Abstract

Observational data from multiple population studies demonstrates a linear decline in Case Fatality Rate with increasing transmission of Covid-19 infection. This was also inferred by a similar analysis by Profs Martin Neil and Norman Fenton in their analysis of excess deaths, which declined in countries with more Covid cases circulating (R^2  = 0.3515, p 0.0002) (1).

Solomon et al (2) demonstrated in an observational study of over 3 million adults that had contact and exposure to children were 33% less likely to require hospitalization from Covid and were 57% less likely to enter an Intensive Care Unit for treatment.

With SARS-CoV-2 infection cellular and viral RNAs are subjected to chemical modifications that increase nucleotide diversity from the four canonical bases to over 150 different bases and nucleotides (3). Nucleotide modification is critical to viral RNA functionality, regulating stability, cellular localization, translational control and immune escape. This paper examines how the epitranscriptomic landscape within infected cells might influence viral RNA through post-transcriptional modifications and how these alterations within the progeny contribute to an accelerated reduction in virulence and community protection from more serious infection and evidence for long-lasting transgenerational anti-viral immunity.

Given seasonal infections are endemic in urbanized human societies, it is hypothesized post-transcriptional modifications of viral RNA was critical to human-viral co-adaptation or co-evolution. Parallel feedback process by which agents continuously adapt to the changes induced by the adaptive actions of other agents, is a ubiquitous feature of complex adaptive systems, from eco-systems to economies.

This paper explores new concepts in adaptive immunity in human populations through epigenetic or post-transcriptional viral RNA modifications that have profound implications for the management of future pandemics.

Background

Human co-evolution and co-adaptation refer to the ways in which humans and other organisms have evolved together over time, with each influencing the other’s evolution.

One of the most well-known examples of human co-evolution is the relationship between humans and domesticated animals. Domesticated animals, such as dogs, cats, and cows, have co-evolved with humans over thousands of years, adapting to live in close proximity to humans and to provide resources such as food and labor. In turn, humans have also adapted to living with domesticated animals, developing immune systems that can tolerate exposure to animal pathogens and learning to utilize animal resources.

Another example of human co-evolution is the relationship between humans and infectious diseases. Over time, humans have co-adapted to the pathogens that infect them, developing immune responses that are able to recognize and fight off these diseases. In turn, the pathogens have co-evolved with humans, developing strategies to evade the immune system and persist in the human population.

Human co-evolution and co-adaptation also extend to the relationship between humans and the natural environment. Humans have co-evolved with plants and animals, learning to cultivate crops and domesticate animals for food and other resources. Humans have also adapted to different environments, developing physical and cultural adaptations to survive in diverse climates and ecosystems.

In addition to these examples, there are many other ways in which humans have co-evolved and co-adapted with other organisms and the natural environment. Understanding these relationships can provide insights into human evolution and the evolution of other organisms, as well as inform strategies for mitigating population risk from epidemics and seasonal infections. Overall, human co-evolution and co-adaptation demonstrate the interdependence of humans and other organisms, highlighting the importance of considering the broader ecological context in understanding human biology and behavior.

The emergence and ongoing spread of SARS-CoV-2 represents a new chapter in the ongoing co-evolution and co-adaptation between humans and viruses. One aspect of this co-evolution is the way in which the virus has adapted to humans as its primary host. SARS-CoV-2 is a zoonotic virus, meaning it likely originated in animals before being transmitted to humans. However, the virus has since adapted to be highly transmissible between humans, with human-to-human transmission now the primary mode of spread. This adaptation has been facilitated by the virus’s ability to spread through respiratory droplets, which can be generated through talking, coughing, and sneezing.

At the same time, humans have been adapting to SARS-CoV-2, developing immune responses that can recognize and fight off the virus. This co-adaptation has been facilitated by the fact that SARS-CoV-2 is a single-stranded RNA virus, which makes it more prone to mutations compared to DNA viruses. This mutability has enabled the virus to evolve rapidly, but it has also created opportunities for the human immune system to recognize and target the virus.

Another aspect of the co-evolution and co-adaptation between humans and SARS-CoV-2 is the way in which the virus has impacted human behavior and society. The pandemic has led to widespread changes in how people live and work, with many individuals adapting to remote work and social distancing measures. These changes have had both positive and negative impacts on human health and well-being, and they have highlighted the importance of considering the social and behavioral aspects of the pandemic alongside the biological aspects.

