In January 2020, research was conducted into an antiviral drug against Sars-CoV-2 similar to Remdesivir, but unlike Remdesivir – which requires daily intravenous injections for five consecutive days – it was administered as a pill, or nasal spray, or one-time intramuscular shot.
How could the supply of such a medicine have changed the course of the epidemic?
Remdesivir (and other similar molecules) are known to attack an enzyme, the polymerase, which is common to a number of viruses (including coronaviruses) studied in recent years, such as Ebola and Mers-CoV. Yet the question remains of whether there are tools to transform drugs from being intravenously to orally, or from nasal sprays to intramuscular shots, and if so, why has a formulation alternative to intravenous injections not been pursued by global scientific communities to protect us against these or putative new monsters sharing the same Achilles’ heel?
We do not talk much about preclinical research in general, and of nonhuman primate research in particular, but we should: although the latter uses only 0.5% of animal studies run throughout the world, it can produce precious information for the timely screening of antiviral drugs for humans, a theorem well-known to virologists. A brief overview on the sequence of studies designed in 2020 in nonhuman primates to test antivirals against COVID-19 worldwide, suggests that scientific communities may have missed an important opportunity to translate the scientific knowledge of the past decade into an effective countermeasure to the public health crisis we are currently dealing with.
The use of nonhuman primates in biomedical research is, of course, a sensitive area of public debate. Its ethical and bioethical complexities have led to a significant analysis by experts outside of the biomedical world, to be contextualized within the missions historically endorsed by those countries that, using those resources, have been generating guidelines used in public health worldwide.
Let us consider for a moment a scenario in which five years from now, after having eradicated SARS-CoV-2 from the planet, a new respiratory RNA-virus jumps from the wild to the human species, with one of its genes, for instance, the polymerase – being present in other RNA-viruses, which renders it similar to the polymerase of SARS-CoV-2. However, beyond the polymerase, there are no other genes in common between the new pathogen and SARS-CoV-2, hence vaccines and monoclonal antibody therapies developed against SARS-CoV-2 in the previous years would not protect against the new pathogen.
The viral polymerase is an enzyme that works in the same way as a copy machine, incessantly replicating the viral genome to give rise to new viral progenies. This machine is thus vital to the reproductive process of the virus. Remdesivir is a drug that acts by blocking it, but to win the battle against a virus, the drug needs to be present at sufficient concentrations in all the tissues of the body in which the virus replicates1. In other words, even if a drug is powerful, the battle will be lost if it does not effectively penetrate the tissues where the virus likes to replicate.
For instance, if administered orally, Remdesivir would not be able to reach the lungs, which is why it needs to be administered as intravenous infusion. Suppose also that, by then, we possess an antiviral drug similar to Remdesivir that can be administered as a pill or inhaled for a few days, or that could be administered through an intramuscular shot (in other words, without the support of a nurse for daily intravenous injections which the current formulation of Remdesivir requires); more importantly, let us imagine that it has proved to be effective in humans against SARS-CoV-2 and, because of the shared polymerase, shows similar potency against the new virus. Last but not least, this hypothetical drug will be assumed to have a favorable toxicologic profile.
Now, suppose also that the new pathogen disseminates among us as fast as SARS-CoV-2, i.e., in absence of any mitigation strategy (such as social distancing or wearing masks); it would be able to infect more than 50% of people within five-six months. Certainly, the quality of life of those more directly affected by the new disease would be greatly improved by knowing that an antiviral formula circulating in the body is doing its part to get through to the end of the ordeal as soon and smoothly as possible. That would already be an important achievement since when we think of the danger of an epidemic, it is not how fast the pathogen transmits in society, but how much suffering it causes per unit relative to time.
In Italy, for example, this virus caused over 35,000 deaths during the first nine months of the epidemic (a similar number to the AIDS death toll over 30 years). If we multiply this number by six, we reach a figure of over 200,000 deaths for COVID-19. However, the severity of the virus is only further highlighted when a country like the US is considered – although its population is six times that of Italy, the rapid infection rate was comparable.
Yet beyond enhancing the patient’s quality of life (and those around herhim), could an antiviral drug also impact the course of the epidemic? How many individuals would need to be treated during the early phases of a viral outbreak or following a phase of effective lock-down to keep things under control?
Perhaps we would start by following the test-and-treat approach – a public health measure that is well-known to people living with HIV. Soon after a test confirms the infection with the new virus, treatment would be offered to those individuals at higher risk of developing the disease (for instance the elderly, and those with chronic health conditions) regardless of the manifestation of symptoms. If the toxicologic profile is particularly favorable, the antiviral drug could be offered to all adults who test positive (say to the over 40s) or to those individuals negative to the pathogen, but living under the same household of people already infected.
