If you were born in the United States in 1900 you had about a 1 in 3 chance of dying from an infectious disease. If you were one of the unlucky third, 40% of you would die before the age of 5. In fact, the top three causes of death were infectious disease at this time- namely, pneumonia and flu, tuberculosis, and diarrhea/enteritis. Fast forward to today and you’ll normally only find 1 infectious disease in the top 10 causes of death in the United States- Influenza & pneumonia at number 8.
For the curious about the full list here, it is: #1- Heart disease (647,000 deaths annually in the U.S. or 1 in 4 deaths, or about 17 million people dying of this per year world wide), #2- Cancer (about 600,000 deaths in the U.S. or, again, about 1 in 4 and an estimated 10 million deaths per year worldwide… so like, once we resolve the covid problem, can we all collectively agree to panic and globally throw extra trillions at more research for these top two? Because, just saying, just because it’s familiar doesn’t mean we should accept it… If half of us are destined to die this way, best to die trying not to.) In any event, rounding out the rest of the top 10 we have- #3- Accidents (170K people per year in the U.S.), #4- Chronic respiratory diseases (160K people), #5- Stroke (146K), #6- Alzheimer’s (121K), #7- Diabetes (83K), #8- Influenza pneumonia (55K), #9- Kidney Disease (50K), and #10- Suicide (47K).
No anti-vaccinator today is worried about their children getting things like small-pox or polio thanks to vaccines, and child mortality rates reflect that. Sadly on the other side, child mortality rates also reflect that in regions of the world where people don’t have access to such medical miracles. For further reference here, smallpox, a disease that’s been around for over 2000 years, was completely eradicated from the wild in 1980! Before that, however, in the 20th century alone- a time when a vaccine had long existed- it still killed off an estimated half a billion people before humanity drop-kicked it in the gonads because our scientists are kind of awesome sometimes.
Given that for most of human history you could expect at least one, and very likely more, of your children to die before they reached adulthood, often from such rampant diseases, and today losing a child is relatively rare in the developed world- not to mention the many, many millions of adults who get to keep on keeping on because of vaccines- these miracles of medicine are collectively thought to be one of the greatest achievements in human history.
This might all have you wondering, if we can create vaccines for everything from Chickenpox to Tetanus, why, with the obscene amounts of money and brain power leveled at viruses like HIV, can’t we make a vaccine for these banes of human existence? And why despite such failures is there reasonable confidence that at some point in the not too distant future we’ll have a vaccine for covid-19?
To begin with, while there are other factors involved which we’ll get into, it turns out one of the biggest reasons we don’t have vaccines for everything is simply because we don’t try hard enough. In other words, it’s really, really expensive to make a vaccine, taking many years and often in excess of a billion dollars to get a single vaccine to market. And that’s talking about the ones that actually make it through the extensive processes to something successful and safe. So unless there is a major financial incentive on the other end, odds are strong even if it’s something that we could in all likelihood make a vaccine for, it just doesn’t happen in most cases. Or at least, in these non-profitable cases, which is most, it doesn’t happen unless significant funding from sources like governments and/or mass funding organizations like the Bill and Melinda Gates Foundation occurs.
On the flipside, as a testament to what humans can do and how quickly when we feel like it, we have covid-19 as the poster child, which at the time of this writing has 8 vaccines already in human trials, only about six months after the virus reared its murderous head. This is a stage of the process that normally takes 3-6 years to get to.
For reference here, the general high level process for vaccine development is, first, exploratory and pre-clinical stages, which again usually takes years to achieve something promising. Then after that, there are three phases of the clinical development stage, starting with a small group of very healthy volunteers for phase 1. In this one, beyond general safety, researchers are looking at what the lowest effective dose is (assuming there is an effective dose in a given potential vaccine), typically starting small and building up as needed.
If that works out, next up in phase two, hundreds of people are selected, this time from a bit more diverse sample than the ultra-healthy group before. Researchers are again looking at how well the vaccine is actually doing its job and if there are any major side effects popping up.
If all is good there, in phase three thousands of people get the vaccine. However, in this case significant time is needed to see if this group in real world conditions seems reasonably immune and, again, further confirmation that the vaccine is safe.
If all that didn’t seem time consuming enough, once the vaccine is shown to be both safe and effective in real world scenarios on a large sample size of people, there are regulatory review and approval processes from governments the world over. And then after that, we have the issue of ramping up the manufacturing and making sure quality control is being maintained in that process, which isn’t exactly something that can be done overnight.
