The Complex Adaptive Landscape Created by SARS-CoV-2 Vaccines Shows Us Why Evolution Will Not Allow Effective mRNA Vaccines Against mRNA Viruses, Part 1.

Interaction among multiple selective factors and evolution at multiple levels assures unpredictability. One thing is certain: the simple expectation of disease eradication was never possible.

The hype surrounding mRNA vaccines, hailed as groundbreaking, has masked a critical reality: the natural evolutionary dynamics of RNA viruses and the nature of the vaccines themselves will inherently limit their effectiveness in the long term. This was clear before 2020.

Significant biological concerns regarding mRNA vaccines themselves are emerging. Biodistribution studies have shown that the lipid nanoparticles (LNPs) used to deliver mRNA spread throughout the body, accumulating in organs like the liver, spleen, and ovaries—far beyond the intended injection site. This raises questions about long-term safety, particularly as evidence mounts of LNP toxicity in various tissues.

Laboratory evidence suggests that genotoxicity is a real risk. mRNA can potentially integrate into the human genome in the presence of reverse transcriptases, which are naturally present in the body. This concern is not limited to the mRNA in the jabs but extends to any DNA or RNA contaminants that may be introduced during manufacturing, posing additional risks.

Multiple Selection Types and Targets Thwart Lasting Protective Immunity from mRNA Vaccines

Vaccine-Induced Selection Pressure: The use of vaccines, especially those targeting only specific viral epitopes like the spike protein in SARS-CoV-2, focus the immune system on those targeted regions. This creates strong selection pressure on the virus to evolve variants that can evade the immune response trained by the vaccine. This process called vaccine-induced immune escape, can lead to variants with mutations in the spike protein that reduce vaccine efficacy, which is why variants like Delta or Omicron emerged with mutations specifically in the spike protein.

One dangerous consequence of this narrow immune focus is the potential development of Antibody-Dependent Enhancement (ADE). ADE occurs when antibodies produced by vaccination or prior infection, instead of neutralizing the virus, enhance its entry into host cells, leading to more severe infections. This phenomenon arises when the virus mutates so that vaccine-generated antibodies bind to it but fail to neutralize it, facilitating its entry into cells.

Vaccine-induced selection pressures can accelerate this risk by pushing the virus to evolve variants that partially escape immune surveillance. The immune system may recognize these escape variants but not thoroughly neutralize them, providing the perfect conditions for ADE. Thus, viral evolution driven by vaccines could lead to an increase in pathogenicity rather than a reduction, especially in populations where the vaccine induces intense but narrowly targeted immune responses.

Vaccines designed against a narrow set of epitopes can inadvertently accelerate the evolution of escape variants, as the virus needs only to mutate in specific regions to evade the trained immune response. Evolutionary biologists have long been aware of this risk in pathogen evolution, mainly when dealing with RNA viruses, whose rapid replication and error-prone polymerases provide a high mutation rate.

Natural Infection-Induced Selection Pressure: Unlike vaccine-induced immunity, natural infection exposes the immune system to a broader range of viral epitopes, including those outside the spike protein. This broader exposure generally reduces the chances of immune escape because the virus would have to mutate simultaneously across multiple regions of its genome to evade natural immunity. However, natural immunity still exerts selection pressure, particularly on epitopes recognized and targeted by the immune system. The virus may evolve to avoid these natural immune responses, leading to changes in viral genome regions previously targeted by the host's immune defenses.

PCR Testing-Induced Selection Pressure: The widespread use of PCR testing, which relies on detecting specific viral sequences, inadvertently creates a unique selection form. PCR tests use primers complementary to specific regions of the viral genome, and if mutations arise in those regions, the virus could evade detection. Over time, this selects viral variants that no longer match the primer sequences used in PCR tests, thus escaping detection. This scenario creates an artificial selection pressure on the virus at the genomic level, favoring variants that either mutate away from the tested regions or reduce their expression, enabling the virus to spread undetected.

We saw this in the UK with the infamous S-gene drop out, in which a PCR diagnostic test primer location on the spike protein coding region evolved away from a primer match to prevent that primer pair from reporting the presence of the virus when it was, in fact, present. Andrew Rambaut was evidently unaware of the problem that in a 2/3 diagnostic rule, one dropping out would reduce senstivity to by 50%. I pointed this out to him by email after he had published that the S-gene drop-out was potentially a useful way to differentiate among variants (not true). The S-gene drop-out occured 8 months before it was detected, meaning that people in the UK testing negative had approximately a 50% chance of a negative PCR result if they had the S-gene dropout variant, believing themselves to be free of the virus. (NB: I am not arguing for the use of PCR testing for mRNA viruses; I am simply sharing facts).

