As the BM is not connected to the lymph circulatory system but only the blood circulatory system, the BM might be an important factor for controlling systemic infections. Besides CD11c
+ dendritic cells, neutrophils have also been described as a source of antigen transport to the BM
[107][31]. Specifically, virus from the dermis is carried to the BM and induces CD8
+ T-cell responses. Along with these primary immune responses, secondary immune responses where memory CD4
+ T-cells are reactivated by antigen have been observed to cause aggregation of immune clusters between MHC II expressing cells and antigen-specific T-cells in the BM
[131][32]. The MHC II expressing cells were mostly defined as B lymphocytes. This process amplified the T-cell memory and following the termination of the immune reaction, the CD4
+ memory T-cells remained in the BM. These reactions were autonomous to the BM, ergo independent of immigrating T-cells. Even though B-cells were involved, no humoral memory adaptation or GC formation was detected. Furthermore, the expression of signature genes of follicular helper T-cells was significantly lower than in the spleen, indicating a non-follicular reactivation. However, there is some evidence, that dendritic cells may activate CD4
+ T-cells and license them to differentiate into resting memory cells in the BM during primary immune responses, while some activated CD4
+ T-cells interact with bystander B-cells as a follow up to the initial antigen presentation, leading to their differentiation into T
FH (Figure 3)
[110][33]. Furthermore, some studies suggest that BM memory CD4
+ T-cells can differentiate into T
FH cells during a recall response, indicating that some are committed to the T follicular helper lineage
[120][34]. T
FH cells are important for many processes typically associated with SLOs. Memory T
FH cells are most likely sustained by a persistence of antigens, potentially via CD11c
+ or B-cell presentation
[132][35]. On the other hand, BM resting memory CD4
+ T-cells are typically independent from antigen signals; hence, the ratio of T
FH cells and BM resting memory cells might be affected by antigen persistence. Interestingly, while T
FH cells play an important role in promoting plasma cell survival in SLO via production of IL-21, the plasma cell maintenance in the BM is independent of T
FH support as BM plasma cells do not express IL-21R
[133][36]. Overall, while the BM has some competences of a SLO, it is not capable of fulfilling the complete role of a SLO. However, it is unique in the sheer amount of functions it has to implement, being capable of performing primary and secondary immune functions and hemato- and lymphopoiesis. Particularly, the systemic immune control of blood-borne antigen heavily relies on the BM.
5. The Relevance of the BM for Vaccinology
5.1. Disparity between Memory Established by Natural Infections and Vaccination
Considering the importance of the BM in long-lasting immunity, it is very interesting to take a close look at its role in vaccination. While some vaccines are able to induce life-lasting immunity, others have to be refreshed every year. Additionally, comparing a vaccine to its natural infection often reveals big differences in the quality of the immune reaction. This disparity is especially pronounced in current influenza vaccines, as they are especially bad at eliciting a long-lasting immune response, sometimes not even protecting for the whole flu season. Rafi Ahmed’s group elucidated this phenomenon by collecting blood and BM samples at multiple points in time of individuals receiving the inactivated influenza vaccine
[134][37]. They showed that BM plasma cells elicited by the influenza vaccine were only short lived, typically lost within a year. Interestingly, the initial BM plasma cell induction was good, indicating that the quantity of plasma cells induced was not the issue at hand. As it appears that the intrinsic potential of plasma cells and the quality of the survival niche received in the BM determine the longevity of plasma cells (discussed earlier in this review), one or even both factors are not sufficiently achieved with current influenza vaccines. An inadequate CD4
+ T-cell response, whose support is needed for the induction of long- lasting immunity, could also play a role.
On the other side of the spectrum are live-attenuated vaccines such as the ones for MMR (measles, mumps, rubella) or smallpox, which elicit strong cellular and humoral immune responses often lasting for several decades
[135,136][38][39]. What makes this type of vaccine advantageous when it comes to longevity and protective capability and how to transfer these properties to other vaccine technologies is intriguing to investigate, as other types of vaccines are often preferred for safety and manufacturing reasons. One of the advantages of live-attenuated vaccines is that they signal through many different pattern recognition receptors (PRRs), resulting in strong immunogenic capabilities
[137][40]. As full virus particles are able to initiate a bigger variety of PRRs, vaccines that preserve the full virus particle tend to be more immunogenic. For example, virus-vector vaccines, such as the ones based on adenoviruses, appear to be very potent when it comes to the induction of CD8
+ T-cell response
[137,138,139][40][41][42]. Considering the aforementioned connection between BM memory CD8
+ T-cells and neutrophils, this might partly be achieved by means of activating neutrophils via stimulation of their PRRs, promoting the efficient transportation of antigen toward the BM where a potent systemic immune response can be mounted
[107][31]. Adjuvants are often able to make up for the lack of PRR engagement and are therefore hugely important for an efficient vaccine formulation, especially for non-live-attenuated vaccines
[140,141][43][44].
5.2. Possible Indications for a SARS-CoV-2 Vaccine
Despite worldwide efforts, thousands of lives are still lost every day to the coronavirus disease 2019 (COVID-19) pandemic, with no end in sight
[151][45]. The development and deployment of a vaccine is essential to stop suffering and return to a normal way of living, and the scientific community has reacted accordingly, with currently more than 180 vaccines at various stages of development
[152][46]. The induction of protective immune memory could prove difficult to achieve as the antibody response toward the virus’ spike protein is very varied
[153,154,155][47][48][49]. However, similar to other respiratory viruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appears to induce an initial surge in virus-specific plasmablasts leading to an increase in the SARS-CoV-2 targeting antibody levels, followed by a decline and stabilization at a baseline. These stabilized antibody serum levels are maintained by long-lived plasma cells and will decide if the individual is protected against re-infection
[155,156][49][50]. Indeed, studies in non-human primates (NHPs) demonstrated that neutralizing antibodies, but not T-cell responses, correlated with protection
[157][51]. Furthermore, investigating an outbreak of SARS-CoV-2 on a fishing vessel provided evidence that neutralizing antibodies protect humans from SARS-CoV-2 infection
[158][52]. While mucosal antibodies are induced by the virus
[159][53], mucosal immunity typically does not last long, whereas systemic memory can be maintained for extensive periods of time
[150][54]. All of this indicates that the induction of BM resident long-lived plasma cells is key for an effective SARS-CoV-2 vaccine. Looking at the current frontrunners for a successful SARS-CoV-2 vaccine race, two doses of a vaccine will most likely be required in order to elevate the antibody serum levels above the needed threshold
[152][46]. Additionally, booster doses might become necessary at later time points to keep up protective antibody levels. This shows that even with the enormous budgets for COVID-19 research and the modern vaccine technology applied, the induction of long-lived plasma cells can be tricky. More in-depth knowledge about their recruitment is required in order to accelerate the development of vaccines against this and subsequent pandemics.