August 20, 2022

Novel bivalent C-19 vaccines: What does common immunological sense predict in regard to their impact on the C-19 pandemic?

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Bivalent mRNA booster candidates[1] have been developed as a next step in the development of C-19 vaccines to combat the virus; these new vaccines target the induction of a broader immune response than the original vaccines and have to some extent already been approved by regulatory authorities (e.g., FDA, MHRA).

One wonders though why studies conducted to test these new vaccines have only enrolled baseline seronegative participants whereas the new vaccines will predominantly be administered to people who have already been vaccinated with first generation C-19 vaccines. This is quite striking as usage of these updated C-19 vaccines to fight dominantly circulating Omicron variants in previously C-19-vaccinated populations is highly contra-indicated as it violates all basic principles of vaccinology. The latter dictate that infection-enhancing antibodies (IEABs), which are directed at a conserved antigenic site comprised within spike protein (S), will be rapidly re-stimulated by the Omicron-adapted S-based vaccine. While re-stimulation of these antibodies (Abs) will not require cognate T help (Th), priming of immune responses against variable and previously unrecognized antigenic motifs (so-called ‘epitopes’) of S is cognate T help-dependent and will therefore require uptake, processing, and presentation of the corresponding antigenic peptides (i.e., derived from those epitopes) by antigen-presenting cells (APCs).

As previously reported, C-19 disease in C-19 vaccinees is most likely mitigated by inhibition of trans infection of viral particles that are tethered to the surface of tissue-resident dendritic cells (which subsequently migrate to distant organs) and by strengthening activation of cytotoxic CD8+ T cells/ lymphocytes (CTLs) directed at a universal epitope comprised within S protein (; Both mechanisms are facilitated by IEABs that typically enhance receptor-mediated viral entry when anti-S Abs lose their neutralizing capacity due to growing resistance of SARS-CoV-2 (SC-2) variants. Sustained, Th-independent activation of CTLs will allow these lymphocytes to also recognize and kill APCs that cross-present (on MHC class I molecules) the universal, S-associated CTL epitope following uptake and processing of vaccinal antigen (Ag) by professional APCs (i.e., dendritic cells). This will prevent these APCs from priming Th-dependent Ab responses towards new (i.e., Omicron-specific) immunogenic B cell epitopes comprised within vaccinal Omicron-derived spike protein. More specifically, immune responses in healthy vaccinees not only sideline the innate immune response but also prevent APCs from inducing new adaptive immune responses either by blocking Ag uptake (i.e., due to adsorption of SC-2 particles to their surface) or preventing Ag presentation by killing professional APCs after they’ve internalized the vaccine-derived S antigen (comprising the conserved CTL epitope) as previously illustrated (see figure attached below).
Consequently, the immunological effect of vaccination in thoroughly C-19 vaccinated subjects is much different from that of a natural (breakthrough) infection. In the case of a breakthrough infection, the aforementioned defense mechanisms largely fail to result in APCs preventing trans infection or activating cytotoxic CD8+ T cells, and thus fail to protect the host against C-19 disease.
This implies that the immune system of a C-19 vaccinated person cannot rely on conventional Ag-presentation to enable immune recognition of new, S-associated epitopes unless the virus breaks through the host’s (temporary) immune defense facilitated by short-lived IEABs. However, increased frequency of re-infection (i.e., as a result of enhanced susceptibility of vaccinees to infection; leads to a reduced likelihood that the virus will break through the fragile, Th-independent immune defense of vaccinees. This in turn will lower the chances for the vaccinees to generate natural immunity against any new variant, or for that matter any new S-derived vaccinal antigen (i.e., regardless of the antigenic characteristics of the Omicron (sub)variant it originates from).


Updated C-19 vaccines comprising new mRNA- or protein-derived S-associated sequences of one or more Omicron (sub)variants will only further deteriorate the already dire consequences of C-19 mass vaccination—abundant cell surface-expressed and/ or free circulating S protein will cause a unilateral and potentially protracted recall of IEABs without priming neutralizing Abs against new Omicron-specific antigenic sequences in the vast majority of healthy vaccinees. Whereas the purpose of these novel vaccines is to enhance protection against continuously evolving variants, they will have exactly the opposite effect, in that they will enhance the evolutionary dynamics of the virus. Continued mass vaccination with novel Omicron-adapted vaccines will only increase population-level immune pressure on viral virulence by the IEABs (which currently have a virulence-inhibiting effect at the level of the lower respiratory tract). Large scale vaccination with these updated vaccines will merely expedite natural selection and expansion of SC-2 variants that will exhibit a high level of virulence and infectiousness in vaccinees, while sparing the unvaccinated from this impact.



Acute, self-limiting viral infections that don’t lead to systemic/severe disease (and possibly death) are terminated by
M(ajor) H(istocompatibility) C(omplex)-unrestricted, cytotoxic CD8+ T cells that have no memory and the activation of which is triggered by a universal, pathogen-nonspecific Tc epitope comprised within the spike (S) protein. Unless an infected person progresses to developing severe disease, this is what allows a fairly rapid recovery from disease after primary productive infection (and certainly before fully functional virus-neutralizing Abs peak) [according to 2a-2b-2c-2d pathway]. However, rather than stimulating de novo generation of new neutralizing Abs towards variants that escaped the neutralizing activity of vaccine-induced Abs, exposure of vaccinees to these immune escape variants will rapidly recall their non-neutralizing, infection-enhancing Abs (those are directed against an antigenic site that is conserved within the N-STD of all SC-2 variants).

In vaccinees with poor experience in fighting productive infection (and hence, poor training of their innate immune defense according to pathway 1a-1b-1c) prior to C-19 vaccination, infection-enhancing Abs[2] that are responsible for preventing severe disease by binding to DC-tethered virus (according to 3a-3b-3c-3d pathway) can synergize with strongly activated cytotoxic CD8+ Tc-mediated killing (3c’) to even prevent C-19 disease all together and hence, render vaccinees asymptomatic despite their high susceptibility to re-infection (B + C   D). As prevention of disease is not due to prevention of productive infection but to accelerated abrogation of infection, these vaccinees will continue to shed and transmit SC-2 upon re-infection.  Whereas innate immune effector cells are MHC-unrestricted and polyspecific (i.e., NK cells) and, therefore, don’t drive immune escape, the infection-enhancing-Abs are Ag-specific (i.e., S-specific) and – if sustained at high enough titers for a long enough time by a large part of the population – will promote natural selection of immune escape variants that can resist  the virulence-inhibiting capacity of these Abs. This is because vaccinees cannot prevent productive viral infection; consequently, the immune pressure they exert on viral virulence is suboptimal in that it cannot prevent the expansion in prevalence of immune escape SC-2 variants that have the capacity to overcome this immune pressure. Resistance of viral variants to the virulence-inhibiting activity of infection-enhancing Abs will inevitably cause Ab-dependent enhancement of severe disease (ADESD).  

[1] Based on both the original Wuhan variant and either Omicron subvariant BA.1 or Omicron subvariant BA.4/5 lineage

[2] As previously explained, the non-neutralizing, infection-enhancing Abs are currently hampering trans infection at the level of distant organs such as the lower respiratory tract; this is what’s currently exerting population-level immune pressure on viral virulence:

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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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