UPDATE 14 APRIL 2022: In his blog Horizons in vaccine production, we explore pressing need to increase vaccine production capacity, not only for the current coronavirus vaccines, but the next generation and those against the next major emerging disease.
UPDATE 4 APRIL 2022: In his blog A much-needed boost: the future of coronavirus vaccines, we explore society's transition away from responding to the specific crisis of Covid-19 and towards managing coronavirus infections in the long term.
UPDATE 24 MARCH 2020: This article was updated on 24 March 2020 to reflect new developments in the Covid-2019 outbreak.
At the time of writing, the Covid-19 coronavirus outbreak has been declared a pandemic by the WHO, with confirmed cases in practically every country in the world. It is the latest in a line of outbreaks of emerging diseases gripping the headlines, including Ebola, Zika virus, bird flu, SARS, and antimicrobial resistant strains of bacteria. However, for many people round the world, and particularly those in the affluent West, this outbreak is the first in living memory to come for them where they live.
The response to the coronavirus outbreak has been extensive, and as the infection is now critical the advice is clear - stay at home where possible, practice social distancing where it is necessary to go outside, frequently wash hands, and self-quarantine for 14 days if symptomatic. At the governmental level, multiple countries and territories (including the UK and Munich, where Mewburn Ellis is based) have been put on lockdown in order to establish a quarantine and slow further the spread of the virus in order to prevent overwhelming health services and provide more time for vaccine development. The effectiveness of these measures is still a matter of debate. Meanwhile, the WHO and Coalition for Epidemic Preparedness Innovations have coordinated the response from the scientific community. These efforts, and especially the early and decisive action taken by the Chinese Centre for Disease Control and Prevention, should be commended. However, as with all emerging diseases, the response has been hindered by a lack of effective tools.
When faced with an outbreak of an emerging disease, treatments specifically tailored to the new strain are often not yet available. However, the need for an immediate response means there is little time to develop new therapeutic agents. This need to act quickly with limited resources to contain, treat, and eventually cure the outbreak poses a unique problem for public health responders.
What is Coronavirus?
Covid-19 is a respiratory disease caused by the coronavirus SARS-CoV-2. It is closely related to the virus responsible for the 2003 outbreak of severe acute respiratory syndrome (SARS).
The coronavirus family is large, and causes respiratory infections humans, mammals and birds. Most family members cause only mild symptoms in healthy patients and, as they are cause of about 15% of cases of the common cold, it is likely that you have successfully fought off a coronavirus infection without even noticing. However, the family also includes the highly pathogenic viruses responsible for SARS, Middle East respiratory syndrome (MERS), and of course Covid-19. These diseases are not only highly infectious but particularly virulent, with estimated death rates between 2 and 5%. The dangers of highly aggressive coronavirus diseases such as Covid-19 should not be understated.
Emerging highly pathogenic coronaviruses were listed by the WHO as a likely cause of future pandemics and the need for urgent R&D was identified as early as 2016.
Treatment: Teaching old dogs new tricks
Sometimes, a general purpose treatment is available against a class of emerging disease. Bacterial diseases can usually be tackled with antibiotics, whilst antiviral agents such as Tamiflu are effective weapons against a wide range of influenza strains. However, there is currently no equivalent broad-spectrum treatment that works against Covid-19. Instead, healthcare agencies have been forced to make do with the tools available to them.
Interestingly, there is emerging evidence that existing antiviral agents developed for treating other diseases might be repurposed for the fight against coronaviruses. During the 2003 SARS outbreak, certain HIV patients who were infected with the virus responsible for SARs were found to have better outcomes. It turned out that these patients were taking an antiviral drug called Kaletra (lopinavir/ritonavir) to manage their HIV, suggesting that these medicines might be effective against coronaviruses in general. AbbVie, the creators of Kaletra, are suspending their patent rights in the combination therapy as a treatment for Covid-19, in order to increase access to the treatment should it prove effective. Whilst pilot studies have so far found no benefit lopinavir/ritonavir against Covid-19, the WHO is launching further trials of the combination, alone or with the addition of interferon-beta, an immune system messenger that may help boost effectiveness of the combination.
Other putative candidates which will be trialled by the WHO’s SOLIDARITY trial and other bodies include the experimental antiviral agent remdesivir, the flu drug favipiravir, and the malaria medications chloroquine and hydroxychloroquine. This last medication garnered significant media attention following promising trials in France of hydroxychloroquine in combination with the antibiotic azithromycin. However, this study is very much an early stage pilot, and additional verification will be required before conclusions can be drawn. Encouragingly, now that the interactions between the virus and human proteins have been mapped, more putative agents can be identified which may be effective against Covid-19.
