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Monday, October 18, 2021
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Why didn’t historical plagues like Polio and Smallpox mutate into different strains like COVID-19?

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Article and Visuals by: ZOTHANZUALA HMAR, The North-Eastern Chronicle

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As the well known Covid-19 virus grabbed the whole world, we are facing a whole new level of reality. Coronavirus is a category of viruses that are known to impinge on the respiratory tract of living beings.

The virus can multiply rapidly as it is spreading from person to person. The first case of novel coronavirus (COVID-19) was reported in Wuhan, China on December 1, 2019, and since then its outbreak has been confirmed in different parts of the world.

“COVID has not mutated into multiple strains”

COVID

First of all, COVID has not mutated into multiple strains. There are multiple variants, all of which are controlled well by the vaccines.

So instead of asking why smallpox, measles, mumps, polio, yellow fever, rubella, HIV and a thousand other viruses don’t form new strains, the question is, Why is influenza unique? Because nothing else acts like that.

Where flu is unique, or at least very unusual, is in its ability to tolerate mutations. 

When a virus like measles mutates, it’s likely to end up in a defective state. Influenza is amazingly tolerant of mutations in its surface proteins (hemagglutinin especially, but also neuraminidase).

It’s those surface proteins that antibodies recognize, so it works out that flu is able to avoid antibody recognition without suffering serious consequences otherwise. Because its immune-evading mutations don’t cripple it badly, so it’s possible for it to circulate continuously and keep moving along an evolutionary path that allows it to avoid population immunity – forming new strains.

COVID hasn’t formed new strains yet, but we’re only a year and a half in, and most flu strains take several years to fully arise. So it’s possible that we will see new strains of COVID at some point.

Studies on human endemic coronaviruses suggest that these viruses can form new antigenic drift variants, which might be called “strains”, though more slowly than influenza.

There’s a general expectation among virologists and vaccinologists that COVID vaccines will need a booster at some point in the future – another year? Two years? Five? To deal with antigenic drift and with immune waning (though the vaccines seem to have pretty durable immunity). 

Part of the problem is that the slow and incomplete rollout of global vaccination allows an enormous SARS-CoV-2 population, meaning that more variants spontaneously arise. The best way to limit the number of variants and therefore antigenic drift is widespread global vaccination.

What’s the difference between a “variant” and a “strain”?

A variant is when you see distinct mutations, but a strain has physical differences. i.e the delta variant has a mutation in the S protein, but this does not produce a conformational change to the antigen or the virus itself.

A new strain that has multiple conformational changes will then become a new species.

Small Pox and Flu

“One of the medical profession’s greatest boasts is that it eradicated smallpox through the use of the smallpox vaccine. I myself believed this claim for many years. But it simply isn’t true!” ― Dr. Vernon Coleman

Smallpox has no non-human hosts and it exclusively infects humans and has no other reservoirs. That is why eradication was possible – if you immunize every (almost) human on the planet, there’s nowhere else for it to go.

All viruses mutate but some mutate faster or slower than others. That’s determined by each virus’ specific DNA/RNA machinery and how faithful it is. If it is error-prone, then mutations accrue quicker. 

Flu is very different. Flu has many non-human hosts and can hang out in those hosts. Moreover, it can “mix and match” its genetic material with other flu types when infecting the same host and emerge with a new super strain that no one has protection against. That’s incredibly dangerous and causes flu epidemics.

But the bottom line answer to our question is how faithful each virus’ DNA/RNA replication machinery is.

Polio

Polio did evolve three strains. Two were eradicated, and one is still circulating (or vice versa).

We also now have the vaccine derived strain. The difference is that emergent viruses have more potential to mutate since there is a wealth of hosts to infect.

Polio on the other hand emerged in the 1700’s and so most of the variants died out.

Influenza

Influenza 1 COVID The North-Eastern Chronicle

Seasonal influenza is a recurrent threat to human health, largely because it rapidly accumulates amino-acid mutations in proteins targeted by the immune system.

Measuring the functional impact of every possible amino-acid mutation to influenza can therefore provide useful information about which evolutionary paths are accessible to the virus. Such measurements are now possible using deep mutational scanning.

When applied to influenza, this technique involves creating all codon mutants of a viral gene, incorporating these mutant genes into viruses that are subjected to a functional selection, and estimating the functional impact of each mutation by using deep sequencing to quantify its frequency pre- and post-selection. 

Scientists have used deep mutational scanning to estimate the effects of all amino-acid or nucleotide mutations to several influenza genes, and Heaton and coworkers have used a similar approach to examine influenza’s tolerance to short insertions.

However, these studies suffered from substantial noise that degrades the utility of their results. For instance, in every study that reported the results for independent experimental replicates, the replicate-to-replicate correlation was mediocre.

This experimental noise arises primarily from bottlenecking of mutant diversity during the generation of viruses from plasmids. 

The influenza genome consists of eight negative-sense RNA segments. During viral infection, gene expression from these segments is a highly regulated process.