Overall, the ongoing co-evolution and co-adaptation between humans and SARS-CoV-2 highlights the complex and dynamic relationship between humans and viruses. Understanding this relationship is critical for developing effective strategies to control the pandemic and mitigate its impacts on human health and well-being.

Post-transcriptional modification of viral RNA is a critical step in the viral life cycle, as it affects many aspects of RNA function, including stability, transport, translation, and replication. In general, these modifications can be divided into two categories: (1) modifications that occur co-transcriptionally, or during the process of RNA synthesis, and (2) modifications that occur after transcription, or post-transcriptionally.

One important co-transcriptional modification of viral RNA is the addition of a 5′ cap structure to the RNA molecule. This cap consists of a methylated guanine nucleotide that is added to the 5′ end of the RNA molecule, and it plays an important role in RNA stability and translation. The cap structure also facilitates the binding of the RNA molecule to the ribosome, which is the cellular machinery responsible for protein synthesis. It also allows Covid-19 to evade immune detection in humans.

Another important co-transcriptional modification of viral RNA is the addition of a poly (A) tail to the 3′ end of the RNA molecule. This tail consists of a string of adenine nucleotides that is added to the 3′ end of the RNA molecule, and it also plays a critical role in RNA stability and translation. The poly (A) tail helps to protect the RNA molecule from degradation, and it also facilitates the binding of the RNA molecule to the ribosome.

In addition to these co-transcriptional modifications, there are also many post-transcriptional modifications that occur to viral RNA. One common modification is RNA splicing, which involves the removal of introns, or non-coding regions, from the RNA molecule. This process is catalyzed by a complex of proteins and RNA molecules known as the spliceosome, and it plays an important role in regulating gene expression.

Another important post-transcriptional modification of viral RNA is RNA editing, which involves the chemical modification of individual nucleotides within the RNA molecule. This process is catalyzed by enzymes known as RNA editing enzymes, and it can result in changes to the amino acid sequence of the viral protein. RNA editing is particularly important in RNA viruses, which have high mutation rates and may require this process to generate functional proteins.

Overall, post-transcriptional modification of viral RNA is a complex and highly regulated process that plays a critical role in the viral life cycle. By modifying the RNA molecule in various ways, viruses are able to control many aspects of RNA function, including stability, transport, translation, and replication. Understanding these modifications and their mechanisms is therefore essential for combating viral infections and developing effective antiviral therapies.

Summary of known Post-Transcriptional Viral RNA Modifications

Post-transcriptional RNA modifications are known to play an important role in the virulence of viruses. There are several examples of post-transcriptional modifications that occur in viral RNA:

