Non-Spike, T Cell directed vaccines! In clinical trials! Lead Foil Hat? Covidicy? Excited?
Co-administration of the original spike vaccine along with a new mRNA encoding parts of the N, S and ORF1ab... worked very well.
In vivo, BNT162b4 generates robust, multifunctional T-cell responses against three antigens in multiple mouse models. The combination of BNT162b4 and BNT162b2 broadens the antigen-specific T-cell repertoire but does not negatively impact the BNT162b2 induced neutralizing antibody response against the S protein. Similarly, co-administration of BNT162b4 with BNT162b2 does not impair the repertoire, frequency, and functional phenotype of S-specific T cells induced by BNT162b2. However, a decrease in cytokine secretion in N- and M- specific T cells is detected when BNT162b4 is given in combination with BNT162b2 compared with BNT162b4 alone. This may indicate some competition between the responses to the S protein versus the responses to N and M proteins. While the exact reason is unknown, it could potentially be caused due to differences in epitope abundance and presentation of BNT162b2 versus BNT162b4 epitopes or immunodominance of S-specific T cells. It is important to note that despite this potential interference, BNT162b4 broadens the total T-cell responses to additional SARS-CoV-2 antigens.
Most importantly, we found that the immunity induced by BNT162b4 reduces disease severity in a SARS-CoV-2 hamster challenge model across various viral variants. Combining BNT162b2 with BNT162b4 enhances the protection against viral challenge, and this added benefit is most clearly demonstrated when hamsters are challenged with the Delta variant which is characterized by a more severe disease pathology. The ability for viral-specific T cells to directly protect against severe disease has been suggested in several studies through correlations and preclinical experiments. Here, we directly demonstrate that the addition of the T-cell-targeting vaccine component BNT162b4 further enhances immune protection to that conferred by BNT162b2 when the two are combined, as measured through lower viral titers, improved lung pathology, and a decrease of weight loss seen in animals challenged with SARS-CoV-2 variants. Interestingly, when animals are challenged by the WT strain or the Delta variant, BNT162b4-driven immune responses confer protection that appears to be particularly influential in nasal turbinates, potentially suggesting a role for increased immunity in the mucosal membrane, where accessibility to IgG is limited and offers less protection. When animals are challenged with the Omicron BA.1 variant, the lack of detection of reduction in viral titers could potentially be due to the lower overall viral burden of the variant or the lower inflammatory response associated with the Omicron strain.
The protection in the upper respiratory tract offered by the addition of BNT162b4, whether through the presence of tissue-resident memory T cells or T-cell migration upon infection is particularly attractive, as it could point to a potential for a decreased transmission rate. This phenomenon is similar to a study which suggested that T-cell responses to ORF1ab polyprotein could give rise to more abortive infections, potentially through targeting of early infected cells. Potent memory T-cell responses activated rapidly following infection would likely mean less time for intra-host viral spread and activation of immune-evasion mechanisms.
