How Misunderstood Changes in Pathogen Behavior Fuel Erroneous Definitions and Scientific Confusion

In my previous Substack article, ‘When Experts Disagree, Something Bigger Is Being Missed[1],’ I described how linear thinking frequently drives scientists toward erroneous conclusions when attempting to analyze and interpret complex phenomena. The more multidimensional a system becomes, the greater the temptation to simplify it into linear narratives that are easier to communicate, model, and....defend (!). Yet simplification often comes at the expense of understanding.

One of the most common manifestations of this problem is the use of scientific concepts whose definitions have gradually drifted away from their original meaning. Once this happens, those concepts become intellectually hollow. They continue to be used with confidence, but no longer describe the phenomenon they were initially meant to define.

The ongoing COVID-19 (C-19) immune escape pandemic offers several striking examples of this problem. Two of the most mind-blowing are the concepts of herd immunity and gain-of- function.


When Herd Immunity Stops Meaning Herd Immunity

Today, even many experts use the term herd immunity to describe virtually any form of adaptive immunity that exists at the population level, whether generated by natural infection, vaccination, or so-called hybrid immunity.

This interpretation is scientifically convenient. But it is conceptually wrong.

Originally, herd immunity referred to a very specific biological phenomenon: the type of population-level protection that naturally emerges during the course of a pandemic caused by an acute (self-limiting) viral infection. Such protection is not merely the sum of antibody (Ab) titers or adaptive immune memory scattered across individuals. It is the result of a coordinated interaction and synergy between innate and adaptive immunity across the exposed population.

This is why this distinction matters enormously:

During natural infection, innate immunity acts as the first line of immune defense and eliminates the bulk of viral load before adaptive immune responses fully mature.
Adaptive immunity then consolidates this protection and can be rapidly recalled upon re-exposure. The resulting immune profile is broad, functionally integrated, and capable of suppressing both infection and onward transmission at the population level, without promoting immune escape! That is true herd immunity. It is the only type of population-level immunity that truly protects against viral infection and transmission. It is, therefore, the only type of population-level immunity that is capable of ending a pandemic of an acute viral infection.

By contrast, a population repeatedly exposed to narrowly focused antigen-specific immune stimulation by continuous circulation of newly emerging viral variants, develops extensive adaptive immune reactivity without ever achieving sterilizing protection or durable interruption of transmission.

In such a situation, the population may appear immunologically ‘experienced,’ yet remain incapable of suppressing viral circulation and immune escape. This is precisely what we have observed in highly C-19-vaccinated populations. It is THE paradox many ‘experts’ fail to grasp.


The Dangerous Confusion Between Immune Activation and Protection

One of the most persistent misunderstandings throughout this pandemic has been the assumption that the mere presence of an immune response automatically equates to protection. Of course, it does not.
An immune system can be highly active and yet poorly aligned with the evolving viral phenotype. Under continuous immune escape pressure, adaptive responses increasingly chase a moving target. The result is not efficient viral clearance, but rather perpetual immune stimulation combined with incomplete control of infection and transmission.

This distinction is exactly what I have been trying to draw the WHO’s attention to ever since it gave the green light to a mass vaccination program against SARS-CoV-2 (SC-2), as it lies at the heart of what I have repeatedly described as the immune escape pandemic.

Breakthrough infections, especially vaccine-breakthrough infections in highly C-19-vaccinated populations, do not merely represent isolated failures of protection. At the population level, they contribute to the repeated reactivation of increasingly misdirected immune responses while simultaneously compromising efficient viral clearance. Such misdirected host immune responses could eventually drive a very dangerous form of viral gain-of-function, as will be explained below.

I remain stunned that mainstream analyses never connect vaccine-breakthrough infections and the resulting misdirected, suboptimal immune responses with a key trigger of large-scale viral gain-of-function and its potentially detrimental consequences.



