Sick of the Mucosal Vaccine Magic Show

This is yet another publication on mucosal Covid-19 vaccines that recently made the rounds across social media: https://pubmed.ncbi.nlm.nih.gov/40859051/

When is this madness about mucosal vaccines going to end? Do these neophytes not understand that vaccinologists have been exploring this approach for decades and came to a clear NO-GO conclusion?

Of course, the idea of safely and effectively blocking the pathogen right at its portal of entry is highly appealing, just as the notion that antibodies directed against more conserved epitopes could provide cross-protection. But the absence of such vaccines on the market, or even in late-stage clinical development, is not because vaccinologists are blind or incompetent! It is because there are solid reasons why these vaccines fail to deliver in the field. In short:

• The immune memory induced by mucosal vaccines is short-lived. Unless you boost almost monthly, titers of ‘protective’ mucosal IgA antibodies (Abs) decline rapidly.

• sIgA production is localized and, therefore, cannot protect against systemic infection if the pathogen breaches the mucosal barrier.

• The use of adjuvants in nasal mucosa is risky, given the potential for retrograde migration into the olfactory bulb.

• As for the conserved S2 subunit: it is less accessible to the immune system (precisely why it is more conserved). To target it effectively, you would need very high neutralizing IgA Ab titers, which can be readily achieved in preclinical mouse studies with three doses within 3–4 weeks, but are rarely maintained at levels high enough to withstand infectious challenge beyond three months. This certainly applies when the vaccine-induced anti-S2 Abs are exclusively targeted at the conformationally prefusion-stabilized S2 protein and when other conserved proteins such as the N protein are included in the vaccine because after all, the more the better, right? Throwing in the N protein merely generates an immunological ‘decoy’ as it is not functionally relevant to the infectious process (i.e., it ‘distracts’ the immune system into mounting immune responses against a target that does not significantly contribute to viral entry, replication, or pathogenesis).

In practice, mucosal antibody titers decline too fast to reliably neutralize an incoming viral load in the field. Combined with the short-lived mucosal T cell memory, this means poor durability of protective sIgA responses. The consequence in real life is suboptimal immunity upon post-vaccination exposure. This is exactly the condition that drives viral immune escape, especially when such vaccines are deployed during a pandemic of an acute, self-limiting viral infection (e.g., SARS-CoV-2).

In other words: forget about this overhyped vaccine concept as a solution to end the ongoing immune escape pandemic. What a waste of time and resources! Any potential investors should better stay far away from this!