Seeing Around Corners: COVID-19 an Immunology and Economic Review
Global events that affect human behavior for weeks to months invariably have severe, long lasting economic impact. The pandemic of 2020 isn’t a simple ‘Black Swan Event’, this is a flock of Black Swans, that we were ill prepared for and they have come home to roost.
Pandemic spread of the SARS-CoV2 virus and rampant COVID-19 infection is not a standard natural disaster with a clear beginning, middle, and end. Our thinking around this must evolve in order to successfully weather the economic and personal toll that societies and individuals will face in the next two to five years.
New viral infection in communities may last up to 18 months. At the moment, the hope is that endogenously produced antibodies retain effectiveness such that re-infection is not possible. In the meantime, scientists are working to implement neutralizing antibody therapy (convalescent serum) and find small molecule treatments to buy time for development of vaccines, and commercially produced neutralizing antibodies. Although natural immunity to Coronaviruses may only last two years, these early efforts will minimize the spread of the virus, and eventually, we will succeed. However, significant damage to our economic system will be done.
DISEASE CONTROL MEASURES
SARS-CoV2 is an extreemly successful virus, distinct from Influenza and other Corona viruses. SARS-CoV2 is epidemiologically distinct in terms of spread and delays in symptom presentation, allowing it to have massive traction.
Influenza virus, SARS, and MERS have an asymptomatic period of 1–4 days, 2–7 days, and 5–14 days , respectively. Symptomatic people are less likely to spread a disease as they simply aren’t feeling well and reduce contact with society naturally. Similar to MERS, SARS-CoV2 has an average 5.5 day period in which the infected are likely shedding virus before becoming symptomatic. Asymptomatic infection can last up to 11 days. Early symptoms are often reported as mild, increasing the likelihood of continued activities that lead to viral spread for an additional 5 to 10 days.
Viral spread from the ‘walking wounded’ occurs with Influenza and Coronaviruses and make viral spread difficult to track. Both Coronaviruses and Influenza viruses have protracted persistence in the human population which has been difficult to mitigate. Currently we only manage these viruses as the ‘seasonal flu’ or ‘common cold’. Most viruses are mild and do not cause significant widespread illness, until now. Viral spread post-infection and during a protracted asymptomatic period is a feature of COVID-19 infection. This is why it is imperative to stop viral spread that social distancing and reduction in mobility is introduced and adhered to broadly.
SARS-CoV2 has a half-life on surfaces and in the air that is comparable to other coronaviruses. This is good. A reasonably short half-life indicates the novel virus has not mutated to increase survivability outside the host, though increased half-life outside of a host is a possibility in viral mutations, it is not selected for evolutionarily in the viral life-cycle. The reported half-live of SARS-CoV2 is long enough to sustain transmission in closed spaces or on surfaces when human mobility is introduced. A three-hour viral persistence in the air means you may never see the person from whom you contracted the virus.
SARS-CoV2 is mutating. Viral mutation typically trends towards development of a less devastating disease, although this not always the case and host-virus interactions play a complex role in virulence. Viruses with rapid onset, high mortality, and extreme symptoms are often considered self-extinguishing, in that a host does not have time to broadly spread the virus before significant mobility reducing symptoms or death. This is partially the cause of virus mutation drift towards the less virulent form of the disease. A more ‘successful’ virus allows a host to continue to spread the disease. COVID-19 however, due to it’s long asymptomatic and mild symptom life cycle is unlikely to exhibit natural selection for a lower virulence strain.
Natural selection for this virus will therefore likely be relegated to antigenic drift. Antigenic drift in viruses without a shift in symptom profile represents a worst case scenario in which humans experience the severity of the disease a-new each on a seasonal-life cycle similar to Influenza. Scientists know this, and they are fighting back.
HOW SCIENTISTS ARE FIGHTING BACK
First, scientist are working as fast as humanly possible on the development of a broadly effective vaccine. This means the vaccine would be targeted to elements of the virus that are necessary for viral function and do not have a high mutation rate. In Influenza these are called ‘stalk proteins’. Spike proteins, which are responsible for viral entry into cells mutate often, and are the reason we have a new Influenza vaccine each year. Spike proteins readily mutate both in Influenza and Corona Viruses making the viruses antibody resistant. Indeed, early reports of a novel spike protein mutation in SARS-CoV2 are linked to increased infectivity unique to this Coronavirus. Such a vaccine would confer partial immunity and reduce disease severity regardless of normal antigenic drift. This is the slowest mode of action we have and will require between 1–2 years to be tested and distributed. Here is the CDC Reference on Influenza antigenic Shift and Drift.