Vaccine-Induced Selection via Iatrogenic Illness: Vaccine-induced iatrogenic illness introduces an additional selection pressure on viral evolution, but only if the epitopes responsible for the adverse reactions are also present in circulating viral variants.

Moreover, iatrogenic autoimmune effects could create new evolutionary pressures on both the immune system and the virus. If specific individuals develop autoimmune responses due to molecular mimicry between viral and their private human epitopes (as seen with the Titan protein homology (found first by Lyons-Weiler, studied intensively by Kanduc)), this creates a dual challenge. The virus faces selective pressure to evade vaccine-induced immunity and may also evolve to exploit populations experiencing vaccine-induced immune dysregulation. This could encourage the emergence of variants that target the immune-compromised individuals more effectively, maintaining transmission despite increased immune activity. The vaccines are known now to produce many other conditions, including cardiovascular (myocarditis and pericarditis), menstrual irregularities, blood clotting disorders, neurological symptoms, autoimmune disorders, and dysautonomia. This interaction between iatrogenic illness and viral evolution requires careful study, as the long-term impacts of chronic illness have numerous potential inputs and responses induced by vaccines, each of which may reshape how viral populations evolve within the human host - and the human host evolution as well.

Autoimmunity via Pathogenic Priming

When a vaccine targets specific epitopes and induces harmful autoimmune responses (iatrogenic illness) in some individuals, these epitopes become selection factors that could influence viral evolution. Suppose the circulating virus contains the same epitopes causing autoimmune reactions. In that case, the virus faces selective pressure to evolve variants that modify or evade these epitopes to survive in the vaccinated population. Over time, this dynamic could favor the spread of variants with altered epitopes, thus shaping the viral population in response to vaccine-induced immunity and the potential for iatrogenic effects. However, this evolutionary pressure is only relevant when the viral and vaccine epitopes overlap significantly.

Each of these mechanisms represents an evolutionary pressure that pushes the virus to adapt and evolve in ways that thwart public health control measures. In some ways, these pressures act synergistically, each focusing on different aspects of the viral genome or life cycle, potentially accelerating the virus's evolutionary rate. In other ways, selection could counterbalance (negative selection on specific mutations on the PCR primer binding site could counterbalance selection of those mutations given their contribution to viral fitness for virulence or transmission.

This should have raised red flags for evolutionary biologists and virologists from the onset, as it speaks to RNA viruses' dynamic and rapid adaptability, especially under the influence of human intervention strategies like vaccines and testing.

Combined, these issues highlight the broader problem: the complex interaction between rapidly evolving viruses and the human immune system cannot be controlled with mRNA technology alone. As these challenges become clear, it becomes increasingly clear that the long-term consequences of relying on mRNA vaccines may outpace their short-term gains.

Multi-Level Selection: Long-Term Selection Dynamics

Multi-level selection comes into play when considering how different evolutionary pressures operate at multiple biological levels: within-host, between-host, and population-wide.

It’s important to clarify that we primarily observe multiple selection pressures operating at the same biological level—on the virus population. Multi-level selection involves evolutionary pressures acting at different biological levels, such as within-host competition between viral variants (as seen in chronic infections) and between-host transmission dynamics. For instance, a variant that evolves to persist within an immunocompromised individual might have a fitness advantage within that host but could be less successful at transmitting to new hosts, where different selective pressures apply.

The distinction between multiple selection factors and multi-level selection is crucial, as most of the pressures discussed—vaccine escape, PCR detection evasion, and natural immunity escape—act on the virus population as a whole.

The interplay between these levels, especially when chronic illness becomes a factor, provides a more robust framework for understanding the evolutionary trajectory of both the virus and the human population.

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Within-Host Selection (Viral Evolution Inside the Individual)

Within an infected individual, viral variants are competing to replicate and spread. In the context of chronic illness, individuals with immune systems that can’t fully clear the virus may become reservoirs for long-term viral replication. These hosts provide environments for the virus to evolve under immune pressure. As the host’s immune system targets multiple epitopes, this favors viral variants that can escape natural immune responses. Over time, these immune escape variants can become more prevalent within the host and possibly more virulent as they continue to evade detection and clearance.

Here, within-host selection promotes variants that escape immune surveillance, particularly in chronically ill individuals with weakened or dysregulated immune systems. It also causes variants to emerge that can persist in hosts for extended periods, potentially increasing viral loads and transmission rates.

Between-Host Selection (Transmission Across Individuals)

When we consider between-host selection, viral transmission dynamics are shaped by factors like transmissibility, the immune status of the host population, and the effectiveness of vaccines and diagnostics. Vaccinated individuals place vaccine-induced immune pressure on the virus, pushing it to evolve variants that can escape the immune response, particularly those targeting the spike protein. Similarly, natural immunity selects for variants evading multiple immune epitopes, though this is generally slower.