Could this approach make research for a vaccine impossible? Or would it be too slow, and therefore unnecessary? What public health intervention would be considered the optimal countermeasure if we one day find ourselves dealing with a new epidemic like the one described in the scenario above? Would everyone wearing masks and hospitals offering symptomatic treatment, without any social distancing regulations in place over the general population, be sufficient to contain the outbreak?
An article published this month on CNN from Sarah Murray and Jeremy Diamond entitled “Trump pursuit of coronavirus vaccine comes at the expense of therapies he now claims as ‘cure’” caused me to think harder since it offers an opportunity to elaborate on an important topic that flows directly from the answers to the two questions formulated above for that hypothetical scenario.
The decision to invest in vaccines rather than antivirals appears to have been endorsed primarily by worldwide scientific communities rather than the White House. It is sufficient, I think, to look at the course of preclinical studies, as countermeasures to COVID-19 advanced during the first months of the pandemic. Although studies on primates are politically and socially unpopular, their use in immunological studies is undeniable, and they constitute only 0.5% of animal studies carried out throughout the world.
It is well-known to virologists that nonhuman primate studies, although less useful to predict vaccine efficacies (since vaccines are meant to stimulate a host-specific immune response), have a strong predictability of antiviral efficacies for humans. Monkey models have already proved to successfully accelerate antiviral strategies for other infectious diseases through rigorous ethical research practices run in the past decades throughout the world, although primarily in the US.
AIDS prophylaxis, for instance, was mostly developed through studies that used macaques in American laboratories, which had a profound impact on global public health. There are two types of AIDS prophylaxis. The first is called PEP, the post-exposure prophylaxis, and was developed in the early 1990s to protect health care workers from being infected with HIV, as many of them were exposed to infected blood from needle-inflicted injuries. It worked so well that it was soon extended to non-occupational exposure (e.g. sexual exposure). The animal studies using macaques were the only ones that could quickly produce information on how much of the drug had to be administered and within how many hours from exposure.
Thanks to those studies, we learned that, soon after exposure, if we take the drugs within 72 hours (for 4 weeks) we have a good chance to prevent any infection. Consider how deeply this has changed the perception of the level of hazard associated to this virus (and with it, the stigma associated with being HIV positive), if contextualized for instance within the life of a serodiscordant couple (one of the two is HIV positive, the other HIV negative), in which accidents, such as a condom break, during the years can happen.
Twenty years later, a vaccine for AIDS still only existed in the realm of ideas, hence pharmacologists attempted another HIV prophylactic approach, the pre-exposure-prophylaxis (PrEP). The reasoning behind it stemmed from prior knowledge that they will be exposed to the virus, so to protect themselves they take pills in advance; this prevents the infection from taking root and replicating in the body if it finds a point of entry.
Truvada is a pill made up of two nucleoside analogues (Tenofovir and Emtricitabine). These molecules, like Remdesivir, belong to a family of drugs called nucleoside analogues (several drugs from this family, including Tenofovir, have a molecular structure very similar to Remdesivir and Emtricitabine), and have all been administered daily for several years (or decades in some cases) to treat HIV-infected patients along with other anti-HIV drugs).
For the Truvada-PrEP, clinical guidelines were developed through primate studies, specifically from two papers published between 2008 and 2010. These are examples of nonhuman primate studies that have had a profound impact on public health worldwide, saving many lives.
For years now, Truvada and other nucleoside analogues against HIV have been administered in patients with HIV (or in HIV negative subjects) but at high risk of contracting the infection. It is also known that these are regular medications, and must be taken every day; there are currently 180,000 adults in the US at high risk of HIV infection taking these pills daily. In addition, approximately half a million people infected with HIV in the US take anti-HIV pills as part of a heavier cocktail called HAAR on a daily basis – some have an excellent toxicologic profile, while others exhibit some long-term side effects.
Of particular note is the French use of data produced from macaques. Clinical studies have shown that HIV protection can be achieved with only four pills of Truvada to be administered around the time of the viral exposure, an approach that was later endorsed by the American Antiviral Society. Primate studies have not only helped HIV pharmacologists discover prophylactic strategies, but also treat HIV infected patients. The test-and-treat guidelines for AIDS, followed since the early 2000s, encourage any HIV-infected patient to start anti-HIV therapy soon after the confirmation of the infection: this includes during the asymptomatic period of the infection, which lasts (in absence of antiviral therapy) on average seven years from the infection. It was the distribution on a global scale of anti-HIV drugs (with the test-and-treat preventive approach) that became the dominant factor in reducing the new rates of HIV infection worldwide, overtaking consistent use of condoms (which is to HIV as the mask is to COVID-19) or sexual abstinence (which is the HIV equivalent of social distancing for COVID-19).
From my experience, antiviral strategies that have proved to be effective in primate populations have performed well amongst humans; likewise, those that failed monkeys have failed humans too.