Second, the strategy of development and use of human antibody therapy. Human antibodies confer protective passive immunity for up to 3 months with a single dose. This is enough time to extinguish viral spread within a community. Dosing a patient with a human antibody confers passive immunity, which prevents the virus from gaining a foothold but does not allow for the development of long-lived memory. Passive immunity is the same mechanism that mothers milk containing antibodies protects a child exposed to local pathogens. Due to technologies developed in the last 5–10 years identification and production of antibodies is a rapid mode of action. Convalescent serum (antibody containing serum from an infected patient) therapy does not typically require extensive testing in humans. To implement antibody therapy on a broad scale, the sequence of virus neutralizing antibodies must be identified and production must be scaled to widely distribute. Three companies are actively working on this; Regeneron, DistributedBio, and Takeda which will use the plasma from infected individuals that contains antibodies. The use of human antibodies does not reduce genetic drift or shift of the virus. Therefore to be used as an effective therapeutic to emergent disease, antibody identification must outpace viral evolution of spike proteins or be targeted to a region of the virus that exhibits low rates of mutation.
Third, is the rapid scale up and distribution of a small molecule antiviral. As this situation rapidly evolves small molecule therapeutics are being investigated in the field for activity against SARS-CoV2. As of this writing (March 19th, 2020) efficacy has been reported with: Favipiravir and Chloroquine. In sum, a list of 120 broad spectrum antiviral agents (BSAAs) known to be ‘safe in man’ has been made public. The broadness of efficacy, side effect profiles, and best treatment protocols remain to be established. Repurposing antivirals is the fastest mode of action we have. Drug stocks can be distributed to patients nearly immediately while manufacturing can be ramped up.
If one or several of these small molecule drugs works to reduce viral replication, humanity will be lucky. This is not a guarantee, or a reliable mechanism of preparation. However, scouring our collective pharmaceutical ‘bathroom cabinet’ for something that may work should not be disregarded as an important approach for treating emerging diseases. Therapeutic repurposing to address emergent disease or novel existing diseases is a deeply under appreciated and under utilized approach. Drug repurposing would benefit from attention from predictive modeling methods to improve speed and meaningful results.
THIS CAN (WILL) HAPPEN AGAIN
Zoonotic transfer of viruses from animal to human is a known phenomena, which can be limited by minimizing in human contact with wild animals. But the world is a big place, with many species including migratory wild birds serving as zoonotic viral reservoirs, therefore this is not something that can be completely eliminated.
High population density exacerbates viral spread and strains medical response systems. Often, as seen with SARS-CoV2, we are unable to gauge the impact of a virus will have within a population until widespread population infection occurs. Harbingers of impact on society include: How easy it is to transmit a virus? How long does the virus survive outside a host? How ill someone will become when they have the virus? What is the period of asymptomatic spread? How long does it take the immune system to clear the virus? What is the severity of secondary health effects or comorbidities that arise as a result of viral infection?
It has been a quiet period in the history of plagues and pandemics. This is largely attributed to sanitary living through global distribution and use of soap, pest control, scientific understanding of disease, modern medical intervention, and monitoring of water and food supply chains. Collectively, these measures have relegated the term ‘Plague’ to the history books, or a further corner of the undeveloped world. We are experiencing our first modern plague that has circumvented societies firewalls. Over generations, resources were shuffled away from what was becoming a historical footnote in the survival of early societies. Medical teams were only lightly trained, if at all, for a global pandemic. Despite the specters on the horizon, our society was not prepared for an outbreak of this magnitude.
Much like epidemics of cholera, yersinia pestis (Bubonic Plague), and influenza, SARS-CoV2 will undoubtedly precipitate broad safety measures and monitoring that will become normalized.
