Virology 101: Antigen drift

The world is getting a crash course in virology and immunology. The course is brutally intensive. Attendance is mandatory. It’s time to learn about antigen drift. It refers to the accumulation of mutation in the part of the virus recognized by antibodies – the antigen. If we get Coronavirus pandemic wrong, it could keep us indoors for years.
If you thought “Tokyo Drift”was fast and furious, wait till you see antigen drift.
Welcome to the Lab.
(Screen-shot of Trump in the lab; not a playable video).
The sudden attention to virology is warranted. The lockdowns are nearly universal and every conversation turns to Coronavirus. It is hard to avoid facing the grimly high mortality rate of the virus. On top of that, the disruption of social activities and economic freeze from the lockdown, which were aimed to minimize the spread of the disease, are now part of daily life. The resulting economic effect in the US has been described to be more like an ice age than a recession.  
The global lack of preparedness is troubling. There have been plenty of warnings in the past: Spanish flu of 1918, polio, SARS, swine flu, EEE, Zika. Despite this, the US Center for Disease Control budget has shrunk from $18B in 2010 to $8B in 2019. The rest of the world is equally unprepared.
In this challenging time, it’s important to focus on silver lining -- taking stock of anything positive is an important psychological tool. The pandemic could have come at a worse time. The fight with COVID-19 should be a call for action, not despair. In a world is with free global trade and travel there is a perpetual risk of pandemics. This threat should be met with investment in the technologies which could help with the long potential battle with the Coronavirus, as well as guard against future epidemics.

A sober examination of the global strategy of lockdown could be described as merely reactive and may lead to unrealistic expectations and unintended consequence with the antigen drift. The many challenges can be divided into two main categories: biology and politics. Getting the politics right is key to executing the right strategy for a global fight against the virus. The experiences so far revealed a fragmented response by politicians as well as a lack of realism in policy and individual behavior. These limitations need to be taken into account in a realistic model of using lockdown as a long-term tool against coronavirus.

Politics is playing a destructive role. The first challenge in combating Coronavirus is to remove political obstacles. The signs are not good. Political polarization is not diminished; politicians everywhere are complicit. The Trump administration continues to refer to the virus as the “Chinese virus”. The Chinese officials are openly blaming the US not only for being ineffective and lacking transparency, but actually using its military to seed the virus in Wuhan province. Protests from scientists that attempt to dispel conspiracy theories are saying that the virus is clearly natural in origin and does not seem to impact the hardening positions. Meanwhile, the EU is showing signs of fragmentation with little internal cooperation. Germany actually banned export of much-needed face masks and ventilators to Italy after the Italian government made a direct appeal to the rest of the EU for help. Assistance for hard-pressed hospitals in Northern Italy came not from nearby French or Swiss hospitals, but from Chinese. Can the EU withstand the strain of nationalist policies to combat the virus? The second wave of infections has a lot of cases in Europe which may have exacerbated the pandemic by its anemic response.

There are many models for the spread of Coronavirus including a simple model from NY Times which decided to provide something useful for a necessary break from Trump bashing. Unlike the economy, the polarization in US is going strong. The debate is turning to the third phase of economic stimulus with the price tags of 3 trillion. Is the US going to have to nationalize entire industries? Will the USA be the same after nationalizing Boeing and granting unprecedented emergency powers to detain people breaking curfew?

Economic clock. Governments, including the US, have purposefully chosen to crash their economy to save lives. The pursuit of this humanitarian mission is problematic. The shutdown is killing the economy and it is only a matter of time until the loss of businesses, individual income, and housing lead to an increase of despair and death. According to various estimates, the shutdown would last at least 6 months, possibly longer than a year. In addition to the economic pain, there is a biological problem with this approach which brings us to the subject title.

Antigenic drift.  It is necessary to discuss another chapter on viruses: antigenic drift is accelerated in RNA viruses. First, a reminder of definitions: the portion of a protein recognized by antibody is called an antigen. The accumulation of individual mutations in the viral genome over time mutations is called antigenic drift.

Coronavirus, like HIV, influenza and polio uses RNA, not DNA to store its genetic material. Majority of RNA in the cell is in the form of messenger RNA (mRNA). These mRNAs are used for transcription of the programs (encoding proteins) from long-term storage in DNA, which has higher chemical stability than RNA. These mRNAs are short lived, and their usage places lower requirement on fidelity of information transfer, compared with DNA. DNA replicase enzyme has a proof-reading activity, which allows it to replace an improperly chosen nucleotide. RNA replicase has no need (or space in its tiny genome) for a proof-reading module. So, RNA viruses have a mutation rate that is 100,000- to 1000,000-fold higher than DNA viruses. In consequence, coronavirus has the potential for fast mutation rate and significant antigen drift, given time to evolve.
Why does antigenic drift matter? Consider that pandemics that began in 1889 and 1918 -- caused by influenza viruses that had similar levels of infectivity to the coronavirus -- had three waves of infections, with the later waves more lethal than the first. In 1918, three waves hit in quick succession within the space of a year, with the latter two waves accounting for most of the 50 million total death toll.
Researchers suspect that the cause of increased morality of later waves of Spanish flu was antigenic drift. This should serve as a warning regarding Coronavirus. Spreading out the peak of infection, the burden on healthcare should be made more manageable, as shown below.
 