1. RNA splicing: RNA splicing is a process that removes non-coding regions (introns) from pre-mRNA molecules and joins the coding regions (exons) together to create mature mRNA molecules. Some viruses, such as the human immunodeficiency virus (HIV), use alternative splicing to generate different forms of their viral proteins. This allows the virus to produce multiple proteins from a single gene (4).
2. RNA editing: RNA editing involves the chemical modification of individual nucleotides within the RNA molecule. This process is catalyzed by enzymes known as RNA editing enzymes, and it can result in changes to the amino acid sequence of the viral protein. RNA editing is particularly important in RNA viruses, which have high mutation rates and may require this process to generate functional proteins. For example, the hepatitis delta virus (HDV) uses RNA editing to generate a functional form of its delta antigen protein.
   C-to-U mutations have been observed in SARS-CoV-2, the virus that causes COVID-19. These mutations involve the conversion of cytosine (C) to uracil (U) at specific sites in the viral RNA genome. 
   RNA editing is a process that can introduce genetic diversity without altering the DNA sequence. In the case of SARS-CoV-2, RNA editing can lead to changes in the viral proteins that are produced, potentially altering viral replication, infectivity, and pathogenesis.
   One notable example of RNA editing in SARS-CoV-2 is the editing of a specific site in the viral RNA encoding the spike protein, which is the target of many vaccines and therapeutics. This editing leads to a change in the amino acid sequence of the spike protein, potentially altering its structure and function.
3. m6A modification: The addition of a methyl group to adenosine at the 6th position (m6A modification) is a common post-transcriptional modification of RNA. Some viruses, such as the Zika virus, have been shown to have a bias towards m6A modification of specific regions of their RNA genomes, which may affect viral replication and pathogenesis (5). 
   m6A is a common modification of RNA that involves the addition of a methyl group to the adenosine nucleotide at the 6th position. This modification is catalyzed by a complex of proteins known as the m6A writer complex and is recognized by various m6A reader proteins, which can influence RNA processing and function. The distribution of m6A modifications in RNA is not random, and there are certain patterns and biases that are observed both in viral and cellular RNA.
   One important pattern of m6A modification is the presence of m6A clusters, which are regions of RNA that contain multiple m6A modifications in close proximity to one another. These clusters are particularly common in the 3′ untranslated regions (UTRs) of mRNA and are thought to play a role in regulating mRNA stability and translation. In viral RNA, m6A clusters have been observed in the genomes of various RNA viruses, including coronaviruses, influenza viruses, and retroviruses. 
   Another important pattern of m6A modification is the presence of DRACH motifs, which are short RNA sequences that are recognized by the m6A writer complex. These motifs consist of a conserved core sequence of “DRACH”, where D represents any nucleotide except for C and H represents any nucleotide except for A, C, or U. The presence of DRACH motifs in RNA is strongly correlated with m6A modification, and this motif bias is thought to reflect the specificity of the m6A writer complex.
   Interestingly, there are differences in the m6A pattern changes and DRACH motif biases observed between viral and cellular RNA. For example, in some cases, viral RNA has been observed to have higher levels of m6A modification compared to cellular RNA. Additionally, some viruses appear to have a bias towards m6A modification of certain RNA regions, such as the 5′ UTR or specific coding regions. These differences may reflect adaptations that the virus has made to optimize its replication and evade host immune responses.
   In summary, m6A modification is an important aspect of RNA biology that plays a role in regulating RNA function and processing. The distribution of m6A modifications in RNA is not random, and there are certain patterns and biases that are observed both in viral and cellular RNA. Understanding these patterns and biases is important for understanding viral replication strategies.
4. RNA methylation: RNA methylation involves the addition of a methyl group to the nitrogen or oxygen atoms of specific nucleotides in RNA molecules. This modification is catalyzed by RNA methyltransferases and can affect RNA stability, translation, and processing. RNA methylation has been observed in a variety of viruses, including hepatitis C virus, Zika virus, and influenza virus. For example, the influenza virus polymerase complex contains an RNA methyltransferase that is required for viral replication.
5. Pseudouridylation: Pseudouridylation is a modification that involves the isomerization of uridine to pseudouridine. This modification is catalyzed by pseudouridine synthase enzymes and can affect RNA stability and function. Pseudouridylation has been observed in both cellular and viral RNA. For example, the HIV genome contains pseudouridine residues that are thought to affect the stability of the viral RNA (6). 
6. Non-templated nucleotide additions: Non-templated nucleotide additions involve the addition of nucleotides to RNA molecules in a template-independent manner. This can occur through a variety of mechanisms, including terminal nucleotide addition, internal nucleotide addition, and stuttering. Non-templated nucleotide additions have been observed in a variety of viruses, including retroviruses, coronaviruses, and filoviruses. For example, the Ebola virus genome contains a number of non-templated adenine additions, which are thought to play a role in viral replication (7).
7. APOBEC (Apolipoprotein B mRNA Editing Catalytic Polypeptide) proteins are a family of cytidine deaminases that play a role in the innate immune response against viruses. These proteins can edit viral RNA, leading to mutations and potentially inactivating the virus. However, recent studies have also shown that APOBEC proteins can lead to epigenetic changes in host cells that may impact the host response to viral infection, including COVID-19 (8).
   Research has shown that APOBEC3G, a member of the APOBEC family, can induce hypermutation in the SARS-CoV-2 genome, leading to potentially non-functional viral particles. However, APOBEC proteins have also been shown to impact the epigenetic landscape of host cells. A recent study found that APOBEC3B, another member of the APOBEC family, can induce epigenetic changes in lung epithelial cells that can impact the host response to SARS-CoV-2 infection. Specifically, the study found that APOBEC3B can induce DNA methylation changes in genes that are involved in the host immune response, including interferon-stimulated genes (ISGs) and cytokines (9).
   These changes can potentially lead to a dampened immune response to viral infection. The study also found that APOBEC3B can induce histone modifications that may further impact the regulation of genes involved in the immune response.The study suggests that APOBEC3B may play a role in the host response to COVID-19 and could be a potential therapeutic target.
   In summary, while APOBEC proteins are known for their role in viral RNA editing and hypermutation, recent studies have shown that they may also impact the epigenetic landscape of host cells. APOBEC-induced epigenetic changes may play a role in the host response to viral infection, including COVID-19, and may be a potential therapeutic target. Further research is needed to fully understand the mechanisms underlying APOBEC-induced epigenetic changes and their impact on viral infection.  
8. Recent studies have shown that SARS-CoV-2 has a deficiency in CpG dinucleotides, which are recognized by host antiviral defense mechanisms. CpG dinucleotides are recognized by toll-like receptor 9 (TLR9) and stimulate the production of type I interferons (IFNs), which are important in the antiviral response. However, SARS-CoV-2 has a low CpG content, which may allow it to evade recognition by TLR9 and escape the host antiviral response. 
   Studies have shown that SARS-CoV-2 has a CpG deficiency compared to other coronaviruses, such as SARS-CoV and MERS-CoV. This deficiency may be due to the RNA editing activity of the host cytidine deaminases, which can target CpG sites and lead to a decrease in CpG content (10). 
   The CpG deficiency in SARS-CoV-2 may have important implications for the pathogenesis of COVID-19. It may allow the virus to evade recognition by TLR9 and escape the host antiviral response, leading to increased viral replication and potentially more severe disease. Additionally, the CpG deficiency may impact the development of vaccines and therapeutics, as CpG motifs are often used as adjuvants to enhance the immune response.

