Virology 101: Antigenic drift

Virology and Immunology during a Pandemic

Society's sudden attention on virology, the branch of science that deals with the study of viruses, is warranted. The lockdowns of economies are almost everywhere and every conversation turns to the pandemic. On top of this, there is disruption in social activities as well as the economic freeze from the lockdown. These measures were aimed at minimizing the spread of the disease. The resulting economic effect in the US has been described to be more like an ice age than a recession. [1]  

Every economy was unprepared for the pandemic which is troubling considering the many warnings in the past including SARS, H1N1, The Black Plague & The Spanish Flu. Despite this, the US's Center for Disease Control (CDC) budget shrunk from $18B in 2010 to $8B in 2019. The rest of the world was equally unprepared. Overall, the price tag of closing the US economy to this date is $3T US dollars and rising. If economic shutdowns were to continue until May and August of 2020, the global expected loss in economic activity is $5.2T and $12T, respectively. Governments including the US purposefully chose to crash their economies to save lives.

We all need silver linings during the pandemic as these are important psychological tools. The fight against COVID-19 should be a call for action rather than despair. After all, in a world with free global trade and travel, there is perpetual risks of pandemics. This threat should be met with investments in technologies that help fight the potentially lengthy battle against COVID-19 as well as guard against future epidemics and pandemics.

The many challenges during this pandemic can be separated into two main categories: biology and politics. The right politics is key to executing an effective strategy for fighting the virus across the globe. Our experiences so far have revealed fragmented responses from politicians as well as a lack of realism in policy and individuals. These limitations must be taken into account in a realistic way - Lockdown should be a long-term and universal tool against the spread of the virus.


The Economic "Clock"

Governments including the US purposefully chose to crash their economies to save lives. Economic shutdowns are destroying economies. We are losing businesses, individual incomes and housing leads to increases in despair and death across the globe. The shutdown of transportation and entire industries for months is a damaging prospect to economies and societies. There is also the danger of low compliance and antigenic drift which could plunge the world into an airborne virus. The issues surrounding lockdown need to be considered for both the short and long terms. 

In addition to the economic pain caused by this virus, there is a biological problem with the lockdown approach which brings us to the subject title: Antigenic Drift.


Antigenic Drift: An Overview

Antigenic drift is accelerated in RNA viruses. First, an antigen is the portion of a protein recognized by antibody. Second, the accumulation of individual mutations in the viral genome over time mutations is called antigenic drift. 

Similar to HIV, influenza & polio, the COVID-19 virus uses RNA rather than DNA to store its genetic material. The majority of RNA in a cell is in the form of messenger RNA (mRNA). These mRNAs are used for transcription or programing. They encode proteins from DNA (long-term storage) which are more chemically stable than RNA. These mRNAs are short lived. Compared to DNA, mRNAs have a lower requirement of accurate information transfer. 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. Thus, RNA viruses have a mutation rate that is 100,000 to 1000,000-fold higher than that of DNA viruses.

If given time to evolve, COVID-19 could have potentially very quick mutation rates and significant antigen drift.

Trends in Past Pandemics

The pandemics that began in 1889 and 1918 caused by influenza viruses had similar patterns of infectivity to COVID-19. These pandemics had three waves of infections, with later waves more lethal than the first. In 1918, three waves hit in quick succession within the space of a year. [2] The two latter waves accounted for a majority of the 50 million deaths. Researchers suspect that the cause of increased mortality in the later waves was antigenic drift.

The process of spreading the peak of infection during a pandemic makes the burden on healthcare workers should be made more manageable [Figure 1]. However, this neither reduces the total number of people infected nor gains for vaccine developement. The spreading of the peak also strains economies and limits compliance. The process of spreading the peak also creates the potential for strains of COVID-19 to evolve using antigenic drift.

Figure 1: Spreading the peak of infection during a pandemic

 

However, the idea that lockdowns prevent hospitals from being overwhelmed was disproved in New York City, the epicenter of infection in the US. Even while the entire state was on lockdown, NYC hospitals ran out of beds, respirators and noninfected personnel. In Italy, ventilators are only provided to people under 60. [3] Italy has the world’s highest COVID-19 mortality rate of 8.6% in spite of the country's lockdown. It is difficult to predict how much worse societies would be without lockdowns as well as the changes that may occur due to antigenic drift with isolation lasting months or even years in various countries.