However, this model does not reduce the poor of people who can get infected, nor gain enough time for a vaccine, and the total number of infected is expected to remain the same.
The spreading of the peak does not only strain the economies for a long time, and limit compliance, but has the potential to evolve strains of COVID-19 with antigen drift. This would make the problem worse in multipole ways.  
First, it threatens “herd immunity”, an essential adaptation tactic. Is a previously infected person rendered immune to subsequent infection? The answer may be “No”, if the antigenic drift is great enough that the new virus looks unrecognizable to the immune system. In that case the COVID-19 snake would become a hydra. Both HIV and influenza illustrate this. In the case of the common flu, as the graph below shows, there were two separate waves of H1N1 and H3N2 strains of influenza during the winter of 2018-19. Viruses like HIV have over time developed additional strains; HIV-1 tests are distinct from HIV-2 tests because the immunological distinction of the viruses has implications for diagnostics.
Coronavirus has a rapidly growing number of infections, which over time could provide great opportunity for antigenic drift of COVID-19. By flattening the peak, virus could be given longer time to evolve in a large population, and with partial shutdowns of transportation local COVID-19 strains could evolve in isolation. This could result in greater antigen drift and evolution of more strains that experienced during the Spanish flu which passed faster without transportation freeze, although at a terrible cost in lives. The leaky lockdown places the world in uncharted territory with respect to a virus. Can we outcompete the virus, or will it evolve faster than our antibody and vaccine-producing technology can keep up?!

The risks of lockdown. One of the biological challenges with the lock-down is that the spread of the peak to enable healthcare systems to cope is the increased opportunity for the antigenic drift. Appearance of multiple strains places “herd immunity” at great risk.

The lack of “herd immunity” means that all people continue to remain in danger of infection. Combined with the problem of transmission before onset of symptoms could make containment a permanent solution.
“The virus is constantly growing and changing, which makes total containment impossible,” said Chan Kung, health policy analyst at Beijing-based consultancy Anbound, who advised the local government during the SARS outbreak. “The only way to go forward is to understand it, adapt to it and make sure the virus doesn’t cause dramatic outbreaks so that the existing healthcare system can handle it.”
The adaptation to the virus can take a few forms. Both “herd immunity”, and mass vaccination (injection of antigens, and immune stimulants) or antibody treatments might be untenable if COVID-19 mutates and evolves different strains. Current technologies take up to 18 months to produce the vaccine, according to WHO. Clinical trials take time: J&J CEO said about the potential vaccine: ”I think we’ll have important data by the end of the year”. Coming from the maker of vaccines for Ebola and Zika, among others, this is an authoritative statement, but still deeply unsatisfying. By the end of the year well have data?! This is the pace of development using the best available resources. It does nothing for the well-being of people and businesses in danger next week or next month.

Compliance. Another complication for lockdown strategy is compliance. Stories of non-compliance abound from Russia to Europe and USA. While some non-compliance is individual, some could be better controlled by the government. It took officials in US weeks to shut down Florida beaches for the college students, who were out for the spring break, as usual. Now, multiple students are testing positive for Coronavirus, spreading the disease to their states, and homes. It’s even harder to enforce compliance from adults who took to partying on boats off-shore. Miami-Dade mayor expressed disappointment in irresponsibility, but shaming might not be enough. Will it require coast guard policing?
United States Department of Justice (DOJ) has faced an uproar over their request for “emergency powers” which include indefinite detention without trial – dictatorial powers, that has some Congressman concerned about the rush to abandon due process of Constitution in this emergency.

Meanwhile, Trump administration is presenting him as a “wartime president”. Despite the immediate criticism of this declaration, it is rational to elevate the fight to that level, especially since the administration is touting mobilization effort not seen since WWII.  Indeed, the refocusing of the world on common challenges is a welcome distraction from fratricidal conflicts. Organizations as diverse as ISIS and UN have discussed the need for change of behavior or achieve cease-fire during the pandemic.

The strategy in US appears to be to enforce months-long lockdown, as governor Andrew Cuomo of NY state with the majority of infectious has suggested. However, the message is mixed. The White House appears to be hoping for re-opening for business in May or June. That appears to be unrealistic, if the peak of mortality will fall at that time. However, keeping vast segments of the country unemployed and locked for more than 2-3 months appears to be unrealistic. There is already an existing problem with compliance, and it is likely to get worse with economic and psychological exhaustion.

If an effective containment strategy requires lockdown lasting 6 months or more, it may be completely unrealistic about the compliance side. Is US going to take China’s approach and police it’s citizens with dictatorial emergency powers? If compliance is moderate, the impact of lock-down will be modest, or even devastatingly counter-productive if antigen drift occurs.

In fact, it is fair to ask about the impact of the lock-down. A top health official in NJ, which is one of the states under official lockdown, shared her expectations: “We’re all going to get it”. Saving lives at the cost of crushing the economy seems like a humane option, but with the current approach we might achieve neither. Can the financial crash from absence of economic activity be justified in light of expectation of multiple strains evolving due to rapid antigen drift of an RNA virus? Each infection is capable of producing hundreds of mutations. Multiply that by millions hosts – that’s a lot of evolutionary room for the virus. Will diagnostics and treatments will keep up with new strains?

