May 10, 2022

Wastewater-based epidemiology does not allow to predict the evolutionary dynamics of the Omicron pandemic

I take issue with the conclusions of a paper published in the peer-reviewed journal Science of the Total Environment under the title “Managing an evolving pandemic: Cryptic circulation of the Delta variant during the Omicron rise.” (

These authors tend to believe that wastewater-based epidemiology combined with mathematical modeling allows for making predictions in regard of the evolutionary dynamics of this pandemic:

According to the developed model, it can be expected that the Omicron levels will decrease until eliminated, while Delta variant will maintain its cryptic circulation. If this comes to pass, the mentioned cryptic circulation may result in the reemergence of a Delta morbidity wave or in the possible generation of a new threatening variant.”

One should - per definition -  always be careful and skeptical about conclusions and predictions proposed by scientists who don’t seem to have an in-depth understanding of the immunology involved!

Variants can only replace previous variants provided they have a higher level of INTRINSIC infectiousness! It’s not because Omicron is highly infectious in vaccinees (i.e., in the vast majority of highly vaccinated population such as the population of Israel) that Omicron will replace Delta in wastewater!  It has been published that diminished neutralizing capacity of anti-spike (S) antibodies (Abs)results in disproportionally high binding of non-neutralizing Abs to S-NTD (N-terminal domain of S protein), which explains enhanced susceptibility of vaccinees to breakthrough infection with Omicron but inhibits viral shedding and trans infection of Omicron at distant organs, including the lower respiratory and gastrointestinal tract, thereby reducing the incidence of severe disease in vaccinees (….). So, in other words, Ab-mediated enhancement of infection with Omicron in vaccinees does not translate into enhanced viral shedding from the gastrointestinal tract, which is the primary source of wastewater contamination.  On the other hand, diminished shedding in vaccinees is likely compensated by its prolonged duration due to a delay in viral clearance (…). Selective shedding of highly infectious Omicron in vaccinees causes Omicron detection levels in wastewater to rapidly increase to then level off at wastewater detection levels that are higher than those observed for Delta. However, as the amount of Omicron virus shed from the gastrointestinal tract of vaccinees is not determined by the level of Omicron infectiousness in these vaccinated individuals but by the percentage of the population that got vaccinated and because Omicron’s intrinsic infectiousness is similar to that of Delta and,therefore, shed in comparable amounts by the non-vaccinated fraction of the population, it is not surprising to find that – although shed at a somewhat higher concentration in a highly vaccinated population – the Omicron variant is not replacing the Delta variant unless the population were to become  vaccinated across all age groups (i.e., including children). Consequently, wastewater-based epidemiology does not supply a real-time image of viral infectivity / transmissibility in highly vaccinated populations as viral infectious behavior in such populations is not primarily determined by the intrinsic infectiousness of the viral variant but by Ab-mediated enhancement of viral infection in vaccinees.

In conclusion, monitoring of Delta and Omicron detection levels in wastewater restricts surveillance of prevalent variants to virus shed from the gastrointestinal tract and thereby ignores antibody-mediated mitigation of shedding. It, therefore, misrepresents differences in viral infectiousness, which is known to be very high for Omicron in a highly vaccinated population due to Ab-dependent enhancement of infection at the level of the upper respiratory tract.

Once again, mathematical modeling may be a challenging and fascinating exercise but is to be considered totally worthless when the immunological assumptions are wrong. It inevitably implies that the essence of the model predictions will also be wrong. There can be no doubt that population-level immune pressure on trans infection-inhibiting Abs is now paving the way for breeding variants that are not only highly infectious but also highly virulent in vaccinees. However, in contrast to what the authors of this publication believe, these new variants will not emerge from previous Delta variants. Delta does not enable highly vaccinated populations(e.g., the Israeli population) to exert immune pressure on viral virulence, simply because it is not fully resistant to potentially neutralizing anti-RBD Abs. So, please forget about any predictions derived from mathematical modeling that – despite lots of complexity – totally ignores the impact of population-level immune pressure on the infectious behavior of the virus. Such predictions are, of course, completely useless when it comes to understanding the evolutionary dynamics and management of a pandemic that has fully changed its natural course as a direct consequence of mass vaccination.      

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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.


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