Scientifically speaking, it cannot be ruled out that the bird flu panzootic is currently accelerating the evolutionary dynamics of the SARS-CoV-2 (SC-2) immune escape pandemic and expediting its final hyperacute stage. Public health authorities should therefore be on high pandemic alert for a new coronavirus (CoV) rather than bird flu! This article further explains why the end of the SC-2 pandemic would automatically result in the end of the bird flu panzootic.
There is currently a growing concern among public health officials and experts that enhanced spread of avian Influenza virus to immunologically naïve humans could result in the next flu pandemic and prompt the WHO to declare another health emergency of international concern. The potentially (!) highly pathogenic strain of avian influenza (HPAI), named H5N1, is causing a global animal pandemic (aka panzootic); it has already inflicted serious damage on various bird populations and has meanwhile also claimed victims among several mammalian species (a list of significant outbreaks, including in mammals, can be found at:
https://www.cdc.gov/flu/avianflu/timeline/avian-timeline-2020s.htm).
Up to now, public health authorities have qualified the risk of these viruses spreading from birds to people as low and essentially limited to individuals with work or recreational exposures to H5N1 virus-infected animals. Although the case fatality rate from H5N1 infection is considered relatively high, all fatalities reported so far have occurred after direct exposure to sick or dead infected poultry. However, the widespread presence of bird flu in dairy cows and milk has recently put public health authorities on high alert, as it is considered the first instance of likely mammal-to-human transmission. Consequently, many are questioning whether direct contact with infected cows or drinking untreated (or insufficiently treated) cow's milk could increase the risk of deadly infection and whether the increasing presence of the virus in domesticated animals could facilitate viral adaptation to the host species (i.e., via adaptation in the hemagglutinin surface protein that influences cleavage by furin-like proteases).
As usual, public health authorities resort to testing when they are in the dark about causal relationships. Testing of both humans and animals (via reverse-transcription polymerase chain reaction [RT-PCR] assay) has meanwhile clearly shown that both can become infected more often without developing severe disease symptoms. This raises even more questions, particularly regarding the 'obligate pathogenic' nature of the virus and the role of the immune system in controlling viral replication in the body. Indeed, one cannot assume that the avian flu virus (AFV) only transmits through direct contact. Just as birds move through the air, so does the bird flu virus. Therefore, the virus can undoubtedly infect both humans and animals through the air. It is reasonable to assume that in such cases, exposed individuals are infected with a lower viral load, most of which can be eliminated by the first line of immune defense (i.e., our innate immune system). This could explain why many airborne infections with bird flu are mild or even asymptomatic and cause only moderate or no seroconversion.
There are solid immunological arguments to suggest that natural killer (NK) cells, recognizing and killing host cells at an early stage of Sars-CoV-2 (SC-2) infection (or more generally, coronavirus [CoV] infection), could also eliminate cells infected with influenza virus, regardless of the specific type of flu virus. I therefore have little doubt that the portion of the population that has not been vaccinated with Covid-19 (C-19) vaccines and has consequently strongly trained their cell-mediated innate immunity (CMII) over the course of this C-19 pandemic, enjoys additional protection against a range of other viruses, including seasonal flu virus (sFV) and AFV. I also tend to believe that even the C-19 vaccinated portion of the population is equally capable of avoiding the risk of severe disease after contracting avian flu. Their defense, however, is based on the strong activation of T cells that – at a later stage of SC-2 infection - recognize a highly conserved, self-mimicking T cell epitope presented on MHC class I molecules and thus target and kill CoV-infected host cells that present this peptide epitope on their membrane (see fig. 1). This conserved epitope shows a high degree of homology with a similar epitope that is presented on the membrane of cells infected with influenza virus (including AFV). It is therefore reasonable to assume that activation of these universal cytotoxic T lymphocytes (CTLs) by SC-2 can also abrogate productive infection of influenza virus (including AFV) and thereby prevent severe bird flu disease.
In other words, it seems completely unnecessary to vaccinate people in highly C-19 vaccinated countries with a bird flu vaccine. Given the widespread presence of bird flu, there is even a risk that vaccinating people against this disease, as well as against seasonal flu, will have a counterproductive effect, regardless of whether their CMII was previously trained. Here is how this could happen: When vaccinating against bird flu, it should be noted that - as with all non-replicating vaccines - a period of 2-3 weeks elapses before vaccinated individuals acquire a sufficiently high concentration of specific antibodies (Abs) that bind with high enough affinity to the virus to neutralize it. However, if a vaccinated individual becomes exposed to a sufficient amount of AFV, i.e., before the vaccine-induced Abs recognize the virus with sufficient affinity to effectively neutralize it, then this individual may be at risk of contracting Ab-dependent enhancement of disease (ADED). Given the current, widespread dissemination of the AFV, there would be a significant risk for a freshly vaccinated individual to become exposed to this virus in the early stages after vaccination and hence, to develop ADED.
