HIV mRNA Vaccines-Progress and Future Paths
pubmed.ncbi.nlm.nih.gov
pubmed.ncbi.nlm.nih.gov
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915550/
It's always good to remember just how crazy complicated and unusual HIV is, with its self-rewrite immune escape functionality.
The mRNA vaccine for covid-19 was very lucky, not only because coronaviruses are not the devilishly clever co-evolving with the host's immune system HIV type of things, but also because the spike protein was already "solved" ahead of the pandemic. By that i mean we knew how to create a version of the spike protein that doesn't require the full envelope to fold properly. The mRNA sequence was ready in January 2020, the rest was just manufacturing, testing and distribution.
The HIV vaccine will be most likely much more complicated, as the authors point out in the last chapter.
PS. Sometimes I wish I was a research doctor instead of a computer scientist, but I guess the grass is always greener :)
The reality of being a researcher appears to be quite disappointing. Trapped between grant hunting and p-hacking the papers you need to churn out into high impact journals appears to be the grim reality.
The grant hunting, bullshitting, old-stuff-in-new-covers is all the same, but the problems and the topics are just so much more approachable, relevant, interesting, and the community seems to be "nicer".
But then of course, I know people that are in that area an were getting into research, and they did not paint a nice picture. And the community obviously can suck also once you're on the inside. And being a "researcher" without clinic duties is really not easy getting into in Europe it seems. Also, who wants to stop doing clinic completely, when this is what he trained for so long...
There are upsides and downsides to everything - I think it really depends on where your interests are.
Having worked as a programmer for molecular neurobiologists for two years: yeah, they are. Everyone's just hyped at how insanely fast things are developing. Everything I saw when I worked there felt cutting-edge. The engineering involved, the science produced, the speed at which new insights were being gained.
> And being a "researcher" without clinic duties is really not easy getting into in Europe it seems.
The trick is to go the molecular biology route instead, it seems
Part of the secret to success in bench work is finding a seam which you can mine productively. You have some technique or system set up and working, and you can grind out findings from it. But it takes time to establish that seam, and it isn't necessarily anywhere near where the actually interesting problems are.
I worked on cell migration. We used a particular cell type that had very good, consistent migratory behaviour, which made it a good system. But it was a primary culture, made fresh from dissected tissue every day. Primary cultures are highly resistant to having DNA put into them. Pretty much all modern cell biology hinges on putting DNA into cells. I spent a year or so trying different techniques (including making adenoviral vectors!). Eventually, i found something which worked okay. But that was just the start of actually doing interesting work - the year up to that point had produced nothing. This is completely normal in bench work, but would be pretty shocking with computers.
By the time someone is an expert on biology and then physics, there's not much mental capacity left for CS. And unfortunately people that start CS and move to biology are extremely rare.
As an undergraduate I actually first got into computing through a biology-computational project! My current work pays the bills, but my armchair dream switch to research - in biology or another science.
Really, it's the bare basics that they need a big hand with. In bio, a lot of the grad students have literally no calculus or math training outside of stats. They have no training whatsoever in CS, let alone programming. If they are programming, it's matlab, and then they use 15+ nested for-loops (true story). Hardcoded is the only way of things. Github is a way around gmail's 25mb limit. The PIs are these people with a few years under their belts and even worse habits. It's all hacked together with bubblegum and if-statements. And the time/money pressure is intense. They don't have the resources to start fresh with new habits or to learn three semesters of math.
I don't really know where to start on helping them, but it's pretty far back in the the chain. Honestly, given the constraints, it feels like they need someone to write programs for them in a pair coding style for free.
Interesting! Could you elaborate on this or provide a link?
> but also because the spike protein was already "solved" ahead of the pandemic.
I would also be interested in further information on that?
Thanks
For the second see something like "covid spike sequence modification", for example this seems like an accessible article: https://cen.acs.org/pharmaceuticals/vaccines/tiny-tweak-behi...
It was all thanks to the research on previous coronaviruses, MERS specifically. The Pfizer/Moderna vaccines have just copied it (of course that simple modification is not all it took, but that was definitely required for success).
Could I get some more context on this or a direction to start researching?
