An article by Nobel Laureate Professor Peter Doherty, giving his commentary/explainer, “Setting it Straight” on all things infection and immunity, in the midst of this global pandemic. What types of therapeutics and prophylactics do we need for COVID-19?
As an Institute devoted entirely to infection and immunity, various research and diagnostic teams across our wonderful, still new, high security, high-tech building are working flat out at the coalface, as they drive forward to develop technical solutions and minimise the human toll of COVID-19. Central to that are the efforts of clinical infectious disease colleagues (real doctors!), many of whom have their offices and laboratories in our building at the top end of Elizabeth Street, while they care for patients at The Royal Melbourne Hospital across the street and at the Austin Hospital in Heidelberg.
As is central to our evidence-based and ever-questioning culture, our coordinated COVID-19 SWAT team is in deep discussion at least three times a week, via Zoom, in these extraordinary times. Our Director, Sharon Lewin, a leading HIV cure researcher and physician, is now a household name. Just about everyone will now know Sharon’s face and voice from the TV, radio and newspapers. I’m helping with the public interface as we try to ensure that we get good, sound information out to all of you.
Rather than just go over the territory that’s being explored thoroughly in podcasts, TV, radio, print and online articles, I’ll take a different tack in my column, aimed at providing a deeper level of familiarity with what’s happening and what’s being discussed. And, as we’re doing this in a series of relatively short articles, I’ll use the “dog food” model of “handy, bite-sized chunks”. Rather than try to summarise complex issues in an abbreviated format, the intent is to give you a bit more background, a better understanding of the basics. This will move slowly, but we have time. Let’s begin.
Words matter. For research scientists like me, the first thing we must do in any discussion is to get our terminology straight. When we use a word, or a phrase, to describe something, it’s essential that we’re all on the same page. Beyond the “academy”, the big mistake that many professionals make in public communication is to think that non-technical words they regard as both commonplace and obvious in their meaning are “heard” in the same way by those in the broader community.
From what I read online and in print media, for instance, I get the impression that even some experienced journalists just don’t understand the very basic difference between a drug and a vaccine. That’s fundamental to any understanding of infection and immunity.
Let’s start with drug. What drug means to me is some chemical, or mix of chemicals, that we use to treat people. That might be injected, inhaled, swallowed (as a pill or in liquid form), administered as a suppository or “attached” as a slow-release “patch” on the skin. Some of the existing commercial products that are in (or will soon go into) efficacy trials for COVID-19 are the old anti-malarial drug, Hydroxychloroquine; Kaletra, a combination of two anti-HIV drugs; and Remdesivir, an experimental anti-Ebola drug. Apart from participation in major international trials, Steve Tong from our Institute is heading the multi-centre, Australasian COVID-19 Trial (ASCOT) that will look initially at Hydroxychloroquine and Kaletra, but is designed so that compounds that are obviously not working can be swapped out for new candidates that look to be more promising.
Right now, pharmaceutical companies and academic researchers across the planet are working flat out to screen various chemical “libraries” in a search for novel (new) drugs that specifically block SARS-CoV-2, the virus that causes COVID-19. Other chemists and structural biologists are “playing” on computer screens with three-dimensional molecular images (generated via such places as the Synchrotron) as they seek to create “designer” molecules for chemical synthesis. If you’re both a smart young person and a computer nerd, this may be the career for you!
Once a promising compound is identified and screened to see whether it stops the SARS-CoV-2 virus growing in lab cell cultures (the fabled Petri dish), the next step is to produce the drug in sufficient quantities for testing in animals, then people. Following strict protocols set out by regulatory agencies, especially the US Food and Drug Administration (FDA), the first step is “pre-clinical” studies with e.g. mice and ferrets, followed by non-human primates (various macaque species), then through a progression of human trials.
Before any such drug is approved in Australia, it must also be evaluated by our own TGA, the federal Therapeutic Goods Administration. Following careful scrutiny of the available evidence by experienced scientists and clinicians, the TGA recommendations then go to the Federal Health Minister for final approval. The same protocols apply for evaluating and approving a vaccine. But I can’t say it too strongly: a vaccine is not a drug!
Therapeutic goods? The other word doctors use for a drug is a “therapeutic”. Not all therapeutics originated as chemicals made by a major pharmaceutical company. Early on, the doctors of the day recommended “natural medicines” like quinine, a compound that was first extracted from the bark of the Cinchona tree for use (from the early 19th century) as an antimalarial. Anyone who is partial to a G&T “well-being therapy” knows the taste of quinine in what used to be called “Indian Tonic Water”, reflecting that therapeutic history.
Another “natural medicine” exploited more recently as an anti-malarial is Artemisinin, which is made naturally by sweet wormwood (Artemesia annus). In 2015, Tu Youyou was the first resident Chinese researcher to be awarded the Nobel Medicine Prize for her 1972 discovery that provided a bright light at the end of the multi-drug resistant malaria tunnel. Quinine (plus its various chemical derivatives) and Artemisinin are now made synthetically, both to ramp up production and to ensure precise dosing. Apart from availability, the problem with using natural products directly as medicines is that the levels of active ingredient vary.
As anyone who has taken malaria medication in association with some tropical travel itinerary knows, drugs are the primary resource (taken before, during and after) for prophylaxis (prevention). Then, if you’re unlucky enough to be bitten by a mosquito carrying a Plasmodium (malaria) species that’s resistant to your prescribed prophylactic, a different anti-malarial will be required for therapy (treatment).
Antiviral drugs are also used as preventives. Perhaps the best known example is PrEP, where those who are currently uninfected but have a high risk of contracting HIV (the virus that causes AIDS) take a combination of two anti-HIV drugs (Truvada) that are normally used for the treatment of those with the disease. The same drugs are thus “dual use”, for prophylaxis and therapy.
So, if we were enduring a catastrophic influenza pandemic rather than COVID-19, we could be dosing frontline, uninfected healthcare workers, police and supermarket check-out operators prophylactically with the long-acting anti-influenza drug, Laninamivir, while, when it came to treating a patient with the flu, the attending doctor might choose the more familiar, short-acting Oseltamivir (aka Tamiflu) as a therapeutic. Both products are “designer drugs” that target a key molecule in virus production pathway. Neither would work to inhibit SARS-CoV-2, but these are the types of therapeutics and prophylactics we need for COVID-19.
This article was first published on 6 April 2020 by the Doherty Institute as part of an ongoing series called “Setting it Straight” by Laureate Professor Peter Doherty