Searching for the COVID-19 cure in the wrong places

photo: Reuters
photo: Reuters

The coronavirus, Sars-CoV-2, which causes the disease COVID-19, presumably jumped the species barrier from wild animals to humans in December 2019. For a disease that would never have existed were it not for our desire to feed on animal flesh, the resulting loss of animal lives in our battle to cure it is deeply unsettling.

Each year, over 115 million animals are used worldwide in biomedical research and drug testing. The ethical and moral questions surrounding animal research are often considered a grey area, even among animal advocates.

However, there is now overwhelming evidence that medical research conducted on animals is hindering rather than helping human medical progress.

Decades spent studying biological systems of animals that are evolutionarily, genetically and physiologically different from ourselves has distorted our understanding of human health and disease, wasting resources, obstructing successful drug discovery and ultimately compromising human health.

medical research conducted on animals is hindering rather than helping human medical progress

Animals left behind in laboratories
As the virus spread, scientists, like everyone else, went home to their living rooms, and what was left were laboratories full of mice and monkeys whose lives had just been canceled. Looking after animals in a lab where science has shut down is not an essential service.

With no one left to feed or ‘care for’ them, and in some cases fearing further disease spread, there was apparently no better option than to mass kill thousands of animals.

But maybe there was a better option – one that should have occurred much earlier in the story – in the decision to breed and house them in the first place.

150 vaccine candidates in record time
Around the world, scientists tried to develop a vaccine that would stop the spread of the disease and investigate drugs that might control its symptoms.

By June 2020, over 150 vaccine candidates were in development and ten had already reached clinical trials in humans. Never before in history had a vaccine been produced for an infectious disease that was not preceded by several years of evaluation – first through rigorous animal testing, and afterward in human trials.

Even the accelerated development of the Ebola vaccine was a five-year project, and most take over ten years.

Necessary medical awakening
When drug companies announced plans to fast-track COVID-19 research efforts by skipping or reducing animal trials, there was a sense that this issue – already widely recognized – was finally being acknowledged and put into practice – or in this case, out of practice.

Obviously, plans to provide an effective COVID-19 vaccine within a year simply would not be possible under the traditional formula, which takes about two years for animal testing alone.

The first vaccine entered human testing on the 16th of March – only two months after the genetic sequence of the virus had been published.

This was an unprecedented speed that would normally be pillowed by months and months of preclinical trials in animals. Briefly, it seemed that people dying in their thousands had caused a necessary medical awakening, but it did not take long for this news to disappear from the media.

Animals would indeed continue to be subjected to testing each time a new vaccine candidate was imagined, and regrettably, COVID-19 was not going to be any different.

Success rates are low
Vaccine development might start with many options but ends in a single outcome. There is usually about a 50% chance that a vaccine candidate will pass from animal trials to humans, progressing as long as it appears to be both safe and effective.

Plainly, if the vaccine fails to generate the desired immune response at an appropriately low dose and without toxic effects in animals, it will be abandoned. However, the success rate through human trials is dramatically lower, with less than 10% of vaccine candidates making the full transition.

In this battle, the odds are clearly not stacked in our favor, and they are certainly not stacked in favor of the thousands or more animal lives that are likely to end in vain.

How much can we rely on animal models?
Supporters of animal research insist that animal data is critical for understanding how coronavirus vaccines work so that the most promising candidates can be selected for further development.

But with no reliable data backing these claims, we have little reason to believe that those vaccines identified as the best candidates in animals will be the best candidates in humans.

Across a range of disease categories, an astounding rate of drug development failures can be attributed to animal models, which simply are not translatable.

Every time a new drug is tested in a human, that drug was shown to be both safe and effective in an animal model. If animal models predict human outcomes accurately, then every drug that goes as far as human trials should be successful. But that’s not the case.

In truth, about 96% of drugs that pass from animal to human trials never end up on the market. How many animal failures could have been human successes if 96% of animal successes become human failures?

How many animal failures could have been human successes if 96% of animal successes become human failures?