I feel this would be great information to share with the vax hesitate crowd. I have heard a few people say the vaccines are too new and not tested enough.
Also, replying to the grandparent: vaccines per se are not necessarily safe out of the door, they're medical products and as such can have potentially many unforseen and troubling consequences. However, in the past all the unforseen consequences of any vaccine (whether still used, or since then retracted from the market due to problems) would become known a few months and a few tens of million people into the phase 3. That's when it is very, very safe to jump on board. And this is definitely already the case with all the popular covid vaccines.
To summarize: human data trumps everything in medicine, and we've had A LOT of data points.
New Zealand did not use Emergency Authorization for the pandemic, because they had elimination so they were able to wait while their medicines agency performed full (but expedited) assessment for the Pfizer mRNA vaccine and gave a recommendation based on that assessment. As a result they didn't even begin vaccinating people until months after some other countries, but (because of elimination) they had zero deaths meanwhile.
So, in some countries regulators might decide an HIV vaccine is something that needs Emergency Authorization and in others not.
Another factor in what you're calling a "10 year process" is how long it takes to collect data from a Phase III trial. I think lots of people still do not appreciate why the Phase III trial for these coronavirus vaccines was so fast. The pandemic meant that huge numbers of people in your control group get infected. This is terrible news for them, some will die, but it means you get very rapid trial results.
So if you're confident that HIV has similar levels of spread, this is "good news" there too, the vaccine trials won't take very long to give results, regardless of whether you are intending to do Emergency Authorization or a normal process.
It does if you do phase III trials in the right countries. In South Africa, there's 15 million HIV cases give or take, and a million infections per year - so trials could yield results rather quickly...
In the ideal case you'd somehow randomly sample the world population, but practical considerations have to be taken into account. As a result it is often the case that we don't yet have a medicine targeted precisely at your gender, age, ethnicity, build, pregnancy status, co-morbidities, profession, and favourite musical genre, but ultimately the medicine which worked on another human who is quite unlike you in almost every way is surprisingly likely to be effective anyway, and so maybe you should try that meanwhile.
Everyone has heard of the covid strains and the anxiety around them (are the strains much worse? will there be cross strain immunity?). This is like child's play compared to HIV, where essentially every infected person has a separate HIV variant, evolutionally crafted to evade the specific host immune system as best as it can. I would call it "amazing" had it not been inappropriate to call "amazing" a deadly disease.
Read the full paper, they go in detail on how the vaccine would have to create a "portfolio immunity" against the parts of the virus that are known to be most important. For example in terms of the humoral immunity they call them broadly neutralizing antibodies (bnAbs). Those will have to cover a range of variants.
> Nucleotide sequences of the hypervariable V3 region of HIV-1 obtained from different organs of one patient demonstrated distinct viral variants.
look scary at first blush. But if you've ever worked in a molecular biology lab, you know how competition, FOMO, and other pressures force shortcuts that should never be taken. In addition, the high traffic and 'density' of 'dangerous' agents and reagents makes errors exponentially more likely. These places are also high profile and as such targets for espionage as well as 'other' events (rhymes with error-ist and starts with a 't') .The resulting irony is that professional mol bio labs might be less safe for the workers and the environment than someone's basement. A contained low profile workplace is safer based on epidemiological arguments. An 'error' there is much more likely to result in a failed experiment than a disaster.
Both HIV and COVID came from animal hosts originally. They weren't "bread" by humans.
> Watching covid varriants pop up worries me, but perhaps a quicker to production mRNA vaccine will allow us to remain ahead of it.
Well its possible that covid will mutate to escape the vaccine, its hardly a sure thing and hasn't happened yet (variants dont matter much if existing vaccines take care of them). Its entirely possible that new mRNA vaccines not only would be fast enough, but that we will never actually need them at all.
The jury is out on COVID. We don't know.
What we don't know yet is how it jumped from bats to humans. Is it direct? Is there an intermediate host? (pangolin?)
The more reasonable conspiracy theory is that the virus escaped from the Wuhan lab, possibly as a result of gain of function experiments. But originally, it is still bats, and what they could have done is not something nature is incapable of.