While some studies suggest that epigenetic modifications may contribute to the virulence of SARS-CoV-2, other studies have suggested that certain epigenetic modifications may have a protective effect in reducing the severity of COVID-19.

For example, one study found that individuals with a history of Bacillus Calmette-Guérin (BCG) vaccination, which is known to induce epigenetic modifications in immune cells, had a lower risk of severe COVID-19. The researchers suggested that the BCG vaccination-induced epigenetic modifications may have enhanced the innate immune response and provided protection against severe disease (12).

Another study found that individuals with higher levels of vitamin D, which can also induce epigenetic modifications, had a lower risk of severe COVID-19. The researchers suggested that the protective effect of vitamin D may be due in part to its ability to regulate the expression of genes related to the immune response.

Overall, while the role of epigenetics in SARS-CoV-2 virulence is still being studied, there is evidence to suggest that certain epigenetic modifications may have a protective effect in reducing the severity of COVID-19.

Post-transcriptional viral RNA modifications can have a significant impact on the viral progeny, affecting various aspects of viral replication, pathogenesis, and evolution.

One effect of RNA modifications on viral progeny is on RNA stability. For example, methylation and pseudouridylation can increase the stability of viral RNA, allowing for increased viral replication and progeny production. On the other hand, editing and nucleotide addition modifications may destabilize viral RNA, leading to reduced viral replication and progeny production.

RNA modifications can also affect viral protein expression and virulence. For example, m6A modifications have been shown to regulate viral protein translation and increase viral replication, while editing modifications can alter the sequence of viral proteins, potentially affecting their function and virulence.

Additionally, RNA modifications can influence viral evolution by affecting the mutation rate and spectrum. For instance, RNA editing and nucleotide addition modifications can introduce novel mutations into the viral genome, potentially increasing the variability of the viral population and driving viral evolution.

Overall, post-transcriptional viral RNA modifications can have a significant impact on various aspects of viral replication, pathogenesis, and evolution, ultimately affecting the production and characteristics of viral progeny. Understanding the mechanisms underlying RNA modifications in viral infections may provide new understanding in controlling viral infections.

A study published in Nature Communications in March 2021 analyzed the frequency and diversity of post-transcriptional modifications in the SARS-CoV-2 RNA genome isolated from clinical samples collected from patients in the early months of the pandemic. The study found that the SARS-CoV-2 genome contains a diverse array of RNA modifications that may play a role in viral replication, transmission, and pathogenesis.

Another study published in the journal Cell in August 2020 investigated the dynamic changes in SARS-CoV-2 RNA modifications during viral replication in Vero E6 cells, a cell line commonly used in laboratory studies (13). The study found that SARS-CoV-2 RNA undergoes extensive modifications during replication, with different modifications appearing at different stages of the replication cycle.

A preprint study published on bioRxiv in November 2020 characterized the post-transcriptional modifications of the SARS-CoV-2 genome in clinical samples collected from patients with COVID-19 in the United States. The study found that the SARS-CoV-2 genome undergoes extensive RNA modifications, including methylation and pseudouridylation, that may affect viral replication and pathogenesis.