Unfortunately, preclinical studies are under no obligation to be made public, so it is difficult to estimate how many clinical opportunities may have been missed, but it is certainly not zero.

Aspirin would not pass animal testing
Many of the most useful medicines taken safely by humans for decades – such as aspirin and penicillin – would probably never have made it through the pipeline if the current strict regulatory requirements based on animal testing were in practice at the time of their development.

So what other blockbuster drugs have we missed out on since? How many medical blank spaces will our future hold? Has an effective COVID-19 treatment already been discovered and promptly discarded because of non-human warning signals?

There seems to be a lot of holes in the reasoning that it is absolutely necessary to do X in order to provide evidence of Y, when we know that doing X only provides proof of Y less than 10% of the time.

The problem with animal experiments in vaccine development
Most animals do not naturally develop the same viral infections as humans do, which complicates their use in predicting vaccine efficacy.

There are two types of animal models used in vaccine testing – the first so-called ‘natural’ model uses a modified version of the human virus that produces a similar disease in the animal. Then scientists measure the vaccine’s ability to trigger protective antibody production against that modified virus.

In the second so-called ‘surrogate’ model, the animal is vaccinated with the actual human virus. Although technically being infected with the virus, these animals do not typically develop clinical disease.

Because neither of these models accurately reflect the human infection, their predictions are rarely translated into successful clinical development. In fact, the fidelity of animal models in predicting human vaccine responses is pitiful.

Interspecies differences in immune responses that underlie viral infection and vaccine efficacy destroy the validity of animal to human translation.

These genetic differences need to be considered in all medical studies involving non-human animal models but are critical when it comes to the study of viruses that do not naturally cause infection in non-human hosts.

Medicine continues to work away on its broken model
At face value, humans and other animals share largely the same genes, but we differ in the subtleties of function, order, regulation and expression levels of those genes, like pianos played by different hands.

In addition to biological differences, life in an unnatural laboratory environment can elevate stress hormones and alter heart rhythms – factors that themselves can influence disease progression and drug responses in animals.

This is an issue that has already been critically examined and quite extensively reviewed. Yet, medicine continues to work away on its broken model.

Rather than putting an end to or at least dramatically reducing animal experimentation, the more accepted response is to try to improve poorly translatable models by modifying them genetically to a slightly more ‘humanized’ version that suits a particular disease.

Exposing modified animals to a modified virus
In the case of COVID-19, this meant modifying mice with a molecule called ACE2 that the virus uses to transport itself inside human airway cells. A modified version of the virus was also needed to attack animal cells that are not ordinarily susceptible to the virus.

So we end up with these modified animals which, when they’re exposed to these modified viruses, get a disease that’s similar to the one humans do, but their disease progression and response to drugs is often significantly different.

No matter how modified, animal models, whether mice or monkeys, do not develop a similar pattern of clinical symptoms as humans in response to Sars-CoV-2.

mice or monkeys do not develop a similar pattern of clinical symptoms as humans in response to Sars-CoV-2

Our limited understanding of the virus and disease characteristics make the new COVID19-specific animal models even more uncertain than the already flawed animal models of well-established human diseases.

Replicating a complex infectious disease in a non-human animal, while we sparsely understand it in humans, is no easy task. Scientists have recognized now that animal models can at best offer a rough guide to human biology.

The critical next step is acknowledging that rough guides can be found elsewhere that carry a lot less suffering.

Animals and the immune system – what can we learn from the TGN1412 Disaster?
Confirming that a drug or a vaccine is safe and effective in preclinical animal models can never be proven to be safe and effective in humans.

In 2006, a clinical study was conducted in 6 human volunteers to evaluate a drug called TGN1412 that targeted an immune molecule called CD28. Positive findings in non-human primates could never have predicted the dramatic toxic responses that followed in the first human trials.

The treatment resulted within minutes in a hyperactive immune response that led to multiorgan failure and death of five out of six human participants. The same drug, tested over four weeks in non-human primates, at 500 times the human dose, was confirmed to be safe and effective with no adverse effects. This was later attributed to genetic differences in the drug’s target.