That being said, progress towards an HIV vaccine will clearly lead to less deaths than an increased amount of unsafe sex, and remains a noble goal. I just hope we as humanity can develop cures quicker than we can breed viruses. Watching covid varriants pop up worries me, but perhaps a quicker to production mRNA vaccine will allow us to remain ahead of it.
The comment about dying early made sense: Just because we lived with unprotected sex for the last million years (and we changed genetically due to some viruses that we got along the way) it doesn’t mean that we’re now still willing to bear the consequences.
I’m willing to bet that nowadays we have far more sexual partners than we’ve had since we started “society”
Many people can go their entire lives having the internet as their sole partner.
That indicates that the vast majority of people has at least one sexual partner, with many having a lot more thanks to sexual liberation.
For the record, I’m not saying that this is a bad thing at all. I was just alluding to the fact that we can’t compare life and expectations of safety to what it was even 100 years ago, let alone over “millions of years”
As opposed to people being ignorant about statistics and constantly parroting crap like "people only lived to 30 before modern medicine"?
We all live in a single Petri dish now. A few thousand years ago humanity existed in many many isolated communities and was much more resilient to disease. Regular pandemics every ~10 years are very much a side effect of technology.
You're not technically wrong. It's just that up until very recently the ones not preventable by vaccine (HPV, albeit stupidly expensive for men to get vaccinated for which of course means that men don't get vaccinated for it) were mostly immediately obvious and always easily solved by a single dose of antibiotics (basically everything except HIV, HPV, and herpes, which isn't life threatening).
Our impending antibiotic resistant apocalypse is of course terrifying.
This is my main concern. We as a species seem to always be so sure we can engineer our way out of a catastrophe by focusing on reaction to problems vs prevention of problems and always pass costs to the future. I'm all for keeping reactive skills top notch but we need to think about simple and easy preventative measures.
The HPV vaccine reference is a great example. Men should also get vaccinated as a preventative measure but we play it off as too costly or low risk. Men partaking in anal sex can get HPV and not even know it, sometimes leading to penis or colon/anal cancer later in life. It's especially bad because men will likely go long periods of time completely unaware of such an infection. We vaccinate young girls because we know they're all at risk but we often don't vaccinate young men because we don't know who will or won't end up having anal sex and culturally assume men are somehow invulnerable to it because of it.
Men partaking in _any_ kind of sex can get HPV and not know it. It's just as transmissible through oral and vaginal sex, and vaccination among women is also extremely poor in the US.
True, it's definitely possible to overlook or ignore, although symptoms of HPV are far more likely to be observed anywhere else than inside the anus or vagina.
WHY??? 620€ in Germany/Austria for 3 shots is absolutely outrageous.
HPV is responsible for a high amount of penile, anal and mouth/throat cancers. Even if you already have or had a HPV infection, the vaccine can protect you from getting it again or strains you don't have yet. There is some evidence that the HPV vaccine can act as cure for existing infections. +anyone vaccinated protects unvaccinated people.
Fellow German here, this is what I really don't understand, this is the same argument that is used for every other vaccine. Why not this one?
Is it really 620€ I was thinking of getting it at some point, but that's a steep price.
It's a bit of paranoia and maybe even unconscious bias against the group mentioned you're not aware of.
Heterosexual unsafe sex is just as likely to lead to virus mutations and it's certainly a higher proportion of the population, yet you choose to point out gay males in particular?
It's oversimplifying, but it's not wildly off base.
I guess maybe it's not widely known, but half of STIs are bacterial, so antibiotic resistance is exactly the thing people are worried about.
You of course may get drug resistence in std's just like other non-sexual infections, but im not sure why the emphasis on unprotected sex.
Probably just because the thread context is a rise in unprotected sex and a coincident rise in STI transmission.
But now that I think about it, I'm curious which cavities in the body present the widest mucosal surface areas if you cut and open them up and measure them. The pharynx, the throat, the anus and colons, the urethra, the vagina cervix and uterus, how do each of those measure out. I've heard the colon is susceptible to infection because of the large network of lymphatic tissue just on the otherside and because it's designed to absorb stuff being the last mile of the digestive tract where traces of anything left behind at that final stage and still useful can be absorbed by the body. The application of suppositories come to mind in this space.