The Misunderstood Concept of ‘Gain-of-Function’

What scientists and regulators refer to as gain-of-function research is, indeed, another example of conceptual scientific confusion.
Followers recently sent me an article by Jon Fleetwood[2] discussing research funded by the NIH and published by Yao Ma et al. in Applied and Environmental Microbiology[3]. The article frames the work as ‘gain-of-function’ research and raises concerns regarding its implications.

Whether certain forms of genetic viral manipulation should or should not be allowed is ultimately not my role to decide. That responsibility belongs to regulators and oversight bodies, who should define the boundaries transparently and justify them scientifically.
But the debate itself illustrates a much deeper problem: experts frequently fail to place complex biological concepts within their relevant context.

‘Gain-of-function’ is often treated as though it were an intrinsic property of the virus itself–as if a particular genetic modification always automatically, inevitably and universally translates into increased danger. That is a simplistic and misleading interpretation. Whether viral ‘gain-of-function’ observed in vitro should be considered dangerous or harmful is not necessarily determined merely by the genetic modification itself. It largely depends on how that modification is received by the susceptible host or by the susceptible host population when assessing potential individual or public-health harm, respectively.

A viral phenotype cannot be evaluated independently of the host environment in which it operates.

Whether a viral modification confers a meaningful advantage depends fundamentally on:

• the immune status of the host,

• the immunological landscape of the host population,

• or the selective pressures acting on viral transmission and replication.

What follows is what I explained in response to these followers who asked me to comment on the scope of the research in question:

“On the allegedly ‘positive’ side, the publication of Yao Ma et al. relates to an individual prophylactic approach. Such an approach is, of course, largely irrelevant in the context of epidemics or pandemics.

On the allegedly ‘negative’ side, the experimental data reported by Yao Ma et al. relates to a specific environment in which viral survival is threatened by a particular type of epitope-specific neutralizing Ab. Such an environment is, of course, not representative of viral behavior within a given susceptible host or across a susceptible host population.

Conclusion: ‘Gain-of-function’ reflects a viral phenotype or behavior. Because viral replication and transmission inevitably depend, to a large extent, on the immune status of the individual host and the host population, respectively, the impact of any phenotypic change in the virus will likewise depend on the host-specific or population-level immune context.

In other words, in vitro ‘gain-of-function’ observed in a very specific, artificially generated immune environment does not automatically translate into ‘gain-of-function’ across the virus’ host population.

This is particularly relevant for resistance to neutralizing Abs targeting specific epitopes. It is not because a such Ab-resistant variant may be artificially selected under narrowly defined experimental conditions that it will automatically acquire a competitive advantage when introduced into a living mammalian species or host population that does not impose the same selective immune pressure.
In fact, very much the opposite is true.
This is because the host immune response to coronaviruses not only comprises a far more diversified adaptive immune response, but also relies heavily on innate immunity as the first line of immune defense.”


Why In Vitro ‘Gain-of-Function’ Does Not Automatically Translate Into Population-Level Advantage

One of the most overlooked realities in virology is that viral fitness is context dependent.

A variant that demonstrates:

• increased replication in cell culture,

• escape from a monoclonal neutralizing Ab,

• or resistance to narrowly focused immune pressure,

does not automatically become more successful in a real-world host population.

Why?

Because the virus does not interact with isolated Abs in nature. It interacts with:

• innate immunity,

• mucosal immunity,

• heterogeneous adaptive immune responses, which are Ab- and/ or cell-mediated

A mutation that appears advantageous under highly artificial laboratory conditions may therefore confer little or no advantage within a naturally infected population.

This distinction is critical.