The Challenges of Antigenic Drift

When a person is first infected with COVID-19, the viral RNA is not amplified. However, the structural proteins have been made which includes spike proteins, typically the most antigenic regions of the virus. The best method for early detection of HIV is protein biomarkers rather than DNA. This comes at a high price of development of the antibody. Thus, reliable antibody-based early detection would be challenged by antigen drift.

There are complex logistics behind detection and treatment of COVID-19 especially if there are several strains. The process of flattening the infection peak endagers our ability to detect and contain COVID19 by allowing antigenic drift to occur. Can we afford to risk driving evolution of multiple strains of a virus with a lack of early symptoms? (See Additional Information - Failure of Detection for more information on the lack of early symptoms in COVID-19 patients)

Is a previously infected person rendered immune to subsequent infection? The answer may be “No” if antigenic drift is so fast that the a 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, there were two waves of H1N1 and H3N2 strains in the winter of 2018-19. Viruses such as HIV develop additional strains over time. HIV-1 tests are distinct from HIV-2 tests since the immunology of the viruses has implications for diagnostics.


The number of COVID19 infections is growing which could provide great opportunity for antigenic drift. The process of spreading the peak gives the virus more time to evolve in a population. Furthermore, with partial shutdowns of transportation, local COVID-19 strains could evolve in isolation. This could result in the evolution of more strains than were present during the Spanish flu which passed faster without transportation freeze (although there was a terrible cost in lives). So, can we outcompete the virus, or will it evolve faster than our antibody and vaccine-producing technology can keep up?

Antigenic drift threatens "herd immunity" which is an adaptation tactic. Without herd immunity, all people remain in danger of infection. Combined with the problem of transmission before onset of symptoms, antigenic drift 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.”


Both herd immunity and mass vaccination or antibody treatments may be infeasible if COVID-19 evolves different strains. Mass vaccination is the injection of antigens, and immune stimulants, into the human body to produce an immune response to COVID-19. 


 

Additional Information

Additional Information - Vaccine Production

As of March 2020, the technologies available take up to 18 months to produce a vaccine, according to WHO. Clinical trials take time. J&J CEO said about the potential vaccine. [4]

 

"I think we'll have important data by the end of the year"


Coming from the makers of vaccines for Ebola and Zika, among others, this is an reliable yet deeply unsatisfying statement.

Additional Information - The Difficulty of Compliance

Compliance. Another complication for lockdown strategy is compliance. Stories of non-compliance abound from Russia to Europe and USA. While some noncompliance is individual, other noncompliance could be controlled by governments. It took US officials weeks to impose a shutdown on Florida beaches for college students who were on spring break. Many students are testing positive for COVID-19 spreading the disease to their states and homes. [5] It is even more difficult to enforce compliance on adults who took to partying on boats off-shore. [6]
 

The United States Department of Justice (DOJ) faced an uproar over the request for emergency powers including indefinite detention without trial, dictatorial powers that have some congressmen concerned with the rush to abandon the case due to the process of Constitution in this emergency. [7] Meanwhile, the Trump administration presents Trump as a “wartime president”. Despite the immediate criticism of this declaration [8], it is rational to elevate the fight to that level, especially since the administration is touting mobilization effort not seen since WWII. [9] 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 during the pandemic. [10]

The strategy in the US appears to be to enforce a months-long lockdown, as governor Andrew Cuomo of NY state with the majority of infectious suggested. The message is mixed. The White House appears to hope to re-open business in May which is highly unrealistic. Nevertheless, keeping large portions of the population unemployed and locked down for more than 3 months may be unrealistic. 

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.


Additional Information - Failure of Detection

First, there is a lack in early symptoms of COVID-19. There are many contagious individuals who unknowingly spread the infection before they experience any signs of disease. The expected number of cases in the US increased from just over 10,000 to over 70,000 this past week due to improvements in detection.
 

The symptoms of COVID-19 include fever and a decrease in circulation and digestion. Similar to the immune reaction of an organism, resources are being mobilized and amplified to fight the disease: factories are retooling, retired medical personal are being mobilized, and shipping is focused on COVID-19 essentials.

The body's first nonspecific reaction is called innate immunity. Since innate immunity does not involve a specific antibody response, it only weakly impacts new strains of a virus for which no antibodies exist. The body's secondary response is much more specific but takes time to evolve. The body selects from a large repertoire of antibodies and other intricate processes such as affinity-maturation. The body selects an antibody and process(es) to increase its ability to recognize and destroy the pathogen.