I don't have conclusive evidence to prove this, but I don’t rule out the possibility that highly C-19 vaccinated human populations, currently serving as a reservoir for SC-2 variants due to lack of herd immunity, could be the cause of a strong activation of CTLs in SC-2 exposed birds when pre-existing Abs against avian CoV1 cross-react with SC-2 and bind to the virus without neutralizing it (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9467642/). Such binding may lead to the formation of Ab-SC-2 complexes that enhance stimulation of antigen-presenting cells (APCs) and promote CTL activity. These CTLs could then kill AFV-infected bird cells due to the aforementioned cross-protection conferred by the universal T cell epitope expressed on both CoV- and flu-infected host cells. This would suggest that a large part of the bird population transmits the bird flu virus without showing overt disease symptoms. The more the bird flu virus causes asymptomatic infection, the more it spreads across bird populations worldwide and the greater the chance that humans or mammals will come into contact with this virus (see fig. 2).
1 In areas where avian coronaviruses are enzootic, for example in regions producing domestic poultry such as chickens, turkeys, and ducks, or in areas where there have been outbreaks in wild bird species, it's common for bird populations to have antibodies against these viruses. A high prevalence of anti-CoV Abs is commonly found in domestic poultry farming, as vaccination against infectious bronchitis virus (IBV) is a common practice in poultry-producing farms.
Exposure to AFV could promote the activation of CTLs in individuals with high titers of pre-existing Abs against sFV. These Abs could cross-react with avian H5N1 and bind to the virus without neutralizing it. Depending on the affinity and concentration of potentially pre-existing heterologous Abs (i.e., targeted against seasonal flu), humans and mammals could develop immune complexes upon exposure to the bird flu virus that largely promote mild to asymptomatic infection. Due to the limited neutralizing capacity of these pre-existing heterologous Abs against the bird flu virus, non-neutralizing Abs could be generated upon exposure to AFV in sFV-seropositive individuals, akin to the response to Omicron observed in individuals who previously experienced severe C-19 disease caused by an earlier SC-2 variant or were vaccinated with the Wuhan-S(pike) protein. If these non-neutralizing Abs can bind to the AFV in a manner similar to the binding of non-neutralizing Abs to SC-2, they may potentially even facilitate bird flu infection through ADEI (Antibody-Dependent Enhancement of Infection). ADEI is a phenomenon caused by the binding of non-neutralizing Abs to the virus, triggering a conformational change that promotes the interaction of the heterologous virus with its receptors on susceptible host cells. Such a mechanism has already been documented for SC-2 (https://pubmed.ncbi.nlm.nih.gov/34139176/). By facilitating bird flu infections in humans or other mammals, this mechanism would promote cross-species transmission of AFV without requiring specific adaptation of bird flu virus to other species. On the other hand, killing of AFV-infected cells by MHC-unrestricted CTLs would equally preclude the selection of specific bird flu variants that are better adapted to the new human or mammalian host (see under section 7.).
The occurrence of ADEI requires heterologous (i.e., anti-sFV) Abs to be present in sufficient concentration. It is, therefore, rather unlikely that this phenomenon occurs as a result of a previous natural seasonal flu infection, since Ab titers after such an infection are generally lower and persist for a shorter duration. In contrast, large-scale vaccination against seasonal flu strains (H3N2 and H1N1) would likely lead to a high prevalence of elevated titers of vaccine-induced Abs. Consequently, more widespread vaccination of human populations against sFV is more likely to promote the infection rate of bird flu in these populations, without, however, causing alarming rates of hospitalization or mortality. This already suggests that especially elderly individuals, many of whom were previously vaccinated against seasonal flu, could develop (mild) symptoms of bird flu, even in the absence of viral adaptation and, therefore, in the absence of sustainable human-to-human transmission. As (high titers of) anti-sFV Abs could facilitate ADEI in mammalian populations, it is plausible that several mammalian species could facilitate the spillback of AFV to birds/ poultry or promote (non-sustainable) mammal-to-mammal transmission, even in the absence of viral adaptation to the new host species.
