There are no specific anti-viral drugs targeting SARS-CoV-2. Why do we need them more than ever? Professor Sudha Rao explains.

While many experts were aware that new pathogens had the potential to cause major global disruption, few predicted the breadth and persistence of the chaos wreaked by SARS-CoV-2, the virus responsible for COVID-19. Every government found themselves inadequately prepared for this new pandemic. Major economies including the US, UK, and India remain in various states of lockdown, and it is still uncertain when and how we will be able to resume the many privileges we had become accustomed to before the events of 2020.

There has been amazing progress in vaccine development and rollout, at least in industrialised nations. Nevertheless, achieving a level of pre-COVID-19 normality is still going to require a multi-faceted approach that includes new drugs and treatments. While all the data on COVID-19 vaccination programs around the world look promising, it is an epidemiological and biological certainty that a significant minority of vulnerable patients will go on to develop the disease. I have family in the UK, and I would love to travel to see them. While the UK struggled in the early phase of the pandemic and has seen almost 128,000* COVID-19-related deaths, the country has also been at the forefront of vaccine development and rollout. Ahead of every other large country, the UK has delivered first vaccine doses to over a half of the population since the beginning of the year. There is quiet hope that life in the UK will more or less return to normal by autumn. As the vaccine rollout starts over here, Australians are also hopeful that travelling abroad to visit loved ones will soon be possible.

However, vaccines are not a ‘silver bullet’ to end the pandemic. Eradicating the virus will require a truly global vaccination program, which is unlikely to happen in the short to mid-term due to economic, social disparity, manufacturing, and scalability issues. Furthermore, significant proportions of the population – not least the young – will need to wait longer for immunisation.

The biology of the virus and vaccination is also an important consideration. No vaccine is 100% effective, and immunity takes time to build, especially in the elderly and immunocompromised. It remains to be seen how effectively the current crop of vaccines stop the spread of the infection, and although early population data from the UK and Israel are promising, ‘onward transmission’ and ‘silent spreading’ of the virus are likely to remain problems. Perhaps the most troubling barrier to vaccine efficacy is the emergence of new SARS- CoV-2 variants, with those arising in Brazil and South Africa proving challenging in terms of increased transmissibility, but also in evading vaccines and natural immune responses. The consequences of this are that current vaccines may be less effective and fail to prevent reinfection: having COVID-19 caused by one SARS CoV-2 strain does not necessarily mean you will be protected from another virus strain.

So, while vaccines are no doubt massively important for controlling the pandemic, simply ‘tweaking’ them will not solve their inherent limitations, human behaviour, or global disparities. There will remain a need to treat people with COVID-19 for the foreseeable future. With the arrival of effective vaccines, we should not forget that we require multiple tools in our toolbox to fight this disease. Like Tamiflu and Relenza for the flu virus, which is not dissimilar to SARS-CoV-2 in terms of vaccine availability and variant strains, new drugs (or old drugs that work against the virus) will still be needed to prevent and treat severe disease and save lives.

Despite this clear and acknowledged need, very few drugs have been licensed for use in COVID-19 patients. The US Food and Drug Administration (FDA) has approved or authorised for emergency use a few intravenous treatments (remdesivir, convalescent plasma, and some monoclonal antibody therapies) for COVID-19 patients. However, their need for intravenous administration hampers their widespread use, and while some existing drugs have been re-purposed for COVID-19, the results have generally been disappointing.

To continue to reduce deaths from COVID-19 and re-open society in the long term, there is a clear strategic need to keep pursuing coordinated drug development programs that complement and support vaccination. Two types of therapy would be particularly useful: drugs that prevent or treat SARS CoV-2 infection (anti-viral drugs), and those that boost the efficacy of vaccines (‘vaccine-amplifying’ drugs).

While vaccine development largely relies on understanding and targeting the sequence and structure of the virus, COVID-19 treatments tend to rely much more on understanding the complex interactions between SARS-CoV-2 and the human host. Over the last year, there has been significant progress around the world in understanding the details of the unique pathways hijacked by SARS-CoV-2 in humans and how we respond to the virus, including in our own lab. Our focus has been on how the novel coronavirus interacts with epigenetic pathways – gene-independent pathways that control cell behaviour – and how to exploit these pathways to develop new and effective drugs (see Figure on page 6).

Here at QIMR Berghofer, my laboratory has developed first-in-class epigenetic drugs that selectively block the entry and replication of SARS-CoV-2 in host cells by targeting the host epigenetic machinery hijacked by the virus. These drugs are already used in cancer patients and now have tremendous potential as anti-viral agents. Perhaps even more importantly, we previously showed that these drugs can re-configure the impaired immune gene landscape of elderly people to more closely resemble that of a young person. The implications of this dual effect are that these epigenetic agents are not only likely to reduce or prevent infection but also improve – or amplify – naturally developing immune responses or the effect of existing vaccines.

Our intention is to reprogram or ‘re-wire’ immune cells to make them more visible for the vaccine response. Our hope is that these vaccine amplifying epigenetic drugs will form a new type of medicine with the capacity to re-invigorate the immune systems of elderly or immunocompromised patients to enhance vaccine responses (see Figure). Our early results are promising and, with our clinical and infectious disease collaborators, we are moving these novel drugs towards clinical use. Our vaccine-amplifying agents will be particularly useful for patients with immunodeficiencies, sepsis-induced immunoparalysis, and patients with cancer. These vaccine amplifiers may also target evolutionarily conserved pathways in pathogens to facilitate their clearance.

Having made so much progress with vaccines, now is not the time to decrease efforts in other, complementary areas of drug discovery that could form part of an overall strategy to control the pandemic in the long term. Doing so risks leaving vulnerable patients behind and potentially prolonging the pandemic – outcomes we would all like to avoid. 

*As of April 16, 2021.
Source: https://coronavirus.jhu.edu/map.html

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