Importantly, chronic illness also plays a role in between-host selection. Individuals with chronic viral infections may shed the virus over longer periods, even if their overall transmission rate is lower. Variants that evolve within these individuals may find new transmission pathways if the host remains mobile. Additionally, if chronic illness isolates individuals from the population (through incapacitation or death), this removes those immune phenotypes from the viral selective environment, altering how the virus evolves across populations.

Between-host selection drives immune escape variants that can evade the population’s combined vaccine-induced and natural immune responses. Further, variants favored by PCR selection, which evade detection and thus escape isolation, may vary from PCR kit to kit, leading to another selection dynamic. The immune escape variants, by definition, will persist as longer infections, maintaining a reservoir for continued viral evolution.

Population-Level Selection (Long-Term Dynamics)

At the population level, long-term selection pressures manifest both through the effects of chronic illness and the broader population dynamics induced by vaccination campaigns and diagnostic protocols. As chronically ill individuals either isolate or succumb to their illness, their removal from the population removes variants that contribute to long-term chronic illness, say, due to pathogenic priming - but only after they have used the host to replicate and move on. This, therefore, does not shift the immune landscape of the population or the viral response as much as the initial higher lethality.

Vaccine-induced selection pressure accelerates the appearance of immune escape variants, but long-term selection from chronic illness alters the population’s immune diversity. Over time, this could lead to the selection of variants that can thrive in a broader range of immune profiles. The virus may evolve to target those who are still susceptible or find ways to exploit populations with weakened immune systems due to chronic illness or vaccine side effects.

Population-level selection thus leads to chronic illness shaping the immune landscape; individuals who experience long-term effects (whether from the virus or the vaccine) are effectively removed from the viral population, shifting the dynamics of viral evolution. It also encourages vaccine escape variants that may increase in frequency as the immune pressure from vaccines is focused on a limited set of epitopes. Finally, long-term evolutionary adaptations of the virus to exploit a changing population, potentially favoring variants that are more virulent or capable of evading both natural and vaccine-induced immunity.

Diminution of Viral Pathogenicity

In the long term, viral pathogenicity is expected to decrease as the virus adapts to its human host. The principle of virulence evolution suggests that viruses tend to evolve toward a balance between transmission efficiency and disease severity. A virus that kills or severely incapacitates its host too quickly will limit its transmission potential, reducing its evolutionary fitness. This dynamic is even more pronounced in a highly connected human population, as the virus faces intense selection pressures to maintain transmissibility without causing immediate host mortality.

As viral variants are selected based on their ability to evade immune responses (both vaccine-induced and natural), they may also face indirect selection to become less pathogenic. Chronic illness in a subset of the population can limit opportunities for viral spread, reducing the evolutionary fitness of highly virulent strains. Less virulent variants, which allow the host to remain mobile and socially active for longer, may have a transmission advantage, slowly pushing the virus toward lower levels of acute pathogenicity while maintaining its ability to persist in the population.

However, the trajectory of this evolution is complicated by vaccine-induced immune escape, the selective pressures from chronic illness, and the other selective factors.

While viral attenuation (a reduction in pathogenicity) is typically expected as viruses evolve to balance transmission efficiency with host survival, the introduction of modern interventions like vaccines and PCR testing may distort this natural process. Under normal circumstances, highly virulent viruses kill or debilitate their hosts too quickly, limiting their transmission potential. However, with vaccine-induced immune selection, we may see the emergence of variants that are both more virulent and immune-evasive, particularly in populations where vaccine coverage is high but natural immunity is compromised by chronic illness.

These variants might exploit immune suppression or prolonged viral shedding in chronically ill individuals, maintaining transmission even as pathogenicity remains high. This dynamic should lead to unexpected evolutionary pathways where virulence does not decline as rapidly as expected in a naturally evolving virus.

While we might expect a gradual decrease in pathogenicity in a naturally evolving virus, the rapid introduction of vaccine-driven immune selection and diagnostic-driven pressures would distort this process, potentially leading to more virulent or immune-evasive variants under specific conditions. This long-term evolutionary balance will ultimately depend on the interplay between viral evolution, human immune responses, and the effects of public health interventions like vaccination, PCR-based isolation protocols, and the rate at which multi-epitope-based natural immunity can help our species tame the virus.

Part 2: Modeling Evolutionary Dynamics with Timeframes and Relative Intensity

It’s relatively simple to demonstrate that as each selection factor influences the evolution of these fast-evolving viruses, we can, in principle, study dynamics over time. We’ll look at what that might look like in the next article.

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