Author:Geert Vanden Bossche May 10th, 2026
How Misunderstood Changes in Pathogen Behavior Fuel Erroneous Definitions and ScientificConfusion
In my previous Substack article, ‘WhenExperts Disagree, Something Bigger Is Being Missed[1],’I described how linear thinking frequently drives scientists toward erroneousconclusions when attempting to analyze and interpret complex phenomena. Themore multidimensional a system becomes, the greater the temptation to simplifyit 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 thisproblem is the use of scientific concepts whose definitions have graduallydrifted away from their original meaning. Once this happens, those conceptsbecome intellectually hollow. They continue to be used with confidence, but nolonger describe the phenomenon they were initially meant to define.
The ongoing COVID-19 (C-19) immune escapepandemic offers several striking examples of this problem. Two of the most mind-blowingare the concepts of herd immunity and gain-of- function.
When Herd Immunity Stops Meaning HerdImmunity
Today, even many experts use the term herdimmunity to describe virtually any form of adaptive immunity that exists atthe population level, whether generated by natural infection, vaccination, orso-called hybrid immunity.
This interpretation is scientificallyconvenient. But it is conceptually wrong.
Originally, herd immunity referred to avery specific biological phenomenon: the type of population-level protectionthat 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) titersor adaptive immune memory scattered across individuals. It is the result of acoordinated interaction and synergy between innate and adaptive immunity acrossthe exposed population.
This is why this distinction matters enormously:
During natural infection, innate immunity acts as the first line of immune defenseand eliminates the bulk of viral load before adaptive immune responses fullymature.
Adaptive immunity then consolidates this protection and can be rapidly recalledupon re-exposure. The resulting immune profile is broad, functionallyintegrated, and capable of suppressing both infection and onward transmissionat the population level, without promoting immune escape! That is true herdimmunity. It is the only type ofpopulation-level immunity that truly protects against viral infection andtransmission. It is, therefore, the only type of population-level immunity thatis capable of ending a pandemic of an acute viral infection.
By contrast, a population repeatedly exposedto narrowly focused antigen-specific immune stimulation by continuous circulationof newly emerging viral variants, develops extensive adaptive immune reactivitywithout ever achieving sterilizing protection or durable interruption oftransmission.
In such a situation, the population may appearimmunologically ‘experienced,’ yet remain incapable of suppressing viralcirculation and immune escape. This is precisely what we have observed inhighly C-19-vaccinated populations. It is THE paradox many ‘experts’ fail tograsp.
The Dangerous Confusion Between ImmuneActivation and Protection
One of the most persistent misunderstandingsthroughout this pandemic has been the assumption that the mere presence of animmune response automatically equates to protection. Of course, it does not.
An immune system can be highly active and yet poorly aligned with the evolvingviral phenotype. Under continuous immune escape pressure, adaptive responsesincreasingly chase a moving target. The result is not efficient viralclearance, but rather perpetual immune stimulation combined with incompletecontrol of infection and transmission.
This distinction is exactly what I have beentrying to draw the WHO’s attention to ever since it gave the green light to amass vaccination program against SARS-CoV-2 (SC-2), as it lies at the heart ofwhat I have repeatedly described as the immune escape pandemic.
Breakthrough infections, especiallyvaccine-breakthrough infections in highly C-19-vaccinated populations, do notmerely represent isolated failures of protection. At the population level, theycontribute to the repeated reactivation of increasingly misdirected immuneresponses while simultaneously compromising efficient viral clearance. Suchmisdirected host immune responses could eventually drive a very dangerous formof viral gain-of-function, as will be explained below.
I remain stunned that mainstream analysesnever connect vaccine-breakthrough infections and the resulting misdirected,suboptimal immune responses with a key trigger of large-scale viralgain-of-function and its potentially detrimental consequences.
The Misunderstood Concept of ‘Gain-of-Function’
What scientists and regulators refer to as gain-of-functionresearch 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 Appliedand Environmental Microbiology[i][3].The article frames the work as ‘gain-of-function’ research and raises concernsregarding its implications.
