Interestingly, we observed important heterologous effects of BNT162b2 vaccination on IFN-γ production induced by other stimuli as well (Figures S2E, 2F).
BNT162b2 vaccination decreased IFN-γ production upon stimulation with the TLR7/8 agonist R848 (Figure S2F).
In contrast, the IFN-γ production induced by inactivated influenza virus tended to be higher two weeks after the second BNT162b2 vaccination, though the differences did not reach statistical significance.
Besides their effects on specific (adaptive) immune memory, certain vaccines such as Bacillus Calmette-Guérin (BCG) and the measles, mumps, and rubella (MMR) vaccine also induce long term functional reprogramming of cells of the innate immune system. (Netea et al., 2020).
This biological process is also termed trained immunity when it involves increased responsiveness, or innate immune tolerance when it is characterized by decreased cytokine production (Ifrim et al., 2014).
Although these effects have been proven mainly for live attenuated vaccines, we sought to investigate whether the BNT162b2 vaccine might also induce effects on innate immune responses against different viral, bacterial and fungal stimuli.
Surprisingly, the production of the monocyte-derived cytokines TNF-α, IL-1β and IL-1Ra tended to be lower after stimulation of PBMCs from vaccinated individuals with either the standard SARS-CoV-2 strain or heterologous Toll-like receptor ligands (Figures 1 and 2).
TNF-α production (Figure 1B-1G) following stimulation with the TLR7/8 agonist R848 of peripheral blood mononuclear cells from volunteers was significantly decreased after the second vaccination (Figure 1C).
The same trend was observed after stimulation with the TLR3 agonist poly I:C (Figure 1D), although the difference did not reach statistical significance
In contrast, the responses to the fungal pathogen Candida albicans were higher after the first dose of the vaccine (Figure 1G).
The impact of the vaccination on IL-1β production was more limited (Figure 2A-2F), though the response to C. albicans was significantly increased (Figure 2F).
The production of the anti-inflammatory cytokine IL-1Ra (Figure 2G-2L) was reduced in response to bacterial lipopolysaccharide (LPS) and C. albicans after the second vaccination (Figure 2K, 2L), which is another argument for a shift towards stronger inflammatory responses to fungal stimuli after vaccination.
IL-6 responses were similarly decreased, though less pronounced (data not shown).
The induction of tolerance towards stimulation with TLR7/8 (R848) or TLR4 (LPS) ligands by BNT162b2 vaccination may indicate a more balanced inflammatory reaction during infection with SARS-CoV-2, and one could speculate whether such effect may be thus useful to regulate the potential over-inflammation in COVID-19, one of the main causes of death (Tang et al., 196 2020).
On the other hand, inhibition of innate immune responses may diminish anti-viral responses.
Type I interferons also play a central role in the pathogenesis and response against viral infections, including COVID-19 (Hadjadj et al., 2020).
With this in mind, we also assessed the production of IFN-α by immune cells of the volunteers after vaccination.
Although the concentrations of IFN-α were below the detection limit of the assay for most of the stimuli, we observed a significant reduction in the production if IFN-α secreted after stimulation with poly I:C and R848 after the administration of the second dose of the vaccine (Figure 1H, 1I).
This may hamper the initial innate immune response against the virus, as defects in TLR7 have been shown to result in and increased susceptibility to COVID-19 in young males (Van Der Made et 205 al., 2020).
These results collectively demonstrate that the effects of the BNT162b2 vaccine go beyond the adaptive immune system and can also modulate innate immune responses.