Failure of detection. Unfortunate characteristics of COVID-19 include lack of early symptoms. Contagious individual unknowingly spread the infection, before they experience any signs of disease. The failure of diagnostic kits from CDC in the early weeks of infection was an extremely unfortunate. This allowed the disease to spread undetected. In fact, the expectations of increase from just over 10,000 cases in US to over 70,000 this week is expected due to improvements in detection, not a dramatic increase of disease. In addition, there are still shortages of test kits. A young woman died in New Orleans, waiting for the results Coronavirus test, which were expected on Monday.

One of the reasons for the faulty kits is that they use molecular diagnostics – amplified nucleic acid biomarkers. In order to achieve exquisite sensitivity such systems employ virtually unlimited replication, and the amplified signal is notoriously prone to false positives. The way manufacturers have overcome this limitation is to target multiple sequences from viral genome, reducing the rate of false positives.  Molecular diagnostics could be used to keep up with the changes of the sequence of viral strains, however, they suffer from sensitivity issues.
Early in the infection the viral RNA is not amplified, only the structural proteins are made. These include the spike proteins, which are typically the most antigenic regions of the virus. Best methods of early detection of HIV use protein biomarkers, not DNA. That improvement in performance comes at a high price of development of the antibody. So, reliable antibody-based early detection would be challenged by antigen drift.
Imagine the logistics complexity of detection (let alone treatment) if there are several strains of COVID-19. Could our technology keep up with multiple threats? Flattening the infection peak imperils our ability to detect and contain Coronavirus by allowing for antigen drift. Can we afford to risk of driving evolution of multiple strains for a virus with a lack of early symptoms?

Disease worse than the cure? It is appropriate to consider the societal response to COVID-19 in analogy with an immune response of a single body.
Symptoms include increased temperature while circulation and digestion are minimized.  Similar to the immune reaction in a single organism resources are being mobilized and amplified to fight the disease: factories retooling, retired medical personal mobilized, shipping is focused on Coronavirus essentials. In the body the first non-specific reaction is called innate immunity. It does not involve a specific antibody response and has only a weak impact on new viruses for which no antibodies exist. The secondary response, which takes time to evolve, is much more specific. The body selects from a large repertoire of antibodies, and involves other intricate processes like affinity-maturation, resulting in an upgrade of antibody’s ability to recognize the pathogen. This immune response can kill.

The pathology of the disease often shows a period of improvement, follow by a steep deterioration. The latter is caused by the over-active immune system, where efficient antibodies result in increased inflammation. This apparently successful counterattack against the virus can result in overload of inflammatory stimuli and excessive release of signaling molecules called cytokines. This can lead to condition call called “cytokine storm”, characterized by a cacophony of signals. This strong immune reaction causes accumulation of fluid in the lung, and since the virus affects both lower and upper respiratory tract, the breathing becomes extremely restricted. This excessive immune reaction to the pathogen is actually the cause of death in vast majority of cases. Drugs that limit inflammation are being successfully used to reduce mortality, and morbidity – damage to the lungs from formation of lesions filled with fluid that can reduce lung capacity in survivors by 20-30%.
The mechanism of action in the individual body has implication for the society. As the individual is composed of many cells, in society the individual functions as the unit of life. The overzealous immune reaction that is deadly to individuals can be fatal to the society as well.

Governments from China to Italy and USA have decided to attempt to save lives at the cost of lockdown and crashing their economies. The cost is clearly measurable in the estimates of lost economic activity in USA alone, as it considers the magnitude of the assistance package. The price tag is at 3Trillion and climbing. The expected loss of economic activity if shutdown continues till May is 5.2T and 12T if it lasts till August.
The shutdown of transportation and entire industries for months is a very damaging prospect to the economy and society. Worse, is the danger of low compliance and antigen drift which could plunge the world into an uncontrolled sea of airborne virus. The issue of lock-down needs to be considered with view of long-term effects.

Are we able to reduce mortality in the long-term by containment? The theory that lockdown can avoid the hospitals being overwhelmed is being disproved in NYC, the epicenter of infection in the US. Even with lockdown of the entire state, NYC hospitals are running out of beds, respirators, and non-infected personnel.

Since the total number of infected is unlikely to be significantly reduced (vaccine won’t come soon enough), as most of the models suggest, the only benefit of the flattened peak should be improved ability of US healthcare to handle the caseload.

The situation in NYC appears to be already past this point. In Italy ventilators are only provided to people under 60. Italy has world’s highest coronavirus mortality rate of 8.6%, despite the lockdown. It’s hard to know how much worse it would be without the lockdown. It’s also hard to predict the chances for antigenic drift with isolated months-long incubation in various countries.
This is a model the world needs to decide how to eliminate coronavirus like polio, and not to allow it to fragment. If the world cannot rise above factional, nationalist thinking we may see the worst outcome of all: antigen drift of an airborne virus. That could be disastrous.