Failure to take the time and spend the money to properly execute this latter stage can, and has on occasion in the past, been very deadly. Perhaps the most famous case of this occurred after the vaccine for polio was first created which, combined with less thorough regulations on such manufacturing at the time, gave rise to the tragic Cutter Incident. In this case, said company accidentally shipped out 120,000 doses of the vaccine that contained the virulent strain of polio. The result was over 40,000 children getting polio and communities where these doses were administered seeing huge upswings in infection rates beyond those inoculated. Whoopsadoodle.
And note here even after all this, there’s also a phase four trial tracking everything after all approval is done and the vaccine is being widely administered, just to make sure everything is working as intended and remaining safe.
All that said, things can be sped up significantly if certain steps are done at once, such as locating and getting prepped facilities needed to manufacture en masse while the testing phases are still being done. Normally this isn’t something a company would do given the high failure rate of prospective vaccines. They simply wait until they’ve got something proven and approval for it. But with effectively infinite funding, such as with covid-19, short cutting certain things like this is not just doable, but is happening.
The individual trial phases, however, can’t be easily compressed overall if maintaining safety. But there, again, much like in your computer processor, progress can be rapidly accelerated from years to maybe even just a year via, essentially, multithreading- ie trying basically every method scientists can think of all at the same time instead of trying one, seeing if it works out, then repeating as necessary, as is closer to the norm within individual companies because it minimizes overall development cost. But, again, throw infinite money at a problem, and that’s not an issue anymore.
So funding is a huge problem normally. But what about even when we do throw absolutely obscene amounts of money and for many decades at something like, say, HIV? Or why despite being in the top ten causes of death and people getting widely vaccinated already can’t we curb stomp the Flu? (Note here, in both of these cases, as we’ll get into shortly, there’s very good reason for optimism in the next decade or two.)
But in any event, why can viruses like these elude our best efforts at least so far? To answer that, we’re going to have to put on our science caps and talk a little bit about viruses, types of vaccines, and the nuts and bolts of how they actually work, which is all quite fascinating when you go a bit deeper than most mere mortal’s understanding. So stick with us. We won’t go full textbook on you, but hopefully the interesting details we do include you’ll find as fascinating as we do. (And just a note here, in an effort to keep this most pertinent to the topic at hand, we’ll only be discussing viruses able to infect humans.)
So to begin with, viruses, in general, are around 200 times smaller than the tiniest bacteria. They’re inert outside of a living host cell because their genomes don’t contain the necessary instructions to make the proteins they need to replicate and spread- they need a host cell to provide that for them. This is in part why there is such a debate over the issue of if we should consider viruses a life form or not. But that’s a topic for another day. For now, these intracellular parasites’ main goal is to get their genome into a host cell so it can follow N.W.A.’s advice and express itself.
Once inside, it can take advantage of your living cells’ chemical machinery to replicate and spread via messenger RNA (mRNA). Outside of a living cell, they’re much like bullets without a gun- packed with potential danger but no mechanism to become sinister.
Moving on from there, using what’s known as the Baltimore classification system, there are 7 types of human viruses, classified by the structure of their genome or their method of replication, separated by how each particular virus gets to its goal of creating the mRNA allowing it to reproduce and spin its web of woe.
The 7 types are: Single and double stranded DNA (for example all 8 types of human herpes viruses, which nearly everyone reading this has one or more of, are double stranded DNA). Negative and positive single stranded RNA (Corona viruses are positive single stranded RNA viruses). Double stranded RNA (Rotavirus, for example). Single stranded RNA-retrovirus and double stranded RNA-retrovirus. (HIV is arguably the most famous of the retroviruses).
Single and double stranded refers to their genome’s helix containing single or double strands. The positive and negative “senses” refer to it’s ability to create amino acid sequences that make proteins- positive if it will and negative if it won’t. Retroviruses use an enzyme called reverse transcriptase to make DNA from RNA, opposite of the normal process, thus its name “retrovirus”.
This brings us to how our bodies keep these murderous bits of code from killing us all the time. Our immune systems come in two forms- innate and adaptive. The innate immune system is a nonspecific way the body can recognize and kill any foreign invader. When it comes to viruses, this system uses two main methods of detection and destruction.
So how does this work? Cells need to be able to let other cells know what they have inside them. Like a peacock spreading their feathers, they use a class of molecules called class 1 major histocompatibility complex proteins (MHC class 1) to display bits of the proteins within them on their cell surface. If a virus happens to be inside the cell, the MHC molecule will have fragments of the virus proteins exposed on the cell surface as well.
Your innate immune system comes with a type of cell called a cytotoxic T cell. These little hunters circulate throughout the body looking for virus proteins bound to those MHC molecules. They have receptors that can detect specific pathogens. If those receptors detect an infection, it releases what are known as cytotoxic factors. These factors then kill the cell.