In the current context of the bird flu panzootic, I strongly advise against vaccination for both bird flu and seasonal flu due to the risk of ADED (see under section 2.) and the potential to expedite the disastrous evolutionary dynamics of the SC-2 immune escape pandemic (see under section 7.), respectively. People at higher risk of severe illness due to seasonal flu are better served by antiviral medications2.
2 If antiviral chemoprophylaxis is initiated, oseltamivir treatment dosing (one dose twice daily) is recommended instead of the antiviral chemoprophylaxis regimen for seasonal influenza (once daily). Specific dosage recommendations for treatment by age group is available at Influenza Antiviral Medications: Summary for Clinicians (https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm). https://www.cdc.gov/flu/avianflu/guidance-exposed-persons.htm.
If indeed the immunological consequences of the C-19 mass vaccination have fueled the spread of bird flu virus in avian populations and facilitated its infectious transmission to mammalian populations, then there is consequently no need for the AFV to adapt more specifically to humans or other mammals. Based on the above-postulated immunological interference mechanism, I suspect that transmission from mammal to mammal will remain limited to individual cases of ADEI. Consequently, cases of symptomatic infection in humans and mammals will likely remain unpredictable. The occurrence of severe illness would, however, be the exception and limited to individuals exposed to a high virus concentration (e.g., as a result of direct contact with infected birds/ poultry) in the absence of significant titers of anti-sFV Abs and/or a healthy and sufficiently trained cell-based innate immune system.
It is possible that as long as bird flu globally spreads, the panzootic may potentially expedite the evolutionary dynamics of the SC-2 immune escape pandemic. This hypothesis is grounded in the low-affinity binding interactions between airborne AFV and anti-sFV Abs, which could also lead to the formation of Ab-SC-2 complexes that promote strong uptake of APCs and thereby activate cross-reactive CTL responses in parts of sFV-seropositive individuals (e.g., due to vaccination or as a result of seasonal epidemics). Due to the aforementioned cross-protection conferred by the universal epitope expressed on both CoV- and flu-infected host cells, these CTLs could now even kill SC-2-infected cells at an early stage of infection (see fig. 1), thereby causing highly C-19 vaccinated populations to place even more immune pressure on viral transmissibility. It is reasonable to postulate that the higher the immune pressure, the more the emergence of successive, more transmissible SC-2 variants will be accelerated and/or the more transmissible any newly emerging FLiRT3 variant will become. It is interesting to observe that a recently emerged SC-2 variant, KP.2, and even more so KP.3, is characterized by a higher level of competitive fitness and transmissibility than other circulating variants that previously emerged from JN.1. (see fig. 3).
https://www.thailandmedical.news/news/forget-about-sars-cov-2-flirt-variants-kp-1-1-and-kp-2-new-fluqe-variant-kp-3-expected-to-rapidly-become-globally-predominant-wreaking-havoc#google_vignette
In any case, it seems likely to me that the strong spread of the bird flu virus within various bird populations will leave an irreversible mark on the further course of the C-19 pandemic. On the one hand, it can be assumed with great probability that it promotes sustainable protection of the non-C-19 vaccinated part of the population in highly C-19 vaccinated countries (see under section 2.). On the other hand, it threatens to accelerate the increase in immune pressure on the transmissibility of SC-2. As a result, breakthrough infections with newly emerging, more transmissible variants carrying additional S-RBD(receptor-binding domain)-associated mutations could still lead to severe C-19 disease and death among the unvaccinated with weakened and/or untrained CMII. Primarily, however, this risk affects C-19 vaccinees who are now experiencing enhanced immune refocusing to cellular immune responses, thereby failing to sustain anti-S Ab titers high enough to maintain the production of polyreactive non-neutralizing antibodies (PNNAbs). This may explain the current uptick in C-19-related hospitalization and death rates being reported in several highly C-19 vaccinated countries (https://www.thailandmedical.news/news/great-news-kp-variants-starts-gradual-rise-of-covid-19-infections-in-india-324-kp-sequences-found-in-india-in-last-few-days; https://www.thailandmedical.news/news/forget-about-sars-cov-2-flirt-variants-kp-1-1-and-kp-2-new-fluqe-variant-kp-3-expected-to-rapidly-become-globally-predominant-wreaking-havoc#google_vignette).
However, as concentrations of the PNNAbs become increasingly rate-limiting due to the increased adsorption of highly transmissible progeny virus onto URT (upper respiratory tract)-resident dendritic cells (DCs; see fig. 4.), highly C-1 vaccinated populations would rapidly increase their immune pressure on viral intra-host transmissibility. It is reasonable to postulate that this will precipitate the end of the SC-2 immune escape pandemic in these populations (see fig. 2.).
