Comment by mlyle | Hacker News Reader

Comment by mlyle | Hacker News Reader

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> Can you explain how it increases the breadth of antibody protection if the booster is exactly the same as the original shot?

It's complicated! The short answer I gave elsewhere: B cells aggressively replicate and mutate in response to pathogens, and those that match are selected for. Repeating this process gets more B cells, but also broader varieties of resultant antibodies matching not just the original pathogen but things that are close to it.

> Is there any way to know whether that increased breadth of antibody protection isn't coming from a post vaccination exposure that wasn't tested for not tested?

Yes. We collect plasma from people, and then test it against a variety of variants in assays. We have plenty of old plasma to do this with.

Indeed, there's some evidence that many people who were both infected with SARS-CoV-1 and subsequently vaccinated against SARS-CoV-2 may have exceptionally broad immunity to coronaviruses, not isolated to just SARS-CoV variants but also to wild-type coronaviruses circulating in animals and human coronaviruses causing the common cold.

I thought that was what these vaccines specifically don't do: they select for the spike protein of the original variant and ignore others, whereas natural infection generates a broader response that will target a variety of proteins. Has that changed?

It's something I have seen a lot of people say here on HN, but I don't know if it's true. If having the whole virus was more effective than just the spike protein, wouldn't Sinopharm and Sinovac—which are inactivated virus vaccines—be more effective than Pfizer and Moderna? We still don't know their efficacy against Omicron, but they were less effective than mRNA vaccines against all previous variants.

Initially perhaps, but do we have good longer term data on how the sinovac holds up, given we're now saying Pfizer needs to be 3-monthly and Moderna is a much stronger dose? I think there was some over-selling of the mRNA vaccines that needs strong follow-up review given the state of the virus vs last year without vaccines with a more potent variant.

We won't have long-term data until a long time had passed, but so far, it doesn't seem inactivated virus vaccines fare any better than mRNA ones.

https://www.nature.com/articles/d41586-021-02796-w

What you're saying here isn't untrue, but it's nuanced and I think it misses some of the clear distinction.

> they select for the spike protein of the original variant and ignore others

Repeated exposure causes you to get many different kinds of antibodies that react against many things like the original spike protein. There's ample research showing that a 2 shot (and 3 shot) series of mRNA vaccination creates a very broad response that cross-reacts to many spike protein variants.

Reaction against the spike protein is best, because this binding doesn't just activate the rest of the immune system, but it's neutralizing against the virus: it prevents its entry into cells.

Compare this figure:

https://cdn.jamanetwork.com/ama/content_public/journal/jama/...

Many convalescent (prior infected) individuals had very low neutralization activity against variants. All vaccinated individuals had good neutralization titers against all variants measured in this study, though they were still definitely better against A.1 than other types.

> whereas natural infection generates a broader response that will target a variety of proteins.

Natural infection will generate a variety of nucleocapsid antibodies, too (against non-spike portions of the virus).

This is a mixed bag: it means the immune system can be activated and it also means that the immune system will try and break down things that have antibodies bound elsewhere on the virus... but the spike antibodies around that could directly prevent infection of new cells are less effective against variants.

On that part about not entering the cells, as we're seeing that the vaccine does not prevent illness, if covid does escape the vaccine and enter cells, at that point what is the difference between vaccinated or not? I haven't been able to work that out as the explanation has always been that the vaccine blocks cell entry.

It’s not a binary thing. One virus enters a cell and it makes thousands of copies to spread in the body. Each of those get attacked by the antibodies and T cells pre-generated from the vaccine. No vax or no prior infection and the body is learning while also getting ravaged by the virus.

And as for immunity from infection, your body makes antibodies for the prefusion spike (the free floating form that infects cells), the post fusion spike (after it binds to ACE2), and the nucleocapsid. Since prefusion spikes are what bind to cells for entry, you’d want your immune system focused entirely on attacking that vector. China’s sinovac vaccine generates nucleocapsid antibodies and it’s failing in the face of omicron.

I don't quite understand your question. To be infected, the virus must be able to enter your cells.

Against Delta, if you compare a vaccinated population with 2 doses of the mRNA vaccine against an equivalent unvaccinated population that ended up with 100 infections, with about 70 people having symptoms and 10 people with severe illness, you'd expect:

* 60 people who would have otherwise been infected to show no evidence of infection. That is, the vaccine is so strongly neutralizing that a large proportion of people that would otherwise be infected show no evidence of virtal replication at all.

* Another 30 people or so to end up infected, without symptoms. The virus replicated some in their cells, but the severity of the disease before an immune response was mounted was so low that it went unnoticed. Note that this number has not changed too much from the unvaccinated population.

* About 10 people with symptoms, of whom 1 has severe illness.

You could view this as mostly shifting severity "downwards" -- some people who would have been infected ending up not; some people who would have had symptoms instead just being infected; some people who would have had severe illness instead just having symptoms.

From a pure mechanical view: if an infected cell produces 1000 copies of the virus, ordinarily resulting in 50 other cells being infected... and antibodies from a vaccine glom up on spike proteins and reduce this 50 number to 10-- the virus still grows in your body, but the rest of your immune system has a whole lot longer to react before illness becomes severe. And this ignores other benefits from vaccination (earlier mobilization of immune system, T-cell mediated immunity, training of B cell lines to target spike proteins resulting in faster maturation of variant-specific antibodies, etc). So even if the antibody concentration and affinity isn't quite sufficient it's still a benefit.

We already know that infection does not "generate a broader response", actually. Nor does it generate a more effective one.

The opposite is the case.

We don't "know" that. It depends on what data you're looking at. CDC has two papers supporting vaccine-induced immunity, one of which was highly flawed. And then there's the study from Israel clearly supporting natural immunity.

The study from Israel has been widely debunked and has yet to be supported by anything else. It's mostly cited by Fox News as an excuse for anti-vax sentiment.

Widely debunked? I've missed that. Care to share some papers/analyses?

https://www.politifact.com/factchecks/2021/sep/01/gateway-pu...

No vetting of that Israeli study, no peer review, no competent efforts to account for bias in the sample, and it just does not hold up to scrutiny when compared to other results.

I want to compliment your responses. Factual and non aggressive which is needed in this time. Thank you.

Hey, thank you so much! I try. I also have to confess that my understanding of this subject matter is far from perfect (and even experts' understanding is relatively limited).

Thanks! This clears up a lot for me.

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