Many other components of the immune system differ between species, and these differences are still not fully understood, which renders the validity of animal studies, particularly concerning infectious diseases like COVID-19.

If studies in non-human primates – the animals genetically closest to ourselves – are so dangerously unfaithful, how can we continue to rely on findings from rodents, of which scientists are most fond. After all, even men and women of the same species have notable differences in immune responses, disease susceptibility and sensitivity to certain medicines.

Can animal models predict vaccine efficacy?
To understand the predictive value of animal models in vaccine development, it is most telling to look not at the few eventual successes but instead at the crowds of untranslated vaccine trials that history has steadily collected.

Consider HIV/AIDS vaccine development – an effort which for decades has swallowed immense resources and to no avail. By 2008, about 90 HIV vaccines had been created which were all successful in non-human primates. Yet, each time, our closest genetic cousins misled researchers down an unproductive experimental path that never once led to a human cure.

an effective vaccine candidate might be excluded from clinical trials because it did not work in animals

Today, despite huge investments, there is still no HIV vaccine, letting us wonder how many more mistranslations we are facing before one shocks us out of our delusion.

In today’s COVID-19 battle, are we again facing a succession of false promises as vaccine after vaccine proves effective in animals but without hope for ourselves?

Even more disturbing is the thought that in these times of urgency, an effective vaccine candidate might be excluded from clinical trials because it did not work in animals.

Can animal models predict vaccine safety?
Usually, vaccines go through years of safety testing both in vitro and in vivo before approval, but for COVID-19, we are rooting for a licensed vaccine within the next year. This will mean safety tests will be less rigorous.

But what stages should we compromise? Testing vaccine efficacy in animals is clearly unnecessary and burdensome, but what about safety? Is it ethical to test a drug or vaccine in humans when we don’t know whether it might cause harm?

The real question here is: do animal models give a stronger indication of the drugs safety than in vitro models do? Certainly, testing any drug or vaccine in humans for the first time places them at some level of risk, but as has been demonstrated time and time again, this is not a risk that can be erased by proven safety in another species.

Concern for human safety is therefore equally a weak excuse for the continued large-scale exploitation of research animals, which in fact often amplifies and prolongs human suffering unnecessarily and unjustifiably.

Indeed, there are cases where clinical trials have been forced to end prematurely due to the toxic effects of vaccines that were deemed safe in animals. The disease itself is not the only threat to human health.

If it is not reliable, if it does not provide a faithful model of human biology and diseases, if it does not yield valuable medical insights and human health benefits, how can anyone justify this continuous suffering?

If it is not reliable, if it does not provide a faithful model of human biology and diseases, if it does not yield valuable medical insights and human health benefits, how can anyone justify this continuous suffering?

Animal experimentation is not only a cruel and wasteful convention, moreover being an unreliable predictor of human biological outcomes and drug responses, but it also poses a significant threat to human health and medicine.

Misleading safety studies, unwarranted abandonment of effective therapies, and the direction of resources away from more human-relevant technologies are disfiguring human medicine.

Collectively, the harms and costs of animal experimentation overrule its potential benefits. The harm to humans already tips the ethical scales against its favor, even before factoring in the appalling loss of non-human lives.

In these times of unprecedented urgency, resources would be more responsibly directed towards well-designed, human-based in vitro testing and fast-tracked human clinical trials.

Viewing animal models as a “necessity”, a “gold-standard”, an “evidence-based” model, is deeply flawed. What they are more accurately is the default, and that is the fault.

Viewing animal models as a “necessity”, a “gold-standard”, an “evidence-based” model, is deeply flawed. What they are more accurately is the default, and that is the fault.

The disease itself is not the only threat to human health
To date, over 400,000 people have died from COVID-19, and while the curves are flattening in most western countries, the developing world is still being hit hard. By 2021, deaths from COVID-19 are predicted to be over 1.7 million.