The pathology of COVID-19 normally demonstrates a period of improvement followed by steep deterioration. The latter is caused by an overactive immune system where efficient antibodies increase inflammation. An overactive immune system can overload the inflammatory stimuli, leading the body to release too many signaling molecules called cytokines. In some cases this leads to “cytokine storm”, a condition that is characterized by a cacophony of signals. This immune reaction causes accumulation of fluid in the lungs. Since the virus affects both the lower and upper respiratory tracts, breathing becomes restricted. This immune reaction is often the cause of death in the majority of cases. Certain drugs that limit inflammation are being 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%.

Second, the diagnostic kits from the CDC in the early weeks of the spread of the virus in the US failed to detect COVID19 in infected patients. There are many faulty kits available that use molecular diagnostics, amplified nucleic acid biomarkers. In order to achieve good results, these systems employ virtually unlimited replication. In addition, the amplified signal is very prone to false positives. The way manufacturers have overcome this limitation in the past is by targeting multiple sequences from the viral genome. In the future, molecular diagnostics could be used to keep up with changes in the sequence of viral strains but will continue to lack accurate sensitivity. The shortage in test kits caused a young woman from New Orleans to die while waiting for the results of her COVID19 test which were expected the following Monday. [11]

References

  1. Lowrey, Annie. “This Is Not a Recession. It's an Ice Age.” The Atlantic, Atlantic Media Company, 1 Apr. 2020, www.theatlantic.com/ideas/archive/2020/03/quantifying-coming-recession/608443/. 
  2. “1918 Influenza: the Mother of All Pandemics - Volume 12, Number 1-January 2006 - Emerging Infectious Diseases Journal - CDC.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, wwwnc.cdc.gov/eid/article/12/1/05-0979_article.
  3. 161385360554578. “Shortage Means Virus Docs in Italy Have No More Ventilators for over-60s.” The US Sun, The US Sun, 23 Mar. 2020, www.the-sun.com/news/576232/doctors-in-coronavirus-ravaged-italy-can-no-longer-give-ventilators-to-over-60s-because-of-chronic-shortage/. 
  4. Kaplan, Talia. “Johnson & Johnson CEO on Potential Coronavirus Vaccine: 'I Think We'll Have Important Data by the End of the Year'.” Fox News, FOX News Network, 22 Mar. 2020, www.foxnews.com/media/johnson-johnson-ceo-coronavirus-vaccine-data. 
  5. O'Kane, Caitlin. “Florida College Students Test Positive for Coronavirus after Going on Spring Break.” CBS News, CBS Interactive, 25 Mar. 2020, www.cbsnews.com/news/coronavirus-florida-spring-break-test-positive-covid-19-college-students-not-social-distancing-university-of-tampa/. 
  6. Kaplan, Talia. “Miami-Dade Mayor 'Very Disappointed' to See People Partying on Boats amid Coronavirus Shutdown.” Fox News, FOX News Network, 24 Mar. 2020, www.foxnews.com/media/miami-dade-county-closes-boat-ramps-marinas-after-photos-show-packed-sandbar. 
  7. Blitzer, Ronn. “DOJ Responds to Uproar over Request for 'Emergency Powers' during Coronavirus.” Fox News, FOX News Network, 23 Mar. 2020, www.foxnews.com/politics/doj-responds-to-uproar-over-emergency-powers-report.
  8. Elving, Ron. “Trump Tries On The Mantle Of 'Wartime President'.” NPR, NPR, 22 Mar. 2020, www.npr.org/2020/03/22/819672681/trump-tries-on-the-mantle-of-wartime-president. 
  9. Re, Gregg. “Navarro Says Mobilization 'Just like in World War II' in Progress as Coronavirus Spreads.” Fox News, FOX News Network, 22 Mar. 2020, www.foxnews.com/politics/navarro-coronavirus-mobilization-world-war-ii-jobless-claims. 
  10. Haltiwanger, John. “ISIS Is Urging Its Fighters to Avoid Europe Because of the Coronavirus Pandemic.” Business Insider, Business Insider, 17 Mar. 2020, www.businessinsider.com/coronavirus-isis-issues-travel-advisory-for-europe-to-its-fighters-2020-3.
  11. Farber, Madeline. “Woman with Suspected Coronavirus Symptoms Dies While Waiting for Test Results, Boyfriend Claims.” Fox News, FOX News Network, 5 Oct. 2020, www.foxnews.com/health/possibly-coronavirus-infected-new-orleans-woman-dies-waiting-test-results.