Comments on: mRNA vaccine-induced antibodies more effective than natural immunity in neutralizing SARS-CoV-2 and its high affinity variants | Scientific Reports (nature.com)

Here the article: mRNA vaccine-induced antibodies more effective than natural immunity in neutralizing SARS-CoV-2 and its high affinity variants

First, this study compares the potency of mRNA vaccine-induced antibodies (Abs) and naturally induced Abs in a sophisticated biochemical RBD neutralization assay (so, not an in vitro virus-neutralization assay) that assesses RBD neutralization potency towards variants that only differ by their level of infectiousness but not by their level of resistance to anti-SC-2 (anti-SARS-CoV-2) neutralizing Abs. As the level of SC-2 infectiousness correlates with the strength of binding of RBD to ACE-2, an enhanced level of SC-2 infectiousness enables ACE-2 to outcompete neutralizing Abs that bind in high concentration to RBD (i.e., targeting a limited set of RBD-binding sites). However, an enhanced level of SC-2 resistance to virus neutralization enables ACE-2 to outcompete neutralizing Abs that bind with high affinity to RBD (i.e., targeting a diversified set of RBD-binding sites). In other words, it's not the quantity of RBD-neutralizing Abs but the quality (i.e., their affinity!) that will determine the capacity of the host  immune response to resist immune-evading viral mutations. It has been shown that naturally induced Abs neutralize a broader spectrum of viral variants in comparison to mRNA-induced Abs, which is likely due to their higher level of affinity maturation (https://www.science.org/doi/pdf/10.1126/science.abg9175).

As mRNA vaccine-induced Abs have lower affinity than naturally induced Abs, it is reasonable to assume that they can more easily be outcompeted by innate Abs, especially when innate IgM-producing B cells are trained due to previous SC-2 exposure; This could already explain why the effectiveness of the vaccine has now been reported to be negative across all age groups (https://www.bitchute.com/video/b6l1NY2uPN04/). Of course, the current study did not allow for assessing competition between acquired or innate Abs for binding to the virus as the substrate consisted of recombinant RBD, not of whole virus. Since mRNA-induced Abs have lower affinity than naturally induced Abs, they are also more likely to exert suboptimal immune pressure on the infectiousness of viral variants that escape from virus-neutralizing Abs.   In addition, the mRNA vaccine-induced Abs declined much faster than the naturally induced Abs. This resembles results obtained with intravenous immunization and might be due to lack of stimulation of long-lived Ab-secreting cells. 

The title of this paper is misleading as it suggests that mRNA vaccine-induced Abs have a better SC-2-neutralizing capacity as compared to naturally induced Abs. The title doesn’t reflect the true conclusion of this study (see abstract), namely that mRNA vaccination generates more RBD-neutralizing Abs (as assessed by a biochemical neutralization assay) than natural immunity. The binding affinity of these Abs has not been tested. The strong correlation observed between RBD-neutralizing capacity and the total quantity of anti-RBD Abs already indicates that binding differences in RBD-neutralizing capacity merely depend on the concentration but not on the affinity maturation of anti-RBD Abs. However, the assumption that ‘the more is always better’ rarely applies to immunization strategies. In the current study, ‘the more, the better’ principle was only shown to apply to the RBD-neutralizing capacity of sera directed at variants with enhanced infectiousness but which did not exhibit mutations conferring resistance to neutralizing Abs. 

The limitations of this study as acknowledged by the authors themselves (see below in italics) are such that even their suggestion that natural immunity may not provide sufficient neutralization against a more infectious variant from binding to the cellular ACE2 receptor and that mRNA vaccination may be superior in neutralizing more infectious variants cannot be taken seriously as a rule of thumb. This would definitely not apply to viral variants that combine both a high level of infectiousness and mutations to neutralizing antigenic sites (e.g., Omicron). 

Last, it should also be noted that – alike vaccinal Abs - naturally induced Abs gain their optimal functionality upon re-exposure to the virus. Because of immunologic memory, previously naturally primed subjects will be able to rapidly recall high affinity Abs. Because these Abs will be recalled very rapidly and reach high titers, their protective/ neutralizing capacity is much higher than that of the Abs in convalescent sera. The latter merely indicate that the virus has – to some extent –- broken through the innate immune defense and are, therefore, only a marker of immunity and not a surrogate or even a correlate of protection. Individuals with strong innate immunity develop asymptomatic or mild infection and may not generate any neutralizing Abs at all (https://www.nature.com/articles/s41591-020-0965-6; https://www.nejm.org/doi/full/10.1056/nejmc2025179; https://pubmed.ncbi.nlm.nih.gov/32805631/); and those who do will develop high titers of neutralizing Abs upon re-exposure. Consequently, the study should not have used convalescent antisera but sera from naturally boosted subjects as a comparator.    

‘Likely many other surrogate biomarkers for a medical intervention on a disease, our in vitro receptor-binding neutralization has its limitations. There are factors that cannot be represented in this model. These include the 3D structures of the viral spike protein and ACE2, the surface density of both molecules, the process of viral entry into the cells and more. In addition, the mutation profiles of the variants are drastically simplified in our model. Other RBD mutations, K417N/T and E484K, either alone or in combinations, have not been evaluated in this study. Moreover, the IC50 values that we obtained with in vitro RBD-ACE binding assay, while biochemically informative, is not equivalent to an in vivo protective level. Besides, the quantification of RBD antibody levels of antisera is based on the calibration of a monoclonal antibody for consistency and universal adaptability, where the polyclonal nature of the antisera may be simplified’.

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In conclusion:

• The current study did not compare the affinity of naturally acquired versus mRNA-vaccine induced RBD-neutralizing Abs  
• The study compared the RBD-neutralizing capacity of vaccinal Abs from boosted individuals to naturally induced Abs from primary infection (convalescent sera) whereas the RBD-neutralizing capacity in naturally infected subjects should have been assessed in sera from individuals who were naturally boosted by way of re-exposure to the virus.
• The study used a biochemical neutralization assay instead of an in vitro virus-neutralization assay as a basis for comparison of naturally acquired versus mRNA-vaccine induced Abs
• The study did only include variants of higher infectiousness but not variants endowed with mutations that are resistant to neutralizing Abs.  
• Neutralizing antibodies, and therefore RBD-neutralizing Abs, are only a marker of immunity but not of protection to SARS-CoV.
• The assay described is useless in terms of comparing the protective capacity of naturally acquired immunity and vaccine-induced immunity towards emerging variants. This is because naturally acquired immunity is largely built on (trained) innate immunity, which cannot be measured by the described RBD-neutralizing assay. In contrast to C-19 vaccine-induced immunity, innate Abs produced by long-lived plasma cells enable virus elimination and, therefore, abrogation of viral infection. This biochemical assay does, therefore, not allow to assess the effectiveness of natural immunity towards re-infections by new variants with higher affinity to their cell receptors, let alone to compare natural anti-SC-2 immunity to that conferred by mRNA vaccine-induced immunity.
• Due to all of the above, the suggestion of the authors that vaccines capable of inducing higher antibody levels could improve virus neutralization and protection from future variants is simply wrong. On the contrary, as innate immune effector cells largely contribute to natural anti-CoV immunity, the latter will always be superior to C-19 vaccine-induced immunity. This is because innate CoV-reactive immune effector cells enable sterilizing immunity towards all SC-2 variants (even including all CoV) and can be trained such as to acquire a type of memory (via epigenetic reprogramming) that provides an even better immune protection upon future viral challenge without risk of promoting immune escape.