which was published last year in Science Translational Medicine. This paper describes how the Generation Gold Standard vaccine was tested. And beginning with the first figure in the paper, it is clear that this vaccine could not have been tested without GOFROC.

Figure 1 from Park et al, Sci Trans Med, 2024. A. Reconstructed 1918. B. Highly pathogenic H7N9. C. Avian H5N8 isolate from the Netherlands. D-H. Recombinant avian reassortant viruses generated with reverse genetics and selected based on increased lethality in mouse challenge studies.

Vaccines are tested in animals using “challenge experiments,” where you “challenge” an animal that has been immunized with the vaccine you are testing by infecting it with the virus that the vaccine is targeting. This figure shows what happened when mice that were immunized with Generation Gold Standard (or “multivalent heterosubtypic vaccine” as it is described in the paper) were challenged with an assortment of flu viruses. It is a good experiment, but well…let’s talk about these challenge viruses.

A/Brevig Mission/1/1918 (H1N1) is fully reconstructed 1918 H1N1 pandemic flu. As I have written previously, critics of 1918 reconstruction have argued that pandemic virus “de-extinction” was reckless and had no scientific value. This is a direct counterargument, given that here Memoli and Taubenberger are using that virus to show that their vaccine protects against a pandemic virus. In Figure 1C above, we see that mice immunized with Generation Gold Standard survived 1918 challenge, while mice that received a saline control instead all died. The same thing happened when mice were challenged with a high path isolate of H7N9 (another subtype of bird flu), as well as all these chimeric avian viruses.

So what are all these “chimeric” viruses? In virology, a chimera is a hybrid virus made from components of two or more viruses. Because influenza is a segmented virus (its genes are encoded on 8 separate pieces of RNA), it’s easy to make chimeras by mixing up these segments, although we often call them reassortants if we are just talking about mixing up these segments and not making a chimeric segment itself. I looked into these chimeric viruses and found another paper published in 2014 in mBio describing how they were made and selected. And guess what? These viruses are all the product of GOFROC.

Figure 1 from Qi et al, mBio, 2014. This shows body weight loss in mice that were tested with reassortant viruses with different HA subtypes. Of these, H1, H1b, H6, H7, and H10 caused severe, lethal disease

In this paper from Taubenberger’s lab, the authors tested different HA subtypes in a H1N1 backbone. They also inserted the E627K mutation into the PB2 gene, since we know from Fouchier and Kawaoka’s H5N1 aerosol experiments that this mutation makes the virus replicate more efficiently in mammalian hosts. Inserting PB2 E627K is itself GOFROC, since it is known this increases fitness and virus production in mammals, including humans. But this went one step further: the H6, H7, and H10 viruses gained the ability to kill mice. They were evidently selected by Memoli and Taubenberger to test Generation Gold Standard for their increased pathogenicity. Let me repeat this for emphasis: these are viruses that don’t exist in nature, were made in a lab, and were used because they demonstrated a clear gain-of-function in their ability to kill their host. It is, by the definition of NIH’s new biosafety policy, GOFROC.

Gold Standard Hypocrisy

In 2022, Bhattacharya wrote a commentary in Newsweek lamenting President Joe Biden’s pandemic plan, demonstrating once again his both his incompetence at public health policy analysis and seemingly infinite capacity for dishonesty in service of his extremist antipathy toward science and health.

Bhattacharya really earning that “fringe epidemiologist” epithet he’s so bitter about

In this piece, Bhattacharya claims that GOFROC is responsible for the pandemic despite there being no evidence supporting that hypothesis. He goes on to say that Biden’s plan to develop vaccines for emerging pathogens in 130 days (modeled after Operation Warp Speed) is a terrible idea because somehow mRNA COVID vaccines would not have been developed without the NIH-funded GOFROC he claims occurred at the Wuhan Institute for Virology. Bhattacharya thinks that the spike protein would never have been discovered without enhancing bat coronaviruses to “study their potential” for vaccine design purposes.

No GOFROC at WIV was required for making the Moderna vaccine

In reality, the research at WIV had nothing to do with the development of the mRNA vaccines. We already knew about the spike protein from extensive work that has been going on for 2 decades on SARS-CoV-1 and MERS-CoV in labs around the world, both with and without NIH funding. No GOFROC on SARS-CoV-1 or MERS-CoV was required to “study their potential” since they are both zoonotic viruses that emerged naturally through human interactions with animals (wildlife and dromedary camels) and started killing people. Evolution made these viruses deadly, not virology research. And 20 years ago, studies on unmodified SARS-CoV-1 across multiple vaccine platforms very clearly showed that spike was antigenically superior to other coronavirus structural proteins (envelope, membrane, and nucleocapsid) as an immunization target.

The only vaccine tested using GOFROC here is Generation Gold Standard

Granted, Bhattacharya wrote this almost 3 years prior to being confirmed as the NIH Director. I can’t completely blame him for his ignorance in claiming that GOFROC is critical to rapid vaccine development. Bhattacharya is a physician who has never treated a patient and wrote many middling health economics studies prior to COVID-19. But he should be accountable for his fruitful pandemic career of professional contrarianism, propping up right wing anti-science politicians in their quest to promote SARS-CoV-2 mass infection and undermine public health. It was in this spirit that he wrote that rapid vaccine development will result in eternal GOFROC and “the possibility of a deadly laboratory leak will hang over humanity into perpetuity.” A bold claim coming from a guy whose signature Generation Gold Standard vaccine platform was tested with the products of GOFROC by his chosen Principal Deputy Director and Acting NIAID Director.

No word on whether or not Bhattacharya is going to provide “permanent support for research enhancing the capacity of viruses to infect and kill humans” but you can juice up a lot of viruses’ pathogenicity and transmissibility with the half a billion dollars that he gifted to Memoli and Taubenberger in order to develop this supposedly universal vaccine platform. And uh oh…according to their press release, they’re going to use the same ancient vaccine tech to make pan-coronavirus vaccines as well, so I suppose that means cooking up more SARS-related and MERS-related chimeras at NIAID. In other words, Bhattacharya is funding the exact same type of GOFROC that he thinks created SARS-CoV-2 at the Wuhan Institute of Virology, all of it violating multiple provisions in the new NIH policy forbidding dangerous gain of function research.

And he says virologists are reckless. At least we’re not hypocrites.