That said, these viruses do not go quietly into that good night. They have evolved to fight back, and some don’t allow MHC molecules to reach a cell’s surface. These ninja-like warriors then hide from those cytotoxic t cells. Up on their tricks, however, our innate immune system is also equipped with natural killer cells, which are totally officially called that by the way. These little storm-troopers that can actually hit what they’re aiming at roam around looking for cells who have too few MHC molecules on their surface. Assuming a pathogen must be hidden inside, when they find one, they also release cytotoxic factors, killing the cell. Once they contact the offending cell, they also produce what are known as cytokines, like interferon-g and tumour necrosis factor-a. These signaling proteins also help in enhancing the killer cells’ ability to destroy the invader.
Another way our innate immune system fights viruses is with interferons. When a cell does become infected with a virus it will release interferons. These inhibit the virus’s ability to replicate itself, while also signaling nearby cells a dastardly plot is afoot (ie there is a virus). That signal causes the neighboring cell to increase the amount of MHC molecules on their surface. Thus the whole process here essentially works like Karens the world over, helping let the cytotoxic T cells know where the problem lies and that it’s simply not going to stand for it.
This brings us to our adaptive immune system. It is this system that vaccines are trying to take advantage of.
The adaptive immune system uses 2 main types of lymphocytes called B and T cells, named T-cell because they’re created in your Thymus and B cell because of where they were first found- the Bursa of Fabricius in birds. Working together, they produce a way to recognize any attacker (antigen), multiply themselves, mobilize, then quickly envelope and kill the virus before it can enter a cell. Once they complete their task, they leave behind antibodies that will remain for a lifetime. This way any further contact with that specific virus will end in the virus’s destruction.
How do they do this?
Viruses have what are known as epitopes. These are segments of proteins (approximately 5-6 amino acids in length). When a new virus your body hasn’t seen before gets presented to a B cell (your body has around 10 billion of them), it will attach to the epitope and begin creating antibodies that will specifically bind to that particular epitope. This process is called Somatic Hypermutation. Helper T-cells then release chemicals allowing the B cell, with its perfectly formed epitope, to begin making countless copies of itself. Some of those B cells then turn into plasma cells. Those plasma cells then make thousands of antibodies per second and send the army throughout your body looking for any other virus with the same epitope. When found, they surround the virus and trap it in large clumps for other cells, like macrophages, to come along and get rid of them. The remaining antibodies then slowly decrease in number but leave behind memory B cells in case the virus tries to attack again. When a virus gets coated in an antibody, it cannot infect your cells. Therefore, you won’t get sick from any specific virus your body has already fought off.
While our innate immune system is the army we need to defend us from any type of virus, if we could artificially create our adaptive immune system’s antibodies, we’d be immune. We could win the war without ever actually getting sick from the thing. This is where vaccines come in.
As stated before, viruses come in many forms, and work differently depending on their genome. Because of this, different types of vaccines are needed for different types of viruses. In the general case, the vaccines all present the known virus epitopes to your B cells for recognition and antibody creation. But key here, the known virus has already been manipulated by our beloved science superstars so that it won’t create systemic infection. Once you’ve gotten the vaccine, it takes several days for your body to build up to a maximum number of antibodies in your blood. They will peak around 14 days after injection. You have now won all future wars against that specific virus via a combination of mankind’s big brains and your immune system itself being kind of badass.
This brings us to the vaccines themselves. There are 4 main types of vaccines- live-attenuated, inactivated, toxoid, and finally SRPC, which stands for subunit, recombinant, polysaccharide, and conjugate.
Live-attenuated vaccines use weakened forms of the virus causing the problem. Because they’re the closest thing to the actual virus you can get without risking infection, they usually need only 1-2 doses to protect you for life. Unfortunately, they will also need to be kept cold. Thus, they can’t be used in areas where reliable refrigeration isn’t readily available. Measles, mumps, rubella, smallpox, and chickenpox are all examples of Live-attenuated vaccines.
Inactivated vaccines use dead versions of a virus. Unfortunately, this won’t provide you the same immune response as live-attenuated. You might need booster shots to maintain the necessary antibodies. Examples of this include Hepatitis A, flu, Polio, and Rabies.
SRPC vaccines are a little more specific. Lab-junkies slice and dice the virus into specific pieces that allow our B cells to create antibodies for key parts of the virus. The good news about this is that they can be extremely safely used on people with weakened immune systems. This is something doctors occasionally worry about with the other types. Unfortunately, they also require booster shots to maintain your protection. Examples here include Hepatitis B, HPV, shingles, and Whooping cough.
Toxoid vaccines are something a little different. Protecting you from bacteria, not virus, they target the toxic secretions of the bacteria and not the bacteria itself. Examples on these ones are protecting against tetanus and diphtheria.
So now that you understand the nuts and bolts, what are some of the problems with creating these vaccines?