The current C-19 immune escape pandemic has repeatedly demonstrated that viral success is not simply determined by molecular escape from specific neutralizing Abs, but by the virus’ ability to navigate the far more complex immune ecosystem of highly C-19-vaccinated populations.
There is one specific scenario, though, in which a single change in, or near, a viral epitope located within a protein responsible for viral infectiousness may trigger a dangerous form of gain-of-function in vivo. This may occur when a variant carrying such a change encounters an immunologically naïve or immunologically weakened individual, or when it infects an immunologically experienced individual at a very high infectious dose.
Under these conditions, such a mutation may enhance or enable the virus’s intrinsic infectiousness and thereby increase its virulence. This is well illustrated by influenza viruses, where point mutations in the hemagglutinin (HA) protein can alter receptor binding, tissue tropism, host range, or proteolytic activation of the virus. For example, mutations in the HA receptor-binding site, such as Q226L and G228S in certain influenza subtypes, are known to shift receptor preference from avian-type α2,3-linked sialic acid receptors toward human-type α2,6-linked sialic acid receptors, thereby facilitating dangerous adaptation to the human upper respiratory tract.
Similarly, acquisition or modification of a polybasic cleavage site in the HA protein of H5 or H7 avian influenza viruses can broaden HA cleavage by ubiquitous host proteases, allowing more systemic viral spread and contributing to high pathogenicity.
A broadly analogous example is the furin cleavage site at the S1/S2 junction of the SC-2 spike (S) protein. This site enables pre-activation of S by furin-like host proteases and can enhance cell entry, cell–cell fusion, tissue tropism, transmissibility and pathogenicity relative to closely related sarbecoviruses lacking such a site. However, as already mentioned, its impact on viral virulence is context-dependent and largely dependent on the innate and adaptive immune status of the exposed individual.

When ‘Gain-of-Function’ Becomes a Population-Level Phenomenon

A critically important nuance must be added to the discussion on gain-of-function. In the previous paragraph, I emphasized that in vitro gain-of-function experiments, such as the artificial selection of variants capable of escaping neutralization by a specific epitope-targeting Ab, should not automatically be interpreted as evidence that the selected variant will acquire a meaningful competitive advantage in a real-world host population. Such experimental systems impose highly artificial and narrowly defined immune pressures that rarely reflect the enormously complex immune landscape encountered in vivo.

However, this does not imply that dangerous gain-of-function cannot occur in vivo. It could even occur at the level of an entire population!

This is where my theory comes in as it argues that mass vaccination during an ongoing pandemic of an acute (self-limiting) viral infection can generate an unprecedented and powerful form of collective immune pressure capable of driving viral evolution toward genuinely dangerous, i.e., harmful, gain-of-function for the highly C-19-vaccinated population.

The difference lies in the scale and nature of the selective pressure involved.

The in vitro experiment criticized by Jon Fleetwood in his Substack article exposes the virus, under artificial laboratory conditions, to a neutralizing Ab, which is directed against a highly specific, narrowly defined epitope.

By contrast, mass vaccination during widespread viral circulation exposes the virus to:

• synchronized in vivo immune pressure exerted by an entire, highly C-19-vaccinated population,

• refocused S-targeting adaptive immune responses, repeatedly induced by large-scale vaccine-breakthrough infections

This results into continuous selection for variants capable of maintaining transmissibility despite widespread immune recognition. This creates a fundamentally different and very complex evolutionary environment.

Under such conditions, the virus is no longer merely selected for resistance to a single Ab or epitope. It is selected for its ability to preserve inter-host transmission under hostile, but increasingly constrained immunological conditions in highly C-19-vaccinated populations.

In my view, this is exactly what drives the prolongation of this immune escape pandemic.
Importantly, this type of collective immune pressure does not simply select for continuous viral immune escape in the classical sense. It progressively narrows the spectrum of viable evolutionary options available to the virus. Incremental mutations capable of preserving transmissibility while escaping immune recognition become increasingly difficult to achieve without compromising intrinsic viral fitness.

The virus continues to evolve, but increasingly within a constrained evolutionary corridor in which extensive S remodelling yields diminishing returns. Yet precisely because this selective pressure operates continuously and on a massive scale, the evolutionary system remains unstable, even though simplistic parameters–such as wastewater viral load, BA.3.2’s failure to rapidly dominate the viral landscape or relatively low mortality rates–may suggest otherwise. This is why I call the current epidemiological situation of SC-2 metastable.

The longer this process continues, the greater the likelihood that the virus eventually acquires a more radical phenotypic solution capable of overcoming the existing constraints.