Regardless of whether or not these particular drugs are effective, it is possible that other medicines effective against emergent diseases are lying unnoticed within existing arsenals. The difficulty is in identifying drugs for repurposing from amongst millions of potential agents sitting on laboratory shelves. This is in stark contrast with the rising threat of antimicrobial resistant (AMR) strains of bacterial diseases, where the tools we do have no longer work, requiring new drug discovery and safety testing. Repurposed antivirals are already known to be safe, and once identified can be trialled and put to use immediately. In this and future outbreaks, the ability to quickly identify candidates amongst existing antiviral agents and to provide proof-of-concept efficacy data against emerging diseases will be crucial for launching a rapid and robust response.
Testing, testing, 1, 2, 3
Effective responses in South Korea, Taiwan, Singapore and Japan have made extensive use of efficient and aggressive testing and contact tracing in order to prevent virus growth. As the virus spreads exponentially (with one patient infecting two, who infect four, who infect eight, etc.), even modest reductions in transmission can dramatically reduce the number of patients further down the line.
Existing tests rely on polymerase chain reaction (PCR) technology. This amplifies the SARS-CoV-2 genetic material present in a sample taken from a patient to a level at which it can be detected. However, this can be expensive and time-consuming, and tests remain out of reach for many suspected patients. Fortunately, manufacturers are ramping up production of existing tests, whilst faster and cheaper tests are in development. Scientists at the University of Oxford are developing a new testing platform which uses a more sensitive detection system, that promises to reduce testing time from 1.5-2 hours to 30 minutes. Similarly rapid tests have been developed by US firm Hologic, which integrates with existing respiratory assay platforms, whilst the CRISPR-based approaches in development by Mammoth Biosciences and Sherlock Biosciences allow detection at lower levels of amplification, which may be able to reduce testing times even further. Meanwhile, home versions of existing tests, where samples can be collected remotely and sent for processing, are in development and may help improve access to testing for suspected cases whilst protecting frontline healthcare workers from exposure.
As testing technology improves, the capacity of health services to detect, trace, and ultimately halt the spread of the virus increases too. Given the knock-on effects of quarantining new cases early, more efficient testing has the potential to be a real game-changer in tacking Covid-19.
The gold standard for disease control is to develop a vaccine. Vaccines expose the body to a small amount of antigenic protein from a pathogen, so that the body can produce antibodies ready to fight the pathogen if exposed in the future. However, vaccine development is a long and arduous process, often taking many years before candidates reach human trials. Faced with a pandemic, this is time that we simply do not have.
As it currently stands, there is no vaccine against SARS-CoV-2. Work towards a vaccine underway, as Chinese health authorities succeeded in sequencing the virus’ genome in January and have made this data available to researchers worldwide. Based on this sequence, researchers in Australia have managed to grow the virus in the lab de novo, allowing further study and vaccine development. These collaborative efforts have allowed multiple players to pool their resources and expertise.
Given the urgency of the situation around the world, there is considerable effort focused on bringing down the long development time for a vaccine. Johnson & Johnson believe they can bring down lead-time for developing a SARS-CoV-2 vaccine to eight to twelve months by using multiple pipelines in parallel, as they did for the Ebola virus in 2016. Meanwhile, biotech companies Moderna, Inc. and Inovio Pharmaceuticals have vaccine development platforms, based on DNA and RNA respectively, which promise even faster turnarounds. In both cases, the vaccine is administered to the patient where it is translated into antigenic protein in vivo. This allows vaccines to be designed in silico and simplifies production. Both companies believe that animal trials are possible within six months. Developing even faster pipelines for vaccine discovery will prove vital for combatting this outbreak, as well as any other emerging epidemics in the future.
An added complication is that, whilst there is an intense period of research activity during outbreaks of emerging diseases, interest and investment usually wanes after the outbreak is contained. This is evidenced by the fact that whilst it has been over 17 years since the SARS outbreak brought the risks posed by emerging coronaviruses to light, vaccine development has yet to reach human trials. This is particularly concerning considering that, as SARS-CoV-2 is an RNA virus, it may be particularly prone to mutation and, as such, recurrent infection waves by new strains for which herd immunity does not exist will remain a risk in the short to medium term. In these uncertain times, it is important to remember that, whilst a rapid response is vital, preparation can be more effective than reaction, and prevention often more effective than cure.
Whilst the Covid-19 situation is serious, and far from under control, it is important to remember that whatever the outcome, future outbreaks of new coronavirus strains or further emergent diseases are inevitable. Whatever the underlying cause, the challenges and technological hurdles in tackling new diseases remain the same. It is essential that we maintain the level of energy, investment, and collaborative spirit prompted by the crisis after it has passed, and ensure that we are equipped with the tools necessary to respond rapidly once the next outbreak begins.
This blog was originally written by Andrew Tindall.
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