3 FLiRT group of variants are named after the so-called ‘FLiRT’ mutations they comprise (F for L at position 456 and R for T at position 346) that have arisen in multiple different JN.1 lineages around the world.
If the above-postulated immunological interference between the ongoing bird flu panzootic and the SC-2 pandemic is real, enhanced reduction of SC-2 transmission in highly C-19 vaccinated populations would expedite the end of the SC-2 immune escape pandemic (see fig. 2.). The end of this pandemic would significantly reduce the reservoir of circulating SC-2 virus, thereby causing reduced exposure of bird populations to SC-2 variants. This would dampen the activation of CTLs by heterologous Ab-virus complexes in these populations, thereby causing AFV to provoke more overt disease. This would result in diminished transmission and enable AFV to transition into endemicity shortly after the end of the SC-2 immune escape pandemic.
Given the high amount of airborne SC-2 variants spread from the human reservoir to bird populations, in particular to industrial poultry farms, and the high turnover of commercial poultry, achieving herd immunity towards bird flu in the bird population is currently a complete utopia; in my opinion, it is impossible to halt the spread of the virus. I therefore believe it currently doesn’t make any sense to undertake efforts aimed at protecting industrial poultry farms from bird flu.
Likewise, I consider testing, confining, or even slaughtering hobby poultry to be absolutely pointless. Additionally, the massive testing of cows for H5N1 virus infection and the fuss surrounding the safety of dairy products are just another tempest in a teapot of a public health authority that fails to understand the public health impact of cross-immunity on viral transmission. They are monitoring the situation with highly sophisticated sequencing and epidemiological surveillance technologies, but as we have often witnessed during the C-19 pandemic, none of this has brought significant progress and the outcome of their efforts in regard of controlling the bird flu panzootic won’t be any different. Governments, however, seem to believe that bird flu could cause another pandemic in the human population (disease ‘X’?) and are already planning to step up their efforts to increase trust in vaccines, and especially to address misinformation and disinformation! (https://www.bbc.com/future/article/20240515-how-a-human-bird-flu-vaccine-could-protect-against-avian-influenza).
I am concluding that vaccine scientists, global and public health authorities are wasting their time in concentrating on the pandemic potential of bird flu, which – as a potential consequence of their colossal blunder (i.e., the C-19 mass vaccination) – is now spreading as wildfire across avian populations. While they are puzzled about the pandemic potential of this virus and already preparing for a new large-scale vaccination program, SC-2 continues to evolve in a highly worrisome direction. This virus continues to be in charge and is now spreading through a new type of variants, the FLiRT variants. The latter all descend from JN.1, which has now become the 2nd most dominant variant, and are all part of the broader Omicron family.
KP.2 and KP.3 are currently showing the most growth. Although highly transmissible, the FLiRT variants do not appear to be as likely to spread serious disease or cause death as previous types of SC-2. So-called experts pretend “that’s likely not because the virus is milder, but because our immunity is so much stronger now: After years of vaccinations and infections, most of the population is better able to fight off an infection without as much concern for severe disease.” https://www.nebraskamed.com/COVID/what-covid-19-variants-are-going-around. As they have no clue about immune refocusing and the nature of the newly elicited adaptive immune response, they don’t realize that the immune protection they are so excited about is not sustainable.
The fact that these different variants have picked up the same set of mutations indicates convergent evolution towards enhanced viral transmissibility. Newly emerging, highly transmissible variants like KP.2 (also called JN.1.11.1.2) only exhibit a marginal increase in viral transmissibility compared to that of other circulating variants. The slight increase in viral transmissibility is likely due to additional mutations in the S protein, which increase the strength with which the variant binds to cells in helping it to become more infectious/ transmissible. As the increase is marginal, though, it suggests that additional mutations in the new FLiRT variants cannot keep up with the steadily rising immune pressure on viral transmissibility, probably due to an increased shift to adsorption onto, rather than internalization into, APCs/ DCs (see figs. 3. and 4.).
I predict that when the contribution of the recently emerged FLiRT variants (e.g., KP.2: see fig. 3) to the overall distribution of viral lineages in the population will no longer increase—an endpoint that may be precipitated by potential immunological interference due to enhanced bird flu infection rates (see under section 7.)— the selection of an entirely new variant/ CoV will occur.
I predict this new CoV lineage to no longer increase inter-host transmissibility, but to enable enhanced INTRA-host spread. My perspective, however, stands in stark contrast to that of the public health authorities who pretend we still don't know enough to predict exactly where the changes will occur next or how they will affect the way the virus moves through the population. Despite acknowledging their lack of insight, public health experts and authorities are concluding that “FLiRT variants are unlikely to cause a significant uptick in case rates this summer because the number of C-19-related hospitalizations and deaths has dropped since January 2024, when JN.1 arrived on the scene”.