Another angle might connect with the point brought up by the other individual about bacteria being a frequent origin of STDs, and bacteria generally share genetic material from what I understand. Maybe that bacteria to bacteria mingling is where the risk comes in?
Generally bacteria-based stds are not the scary ones as we have very good treatments for them (antibiotics).
Antibiotic resistence is a concern of course, but still, virus based stds are much scarier.
Yes, this data exists and can be measured. Viral Load, detectable load, etc are common terms when discussing HIV.
Not a doctor, but from what I've heard the colon is the mucus membrane that presents the greatest risk for STD transmission.
> Maybe that bacteria to bacteria mingling is where the risk comes in?
I think its "simpler" in that we've seen bacteria become resistant to antibiotics. So bacterial infections could become resistant. I'm not sure its a valid concern since most people will kill the infection before spreading it (which increases rate of mutation), which is easier to do for an STD than something airborne by a hospital patient who can't leave.
This is actually a good point applicable to the broader context, that I hadn't really thought about. Billions of people get cold/influenza infections every year. Why don't we see more mutations of strains that are highly virulent/tending to more severe outcomes?
I get this, but it doesn't intuitively follow to me that the incidence of severe strains would be as low as they are. The evolutionary pressure against severe strains shouldn't be enough to stop them from emerging in the short term. And yet, for example, all the severe coronavirus strains seem to be zoonotic, rather than mutations of strains already circulating in humans.
> Higher virulence is occasionally seen though, as was the case with the swine flu some years ago.
I guess higher virulence is also hard to measure. If there's a rhinovirus strain one year that infects twice as many people as normal, who's going to notice that?
(Just pure speculation. Not my field)
Also, people have been having "unsafe" sex for over 40,000 years. There's been gay unsafe sex and straight unsafe sex going on all that time.
I'm not sure how we all made it.
I am not a scientist or any kind of expert. But I thought I read somewhere that there are some ape species for whom SIV is endemic and harmless. Others get sick and die.
So maybe it just takes time for a species to adapt and it's very deadly right now because humans haven't been exposed for very long.
The difference between Stone Age and today is that our civilization managed to conquer most really serious risks that used to shorten the lives of people under, say, 70. Famines, unsafe water, most bacterial diseases are well under control. So, of course, the roster of threats now changed, some of them being civilizational (road accidents), some of them being relatively small holdovers from the ancient days, such as STDs, plus the very aging that makes our mortality curves shoot up in the old age.
But yes, realistically, people are going to bareback one another all the time. Which means that vaccines and cures for whatever bug is transmitted like that are necessary.
To your comment, I'd at least say there's evidence that treatments to previous STI epidemics hasn't caused the downfall of humanity, and so a vaccine or treatment for HIV/AIDS likely won't either.
As an aside, I wonder what role STDs played in the development of religion and the religious superstitions surrounding sex. Can monogamy survive in the long-term in a world without consequences to promiscuity?
Ideally you're both monogamous so unless one had STIs before entering the relationship, it's incredibly unlikely either would acquire one and almost certainly not from intercourse but through some other means.
There are people more interested in the low risk stable sexual benefits of a trustworthy monogamous relationship. I personally doubt it's more than the number of people wanting an intimate relationship beyond sex though.
It's certainly not exclusive to monogamy.
I guess define consequences? I sure as heck wouldn’t be ok with my wife having sex with other people just because STDs aren’t a problem… the consequence would be divorce with or without the STD.
Sure, but after how many people get sick? Seems like a very dismissive comment.
The problem is that not everybody likes to share their partner. The likely consequence of a partner sleeping with other people is separation or divorce.
Also, I'm pretty sure that STDs have virtually never stopped anybody from cheating on their spouse if they wanted to. So no, I don't think that a lack of STDs will have much effect on monogamy, if at all.
Pair bonding is crucial to social organization and casual encounters erode the psychological capacity for such bonds, without nullifying the innate human desire for long term companionship. The result in a "sex positive" society is a growing proportion of perpetually lonely and frustrated people, or dysfunctional relationships. One of the few instances in my opinion where ignorance truly may be bliss.