Whether certain forms of genetic viralmanipulation should or should not be allowed is ultimately not my role todecide. That responsibility belongs to regulators and oversight bodies, whoshould define the boundaries transparently and justify them scientifically.
But the debate itself illustrates a much deeper problem: experts frequentlyfail to place complex biological concepts within their relevant context.
‘Gain-of-function’ is often treated as thoughit were an intrinsic property of the virus itself–as if a particular geneticmodification always automatically, inevitably and universally translates intoincreased danger. That is a simplistic and misleading interpretation. Whether viral ‘gain-of-function’ observed invitro should be considered dangerous or harmful is not necessarilydetermined merely by the genetic modification itself. It largely depends on how that modification is received by thesusceptible host or by the susceptible host population when assessing potentialindividual or public-health harm, respectively.
A viral phenotype cannot be evaluatedindependently of the host environment in which it operates.
Whether a viral modification confers a meaningful advantage dependsfundamentally on:
What follows is what I explained in responseto these followers who asked me to comment on the scope of the research inquestion:
“On the allegedly ‘positive’ side, thepublication of Yao Ma et al. relates to an individual prophylactic approach.Such an approach is, of course, largely irrelevant in the context of epidemicsor pandemics.
On the allegedly ‘negative’ side, the experimental data reported by Yao Ma etal. relates to a specific environment in which viral survival is threatened bya particular type of epitope-specific neutralizing Ab. Such an environment is,of course, not representative of viral behavior within a given susceptible hostor across a susceptible host population.
Conclusion: ‘Gain-of-function’ reflects aviral phenotype or behavior. Because viral replication and transmissioninevitably depend, to a large extent, on the immune status of the individualhost and the host population, respectively, the impact of any phenotypic changein the virus will likewise depend on the host-specific or population-levelimmune context.
In other words, in vitro ‘gain-of-function’observed in a very specific, artificially generated immune environment does notautomatically translate into ‘gain-of-function’ across the virus’ hostpopulation.
This is particularly relevant for resistanceto neutralizing Abs targeting specific epitopes. It is not because a such Ab-resistantvariant may be artificially selected under narrowly defined experimentalconditions that it will automatically acquire a competitive advantage whenintroduced into a living mammalian species or host population that does notimpose 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 afar more diversified adaptive immune response, but also relies heavily on innateimmunity as the first line of immune defense.”
Why In Vitro ‘Gain-of-Function’ DoesNot Automatically Translate Into Population-Level Advantage
One of the most overlooked realities invirology is that viral fitness is context dependent.
A variant that demonstrates:
does not automatically become more successfulin a real-world host population.
Why?
Because the virus does not interact withisolated Abs in nature. It interacts with:
A mutation that appears advantageous underhighly artificial laboratory conditions may therefore confer little or noadvantage within a naturally infected population.
This distinction is critical.
The current C-19 immune escape pandemic hasrepeatedly demonstrated that viral success is not simply determined bymolecular escape from specific neutralizing Abs, but by the virus’ ability tonavigate the far more complex immune ecosystem of highly C-19-vaccinatedpopulations.
There is one specific scenario, though, in which a single change in, ornear, a viral epitope located within a protein responsible for viralinfectiousness may trigger a dangerous form of gain-of-function in vivo.This may occur when a variant carrying such a change encounters an immunologicallynaïve or immunologically weakened individual, or when it infects an immunologicallyexperienced individual at a very high infectious dose.
Under these conditions, such a mutation may enhance or enable the virus’sintrinsic infectiousness and thereby increase its virulence. This iswell illustrated by influenza viruses, where point mutations in thehemagglutinin (HA) protein can alter receptor binding, tissue tropism, hostrange, or proteolytic activation of the virus. For example, mutations in the HAreceptor-binding site, such as Q226L and G228S in certain influenza subtypes,are known to shift receptor preference from avian-type α2,3-linked sialic acidreceptors toward human-type α2,6-linked sialic acid receptors, thereby facilitatingdangerous adaptation to the human upper respiratory tract.
