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Comment by danielodievich | Hacker News Reader

I am good friends with 3 doctors, and talk to them a lot about the amazing science behind the vaccines and the incredible speed with which those were designed and developed. All agree it was done at pretty much the software speed - custom designed on the computer in weeks and then built to order - and both them and I think it's pretty neat.

It is very refreshing to talk to them because they, being good doctors, deal calmly and reasonably with probabilities rather than absolutes.

Very early, even before general public could get vaccines, all 3 of them told me to expect something like that - the virus mutates, it is expected to develop, the mutation for reproductive number going up is likely to occur - and it did - and the vaccines will likely be needing to adjust.

Even the highest levels of vaccination are no protection, and I am pretty tiny Israel in a sea of the largely unvaccinated is going to be swamped.

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> all 3 of them told me to expect something like that - the virus mutates ... and the vaccines will likely be needing to adjust

Your doctor friends were informing you about a phenomenon commonly referred to as "immune escape".

The current mRNA based SARS-CoV-2 vaccines are effective at preventing severe outcomes like hospitalization and death. However, they do not necessarily prevent infection or transmission - and they induce an immune response highly targeted toward the spike protein RBD [1]. Combined with mass vaccination strategies, these factors contribute to a situation that exerts tremendous selective pressure on the virus, and can result in convergent mutations that are advantageous for the virus in a large population of people [1][2]. These mutations can lead to partial or complete immune escape, which manifests as increased transmission or virulence, reduced vaccine efficacy, and reduced immunity in naturally infected individuals.

> Even the highest levels of vaccination are no protection

It's not quite accurate to say "are no protection". I would rephrase as:

Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities [1]

[1] Risk of rapid evolutionary escape from biomedical interventions targeting SARS-CoV-2 spike protein https://pubmed.ncbi.nlm.nih.gov/33909660/

[2] SARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern https://science.sciencemag.org/content/early/2021/06/30/scie...

The Delta variant emerged prior to widespread vaccination.

Yes the delta variant may have originated prior to widespread vaccination, but the dominance of the delta variant (and other VOCs) did coincide with mass vaccination campaigns.

Please see the first source I cited if you're interested in these ideas and want to hear more straight from the experts:

> "The spike protein receptor-binding domain (RBD) of SARS-CoV-2 is the molecular target for many vaccines and antibody-based prophylactics aimed at bringing COVID-19 under control." [1]

> "Such a narrow molecular focus raises the specter of viral immune evasion as a potential failure mode for these biomedical interventions. With the emergence of new strains of SARS-CoV-2 with altered transmissibility and immune evasion potential, a critical question is this: how easily can the virus escape neutralizing antibodies (nAbs) targeting the spike RBD?" [1]

> "Our modeling suggests that SARS-CoV-2 mutants with one or two mildly deleterious mutations are expected to exist in high numbers due to neutral genetic variation, and consequently resistance to vaccines or other prophylactics that rely on one or two antibodies for protection can develop quickly -and repeatedly- under positive selection." [1]

> "The speed at which nAb resistance develops in the population increases substantially as the number of infected individuals increases, suggesting that complementary strategies to prevent SARS-CoV-2 transmission that exert specific pressure on other proteins (e.g., antiviral prophylactics) or that do not exert a specific selective pressure on the virus (e.g., high-efficiency air filtration, masking, ultraviolet air purification) are key to reducing the risk of immune escape" [1]

> "Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities" [1]

It would have spread even faster without vaccination (it is considerably more infectious than other prevalent variants).

To be clear, the primary suggestion put forth by my original comment is:

Strategies for viral elimination should therefore be diversified across molecular targets and therapeutic modalities

Put another way: vaccines are a powerful and useful tool that can help us mitigate the pandemic, but if used indiscriminately they may actually work against us, so we need to proceed with caution and also use other tools where possible.

I don't know how you'd adjudicate it, but I'd bet quite a lot that indiscriminate use of a (tested, safe) vaccine is pretty much always going to be better than not using it.

