
Why does drug resistance easily evolve but vaccine resistance does not? - gwern
http://rspb.royalsocietypublishing.org/content/284/1851/20162562
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paviva
Very good question and a very good answers in this article!

I'll add one more reason not explored by the authors: antibodies don't "leak"
in the environment, in contrast to the antibiotics which are everywhere.

For example, if I'm vaccinated against _S. pneumoniae_ (one of the bacteria
that can cause pneumonia), the bacteria have to get inside my body to gain
exposure to my vaccine-induced antibodies. This makes the emergence of
resistance very unlikely because :

(1) the number of bacteria that are exposed to the antibody is relatively
small, because the antibody response is pretty fast and happens before the
bacteria had a chance to multiply to significant numbers; (2) any bacteria
clones who evolve resistance to the antibody remain susceptible to the myriad
of other immunes peptides, to macrophages, and so on. In other words, as long
as I survive my pneumonia, no resistance can ever emerge, because I will kill
all the resistant clones through other means.

Contrast this to antibiotics. I have pneumonia, I take antibiotics, I'm cured.
However, I excrete those antibiotics in urine and stool. Outside of my body,
enormous numbers of bacteria are exposed to minute doses of antibiotics. The
number of surviving clones is likely to be very high, and those survivors do
not face any supplemental threat. Thus, resistance to that antibiotic can be
transmitted to later generations.

~~~
pishpash
You don't excrete antibodies? I think you might be saying that antibiotics are
passive strategies which are inherently overly broad and thus problematic.

~~~
IIIIIIIIIIIIIII
Antibodies are too large to pass through the filter in the kidneys. Lower
molecular weight fragments of antibodies are usually reabsorbed in the
proximal tubule of the nephron.

Their fate mostly lies in catabolism, i.e. they are broken down and the
components reused. Biliary excretion accounts for a very small amount of the
elimination of IgG antibodies.

[0] "Pharmacokinetics of Monoclonal Antibodies"
[http://onlinelibrary.wiley.com/doi/10.1002/psp4.12224/pdf](http://onlinelibrary.wiley.com/doi/10.1002/psp4.12224/pdf)

~~~
robbiep
Even if an antibody was eliminated, and managed to bind to an antigen, what
good is it if it doesn’t have a complementary immune system to act on it

~~~
IIIIIIIIIIIIIII
Yes, that's actually the main point, thanks!

I missed it when I wrote my reply, concentrating on the immediate question
(interesting psychological problem) - and then I could not edit it. It
bothered me quite a bit but I did not want to write a third reply. Interesting
to see how easy it is to get sidetracked on an irrelevant (albeit interesting)
question, and how hard it is to get the discussion back on track.

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rapsacnz
I like to use a conflict analogy: A drug is a weapon exploiting one weakness
of the enemy. A vaccine is a visual identification of the enemy, passed on to
special forces (your immune system). A single weakness can often be changed
easily, but it's harder to shake off special forces.

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saas_co_de
"Here we argue that vaccines are less vulnerable to pathogen evolution than
are antimicrobial drugs because of differences in the way drugs and vaccines
work. We contend that two key features of vaccines have large, synergistic
effects on the rate at which resistance arises and then spreads"

"(a) Timing of action - For most infectious diseases, hours to days elapse
between exposure to a pathogen and symptomatic infection in a host ...
Pathogen replication during this incubation period creates opportunities for
mutations to arise"

"(b) Multiplicity of therapeutic targets within and between hosts - The
benefit of combination therapy is based on the premise that resistance can
only be acquired by the simultaneous acquisition of resistance to each
component drug. The probability of simultaneous acquisition becomes
vanishingly small as the number of drugs increases. A vaccine, however, often
exposes the host immune system to multiple pathogen proteins (antigens), and
multiple potential binding sites (epitopes) on each antigen. Epitopes are
recognized and bound by components of the immune system analogously to how
biochemical molecules would interact with a drug or its downstream products.
This means that immunity is in effect acting like combination therapy, but
with substantially more component effectors (and hence targets) than any drug
cocktail."

\------

"One set of differences between vaccines and drugs stem from the fact that
vaccine effects are mediated through host immune responses while drugs effects
are mediated through chemical pathways"

They discount this as being a major factor but the only evidence they provide
is that "resistance is seen against drugs such as solfonamides that also act
indirectly."

It could also be considered that the immune system is adaptive and its
capacities evolve during a person's lifetime and that the collective immune
system within a population group evolves depending on the spread (or lack
there of) of disease within the population group.

