Two scientists, Dr. Jean-Marc Sabatier and Prof. Jacques Fantini*, explain why the third vaccine dose can have serious long-term side effects due to the “ADE” phenomenon (Antibody-dependent enhancement: facilitation of infection by antibodies). The benefit/risk ratio would be unfavorable. Explanations.
The immune response and variants of SARS-CoV-2
The immune response to SARS-CoV-2, whether natural or vaccine-induced, produces antibodies directed against the spike protein. In the case of mRNA vaccines, the only molecular target is the spike protein. In the case of natural infection with the virus, the immune response is directed against several viral proteins, including the spike protein. In all cases, the spike protein is therefore crucial. However, SARS-CoV-2 is an RNA virus that mutates a lot, and many mutations affect the spike protein, which disturbs its recognition by antibodies.
The original strain has become obsolete
In the case of the current mRNA vaccines (“Comirnaty” from Pfizer-BioNtech and “Spikevax” from Moderna), the spike protein produced in the vaccinee is that of the original 2019 (so-called “Wuhan”) virus strain. This strain of SARS-CoV-2 has become “obsolete” because it has not circulated for more than a year; it has been replaced by variants, including the Delta variant and its sub-variants, which are now in the majority worldwide. The loss of vaccine efficacy is thought to be due (at least in part) to the different structure of the spike proteins of the current variants compared to the original “Wuhan” virus strain.
Neutralization/facilitation balance differs between SARS-CoV-2 variants
In order to study this crucial aspect for the development of new vaccines in the future (so-called second generation), we have carried out a study on the regions of the SARS-CoV-2 spike protein recognized by “neutralizing” antibodies (which block infection by preventing the virus from attaching itself to human target cells) and “facilitating” antibodies (which, on the contrary, facilitate the infection of cells by SARS-CoV-2 and increase its infectivity according to a phenomenon called “ADE”).
By analyzing nearly one million SARS-CoV-2 genomes described in the Los Alamos database (June-October 2021), we found that the regions of the spike protein recognized by “neutralizing” antibodies are highly variable, while the regions of the spike protein recognized by “facilitating” antibodies are conserved in all currently known circulating variants. Thus, it appears that the evolution of SARS-CoV-2 has significantly affected the “neutralizing/facilitating” balance, which is now in favor of facilitation (“ADE” phenomenon).
More precisely, this molecular epidemiology study coupled with a structural analysis of spike proteins indicates that the balance between “facilitating” and “neutralizing” antibodies in vaccinated individuals is in favor of neutralization for the initial “Wuhan” virus strain as well as for the “alpha” and “beta” variants of SARS-CoV-2, but not for the “gamma”, “delta”, “lambda” and “mu” variants.
A new generation of vaccines
In order not to lose time in this global race against SARS-CoV-2, we decided to pre-publish our study on a dedicated “preprint” website, while submitting it (in parallel) for publication in a peer-reviewed international scientific journal. This approach could potentially help researchers advance the development of a new generation of effective vaccines without deleterious side effects on the human body.
We hope that future vaccine development will take into account such data in order to design novel vaccine formulations adapted to emerging SARS-CoV-2 variants (formulations, if possible, lacking ADE epitopes in the spike protein).
Towards optimization of mRNA vaccines?
A strength of mRNA vaccines is that they allow for relatively easy and rapid modification of the initial vaccine formulation to account for the evolution of the epidemic and for certain drawbacks that may not have been initially taken into account.
The “ADE” phenomenon is a typical case because while it is well known for animal viruses and many human viruses, including the coronaviruses SARS-CoV-1 and MERS-CoV, some scientists thought that SARS-CoV-2 could escape this rule. In fact, early feedback on vaccination did not reveal any “ADE” problems such as had been encountered, for example, during dengue virus vaccination campaigns.
Our results provide an explanation for this paradox by highlighting a previously unknown role of the D614G mutation (an aspartic acid residue replaced by a glycine residue at position 614 of the 1273 amino acid peptide chain of the SARS-CoV-2 spike protein) in this escape. Now that the “delta” variant (and its sub-variants) are well established, it appears vital to monitor these “ADE” phenomena in a particularly unfavorable context: progressive loss of immunity induced by the two doses of vaccines directed against the spike protein of the original “Wuhan” viral strain, in the face of variants that have, on the other hand, preserved the regions recognized by the “facilitating” antibodies.
In this context, does a 3ᵉ dose of vaccine appear appropriate? It would appear not, with an unfavorable “benefit/risk” ratio.
Would a new formulation of mRNA be indicated? It would seem that this is possible in the more or less near future.
In the end, it is the national health agencies that will decide, according to health (and possibly non-health) considerations.
*Jacques Fantini is Professor of Biochemistry and Molecular Biology at the University of Aix-Marseille. He is an honorary member of the Institut Universitaire de France (IUF)
*Jean-Marc Sabatier, Director of Research at the CNRS and Doctor in Cell Biology and Microbiology, affiliated with the Institute of NeuroPhysiopathology (INP), at the University of Aix-Marseille. Editor-in-Chief of the international scientific journals: “Coronaviruses” and “Infectious Disorders – Drug Targets” (DR)
* The authors are speaking in their personal capacity