Yet, until July, only intravenous-Remdesivir has been tested in nonhuman primates infected with SARS-CoV-2 throughout the world, with research run in NIAID labs, to prove the ability of this antiviral to prevent COVID-19 in infected hosts. This paper was published by the same team (and using the same animal models) which showed that Remdesivir could also prevent disease progression if administered soon after the infection of MERS-CoV, one of the two unpleasant cousins of SARS-CoV-2 with a mortality rate approximately ten times higher (an upper estimate for the true MERS-CoV mortality rates is 34%). These studies immediately put into motion clinical studies that demonstrated the ability of Remdesivir to improve the recovery of Covid-19 patients (although, when administered in advanced patients, little effect was observed in reducing mortality). Remdesivir and other similar molecules are capable of attacking so many different viruses because the gene that builds the copy-machine of the infection (the polymerase) is well conserved among all these viruses1.
Of note, several molecules, including other broad-spectrum-antivirals attacking conserved targets of these viruses, some of which were studied in veterinary medicine to treat coronaviruses in animals, have been advancing in these months in clinical studies without testing them in nonhuman primates (but the latter studies could be implemented in 4-8 weeks).
It is also known that if administered solely to hospitalized patients with an advanced disease, these molecules will fail one after the other. If administered too late, the antiviral can still reduce the virus in the body, but may not be able to make a difference to the progress of the disease. When the damage done by the virus is already dramatic, reducing the virus in the body – while still pursued as a course of action – may not be sufficient to save the patient during that critical phase of the disease. Other drugs that attempt to quench the activation of the immune system (e.g. anti-inflammatory, immunosuppressant or anticoagulant drugs) are needed when the infection is more advanced. This point is made to simply remind that an antiviral that turns out unable to significantly save lives if administered too late, may still be able to save lives if administered early on, i.e. soon after the infection or at the time of exposure. This is true for antiviral prophylaxes in general.
I personally doubt the White House or other governments had such a strong influence in pushing or preventing this type of research in high biosafety BSL34 monkey labs in the US or throughout the rest of the world. We had been waiting until September to hear from a French study, and from another NIAID study still unpublished, that hydroxychloroquine has no effect at all in preventing COVID-19 in nonhuman primates; hundreds of clinical studies and associated efforts were wasted throughout the world.
China has more than 100 BSL3 labs, but to my knowledge, no antiviral medication has been tested there; European labs have also not been occupied with this effort. Is it not sufficient to claim that the endorsement of vaccines instead of antivirals comes from other factors/influences on the scientific communities? How more advanced would we be today in our research for prophylaxis if multiple countries endorsed different antiviral strategies in parallel using the same animal models?
Those factors or influences, wherever they stem from, remain an unfortunate choice, in my view, because if an antiviral prophylaxis is available during the early weeks of epidemics, or after an effective lock-down (such as the one in effect until recently in southern Italy), could perhaps lead to long-term control of the epidemics (or even stop it) when combined with an efficient contact tracing system, especially given the recent evidence that Sars-CoV-2 appears to spread in society not uniformly, but through clusters of infections.
The use of antiviral prophylaxis as a mitigation strategy to control a respiratory virus pandemic was suggested by Imperial College London more than a decade ago15, but there has been, surprisingly, little public debate in these months about attacking the pandemic from this angle. The use of prophylaxis would likely reduce the number of cases – and by association the virus itself – but in doing so, it would inevitably slow down the research for vaccines.
Trump’s endorsement of a generic drug (hydroxychloroquine) and other antivirals suggests, that the White House had no specific obsession in investing exclusively or primarily in vaccines; had hydroxychloroquine worked well, we would have all taken that pill promptly and diligently as needed (possibly reducing the number of people that would need to take it, because by taking the antivirals we might be able to reduce the number of new cases), and we would be perhaps talking today about something else.
What reporters have not enough emphasized in the past months is that Remdesivir can only be administered intravenously and on a daily basis, so can only be given to hospitalized and advanced patients. If given orally, little or nothing would get into the lungs. However, there are technologies that pharmacologists have developed in recent decades called nanoparticles, which transform drugs to make them orally ingestible (e.g. a soy-bean, organic-based cochleate, used already for pulmonary absorption of antimycotic drugs in humans at the NIH as “chronic” treatments), or allow them to be taken subcutaneously or inhaled (the latter was endorsed by Gilead, starting on June 2)
This research could also quickly advance with preclinical work in nonhuman primates if more research programs throughout the world had the experimental capacity to perform these tests. These nanoparticle technologies (being transporters) represent transversal tools of pharmacology that can be perfected even before knowing the molecule to be transported (i.e. the enemy that needs to be attacked). Transforming the administration of a drug from being intravenous to oral could also significantly reduce its side effects. From this angle, this seems an important research area in national epidemic preparedness and response plans, especially when nanoparticle technologies are conceived with the objective of transporting broad-spectrum antivirals.
