The world is undergoing its worst public health emergency since the Spanish flu almost exactly 100 years ago. With the advances of technology enabling rapid drug and vaccine development, remote work and coordination, we can and should hope for a quick resolution and a much lower death toll.
In the following note, we will explore the basic biology and epidemiology of Covid-19, the ongoing progress in drug development, and the risks we see in the situation.
Key message: given the striking similarities between the receptor proteins and proteases of SARS-CoV and SARS-CoV-2, we believe, that in larger part the current crisis could have been averted. The funders should have continued to fund the SARS-CoV research in the mid-2000s until we had a working vaccine and a protease inhibitor in place. More should be done by the funders, the policymakers, pharma and the VC community to ensure the same is not repeated for SARS-CoV-2.
Background / basic virology and epidemiology
Covid-19 is caused by SARS-CoV-2, a member of the coronavirus family. Its closest relatives are the SARS-CoV virus, with which it shares roughly 79% genomic similarity, and MERS-CoV virus, with 50% similarity. They are enveloped viruses with a positive-sense single-stranded RNA genome and a nucleocapsid of helical symmetry. The genome size of coronaviruses ranges from approximately 27 to 34 kilobases (29.9 for SARS-CoV-2), the largest among known RNA viruses.
Compared to the seasonal flu virus, SARS-CoV-2 is characterised by both higher infectivity (basic reproductive number 2.0–2.5 vs 1.3 for flu) and higher disease severity, both in hospitalization rate (~20% vs ~2%) and case fatality rate (~3% vs ~0.1%). SARS-CoV-2 also starkly contrasts with its closest relatives in these regards, causing much less severe symptoms than both SARS-CoV and MERS-CoV (with fatality rates around 10% and 35% respectively).
The clinical manifestation of different CoV infections varies greatly with the specific CoV type. Most are mild and asymptomatic infections but can range from the common cold to 30% mortality (MERS-CoV). Most common symptoms include “colds” with fever, sore throat, primary viral pneumonia and/or bronchitis, as well as secondary bacterial pneumonia and/or bronchitis. SARS-CoV severe acute respiratory syndrome (SARS) led to both upper and lower respiratory tract infections. MERS-CoV, Middle East Respiratory Syndrome (MERS), led to fever, cough, shortness of breath, gastrointestinal symptoms (primarily diarrhoea), with or without pneumonia. Some positive patients were asymptomatic. MERS was highly lethal, and symptoms could progress to ARDS, MODS, and sepsis.
Source: BioRender, Akiko Iwasaki (Yale University)
For the moment, unlike the influenza virus, the members of the coronavirus family have shown little ability to reassort, responsible for major genetic shifts behind the known flu pandemics, bypassing existing immunities.
Nevertheless, the coronavirus family has its own adaptations that were observed in MERS-CoV and SARS-CoV, and are likely manifest in SARS-CoV-2. Coronaviruses interfere with multiple steps during an initial innate immune response, including RNA sensing, signalling pathway of type I IFN production, and STAT1/2 activation downstream of IFN/IFNAR. This is not only responsible for the severity of the disease, but likely also for an uncharacteristically long incubation period (up to 14 days compared to 1–4 for influenza).
There is currently no reliable data on long-term immunity to SARS-CoV-2. A study (Bao et al., 2020) published on BioRxiv has shown no reinfection for macaques after the initial infection. Yet, the study is very small (only 4 animals) and only examines short-term response. If SARS-CoV-2 behaves similarly to SARS-CoV and MERS-CoV, long-lasting specific IgG and neutralizing antibodies are reported as long as 2 years after infection with SARS-CoV, indicating a possibility of long-term immunity.
While SARS-CoV-2 is significantly less fatal than its closest relatives (see the section above), its lethality increases rapidly with patient age. The disease is largely asymptomatic in children and a large percentage of younger adults (current estimates point at 50–70% of cases being asymptomatic), but is 5–10% fatal (depending on the quality of hospital care) in the age group over 70.
- SARS-CoV-2 is spread through aerial route, and is able to persist for several hours on various surfaces (half-life in aerosol state and on copper is 1 hour, and almost 4 hours on cardboard, 6 — on stainless steel, and 7 — on plastic, https://www.nejm.org/doi/10.1056/NEJMc2004973).
- SARS-CoV-2 is inactivated by 62–70% alcohol solutions, by 0.5% hydrogen peroxide or household bleach, which all can be effectively used to disinfect affected surfaces or items.
- Initial data shows that SARS-CoV-2 is stable at temperatures up to 37 degree Celsius, and as such little seasonal variability in infection rate can be expected (Wang et al, 2020). SARS-CoV has been shown to be inactivated at temperatures around 60 degree Celsius, and as such, it can be assumed that SARS-CoV-2 should not survive to boil, but is not inactivated by water temperatures that are below scalding hot to human skin.
- Cats, dogs and other household pets are not susceptible to COVID-19 but can act as intermediaries for the spread of the virus to healthy people on their fur/skin if in direct contact with the diseased, same as any other contaminated surfaces.