Similarly, acquisition or modification of a polybasic cleavage site inthe HA protein of H5 or H7 avian influenza viruses can broaden HA cleavage byubiquitous host proteases, allowing more systemic viral spread andcontributing to high pathogenicity.
A broadly analogous example is the furin cleavage site at the S1/S2junction of the SC-2 spike (S) protein. This site enables pre-activation of Sby furin-like host proteases and can enhance cell entry, cell–cell fusion,tissue tropism, transmissibility and pathogenicity relative to closelyrelated sarbecoviruses lacking such a site. However, as already mentioned, its impacton viral virulence is context-dependent and largely dependent on the innateand adaptive immune status of the exposed individual.
When ‘Gain-of-Function’ Becomes aPopulation-Level Phenomenon
A critically important nuance must be added tothe discussion on gain-of-function. In the previous paragraph, Iemphasized that in vitro gain-of-function experiments, such as theartificial selection of variants capable of escaping neutralization by aspecific epitope-targeting Ab, should not automatically be interpreted asevidence that the selected variant will acquire a meaningful competitiveadvantage in a real-world host population. Such experimental systems imposehighly artificial and narrowly defined immune pressures that rarely reflect theenormously complex immune landscape encountered in vivo.
However, this does not imply thatdangerous gain-of-function cannot occur in vivo. It could even occur atthe level of an entire population!
This is where my theory comes in as it arguesthat mass vaccination during an ongoing pandemic of an acute (self-limiting)viral infection can generate an unprecedented and powerful form of collectiveimmune 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 ofthe selective pressure involved.
The in vitro experiment criticized byJon Fleetwood in his Substack article exposes the virus, under artificiallaboratory conditions, to a neutralizing Ab, which is directedagainst a highly specific, narrowly defined epitope.
By contrast, mass vaccination during widespread viral circulation exposesthe virus to:
This results into continuous selection forvariants capable of maintaining transmissibility despite widespread immunerecognition. This creates a fundamentally different and very complex evolutionaryenvironment.
Under such conditions, the virus is no longermerely selected for resistance to a single Ab or epitope. It is selected forits ability to preserve inter-host transmission under hostile, but increasinglyconstrained immunological conditions in highly C-19-vaccinated populations.
In my view, this is exactly what drives the prolongation of this immuneescape pandemic.
Importantly, this type of collective immune pressure does not simply select forcontinuous viral immune escape in the classical sense. It progressively narrowsthe spectrum of viable evolutionary options available to the virus. Incrementalmutations capable of preserving transmissibility while escaping immunerecognition become increasingly difficult to achieve without compromisingintrinsic viral fitness.
The virus continues to evolve, butincreasingly within a constrained evolutionary corridor in which extensive S remodellingyields diminishing returns. Yet precisely because this selective pressureoperates continuously and on a massive scale, the evolutionary systemremains unstable, even though simplistic parameters–such as wastewaterviral load, BA.3.2’s failure to rapidly dominate the viral landscape orrelatively low mortality rates–may suggest otherwise. This is why I call thecurrent epidemiological situation of SC-2 metastable.
The longer this process continues, the greater the likelihood that the viruseventually acquires a more radical phenotypic solution capable of overcomingthe existing constraints.
In that sense, the truly dangerous manifestation of gain-of-function is notnecessarily the one acquired in a laboratory under artificially engineered, narrowlydefined conditions. It is the kind of in vivo gain-of-function that may emergefrom prolonged, large-scale immune selection acting on viral transmissionduring an ongoing immune escape pandemic, as is still occurring in highlyC-19-vaccinated regions.
This distinction is essential because itillustrates, once again, how the same concept–‘gain-of- function’–can becomedeeply misleading when detached from its broader immunological andpopulation-level context.