With vaccines we are triggering the evolution of individual and group immune
systems in ways that we don't fully understand and so unlike with drugs where
once resistance is formed we have to develop a new drug, individual and group
immune systems continue to evolve even if the vaccines don't change. The same
vaccine administered now may be triggering different responses than it did 100
years ago.

~~~
chewbacha
Herd immunity affects timing and variation in the community affects
multiplicity. You aren’t wrong but I believe you are restating the conclusions
in another way.

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mannykannot
While I do not doubt that this difference exists in general, I am wondering if
there is not, to some extent, an issue of terminology here. My understanding
is that influenza vaccination is somewhat uncertain because antigenic shift
and drift produces new, or not-recently-seen, strains. When a bacterium
modifies its genome to survive an antimicrobial drug, we call that
'resistance', yet I guess the drug is still as effective as before against
unmodified bacteria. While the mechanism is, in detail, different in the two
cases, they both involve the pathogen modifying its genome to render the
treatment less effective.

Maybe the distinction is because, in the case of influenza, the strain changes
are not in response to, and driven by, the treatment? HIV, however, seems to
be very effective in mutating specifically in response to every candidate
vaccine that has been tried against it.

~~~
m3kw9
Exatly, the resistance due to evolution and new strains by passing vaccines is
not very comparable

~~~
ianai
As a total amateur, it seems like the bacterial/viruses need only find one way
to breakthrough your immunity. Your immune system has many more attack vectors
to cover. The bacteria only need to be right once, but the immune system
billions.

~~~
alextheparrot
The immune system is also layered - a single viral infection won’t necessarily
kill you right away. If it does penetrate the initial layers, the immune
system will continue adapting and fighting it on each new front. Eventually
your entire body might even engage using things like a fever. In this way, it
doesn’t need to be right initially billions of times, but capable once at one
of many steps.

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refurb
I always figured it was because there were thousands of different types of
antibodies generated against an immunological challenge (e.g. vaccine).

The antibody simply finds a conserved binding site and it works. Therefore,
they don't have to be the same.

As a result, resistance doesn't form as the bacteria or virus would need to
develop resistance to thousands of different antibodies, not just one.

~~~
mirimir
This was my guess, before reading the article.

A couple secondary hypotheses come to mind. First, resistance to monoclonal
antibody based drugs[0] is more likely than resistance to vaccines. Second,
resistance to single-epitope vaccines is more likely than resistance to
complex multi-epitope vaccines.

0)
[https://www.medicinenet.com/monoclonal_antibodies/article.ht...](https://www.medicinenet.com/monoclonal_antibodies/article.htm#list_and_types_of_monoclonal_antibodies_\(fda_approved\))

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lr4444lr
Not a biologist here, but hoping maybe one can correct me on this: isn't it an
important factor that in the immune system the signaling cells themselves have
evolved to respond to variants of a given pathogen's protein marker, whereas
drugs are always presenting the same chemical challenge?

~~~
Xylakant
As far as I read the article and understand your question, this is indeed one
of the factors that they mention. Each persons immune system reacts in a
different way, posing a unique challenge to the pathogen.

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clarents
My understanding is that we're unable to created effective vaccines against
RNA viruses as RNA replication doesn't have the built-in "checksum" mechanism
that DNA has. When DNA replicates, because the two strands of the helix are
essentially mirror images of each other, it is easier to create an exact copy
without mutations. RNA, not having this property, allows for more mutations
during replication. This increased mutation rate is what causes the viruses to
change so quickly and what makes the vaccines we create quickly useless
against the changed virus.

~~~
dnautics
Flu, polio, and measles are rna viruses which are regularly vaccinated
against.

~~~
clarents
Wow, you're right, I guess that kind of kills my theory. I knew that flu was
which explained why there's a new vaccine every year and it's often not
effective against the current strain. But I had thought that polio and measles
were DNA viruses.

~~~
Fomite
You are _partially_ right. Some RNA viruses are hard to vaccinate against
because of their mutation rate, but it's not the sole arbiter of whether or
not it's doable.

There are other issues, like the existence (and lack thereof) of highly
conserved antigenic targets.

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dnautics
The decreasing effectiveness of the flu vaccine suggests to me that the flu
metagenome is evolving resistance to our vaccine generation strategy.

~~~
philjohn
It's not, each year we have to guess which strains will be prevalent, and
sometimes they get it wrong.

~~~
rflrob
Not only that, the strains they choose not to include will likely spread more
effectively than the ones that they do. So even if the vaccine magically
protected 100% of people against the most prevalent N strains, the (N+1)th
strain will be the one that most people get. Did the CDC “guess wrong”, or are
they doing their best to fight an impossible battle?

~~~
richardw
Is developing or producing the vaccine the costly bit?

If producing, then what about creating more and patchworking them? It might
reduce the monoculture type issue.

I.e. everyone gets the worst two, then two of the next 8/16, whatever models
best.

I assume this has already been modelled to death but asking in case anyone
knows.

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exabrial
Don't bacteria have a way of swapping genes that was discovered recently?

~~~
jballanc
If by "recently" you mean 1946, then yeah:
[https://en.wikipedia.org/wiki/Bacterial_conjugation](https://en.wikipedia.org/wiki/Bacterial_conjugation)

Unless you mean across species, in which case there are new and interesting
ways that bacteria can swap genetic elements across species boundaries being
discovered all the time. The first example was the original Griffith
experiment in 1928, but the wiki article here:
[https://en.wikipedia.org/wiki/Natural_competence](https://en.wikipedia.org/wiki/Natural_competence)
has a nice timeline of some of the more recent examples as well.