- Early reports from China show that there is no intrauterine transmission of COVID-19 in pregnant women, and SARS-CoV-2 does not pose a specific additional risk to pregnant women outside normal flu-like symptoms.
Progress: treatments and vaccines
Both the research and the industrial communities moved extraordinarily quickly in response to the epidemic. In particular, the research was spurred on by the very early publication of viral sequences, and the consequent publication of the crystal structure of the key surface proteins. This enabled drug development at a considerable pace.
In the current quickly escalating situation some old generation therapies are used off-label, despite the low level of evidence. One of these is alpha-interferon inhalation and the other is a lopinavir/ritonavir combination which was originally produced to treat HIV (Jin et al., 2020). Also, Gilead recently started clinical tests of the antiviral drug remdesivir designed against Ebolavirus. These remdesivir studies have attracted significant interest from many observers in the biopharma and scientific community due to observed in vitro activity against COVID-19 (Wang, Cao, Zhang et al., 2020) and Gilead potentially having the infrastructure to manufacture and supply the drug in an accelerated fashion in the United States. Besides that, old anti-malaria generic drug chloroquine has shown some positive results in the first cohort of COVID-19 patients in China (Colson et al., 2020). Alongside with the repurposed drugs, there are currently at least 22 COVID-19-specific therapeutics in development by various pharmaceutical companies and academic institutions. The majority of the work seems to be focused on searching for protease inhibitors, in line with other antiviral drugs.
At the time of writing, there are at least 69 separate efforts worldwide at producing a COVID-19 vaccine, with over 20 in China alone. These three COVID-19 specific vaccines currently in development:
a. On March 16 Phase 1 (safety) clinical trials of the investigational vaccine mRNA-1273 were started on 45 healthy volunteers. It was developed by the National Institute of Allergy and Infectious Diseases (NIAID) in collaboration with Moderna, Inc. Previous development projects on other vaccines targeting spikes on the surface of other coronaviruses — SARS and MERS — gave a head start to this work. The active phase of the investigation will take at least 4 months, with a follow-up of more than a year.
b. On March 17 Pfizer Inc. in collaboration with BioNTech SE announced the development of another mRNA-based vaccine BNT162. It will enter clinical testing by the end of April 2020. Their partnership originated in 2018 under the development of influenza vaccine, which promoted the fast progression of the BNT162 vaccine. Besides that, on March 13, 2020, Pfizer issued a five-point plan calling on the biopharmaceutical industry to join the company in committing to unprecedented collaboration to combat COVID-19.
c. On February 26 clinical-stage vaccine company Novavax announced the progression in the development of COVID-19 proprietary nanoparticle vaccine with an adjuvant; they expect Phase I to start in May-June. They previously developed promising vaccine candidates against SARS and MERS, and currently have clinical trials of RSV and Flu vaccines successfully transitioning to Phase III.
Other biotech companies and academic institutions are also working towards a COVID-19 vaccine or treatment. The vaccination approaches include DNA vaccines (Inovio, Entos Pharma and others), protein-based vaccines (Sanofi, AJ Vaccines and others), viral vector-based vaccines (J&J, Altimmune and others), live attenuated vaccines (Institute Pasteur, Codagenix). Multiple routes are utilized for the search of the treatment: antibodies to neutralise viral particles (Takeda, NIH and others), small molecules (Insilico Medicine, Enanta Pharma and others), siRNA (Vir Biotech, Sirnaomics), and even cell therapy (Sorrento Therapeutics). There is no prediction as of yet for the efficacy and timeline of the new anti-COVID-19 drugs development.
Overall, we strongly believe that both routes of vaccine development (novel mRNA/DNA vaccines and classical viral vector vaccines) should be employed and it will be best if two or three vaccines can co-exist. It’s completely unclear right now if a commercial COVID-19 vaccine could ever be successful, so collaboration is vastly preferable to competition as it stands.
Moreover, we think that ensuring the lessons of SARS-CoV are learned well and we do obtain a fully working vaccine as well as an efficient therapeutic drug against COVID-19 should be a priority for charitable institutions and policymakers alike going forward. The successes of cross-reacting CoV-CoV2 antibodies indicate that if we had a vaccine and a therapeutic against SARS, the situation might have been significantly different. However, unfortunately, research funding for SARS dried up soon after the media attention looked elsewhere and the work has never been finalised.
We must do better this time round.
About 4BIO Capital
4BIO Capital is an international venture capital firm focused solely on the advanced therapies sector.
4BIO’s objective is to invest in, support, and grow early-stage companies developing treatments in areas of high unmet medical need, with the ultimate goal of ensuring access to these potentially curative therapies for all patients. Specifically, it looks for viable, high-quality opportunities in cell and gene therapy, RNA-based therapy, targeted therapies, and the microbiome.
The 4BIO team comprises leading advanced therapy scientists and experienced life science investors who have collectively published over 250 scientific articles in prestigious academic journals including Nature, The Lancet, Cell, and the New England Journal of Medicine. 4BIO has both an unrivalled network within the advanced therapy sector and a unique understanding of the criteria that define a successful investment opportunity in this space.
For more information, please visit www.4biocapital.com