Influenza viral cycle 1 COVID The North-Eastern Chronicle

Generating influenza from plasmids involves co-transfecting mammalian cells with multiple plasmids that must yield all eight viral gene segments and at least four viral proteins at a stoichiometry that leads to assembly of infectious virions. This plasmid-driven process is understandably less efficient than viral infection.

A small fraction of transfected cells probably yield most initial viruses, which are then amplified by secondary infection. This bottlenecking severely hampers experiments that require creating a diverse library of viruses from an initial library of plasmids. 

Several strategies have been used to overcome problems associated with bottlenecks during the generation of influenza from plasmids. One strategy is to generate and titer each viral variant individually, and then mix them.

A second strategy is to reduce the impact of bottlenecks by shrinking the complexity of the libraries, such as by only mutating a small portion of a viral gene. Neither of these strategies scale effectively to the deep mutational scanning of full-length proteins, since there are ∼104 unique amino-acid mutants of a 500-residue protein.

To overcome these limitations, experts have developed a novel approach that uses a “helper virus” to generate virus libraries without strong bottlenecking.

They have combined this approach with other technical improvements to perform deep mutational scanning of all amino-acid mutations to an H1 hemagglutinin (HA) with much higher accuracy and reproducibility than existing deep mutational scans of influenza genes. 

Scientists use phylogenetic analyses to show that their measurements accurately reflect constraints on HA evolution in nature. They confirm that antigenic sites in the globular head of HA are highly tolerant of mutations, and identify other regions of the protein that are more constrained. These advances improve our understanding of HA’s inherent evolutionary capacity and can help inform evolutionary modeling and guide the development of vaccines targeting sites with a limited capacity for mutational escape.

Influenza genes evolve mostly via point mutations, and so knowing the effect of every amino-acid mutation provides information about evolutionary paths available to the virus. 

Researchers have combined high-throughput mutagenesis with deep sequencing to estimate the effects of large numbers of mutations to influenza genes.

However, these measurements have suffered from substantial experimental noise due to a variety of technical problems, the most prominent of which is bottlenecking during the generation of mutant viruses from plasmids. 

Here we describe advances that ameliorate these problems, enabling us to measure with greatly improved accuracy and reproducibility the effects of all amino-acid mutations to an H1 influenza hemagglutinin on viral replication in cell culture.

The largest improvements come from using a helper virus to reduce bottlenecks when generating viruses from plasmids. Our measurements confirm at much higher resolution the results of previous studies suggesting that antigenic sites on the globular head of hemagglutinin are highly tolerant of mutations. 

We also show that other regions of hemagglutinin—including the stalk epitopes targeted by broadly neutralizing antibodies—have a much lower inherent capacity to tolerate point mutations.

The ability to accurately measure the effects of all influenza mutations should enhance efforts to understand and predict viral evolution.

Deadly Lambda variant could be neutralizing vaccines

As the US struggles to suppress the rapidly advancing coronavirus Delta variant, new evidence has emerged that the latest Lambda mutation — ravaging parts of South America — won’t be slowed by vaccines. This particular deadly neutralization of the vaccine issue was written in the New York Post.

In a July 28 report appearing on bioRxiv, where the study awaits peer review prior to getting published, researchers in Japan are sounding the alarm on the C.37 variant, dubbed Lambda. And it’s proven just as virulent as Delta thanks to a similar mutation making them even more contagious.

The strain has been contained in 26 countries, including substantial outbreaks in Chile, Peru, Argentina and Ecuador.

“Notably, the vaccination rate in Chile is relatively high; the percentage of the people who received at least one dose of COVID-19 vaccine was about 60%,” “Nevertheless, a big COVID-19 surge has occurred in Chile in Spring 2021, suggesting that the Lambda variant is proficient in escaping from the antiviral immunity elicited by vaccination,”

The Lambda variant is thought to have emerged somewhere in South America between November and December 2020, and has since turned up in countries throughout Europe, North America and a few more isolated cases in Asia, according to GISAID data.

Lambda has so far been labeled a “variant of interest” by the World Health Organization, compared to the Alpha, Beta, Gamma and Delta strains, which have all risen to “variant of concern,” or VOC, status.

The US Centers for Disease Control and Prevention has published scant literature on the Lambda variant, though a COVID-19 vaccine briefing from July 27 cited another pre-print study, dated July 3, which concluded that the mRNA vaccine in particular is thought to effectively neutralize the Lambda variant.

In Chile, where C.37 is proliferating, their notably aggressive vaccine campaign relied predominantly on the Sinovac Biotech vaccine, which employs the inactivated virus to promote the production of COVID-19 antibodies.

Meanwhile, doctors are urging patients to get fully vaccinated in order to mitigate the severity of illness if infected with COVID-19 and its variants.

Studies have shown that vaccines are effective at reducing deadly outcomes of COVID-19 — and a booster shot may be even better, prompting the Food and Drug Administration to consider providing third vaccine doses to people with compromised immune systems.

In a recent appearance on NBC’s “Meet the Press,” White House chief medical adviser Dr. Anthony Fauci concluded, “There’s no doubt that over time, you’re going to have an attenuation of protection.”

Also Read: Decoding the Covid-19 pandemic! Is it the virus or is it us?

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