There's of course no reason to stop at indiscriminate use of it, we should employ whatever vaccine strategy seems to be best (in an empirical sense), and supplement with other measures, I'm going at the banality of the point.

I agree with the general point that diversifying our vaccine targets is important for robust immunity, but you are sort of coming close to advocating that we not use the particular somewhat limited vaccine tech we have at our disposal now.

The best strategy against escape variants available to us right now is to reduce transmission rates (especially to immunocompromised people) as much as possible with high vaccination rates.

https://www.thelancet.com/journals/laninf/article/PIIS1473-3...

The core point of the OP article - and the data coming out of Israel - is that mass vaccination alone is less effective than expected at preventing the surge of transmission and infection by variants of concern.

The article you cited is in agreement with the literature I previously cited - as more people are infected the virus has more opportunity to mutate.

> The best strategy against escape variants available to us right now is to reduce transmission rates ... as much as possible with high vaccination rates

Your comment contradicts the mounting evidence we have available to us. Yes we need to use the vaccine tech we have at our disposal now - but in a highly targeted way, and supplemented by other viral elimination strategies that do not exert specific selective pressure on the virus.

So if I'm understanding you:

I am planning on taking my Governor's cheekily endorsed thumbs up to get a 3rd shot. I'm going to get JJ because it's not the same RNA spike target.

That's probably better than a 3rd RNA shot (no reformulated)?

> That's probably better than a 3rd RNA shot

To be clear, right now there's no scientific literature that conclusively supports your suggestion here.

A better takeaway from my comment and OP would be that there is evidence we must diversify our viral elimination strategies at a population level.

It might actually be best to for you personally to stick with the same vaccines you had previously, but I'm going to stop there because you should consult your doctor for decisions like that.

moderna and pfizer are different. different enough for moderna to be more efficient with delta and pfizer more efficient with alfa

thanks!

What keeps me worried is how much community immunity is required to stop a virus as spreadable as measles. I think it’s something like 95%. That’s a hard bar to pass for a vaccine or even “natural immunity” through letting it spread. Mixed with the possibility of long covid we could see some scary disease rates for the foreseeable future.

Natural immunity gives "ultrapotent" antibodies that works for 23 variants, including delta. That´s what will end this pandemic. Everyone will get infected, vaccinated and unvaccinated.

Ultrapotent antibodies against diverse and highly transmissible SARS-CoV-2 variants

”Wang et al. identified four antibodies from early-outbreak convalescent donors that are potent against 23 variants, including variants of concern”

”The B cells isolated from donor-derived blood samples were sorted for antibody identification. This led to the identification of four potent neutralizing antibodies targeting the spike RBD. These antibodies showed a high affinity for the SARS-CoV-2 spike even at nanomolar concentrations.”

”The findings revealed that of 4 antibodies, two bound to RBDs in the “up position” and two bound to RBDs in the “down position.” Moreover, three out of four antibodies directly blocked the RBD – ACE2 interaction, and one indirectly inhibited the interaction through steric hindrance - the slowing of chemical reactions due to steric bulk.”

”By conducting multiple rounds of selection using combination treatments with two antibodies, it was observed that antibody combinations might reduce the risk of escape mutation acquisition and subsequent development of resistant viral variants.”

https://science.sciencemag.org/content/early/2021/06/30/scie...

>The current mRNA based SARS-CoV-2 vaccines are effective at preventing severe outcomes like hospitalization and death

According to this very article this isn't even really true any more. Of the currently hospitalized population in Israel 60% are fully vaccinated. With 78% of the population vaccinated that implies the protection is actually surprisingly weak.

" “There are so many breakthrough infections that they dominate and most of the hospitalized patients are actually vaccinated,” says Uri Shalit, a bioinformatician at the Israel Institute of Technology (Technion) who has consulted on COVID-19 for the government. “One of the big stories from Israel [is]: ‘Vaccines work, but not well enough.’”