It’s critical therefore to examine the impact of post-translational viral RNA modifications on the spread of Covid cases, on Covid mortality and on the consequent Case Fatality Rate. How do post-transcriptional RNA modifications could affect the replication and pathogenicity of the SARS-CoV-2 virus in the real world?

Method

This is an observational study using data ‘Our World in Data’ website with aim of understanding how virulence of the SARS-CoV-2 virus changed during the course of the pandemic. It is hypothesised that post-translational RNA modifications during Covid-19 infections has a mitigating effect on virulence and mortality within the community from SARS-CoV-2 infection.

The statistical analysis was performed using SPSS correlation analysis on 45 countries across the globe comprising a total population of almost 1.9 billion   using statistical methods to identify any associations between cumulative case numbers, Covid-19 mortality and Case Fatality Rate in April and July 2022.

When recording COVID cases and mortality from observational data, there are several biases that should be acknowledged. Some of these biases include:

1. Sampling bias: The sample of COVID cases and mortality may not be representative of the entire population, leading to biased estimates of disease incidence and mortality rates.
2. Ascertainment bias: There may be differences in how cases and deaths are ascertained across regions or time periods, leading to differences in reported rates.
3. Selection bias: The selection of individuals for COVID testing or treatment may be biased, leading to over- or underestimation of the true disease burden.
4. Reporting bias: There may be differences in how cases and deaths are reported across regions or time periods, leading to differences in reported rates.
5. Confounding bias: There may be confounding factors, such as age, gender, comorbidities, or socio-economic status, that are associated with both COVID incidence and mortality, leading to biased estimates of disease burden.
6. Time lag bias: There may be delays in reporting of COVID cases and mortality, leading to underestimation of the true disease burden.

It is important to acknowledge these biases when interpreting COVID observational data and to take steps to minimize their impact on the analysis. These steps may include adjusting for confounding factors, using multiple data sources to improve representativeness, and accounting for reporting delays.

Consequently an equivalent analysis was also performed on CDC data collected across 40 of the most populous states in the USA at the end of May 2021 and 28 European Countries at July 2021 using the same methodology for comparison. 

Results

The graph below (Fig. 1) displays Covid mortality per million population on the y-axis against Covid cases per million on the x-axis as reported at the end of July 2022 from Our World in Data for 45 countries examined. As can be seen countries recording high rates of Covid infection do not seem to experience any greater Covid mortality than countries with low rates of Covid infection.

This lends compelling support to the idea that community exposure and natural (adaptive) immunity has a substantial role to play in protection during a pandemic. The strength of the correlation is highly significant (R^2 0.368, p<0.001). The data suggests that community exposure lead to an almost 40% reduction in the virulence of the virus during the course of the pandemic. As infection spread within communities the virulence of the virus diminishes dramatically, as demonstrated in the next graph recording Case Fatality Rate (CFR) against Covid cases (Fig. 2).

Deaths from increasing numbers of Covid cases are offset by a near-linear reduction in Covid virulence. The findings from April 2022 are almost identical;

Furthermore this seems to be a consistent finding across different population groups and across different periods during the pandemic.

The following graphs reflect the same at the 40 most populous States in the USA from May 2021 and demonstrate an almost identical phenomenon.

States that experienced higher rates of Covid infection demonstrated no increase in Covid mortality because there was again a near-linear fall in the CFR as cases increased in number.

Further supportive evidence for this comes from a study by Solomon et al. at Stanford University, of over 3 million adults either living in close contact with children with those without contact with children. Adults living without children had 15% less Covid infection by comparison, yet their rates of hospitalization was almost 50% higher and their risk of admission to ICU was increased by 75%. 

Similar findings have demonstrated that teachers are protected from severe infection by exposure in the classroom (14).

In large human societies with increased population density these adaptive processes confer significant survival benefit both to the individual and to the population as a whole. Given children have low susceptibility to severe Covid infection it would be of enormous societal benefit to have kept the schools open during the Pandemic, thereby promoting transmission and accelerated LOF before the virus entered the more vulnerable elderly population.

There is good evidence that adaptive immunity played and continues to play a significant, if not vital role in mitigating the worse effects of Covid-19. The near-linear reduction in CFR seen during community transmission is most convincingly explained by a co-adaptive response between the virus and human. Such a supposition has strong support from other publications and such phenomena are known to be ubiquitous in nature. 

If we accept co-adaptation as the best explanation for the LOF of Covid-19 during the Pandemic, then indeed adaptive immunity was reliably protective both for the individual and the community. Post-translational viral RNA modifications not only have the potential to protect the individual against infection, but also these modifications carried in the progeny potentially reduce downstream virulence and may mitigate mortality risk.