In that sense, the truly dangerous manifestation of gain-of-function is not necessarily the one acquired in a laboratory under artificially engineered, narrowly defined conditions. It is the kind of in vivo gain-of-function that may emerge from prolonged, large-scale immune selection acting on viral transmission during an ongoing immune escape pandemic, as is still occurring in highly C-19-vaccinated regions.

This distinction is essential because it illustrates, once again, how the same concept–‘gain-of- function’–can become deeply misleading when detached from its broader immunological and population-level context.

The Reductionist Trap

This entire debate –once again– exposes a broader intellectual weakness that has plagued pandemic analysis from the beginning: the tendency to isolate single variables from the multidimensional system in which they operate (see my previous Substack article: ‘When Experts Disagree, Something Bigger Is Being Missed[4]’).

Scientists examine:

• mutations,

• viral immune escape,

• viral transmission curves,

• viral load in wastewater,

• vaccine efficacy,

• C-19 hospitalization and death rates,

as though these existed independently from the constantly evolving interaction between virus and host immunity.

But biological systems do not function in isolation.

The evolutionary behavior of a virus cannot be understood without simultaneously considering:

• the quality and level of host immunity,

• the type of immune pressure imposed at the population level,

• the distinction between innate and adaptive immune responses,

• and the feedback loops created by repeated (vaccine-)breakthrough infections.

Failure to integrate these dimensions inevitably produces distorted conclusions.


The Real Danger of Misunderstood Definitions

The greatest danger of poorly defined concepts is not merely semantic confusion.
It is that they generate policies and scientific narratives that fundamentally misinterpret the underlying phenomenon.

If herd immunity is incorrectly equated with any form of adaptive immune exposure, one may falsely conclude that the pandemic is naturally resolving.

If gain-of-function is reduced to isolated laboratory phenotypes without considering population-level immune dynamics, one may radically overestimate or underestimate real-world risk.

And if immune activation continues to be confused with genuine functional protection, scientists will remain unable to understand why extensive immune escape continues despite widespread ‘immunity.’


Overall Conclusion: Complex Systems Cannot Be Understood Through Hollow Definitions

The current confusion surrounding herd immunity, gain-of-function, endemicity, and immune protection is not accidental. It reflects the failure of linear reasoning to capture the multidimensional nature of complex biological systems.

Definitions that were once scientifically meaningful gradually become emptied of substance when detached from the broader context in which they operate. They continue to circulate in scientific discourse, but increasingly function as intellectual shortcuts rather than explanatory tools.

The immune escape pandemic and relevant accompanying changes in the pathogen’s ‘behavior’ cannot be understood through isolated variables or simplistic narratives. It can only be understood by recognizing the dynamic interaction between:

• viral evolution,

• innate and adaptive immunity,

• immune conditioning at the population level,

• and the selective pressures generated by mass vaccination during an ongoing pandemic.

As long as these interactions remain fragmented across scientific silos, the same confusion will persist:

• immune activation mistaken for protection,

• transient calm mistaken for stability,

• constrained viral evolution mistaken for benign endemicity,

• suboptimal population-level immunity mistaken for protective herd immunity

• individual point mutations misinterpreted as having lethal consequences

• large-scale in vivo gain-of-function mistaken for benign viral immune escape.

But complex systems do not obey simplistic definitions. Reality will eventually prove wrong those who generate scientific confusion by insisting on interpreting multidimensional phenomena through linear frameworks, erroneous definitions, and hollow concepts.

---

[1] https://voiceforscienceandsolidarity.substack.com/p/when-experts-disagree-something-bigger

[2]

NIH/NIAID Fund Gain-of-Function COVID Mutant With 679-Fold Antibody Resistance: Journal 'American Society for Microbiology'

[3] https://journals.asm.org/doi/epub/10.1128/spectrum.00006-26?utm_source=substack&utm_medium=email

[4] https://voiceforscienceandsolidarity.substack.com/p/when-experts-disagree-something-bigger

---