What is the age of the hospitalised, and what is the vaccination rate for that age range? I expect most of the hospitalised to be elderly, and most of the non vaccinated to be young.

Wouldn't you have to look at the age of the population that is in hospital and that populations vaccination rate to accurately gauge this?. The overall vaccination rate could be vastly lower or higher than the overall population depending on what priority groups israel had.

If vaccines bring hospitalizations down they are already a win. The percentage doesn't say much about the number of hospitalizations. In a country where lots of people are vaccinated, I would expect lots of vaccinated people in the hospital too. Like others said, it also depends on the cohort (age, vulnerability, etc.).

That's a misinterpretation of the statistics. The most vulnerable population has a much higher vaccination rate than the population as a whole, with well over 90% of Israelis over 70 vaccinated. People over 70 have a much higher chance of being hospitalized, so to only see 60% of hospitalizations be of vaccinated people shows how effective the vaccine still is at preventing serious disease.

I don't know if we have this, but it would be good if we had a technology that enhanced your body's immune system to identify and kill viruses, rather than prime it to respond to a particular viral signal, that then may need to be updated as the virus changes (that's how I understand how vaccines work, but that could be false). You might think it's a subtle difference, but I think the former technology would be leaning into the body's existing ability to form a variety of antigens for viruses it encounters, and boosting its defense/offense against those, rather than 'handing out a series of police composite sketches', and saying 'Be On the Look Out for this specific guy, he might be coming through here.' The former could be more alike to enhancing predictive policing and profiling abilities, and beefing up response and enforcement capabilities.

Beefing up the immune system without garunteeing it something to do seems like a recipe for autoimmune disorders, no?

Yeah, agree. It would be tricky. I'm hoping that by 'enhancing' the immune system you lean into its natural self-regulation equilibrium system and avoid that mostly--but then again autoimmune disorders seemingly emerge from those stasis systems going haywire, maybe without external poking...so it would be tricky for sure.

I guess the intuition is that the human immune system is an incredibly sophisticated, evolving capability that over time, and over the mass population, can respond to become resilient against a wide array of pathogens.

So if you could somehow capture the best of that (like, for illustration, take the immune system of the healthiest, most resilient person, 30 generations from now in the future) and convey that benefit to many other people, that would be truly awesome.

Sort of like an idea of training an AI, more iterations are better, the immune system of any one person at any one point in time, might not be so great, but the best immune system of the population after encountering many pathogens, is going to be really great.

How can we short circuit that "natural training" process and enhance the immune system? But I agree that attempts to do so might run the risk of creating or exacerbating autoimmune diseases...But I still think it's worth it.

The immune system already does that and its the responsibility of CD4+ helper T-cells.

The 2009 pandemic was significantly blunted because people born before 1957 had partial immunity from cross-reactive T-cells to H1N1 which was endemic in humans from 1918-1957. So after mutating in probably billions of pigs for 50 years the H1N1 virus that hopped back to humans was still sufficiently recognized by the immune system of older people to take any edge off of that pandemic.

I'm also fairly skeptical of the data coming out of Israel about waning immunity. Everyone is taking that data at face value while entirely ignoring the disclaimer: "(Potential confounders include the fact that the very oldest Israelis, with the weakest immune systems, were vaccinated first.)".

We really need a lot better data on much better matched cohorts to determine actual immune waning in the presence of the same viral variant.

Oh yeah definitely of course the immune system that already does that, the idea is just enhance its ability so that everyone has sort of Best in class defence against these viruses.

it can be kind of slow on an individual level, but on a population level you will have some people who have evolved better defenses, or more resilient immune systems. If we can share that around that's the idea.

It's very interesting though about that immunity thing you say. People born then.

I think that was the idea that spurred monoclonal antibodies

https://en.wikipedia.org/wiki/Monoclonal_antibody

Interesting, thanks. :)

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