The human immune system is broken into three branches: Barrier (skin, intestinal wall), Innate (broad non-specific response), and Adaptive (specific response). The cleanliness of a society, attention to infectious disease, hospital systems, and scientific understanding can indeed and should, be thought of as the fourth branch of the immune system. Our collective vigilance and maintenance of this system through Pandemic control task forces and scientific research is imperative.
Our ability to adapt is critical for retaining economic functionality and, effectively, life as we know it. Humans are adaptable, however, our entrenched economic systems are often not. At an individual level the majority of Americans are not prepared to become jobless, homeless, or suffer a period of extended quarantine.
70% of the US economy (GDP) is dependent on consumer spending. Downturns in consumer confidence and spending will have a significant ripple effect throughout society. Services, except those tied to basic needs will suffer marked declines.
Over 80% of US workers are part of the service industry. This includes 40.2% of American workers representing retail, leasure, hospitality, manufacturing, and non-agricultural goods production, which will likely be the hardest hit market sectors of 2020.
Over 80 million Americans are hourly wage earners. 75% of whom have less than $500 saved for an emergency expense. In a recent federal survey 40% of all American adults would be unable to pay for a $400 emergency expense.
We were a society living on the edge, and the SARS-CoV2 has pushed us off the cliff. Many people will be able to bridge the gap with extreme credit leveraging, many will simply go bankrupt. Currently, our markets are exhibiting instability only rivaled by the 1929 economic meltdown that preceded The Great Depression.
As a dyed-in-the-wool optimist, I hold hope for a rapid re-bound and economic restabilization. As a consummate analyst of data, this seems unlikely. Instability will ripple through our economy from financial instability to food and housing instability. It is possible that we may endure a significant period of deflation. As a result of these economic factors, we may witness migrations away from expensive cities, vertical integration of family units, complete, though likely temporary cessation in growth, and possibly periods of negative growth for a period of three to five years.
Government response and societal preparedness is coming into sharp focus as the initial wave of infectious disease is not something that the strained US healthcare system was prepared to handle. Our Federal Response Safety nets that are still intact will be tested to their utmost, and are likely to fail.
GAZING INTO THE VOID: KNOWN UNKNOWNS
Immunological Variance: The patients immune system response to SARS-CoV2 infection is widely varied and only somewhat age dependent. It is unknown if there are specific elements of the immune system or prior viral or pathogen exposure are the cause of these distinct responses that vary from mild symptoms to hospitalization and death. The human immune system has tremendous genetic diversity which may be responsible for the heterogeneous profiles seen in the general population. Early reports indicate that blood type may be correlated with severity of viral infection. A historical example of heterogeneous genetics leading to protection from infectious disease can be seen in the Bubonic Plague. Northern europeans carry a CXCR5 mutation (up to 14.6%), at a higher than average rate, while in some populations no carriers are found. The CXCR5 mutation is protective from Bubonic Plague (1347–1352) which decimated one third of the European population, and coincidentally is also protective from HIV infection.
Higher Infectious Capabilities than SARS: Does SARS-CoV2 have mutations that make it more infectious? Part of the life cycle of a virus is outside of the host. In order to replicate, viruses need living cells. As part of this process a virus must bind to and enter a cell. SARS-CoV2 is reported to have mutations in one of the receptors responsible for binding to cells and that mutation may increase the ability of the virus to bind to cells. Early reports state that this mutation may increase the binding strength between virus and cell 1,000-fold over that of SARS. To what degree this makes the virus more infectious is not clear, although this finding does support the hypothesis that SARS-CoV2 is more infectious than a typical coronavirus.
Complications in the Nervous System: Coronaviruses, as a family of viruses, are capable of persisting in the human nervous system. It is unknown if COVID-19 infection will exhibit the same patterns, although early evidence indicates that severe infection does include neurological complications, scientists are actively researching this possibility and persistence of the virus in the nervous system.
Long-term Viral Persistence: SARS-CoV2 may be the beginning of a family of new viruses that become seasonal due to antigenic drift, leading to viral escape of population immunity. What will we, as the human race, do to be prepared for when this happens again? How will be manage a virus that is easier to spread than Influenza, but just as deadly, if not moreso?
Buckle up for the short term with an eye on long term financial and viral control, scientific understanding, social change, and human ingenuity.
Life as we know it is now fundamentally different. Be good to each other.