So, to your question, it's quite possible that we will rediscover the purpose of monogamous marriage, if we can reason past the barriers of some recent ideologies.
Do you have any reading material on this to suggest?
Consequences to promiscuity are not limited to STDs. Bad framing of the issue.
From a cold, logical perspective there are certainly evolutionary benefits to having a pair-bond not least of which is future certainty of care, for yourself and your joint offspring.
So maybe natures optimal path is closer to pair-bonding + promiscuity, rather than either on their own?
Much more likely, the problems with promiscuity were related to 'bastard' children and their role in inheritance; and to the father's uncertainty that a child was biologically theirs. In addition, many religious outlooks favor abstinence from bodily pleasures of all kind, so forbidding sexual pleasure and especially promiscuity seems well in tone with this.
Did the old world have gonorrhea, herpes, genital warts, molluscum, trich, or any other visible STD? It seems like any one of those would be sufficient to cause a superstitious, iron age people to suspect something was plaguing the sexually promiscuous.
Notably, when syphilis was introduced into the Old World population, it was described as a very severe acute disease. It only became more chronic after a period of adaptation that took several decades. This might have made the initial societal reaction more extreme.
https://www.everydayhealth.com/syphilis/painful-history-odd-...
Chlamydia rarely has life threatening complications but gonorrhea and hepatitis can kill. And there aren’t any STDs that don’t often cause infertility. Religions favored not screwing around because you’re guaranteed to get an STD eventually if you do, and that will very likely lead to infertility or worse.
Well yeah, sex is cool and all but I don't like strangers or sharing.
I've never understood the "promiscuous" lifestyle that a different part of society seems to be natural at. Thankfully that's not the norm, just one of many subcultures.
Otherwise, have a blast.
If you insist on people using condoms just in case a novel virus is circulating, then we should all be wearing masks too at all times well into the future. Respiratory viruses can be just as bad as sexually transmitted ones.
Remeber that unsafe sex is the natural norm, especially if you don't have to worry about unwanted pregnancy (as in the case of gay people). Safe sex only truly became a necessity because of HIV, an extremely recent phenomenon.
Considering PREP is targeted almost exclusively to gay men, and HIV is mostly a concern among the sexually active gay male population, saying "young, gay, men" is pretty fitting.
Obviously the value-judgement about how much sex is too much or too risky can't have data to back this up. To me, as long as there is a net reduction in risky behavior that might impact society (not spreading a disease faster than eradicating it), its probably good, but this doesn't seem to be OP's view.
I do not want to discuss a higher incidence of HIV in the group of gay males compared to the whole population. That is a fact that is attributable to the fact that unprotected anal sex comes with a higher infection risk then unprotected vaginal sex.
But the OP claimes that "specifically [young] gay males think as long as they are safe from HIV, they are safe enough." That may be the result of unfortunate wording. But if not it is an allegation that the OP will have a very hard time to prove.
So, first off, you might have a valid point but your approach sounds pretty biased. The wild generalizations about behavior, especially stigmatized behavior from a marginalized group, detracts from point about concern over a super-virus. Yes, gay men are often the topic of convo when it comes to HIV but it's not like they're the only ones passing around STDs.
Also, I'm not sure its true that Prep has had a material increase in unsafe sex. Most gay men seem to think of it more as a means to not worry about dying from sex instead of an opportunity to dramatically change behavior. Thanks in-part to HIV gay men are probably also the population with the best insight into their sexual health - so if a concerning new STD did spread, they'd be the first to take the individual responsibility to stay regularly tested and informed.
Birth-control and abortion and other related tools likely had a similar affect on heterosexual sex that prep had on gay men. There is a lot more heterosexual people to pass things around too. So calling out gay men might not be the most important piece to your worry about promiscuity leading to a super-virus.
Prep-induced gay promiscuity inducing a new pandemic of super-STDs really sounds like a bad talking point for an extremist politician in a conservative country. Obviously, its possible, however improbable, but its probably not the best way to express this concern.