First, there are an obscene number of viruses and variations within a specific virus type. So even though many of these we very much could create vaccines for if we wanted, the cost associated relative to the negative impact on humanity just doesn’t justify such creation in many cases. And even when there is justification, it’s still a daunting task.
Consider the Flu. Traditionally to create a Flu vaccine, scientists take samples of the most common types of Flu virus being circulated during the previous year- usually 3-4 types (quadrivalent and trivalent flu vaccines). Then they create a vaccine for those 3-4 types, which can be done relatively quickly thanks to extensive pre-existing knowledge and techniques via creation of previous similar vaccines and, of course, a whole lot of money thrown at the problem given the Flu is relatively deadly and quite contagious.
The problem here is that this leaves you susceptible to any of the countless other types of Flu circulating around and it’s just not practical to create and administer vaccines for all of them. This is why the Flu is still such a burden on society and hasn’t gone the way of smallpox and, to a large extent, polio.
That said, as a brief aside, there is potentially a light at the end of this tunnel. It turns out if one can find a commonality that can be exploited in all Flu viruses and that doesn’t usually change much, or at all, from year to year and then make a vaccine exploiting that, a universal Flu vaccine could be possible. And, it turns out, one vaccine, called M-001 is currently in Phase 2 of clinical trials. It uses peptide sequences shared by many different types of Flu to create antibodies protecting you from all types containing those epitopes.
Even if that doesn’t work out, still other methods being developed target what is called the HA stem. The H protein in Flu virus (the H part of H1N1) contains a head and a stem. This protein gives the virus its ability to enter a cell. Seasonal Flu vaccine will target the head of H which can mutate readily- again why new vaccines need created regularly. Researchers have discovered, however, that the stem doesn’t usually change from year to year. As such, they’re now attempting to make vaccines which create antibodies for the stem. If successful, this would leave you immune to the new strains that are about to take on the world. And we might finally thus rid ourselves of this troublesome virus.
Going back to the trouble with creating vaccines for everything, let’s discuss HIV, which humanity has thrown obscene amounts of money and brainpower at for decades now and, while treatments to keep it from being deadly in most cases are now extremely good, we still don’t have a vaccine to stop people from getting it in the first place.
As mentioned, traditional vaccines allow the immune system to create antibodies for specific epitopes. Viruses like HIV, however, make these types ineffective. The first reason is that they simply mutate too fast for your immune system’s antibodies to keep up. Remember antibodies tend to peak around 14 days and HIV replicates in around 24 hours. It’s also prone to errors. As such, it makes mutated copies of itself and recombines to create new strains as it goes from person to person and even within the same individual. Thus, any antibody created will be ineffective before it even has a chance to work. The other reason HIV thwarts traditional vaccines is the virus targets the very cells your immune system uses to signal killer t-cells to the site of infection- namely CD4 T-cells.
Yet another reason HIV is such a formidable foe is that it’s a retrovirus. This means it encodes itself into the hosts DNA. So even if your body can get rid of any circulating HIV, there is still HIV in your own DNA that can reactivate and re-start the process of infection. Thus, even with the miracle of modern HIV treatments, which can see your circulating HIV drop to levels not even detectable on HIV tests, at some point down the road these dormant viruses might reactivate and- bam, without having continued proper treatment, you’re going to have a bad time.
That said, even for viruses like this, scientists being awesome, especially when given lots of play money, every day we are getting closer and closer to an HIV vaccine. In fact, beyond a previous mildly successful HIV vaccine (RV144) in 2009 that had a 31% protection rate after 3 years (note many would consider 60%+ to be good enough here thanks to the effects of herd immunity), there are currently two in the late stages of human clinical trials that seem much more promising given the results so far- one called Imbokodo, launched in 2017 and another, called Mosaico, launched in 2019.
But to sum up, the principal reasons we can’t create vaccines for many a virus that mocks us in their deadly simplicity, at least at present, is primarily because the scope of the problem (ie the number of viruses that can infect humans and how rapidly they can change) and the amount of effort needed to create even one successful vaccine for a specific type currently circulating, which in turn means massive sums of money and brainpower needed, which just can’t be justified in most cases where the need isn’t super pressing.
This, of course, is one of several reasons there is such optimism that a covid-19 vaccine will be successful and not take nearly as long as normal- humanity as a whole giving their governments the go-ahead to write a blank check for research, and either way companies themselves seeing the dollar signs of cashing in on the billions of people out there who’ll be going to their doctors’ in droves to get vaccinated.
Combined, this has seen sums thrown at the problem rarely leveled at any area of medical research in such a short time. And as the sage Miss Grande once very accurately noted “Whoever said money can’t solve your problems, must not have had enough money to solve ’em.”
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