They are confident they can control the situation through ongoing surveillance and additional vaccination efforts (https://abcnews.go.com/Health/kp2-now-dominant-covid-variant-experts-us-summer/story?id=110166187). E. Topol, a self-proclaimed expert in this field even pretends that in order to see a significant wave of infection, “it will take a much bigger challenge of our immune system than what we see with the FLiRTs”. In the meantime, the WHO’s incredible ignorance about viral immune escape has led this organization to recommend annual updates to C-19 vaccines.
Given all this erroneous guidance, I continue to reiterate that society in highly C-19 vaccinated countries will be caught off guard, and that the immunological naivety of the public/ global health community and scientific-medical community will only exacerbate this effect.
Fig. 1: Following productive infection, immunodominant proteins that are responsible for viral infectiousness (e.g., spike protein of SC-2) elicit IgMs in sufficiently high concentration to build virus-Ab complexes that are internalized into APCs and thereby activate short-lived CTL responses that kill SC-2-infected host cells. CTLs normally determine the self-limiting nature of CoV infections. A similar mechanism is triggered after vaccine breakthrough infections. In case of the latter, SC-2 virus is complexed by previously primed anti-S Abs that bind with low affinity to the new, ‘breakthrough’ variant, thereby allowing CTLs to clear the virus-infected cells. Cross-reactive CTLs that are activated as a result of increased uptake of AFV by low affinity anti-sFV Abs can directly destroy SC-2-infected cells at an early stage of infection.
Fig.2: Spillover of SC-2 from highly C-19-vaccinated populations to CoV-seropositive bird populations (e.g., highly IBV-vaccinated poultry; IBV: infectious bronchitis virus) is causing the bird flu pandemic to spread even further (1) whereas spillover of bird flu from these CoV-seropositive bird populations to highly C-19-vaccinated human populations expedites the evolutionary dynamics of the SC-2 immune escape pandemic (2).
The accelerated reduction of viral transmission in highly C-19 vaccinated human populations would ultimately stop the SC-2 immune escape pandemic and thereby also enable the end of the bird flu panzootic (3).
Fig.3: I predict that when thecontribution of KP.2 (or KP.3) will no longer increase and no other moretransmissible variant emerges, the selection of an entirely new variant/ CoVwill take place. This new lineage will likely further increase viraltransmissibility; however, enhanced transmissibility would now translate intoenhanced INTRA-host spread.
Fig.4: Early Omicron descendants enter target host cells via PNNAb-dependent enhancement of infection (1). PNNAbs bind to progeny virus tethered to these DCs, which subsequently migrate to the lungs and other distal organs (2). On the other hand, previously SIR-primed Abs bind with low-affinity to the antigenically more distant immune escape variant, thereby generating Ab-virus complexes that are taken up into patrolling APCs (3). Enhanced uptake of large Ab-virus complexes into APCs facilitates strong activation of CTLs, thereby enabling the elimination of virus-infected host cells.
Highly infectious Omicron descendants do not rely on PNNAb-dependent enhancement of infection to enter target host cells. Replication of highly infectious variants generates an immunological environment that promotes their adsorption onto tissue-resident DCs. Progeny virus produced by newly emerging, more transmissible Omicron descendants (e.g., members of the JN.1 clan) will increase its adsorption onto migratory DCs and thereby reduce viral uptake by APCs. Reduced viral uptake by APCs promotes priming of noncytolytic T cells. Some of these T cells may be self-reactive, while others are foreign-centered but fail to serve as T helper cells to assist in boosting of previously SIR-primed Abs due to a lack of immune recognition of the corresponding S-associated B cell epitopes comprised within large Ab-coated virus complexes (so-called ‘noncognate’ T cells). Diminished boosting of previously primed anti-S Abs results in diminished production of PNNAbs.
As these more transmissible variants (i.e., all descendants from JN.1) emerge, enhanced binding of PNNAbs to their DC-tethered progeny virions leads to a steadily increasing immune pressure on viral intra-host transmissibility (i.e., viral virulence) in highly Covid-19 (C-19) vaccinated populations. This could eventually lead to the selection of a new Coronavirus lineage that has the capacity to cause PNNAb-mediated enhancement of vaccine breakthrough infections in highly C-19-vaccinated populations, thereby causing a massive wave of enhanced severe C-19 disease.
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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