In two recent papers published in the journal Cell, researchers explored the germinal center (GC) of antibody (Ab)-mediated immunity towards severe acute respiratory syndrome coronavirus (SARS-CoV-2).
The coronavirus disease 2019 (COVID-19) pandemic has underlined the need for strong immunity to prevent infection, reduce infection severity, and preclude mortality after pathogen exposure. A major technique to mitigate the SARS-CoV-2 pandemic is the establishment of efficient vaccines that elicit long-standing protective immunity.
Vaccine effectiveness is predominantly regulated by long-lasting humoral immunity, which includes high-affinity memory B cells that recirculate and react quickly after exposure to the triggering antigen, and plasmablasts (PBs), which release neutralizing Abs. Further, contacts between T follicular helper (Tfh) cells and naïve B cells in GCs facilitate somatic hypermutation (SHM) and high-affinity antigen-specific B cells selection, required for the production of PBs and memory cells.
The quick generation of several COVID-19 vaccines during the ongoing pandemic has been a phenomenal success, resulting in a considerable and dramatic drop in SARS-CoV-2-related illness severity, and mortality. Contrary to other vaccinations or pathogens that can prevent infectious illnesses for decades, SARS-CoV-2 immunity is short-lived, with SARS-CoV-2-specific serum immunoglobulin G (IgG) levels dropping drastically from six to eight months following COVID-19 vaccination or disease.
Yet, immune responses specific to SARS-CoV-2 constantly evolve after infection, with extended IgG responses and memory B cell SHM correlated with fast recovery from COVID-19. This shows that effective and long-lasting GC reactions are required for protective humoral immunity against SARS-CoV-2. The receptor-binding domain (RBD) on the spike (S) protein, which promotes viral entry, is the target of most neutralizing Abs selective towards SARS-CoV-2. As a result, viral variants harboring S mutations have enhanced immune evasion properties and compromise host immunity.
The knowledge on correlates of long-lasting, widely reactive Ab-mediated immunity stimulated by SARS-CoV-2 vaccination or infection and how immunomodulation affects this is critical in enhancing the understanding of the prerequisites for protective immunity against COVID-19.
Two reports published in the sixth issue of Cell looked at the physiological birthplace of acquired immunity, i.e., GCs, to measure the breadth, specificity, durability, and magnitude of local and systemic Ab-mediated immune responses after spontaneous SARS-CoV-2 infection or COVID-19 vaccination.
1) Study on GC responses to COVID-19 mRNA vaccines in immunocompromised and healthy people
Lederer et al. investigated the immune cell microenvironment evoked in healthy persons following immunization with the messenger ribonucleic acid (mRNA)-based COVID-19 vaccine (BNT162b2) via analyzing lymph node (LN) aspirates. The study demonstrated a robust acquired immunity involving SARS-CoV-2-specific GC cells, PBs, T helper type 1 (Th1)-type Tfh cells, and memory B cells in LNs draining after initial COVID-19 vaccination, elevating further following the second dose. Blood samples revealed high concentrations of SARS-CoV-2 neutralizing IgG, SARS-CoV-2-binding PBs, memory B cells, and Tfh cells with higher proportions upon two vaccine doses.
Correlations were detected among levels of SARS-CoV-2-specific GC PBs and B cells, LN Tfh cells, and concentrations of total or neutralizing IgG, indicating that these cell types’ roles were non-redundant and interdependent. Interestingly, circulating Tfh cell proportions did not overlap with LN Tfh cells, other LN B cells, or blood cell subsets studied. This inference underlined the relevance and advantages of assessing immune responses within secondary lymphoid tissues, at least in the initial post-vaccine timespan.
To better understand the correlates for efficient SARS-CoV-2 immunity, the authors then studied the Ab-mediated immunity of COVID-19 vaccinated and immunosuppressed kidney transplant patients. Compared to healthy subjects, they had significantly fewer GC B cells and a lack of SARS-CoV-2-binding GC B cells in their LNs. Immunosuppressed patients also had significantly lower LN T cell subsets, memory B and PC cells, and lower serum IgG neutralizing ability.
2) Study on GC response following COVID-19 and its vaccination
Röltgen et al. investigated the underlying kinetics of SARS-CoV-2 vaccine responses. Following two doses of BNT162b2, there was an initial peak in anti-RBD IgG immune responses, which declined considerably within nine months but was surpassed after the third dose. SARS-CoV-2-specific IgG generated in uninfected persons by inactivated and adenoviral vector-based COVID-19 vaccines were lower than the BNT162b2 mRNA vaccine. Vaccination elicited an IgG-dominated immune response, with lower levels of other Ab isotypes (IgA, IgM), in contrast to spontaneous SARS-CoV-2 infection. These data suggest that, despite stronger IgG responses, the quality of vaccine-induced protection against reinfection may vary from natural SARS-CoV-2 infection.
The authors also demonstrated how the initial SARS-CoV-2 variant casts an “imprint” on the Ab response specific to the SARS-CoV-2. In the presence of considerable cross-reactivity across antigens, imprinting occurs, resulting in a secondary reaction that favorably increases responses towards the primary antigen. Although imprinting has benefits, immune responses target conserved yet non-neutralizing epitopes, thereby blocking responses against current variants, and causing destructive effects in the host.
Regardless of the SARS-CoV-2 variant inducing initial infection, imprinting happened. Imprinting toward SARS-CoV-2 Wuhan-Hu-1 RBD was more apparent in naturally infected people than in the vaccinated individuals, although immunity from natural infection broadened with time. Ongoing research should explore whether binding breadth corresponds with neutralization breadth against distinct variants.
Overall, both Lederer et al. and Röltgen et al. suggest that rather than SARS-CoV-2 infection, vaccination produces a better immune response owing to more S-specific GC production, which may allow widespread recruitment of germline B cell receptors (BCRs). Thereby, vaccines induce immune responses over more SARS-CoV-2 RBD epitopes.
However, numerous questions remain unattended by these reports, for example, whether boosters enhance immunity in immunocompromised people. The two investigations provide a basis for 1) analyzing real-time GC responses in humans and 2) determining the core non-redundant parameters for building widespread protective immunity against known and new pathogens, and 3) examining vaccine effectiveness.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
Tangye, S., Burnett, D., and Bull, R., (2022). Getting to the (germinal) center of humoral immune responses to SARS-CoV-2. Cell. doi: https://doi.org/10.1016/j.cell.2022.02.018 https://www.cell.com/cell/fulltext/S0092-8674(22)00198-2