Some support for this view is also offered by an analysis performed by Profs Martin Neil and Norman Fenton, using a similar global analysis from Our World in Data. They looked at excess mortality in percentage terms in weeks 1-44 2022 against infection rates in the preceding year and found a significant reduction in excess mortality in countries experiencing higher rates of infection. 

Discussion

The post-transcriptional modification of viral RNA plays a crucial role in co-adaptive evolution in COVID-19 infection and the pandemic.

Co-adaptive mechanisms refer to the interdependent and dynamic relationship between a pathogen and its host, in which both entities evolve and adapt to each other over time. In the case of SARS-CoV-2, the virus has undergone several mutations and adaptations to be better suited to infect and replicate within the human host, leading to more severe disease outcomes in some individuals.

Understanding the co-adaptive mechanisms between SARS-CoV-2 and humans can help inform better mitigation measures in future pandemics in several ways:

1. Early Detection and Rapid Response: By closely monitoring the evolution of the virus and its interaction with the human host, public health officials can quickly identify emerging threats and develop effective mitigation strategies before the disease spreads widely.
2. Personalized Medicine: As we gain a better understanding of the co-adaptive mechanisms between pathogens and their human hosts, we may be able to develop more effective treatments that are tailored to an individual’s genetic makeup, immune response, and other factors that influence disease outcomes.
3. Vaccine Development: By understanding the co-adaptive mechanisms between SARS-CoV-2 and humans, we can develop vaccines that target specific regions of the virus that are critical for its interaction with the human host. This could lead to the development of more effective vaccines that provide long-lasting immunity against future pandemics.
4. Behavioral Interventions: Understanding the co-adaptive mechanisms between SARS-CoV-2 and humans can also inform more effective behavioral interventions, such as social distancing, mask-wearing, and hand hygiene, that can help mitigate the spread of infectious diseases.

A better understanding of the co-adaptive mechanisms between SARS-CoV-2 and humans is crucial for developing effective mitigation measures in future pandemics. By closely monitoring the evolution of the virus and its interaction with the human host, we can develop personalized treatments, vaccines, and behavioral interventions that are tailored to specific populations, and ultimately reduce the impact of future pandemics on public health.

The co-adaptive evolution of SARS-CoV-2 and humans is a dynamic process in which the virus evolves to better infect and replicate within the host, while the host evolves to mount an effective immune response against the virus. Post-transcriptional modifications of viral RNA play a crucial role in this process by allowing the virus to adapt to the host environment and vice versa, leading to long-lasting transgenerational immunity.

Understanding the role of post-transcriptional modifications of viral RNA in co-adaptive evolution can inform the development of new therapeutic approaches for COVID-19. For example, targeting specific RNA modifications, such as m6A, could be a potential strategy for developing new antiviral drugs that disrupt viral replication and transmission.

In conclusion, post-transcriptional modifications of viral RNA play a critical role in co-adaptive evolution in COVID-19 infection and the pandemic. By understanding how these modifications contribute to viral replication and virulence, host immune evasion, and viral transmission, we can develop new therapeutic approaches that target specific RNA modifications and improve outcomes for individuals with COVID-19.

There is compelling observational evidence that during the course of the pandemic co-adaptive mechanisms may have had a substantial impact on the virulence of the organism and a mitigating effect on Covid mortality. In particular older adults received robust immune-protection from contact with children and post-translational modification of the viral progeny RNA provides a plausible explanation for this phenomenon.

Whilst Covid mortality rates rose early in 2020 case fatality rates fell significantly during the course of the pandemic and this may well have been facilitated by the co-adaptive mechanisms described. Notably early modelling used to direct public health responses substantially overestimated health risks posed by Covid in part because they relied on old paradigms to describe transmission dynamics. Amongst other things, they failed to account for the role of co-adaptive mechanisms on virulence of the organism.

A better understanding of post-translational RNA modification could provide substantial benefit in mitigating risk for future pandemics and urgent research is required to exploit the opportunity. A retrospective cohort study, where data on the viral RNA sequences and clinical outcomes of COVID-19 patients are collected and analysed could provide invaluable information. Data on SARS-CoV-2 RNA sequences from COVID-19 patients over the course of the pandemic, as well as information on the post-translational modifications that occur in the viral RNA combined with Clinical data, including the severity of the illness, treatment received, and outcomes, could be evaluated to gain further insights.

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