How many more people will die waiting for another animal trial to give the green light, and keep it glowing? In vitro models conducted outside of living animals are certainly not perfect either, but they could hardly mislead us so pathetically towards a vaccine that would cause more deaths than waiting.

In a 2015 article in the Cambridge University Press – The Flaws and Human Harms of Animal Experimentation – neurologist Aysha Akhtar stirred me with a question: “When considering the ethical justifiability of animal experiments, we should ask if it is ethically acceptable to deprive humans of resources, opportunity, hope, and even their lives by seeking answers in what may be the wrong place?”

The future: Human microdosing or Phase 0
Seemingly, the strongest argument not to progress directly from in vitro tests to humans is to not burden humans by involving them in studies that will not benefit them.

I should point out that of the millions of animals used each year in medical research, not one of them will benefit from its outcome, nor will most humans benefit from the preceding clinical trials that are built on such brittle foundations.

of the millions of animals used each year in medical research, not one of them will benefit from its outcome

As well as measuring safety and effectiveness, animal studies are also used to indicate how well a drug of vaccine can be processed by the body – whether it can effectively traverse biological barriers, reach target tissues in sufficient quantities, stay there for long enough to have a therapeutic effect, and afterwards be safely and completely broken down by the body’s enzymes and excreted.

Since these properties do not translate well across species, some studies, especially where speed is a priority, have opted instead for a strategy known as ‘human microdosing’ or ‘phase 0’ trials.

These are studies in humans where the administered doses are so tiny that it would have neither a therapeutic effect nor an adverse effect. It would allow clinicians to monitor its activity as it passes through the body, using highly sensitive analytical methods.

In this way, without compromising human safety, and without wasteful animal studies, drug candidates that cannot be effectively processed by the human body would be removed from the development pipeline.

These Phase 0 trials, which were incorporated into some COVID-19 research efforts in China, could dramatically reduce reliance on animal models in early drug development as well as massively lowering the time and costs spent developing failed drug candidates.

What will replace the broken model?
If animal bodies are the wrong place to look for answers, the costs now directed towards animal experiments would be better spent improving and expanding human-based model systems such as organs-on-chips and human organoids.

Research into these alternatives has grown exponentially over the past decade, but is still dwarfed by animal experimentation, and so are the funds it receives.

Earlier this year, these minuscule human organ models were used by Canadian researchers to gain insights into early mechanisms of COVID-19 infection in humans, helping them to understand how the virus invades our bodies.

In another study published in April, airway chips that recapitulate the human lung were used to test the ability of several already available drugs to treat COVID-19 infection. Repurposing existing drugs is particularly attractive in times of crisis because their safety profile has already been established.

As they continue to grow in predictive values, organ chips based on the human immune system might also be explored to test the safety and efficacy of vaccines and drugs to fight infectious agents like Sars-CoV-2.

Human organoids – 3D structures engineered using human pluripotent stem cells – offer a unique human-based system with possible value in the study of viral infections. They too have found their place within the COVID19 research effort, helping scientists identify which kinds of human cells can take up the virus.

Both of these ‘alternative’ technologies have so far been considered as accomplices rather than replacements of animal models, but they continue to become more advanced and faithful replicas of human organs, both functionally and structurally. And with deserved investment, they may well be the preferred models the next time a pandemic hits.

And with deserved investment, they may well be the preferred models the next time a pandemic hits.

In our current emergency, misleading safety and efficacy data, abandonment of effective medicines based on non-human findings, and the stubborn and persistent direction of medical research efforts towards our favorite broken models are hurting human medical progress.

With any hope, a COVID-19 vaccine will succeed eventually, and life will recover its prior pace.

But it didn’t have to be this eventually, we could have had a different eventually -one where animals were not bred, drugged and discarded to get us there.

One where we stop ‘recognizing’ and ‘acknowledging’ and ‘taking into account’ everything that’s broken about this model because it’s not as though scientists haven’t done so a thousand times.

One where we actually wake up and do something to fix it.

I hope that eventually, we will have this.

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