Animal studies allow the design of challenge studies which cannot be designed in humans for ethical reasons, without sufficient knowledge of the disease induced by the new pathogen, although UK labs aim to advance challenge studies in normal volunteers shortly as we read in the news this week, to test vaccines, for which, as we said, even monkey models are not overly useful. Studies in primates also allow the measuring of drug levels and viral replication levels in specific organs (this is not possible with humans; we cannot do a lung or brain biopsy in a patient simply to study how much of an antiviral drug gets there). Coupled with challenge designs, as I think is intuitive also to non-scientists, makes these studies much faster than clinical studies.
An antiviral can be as potent as a developer wants in killing a virus, and not toxic for the body, yet if it does not effectively penetrate the lungs or any anatomic compartment in which the virus replicates, it is not overly useful. When Trump asked whether we could inject something as potent as bleach straight to the lungs to fight this virus, most or all the focus from the media has been on stigmatizing the President by catapulting into the web his words for an entire week for a viral proliferation of jokes, fully missing an opportunity to educate the citizens throughout the world, including Trump, about the importance of his question: namely, the meaning of potency speaking of antiviral drugs, and on what are the scientific tools available to enhance drug levels in a given anatomic compartment (like the lungs), before abandoning a drug that shows little effect in curing advanced COVID-19 patients.
Given that the risk for a new “jump” of RNA-viruses (including coronaviruses and the Ebola virus; the latter, like MERS-CoV, has not yet been eradicated from the planet) was perceived to be high in the past decade, and given that Remdesivir was known to attack several of these viruses, why haven’t scientific communities around the world invested time and effort in transforming Remdesivir into an oral or subcutaneous or inhaled drug for antiviral prophylaxis?
Nonhuman primate BSL34 labs are now working at max capacity in the USA – and because of China’s decision to stop exporting monkeys, US labs are experiencing a shortage of animals that prevent the rapid advance of new studies, as we read early in September.
But what about the other BSL34 labs in the rest of the world?
The authors of the report stated that “While Remdesivir showed some early promise with patients, the President was fixated on hydroxychloroquine, thereby missing the opportunity to remind anyone that pursuing an “easy to administer drug” as a countermeasure to COVID-19 is, per se, a laudable cause.
In the same Dr. Bright whistleblower piece mentioned in the Murray & Diamond opinion piece, we learned about pressure from the White House not only to secure more government funds for hydroxychloroquine, but also for the EIDD antiviral from Emory University, a nucleoside analogue which attacks, like Remdesivir, the viral polymerase although with a slightly different mechanism, but that, in contrast to Remdesivir, can be taken as a pill. Isn’t this another laudable cause (regardless if we are pro-Trump or pro-Biden)? A research endorsement appeared that Dr. Bright apparently oppose20 due to his concerns on the side-effects associated with this drug, although clinical studies in the UK and the US to test this antiviral molecule are advancing.
A useful question for scientists and historians could be the following: why have so few monkey studies been launched so far for COVID-19 to study antivirals, and why are they mostly run in US labs?
One reason might have to do with the ability of any research program (private or government) to test molecules protected by patents. To give an example, a laboratory fully funded by the Italian government would not be able to test a drug (or transform it) for research purposes (including in animals) without prior negotiations with the intellectual owner of the molecule. At first glance, without being a jurist, it seems something that should be overcome through payments of royalties from governments to the intellectual owner in order to accelerate the research worldwide; something certainly easier to say than to do, yet not enough debated in society in situations of emergency or extreme urgency like those posed by the pandemic.
The need for such a debate is, however, not new to scientists and lawyers, as it was in part anticipated by Indian and South African intellectuals in the early 1990s while dealing with the imminent catastrophe that AIDS was posing to those countries in those years; matters would have been far worse had antiretroviral therapy not been made promptly accessible through alternative negotiations and support from international programs.
But it is also about how many players are able to contribute to the fight. The high biosecurity laboratories in the United States have been working at their full capacity in recent months, ten to twenty times larger than the efforts of the entire European Union.
In many countries, for instance, Italy, which, after the drama of the Second World War, was busy investing its resources in national reconstruction – have in essence delegated the US to produce guidelines both on preclinical research and on the general management of scientific planning, which took place on a global scale. This, of course, has led to the creation of a biomedical consciousness in the US, such as to justify the movement of significant economic resources to be allocated to science, an aspect that is lacking where decisions have been made, more or less legitimately with the science tasks delegated elsewhere, to occupy resources in other sectors.
It is therefore a question of investing resources, but this requires unitary, rigorous and complex planning, which must come as a result of immediate and unambiguous political choices. Considering the dimension of the crisis we are experiencing, these now appear completely unavoidable and unable to be postponed.