# Does SARS-CoV-2 utilize antibody-dependent enhancement?

The possibility of SARS-CoV-2 having [Antibody-Dependent Enhancement](https://en.wikipedia.org/wiki/Antibody-dependent_enhancement) (aka ADE) looked pretty real, to me.

If you're curious about the challenges of vaccine development for SARS-CoV-2, I recommend [this article](https://www.pnas.org/content/117/15/8218).

UPDATE: It looks like it isn't productively replicating in WBCs, but it probably *is* fusing with them and telling them to apoptose. Receptor uncertain, but they were checking T-cells specifically, which are exactly the WBCs that get severely depleted in severe COVID-19. They were in-vitro studies, but this mechanism matches the in-vivo results I'm seeing better, and I find the idea moderately convincing. ([Article](https://www.nature.com/articles/s41423-020-0424-9), h/t [CellBioGuy](https://www.lesswrong.com/posts/nRX7uwT2wNvvmd2Yd/coronavirus-justified-key-insights-thread?commentId=hRzw8sejgnb5C8C7B)'s post mentioning it). SARS-2 is apparently *much* better at this than SARS-1.

### Define ADE

Producing antibodies that are imperfect matches for one of these viruses (ex: optimized for another strain, or incompletely neutralizing) not only do not inactivate the virus, but instead get repurposed by the virus as a mechanism it can use to anchor and infect the cells that try to interact with those antibodies, most often immune cells.

## Current conclusions

TL;DR: I think something else is having a larger impact than ADE on the immune system in severe COVID-19 disease. I have seen several theories, and listed some below. SARS-1 and MERS have both seen [plenty of bad vaccine reactions](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035421) that only show up at the animal-testing stage, and I still think vaccine development is going to be hard.

While I don't understand the upstream causes of this, Th-2 type activation has been extensively noted in both severe COVID-19 disease and bad vaccine reactions. Th-2 type immunopathology (roughly, allergy-like immune responses in lieu of virus-like immune responses) seems likely to play a large role in both complicating vaccine development, and influencing disease severity.

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Something weird is going on with white blood cell counts, but I'm currently leaning towards believing it might be something else causing it. Specifically, they're seeing T-cell lymphopenia. T-cells seem to be the worst-hit WBC (hyper-activated, decreased numbers), and I'd have expected them to be close to immune to Fc-based ADE once mature; they only express the receptor while young.

SARS-1 and MERS vaccines both seem to have seen instances of bad reactions that required animal testing to become apparent. [SARS-1](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3187504/) and [SARS-2](https://jvi.asm.org/content/94/5/e02015-19) exhibit ADE in-vitro against S-protein vaccines and not N-protein vaccines, but both S- and N-targeting vaccines sometimes had bad reactions in animal testing\*. What I see as an in-vitro/in-vivo divergence boosts my impression that vaccine development will be challenging.

\*For example, [this mouse study with SARS-1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035421) saw hypersensitivity reactions to several S-containing vaccine subtypes (whole virus, VLP, S-protein), while [this paper](https://www.ncbi.nlm.nih.gov/pubmed/17194199?dopt=Abstract) tested S- or N- VRPs and found that their N-inoculation not only had had no protective effect, but made things worse when it "resulted in enhanced immunopathology... within the lungs" upon infection.

Going on the current human results and a tiny [Macaque study with 4 monkeys](https://www.biorxiv.org/content/10.1101/2020.03.13.990226v1?fbclid=IwAR1odmOack-q6I3wm09wG6GcZ0upIB56oTrcphoXeOwjf14wtROb3Szwatw), for SARS-CoV-2 it does appear that getting through the disease once does preclude or largely-preclude reinfection by the same strain. I don't feel I can weigh in on whether this will stay true.

A few theories trying to explain the blood results (I'm sure there's more):

- Glucocorticoid reaction/Too much cortisol as a possible upstream cause of the lymphopenia + neutrophilia reaction seen in SARS, RSV, Ebola
- Something is causing/reacting to the cytokine storm
    - Cytokines essentially steer the strategy of WBCs (activation/direction/activity)
    - Both severe COVID19 disease and bad vaccine reactions steer towards Th-2 type immune responses (vaguely allergy-like)
    - I found this a bit too confusing to wade into
- Some sort of immune-cell suppression effects
    - Indirectly impacting cells at an earlier stage of blood cell development/differentiation (possibly as early as bone marrow stem cells)
    - Infecting cells via its additional receptor-binding affinities, for purely manipulation purposes (probably without viral replication)
        - It seems to clearly prefer lung and bowels for productive viral replication; we aren't seeing viral inclusion bodies in most other tissues. I don't feel this rules it out.

While I don't understand the upstream causes of this, Th-2 type activation has been extensively noted in both severe COVID-19 disease and bad vaccine reactions. Going on both the frequency with which it comes up in these contexts, and [commentary by experts](https://www.pnas.org/content/117/15/8218), Th-2 type immunopathology (roughly, allergy-like immune responses in lieu of virus-like immune responses) seems likely to play a large role in both complicating vaccine development, and influencing disease severity.

### Earlier thoughts

I've repeatedly had to update in the direction of it being plausible, and I currently think it's more-likely-than-not to be a factor that will complicate vaccine development.

However, there do exist viable alternative theories for a lot of what I'm seeing, some of which I couldn't rule out.

### Related Questions

I wanted to consolidate research on this into one place, and am interested in if anyone has additional solid arguments for/against it.

I have a lot of questions about this, but lets boil it down to a few.

1.  Is this virus doing this in-vivo? What induces it? (note: it does happen in-vitro, but in-vitro is apparently easier to induce, and often not conclusive evidence that this happens in-vivo at appreciable levels)
2.  What exactly are the consequences of this ADE interaction? Can we get it down to symptoms?
3.  How does this change things?
4.  What can we do about it?