Game-changing? What the heck! It’s not even close!

I came across some bold statements on X (Twitter) glorifying a new ‘Needle-Free COVID-19 (live attenuated) Intranasal Vaccine’ (https://scitechdaily.com/scientists-develop-game-changing-needle-free-covid-19-intranasal-vaccine/), so I decided to review the publication itself (https://www.nature.com/articles/s41467-024-51535-y) and basically found it confirmed what I had anticipated.

How immunologically ‘naïve’ can one be? Here’s a summary of my comments:

• ‘Antigenically broad immune responses’ alone do not guarantee protection against newly emerging immune escape variants. This is because neutralizing antibodies (NAbs) require a lag time of several weeks to reach their full neutralizing potential. Viral exposure during periods when NAbs have suboptimal titers or functionality—such as after primary vaccination or during declines in antibody (Ab) concentrations—promote immune selection pressure and, therefore, foster viral immune escape.

• Mucosal antibodies are typically short-lived, lacking longevity. Even neutralizing IgG Abs induced by this mucosal vaccine appeared to be not only short-lived but also individually very variable (and by the way, why were they measured in ‘arbitrary units’ ??).

• The preclinical studies conducted do not assess the role of cell-mediated innate immunity in the observed protection. Hence, one cannot rule out that vaccine-mediated cross-protection in hamsters and transgenic mice was largely conferred by innate effector cells.  

• Preclinical experiments in transgenic hACE2 mice may be misleading as some SARS-CoV-2 (SC-2) immune escape variants have the capacity to infect target cells through mechanisms not mediated by hACE2 (i.e., via non-hACE2-mediated viral entry).

• The infectious challenge studies were performed shortly after immunization and thus do not demonstrate the durability of immune protection.

• There is no indication whatsoever that the intranasal vaccine induced T cells with cytolytic activity against SC-2-infected cells. Furthermore, T cell-based immunogenicity does not equate to T cell-mediated immune protection!

• The cross-neutralizing titers (e.g., including SARS-CoV-1) are very low and are unlikely to be long-lasting. Cross-reactivity of poorly neutralizing Abs primarily promotes immune refocusing, thereby fostering viral immune escape.

• Protection studies in non-human primates are conspicuously missing. Why?

• The authors appear enthusiastic about the extremely high levels of the immune response/effector cells, which they label as ‘super-immunity.’ To me, this is concerning, as ‘more is better’ is rarely applicable in immunology.

Conclusion: The mucosal vaccine approach lauded by the authors would, at best, provide only short-lived protection outside a pandemic. It is not going to provide durable protection against SC-2 immune escape variants. On the contrary, it may actually promote the emergence of such variants if administered during this COVID-19 pandemic, which – by the way – hasn’t come to an end.