The Reductionist Trap
This entire debate –once again– exposes abroader intellectual weakness that has plagued pandemic analysis from thebeginning: the tendency to isolate single variables from the multidimensionalsystem in which they operate (see my previous Substack article: ‘WhenExperts Disagree, Something Bigger Is Being Missed[4]’).
Scientists examine:
as though these existed independently from theconstantly evolving interaction between virus and host immunity.
But biological systems do not function inisolation.
The evolutionary behavior of a virus cannot beunderstood without simultaneously considering:
Failure to integrate these dimensionsinevitably produces distorted conclusions.
The Real Danger of Misunderstood Definitions
The greatest danger of poorly defined conceptsis not merely semantic confusion.
It is that they generate policies and scientific narratives that fundamentallymisinterpret the underlying phenomenon.
If herd immunity is incorrectly equatedwith any form of adaptive immune exposure, one may falsely conclude that thepandemic is naturally resolving.
If gain-of-function is reduced toisolated laboratory phenotypes without considering population-level immunedynamics, one may radically overestimate or underestimate real-world risk.
And if immune activation continues to beconfused with genuine functional protection, scientists will remain unable tounderstand why extensive immune escape continues despite widespread ‘immunity.’
Overall Conclusion: Complex Systems Cannot BeUnderstood Through Hollow Definitions
The current confusion surrounding herdimmunity, gain-of-function, endemicity, and immune protection is notaccidental. It reflects the failure of linear reasoning to capture themultidimensional nature of complex biological systems.
Definitions that were once scientificallymeaningful gradually become emptied of substance when detached from the broadercontext in which they operate. They continue to circulate in scientificdiscourse, but increasingly function as intellectual shortcuts rather thanexplanatory tools.
The immune escape pandemic and relevantaccompanying changes in the pathogen’s ‘behavior’ cannot be understood throughisolated variables or simplistic narratives. It can only be understood byrecognizing the dynamic interaction between:
As long as these interactions remainfragmented across scientific silos, the same confusion will persist:
But complex systems do not obey simplisticdefinitions. Reality will eventually prove wrong those who generate scientificconfusion by insisting on interpreting multidimensional phenomena throughlinear frameworks, erroneous definitions, and hollow concepts.
[1] https://voiceforscienceandsolidarity.substack.com/p/when-experts-disagree-something-bigger
[2] https://jonfleetwood.substack.com/p/nihniaid-fund-gain-of-function-covid?publication_id=520511&post_id=196576243&isFreemail=true&r=1rikaj&triedRedirect=true&utm_source=substack&utm_medium=email
[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
Geert Vanden Bossche received his DVM from the University of Ghent, Belgium, and his PhD degree in Virology from the University of Hohenheim, Germany. He held adjunct faculty appointments at universities in Belgium and Germany. After his career in Academia, Geert joined several vaccine companies (GSK Biologicals, Novartis Vaccines, Solvay Biologicals) to serve various roles in vaccine R&D as well as in late vaccine development.
Geert then moved on to join the Bill & Melinda Gates Foundation’s Global Health Discovery team in Seattle (USA) as Senior Program Officer; he then worked with the Global Alliance for Vaccines and Immunization (GAVI) in Geneva as Senior Ebola Program Manager. At GAVI he tracked efforts to develop an Ebola vaccine. He also represented GAVI in fora with other partners, including WHO, to review progress on the fight against Ebola and to build plans for global pandemic preparedness.
Back in 2015, Geert scrutinized and questioned the safety of the Ebola vaccine that was used in ring vaccination trials conducted by WHO in Guinea. His critical scientific analysis and report on the data published by WHO in the Lancet in 2015 was sent to all international health and regulatory authorities involved in the Ebola vaccination program. After working for GAVI, Geert joined the German Center for Infection Research in Cologne as Head of the Vaccine Development Office. He is at present primarily serving as a Biotech / Vaccine consultant while also conducting his own research on Natural Killer cell-based vaccines.
Email: info@voiceforscienceandsolidarity.org
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