Thread by @vipintukur

Do mRNA vaccines induce antibody-dependent enhancement (ADE)-causing antibodies also?

We know mRNA vaccines generate robust neutralizing Abs, but vaccines targeting the S-protein, the possible induction of ADE of infection is a concern. 1/

Recent reports have demonstrated that neutralizing #mAbs against S-protein can exhibit ADE activity in a limited window of Ab concentrations. These reports have demonstrated that some anti-S protein mAbs have the potential to induce ADE of infection. 2/

Several mechanisms leading to #ADE, which can be FcR-dependent but ACE2-independent, FcR-independent but ACE2-dependent, S-protein conformational change-dependent, or both FcR- and ACE2-dependent ADE. 3/

In a recent Japanese study, the researchers investigated sera from mRNA (Moderna)-vaccinated individuals in terms of ADE-causing potential by using the FcR- and ACE2-dependent positive cell lines. 4/

They find that individuals vaccinated with the mRNA vaccine targeting the S-protein also exhibited ADE potential against infection with the original strain. 5/

Although sera collected from mRNA-vaccinated individuals exhibited neutralizing activity, some sera gradually exhibited dominance of ADE activity in a time-dependent manner. 6/

It has been reported that neutralizing Abs induced after mRNA vaccinations decrease in a time-dependent manner. Accordingly, there is a diminishing neutralizing activity in some vaccinated individuals in a time-dependent manner 7/

Simultaneously, the dominant ADE activity was observed at high concentrations of serum. This situation, i.e., observed ADE without neutralization at a low dilution of serum, is unfavorable for protection against infection. 8/

However, it must be remembered that, in contrast to the above-mentioned Ab-involved adverse events, protective cellular immunity is also induced and is involved in anti-SARS2 responses in vivo 9/

Therefore, as a whole, this Ab-mediated adverse potential during virus expansion and the opposing protective effects by T-cell immunity might make it more difficult to recognize the involvement of ADE in SARS2 reinfection or resurrection in vivo. 10/

Some sera from mRNA-vaccinated volunteers (collected on day 175 after 2nd dose) maintained neutralizing activity against the SARS2 original strain. In contrast, none of these sera exhibited neutralization, and some of them even caused enhancement of infection with Omicron 11/

These results demonstrate that Abs raised by double vaccination (at least on day 175 after the second vaccination) are less effective against Omicron. 12/

Omicron strain has acquired the ability to escape attack by pre-existing anti-SARS2 Abs and in part can utilize infection-enhancing mechanisms, possibly including ADE, as a means of survival. 13/

At this time, we need to further investigate what the critical factors are that are included in sera and lead to the enhancement of Omicron infection. 14/

Although Omicron has many amino acid substitutions in the RBD of the S-protein, the receptors (ACE2) on target cells seem to still be required for infection. In fact, it has been reported that Omicron S-protein has high affinity for ACE2. 15/

The unique mechanisms of Omicron infection, such as altered TMPRSS2 usage, still need to be elucidated, and these unique features can be utilized in the development of new drugs. 16/

Coming to the other arm of the study:

We know that certain monoclonal Abs (mAbs) approved as therapeutic neutralizing anti-S-protein mAbs for human usage have the potential to cause ADE in a narrow range of Ab concentrations. 17/

The researchers show that certain mAbs like casirivimab and imdevimab mAbs have the ability to induce ADE, but other like sotrovimab does not. 18/

It is not currently clear what critical factors are responsible for the lack of ADE in the case of #sotrovimab mAb, that is, the target epitope, modification of Fc, or both. 19/

The results suggest that the concentration of Ab is more critical than the amount of virus in inducing either neutralization or ADE as a whole. 20/

So, the results of the above study raise the possibility that SARS2 mRNA vaccines targeting the S-protein also induce ADE-causing Abs as well as neutralizing Abs. 21/

These results also suggest that the rapid spread of Omicron around the world may in part result from the lack of cross-neutralization against Omicron and some ADE activity of sera after vaccination. 22/

Here is the link to above study 👇

nature.com/articles/s4159…