A recent study published in the latest issue of Immunity explored key vaccine features which could help induce and preserve humoral immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Several aspects of humoral immunity elicited in response to primary SARS-CoV-2 infection or vaccinations are unknown. Moreover, there is no consensus on the duration and breadth of the protection conferred by humoral immunity or how long booster vaccination confers protection.
About the study
In the present study, the author explored a framework that could help preserve the duration and breadth of immunity conferred by coronavirus disease 2019 (COVID-19) vaccines reliably. In this context, previous studies that evaluated vaccines against other infections could provide invaluable cues and lessons.
Neutralizing antibodies (nAbs) are unlikely to represent the sole mechanism of immune protection. Consequently, SARS-CoV-2 variants such as Omicron easily evade nAb epitopes. Moreover, nAb production often declines, or its levels wane quickly.
According to the author, while frequent boosters, for instance, every few months, could maintain adequate nAb levels, this isn’t a realistic strategy.
Therefore, it is important to understand and learn from how the inherent host-elicited immune response varies across different vaccines, irrespective of their adequacy to confer protection against the pathogen involved.
After the initial decline/waning, as is seen in response to all vaccines, immunoglobulin (Ig) production can become stable. For instance, nAb-mediated immunity in the recipients of the human papillomavirus (HPV) vaccines is life-long. However, the same does not hold true for most vaccines, including the COVID-19 vaccines. The precise lifespans of the plasma cells that emerge post-immunization are accountable for these differences.
A large fraction of long-lived plasma cells are exported from germinal centers (GCs) to reside in the bone marrow, via C-X-C motif chemokine receptor 4 (CXCR4) and sphingosine-1-phosphate receptor 1 (S1PR1)-dependent chemotaxis. The bone marrow also houses shorter-lived cells. For instance, influenza vaccines lead to the development of plasma cells that fail to persist for more than a few months. In vitro studies have shown that blood plasmablasts have different survival rates depending on the nature of the vaccine or infection. Overall, the infection type and vaccine most likely intrinsically affect the lifespan of plasma cells.
The cluster of differentiation 19 (CD19) is a reliable but not a perfect marker for human plasma cells. B-lymphocyte-induced maturation protein 1 (BLIMP1) can also distinguish between early plasmablasts and mature plasma cells. GC reactions also seem to define the longevity of plasma cells.
Accordingly, in the absence of programmed cell death protein-1 (PD-1)-mediated interactions with T follicular helper (Tfh) cells, plasma cells with only the highest affinity persist durably. Similarly, Tfh-made interleukin-21 (IL-21) is required for durable IgG responses.
Although it still remains challenging to distinguish short- and long-lived plasma cells and compare them at the transcriptional level due to a lack of methods and markers, it is evident that plasma cell longevity is associated with the nature of the vaccine or infection.
A landmark by Amanna et al. tracked antibody titers following different infections and vaccines for decades, allowing an accurate estimation of the half-lives of the produced antibodies and long-lived plasma cells. The study demonstrated half-lives of ~10-20 years of antibodies produced after diphtheria and tetanus toxoid vaccines. Similarly, smallpox and yellow fever vaccines elicited long-lasting antibodies. Conversely, seasonal influenza vaccines elicited antibody production for less than a year. To summarize, the nature of the antigenic exposure appears to determine plasma cell lifespan.
The antibody repertoires of memory B cells and long-lived plasma cells are not consistent in humans. Nevertheless, data suggest that the duration of antibody production is directly linked to the lifespan of plasma cells, which in turn appears to be associated with the specific vaccine or infection. However, data does not indicate why certain types of responses are long-lived while others are not.
It is noteworthy that the Ad26.CoV2.S COVID-19 vaccine induces fewer nAbs initially but those nAbs are persistent over time. Since early antibody kinetics are not predictive of the duration of immune production, it is important to determine vaccine traits that influence the molecular programs governing plasma cell lifespan.
Autopsies of lymph nodes of patients with severe COVID-19 showed few well-organized GCs, likely due to an absence of Tfh cells. The excessive inflammation seen in severe COVID-19 might inhibit GCs, thereby prolonging the extrafollicular short-lived antibody response. This data suggests the right amount of inflammation is needed to drive an optimal antibody response.
Furthermore, the kinetics of antigen delivery influence GC and plasma cell persistence. Therefore, a slower delivery or repeated injections of small doses of antigen leads to substantially prolonged GCs and continuous improvements in antibody affinity. Persistent GCs could induce durable humoral immunity in several ways. For instance, the nature of the GC changes over time to promote plasma cell longevity in correlation with changes in the cytokine profiles of Tfh cells. Notably, mRNA-based COVID-19 vaccines also induce GCs detectable for months.
Antibodies against the SARS-CoV-2 nucleocapsid (N) protein seem to wane more quickly than those against the spike (S) receptor-binding domain (RBD). Similarly, after a booster dose, cross-neutralizing antibodies are lost preferentially over time relative to other variant-specific antibodies.
B cell receptors (BCR) with high avidity expand clonally in GCs and are more resistant to apoptosis than their lower affinity counterparts. Moreover, they are more likely to become long-lived plasma cells. The mRNA and adenovirus COVID-19 vaccines should, therefore, carry immunogens with enhanced valency to qualitatively improve GCs and antibody responses.
Memory B cells more readily give rise to long-lived plasma cells justifying strategies to improve both the magnitude and durability of antibody production with multiple vaccine doses and boosters. For instance, the third dose of a Japanese Encephalitis vaccine enhanced the durability of subsequent antibody production.
Overall, the present study showed that by taking cues from past successes with vaccines against several diseases, researchers should measure and define key features of COVID-19 vaccines. This would be an effective way to elicit broad and long-lasting immunity through these vaccines.