
==== Front
Immune Netw
Immune Netw
IN
Immune Network
1598-2629
2092-6685
The Korean Association of Immunologists

10.4110/in.2024.24.e28
Review Article
Germinal Center Response to mRNA Vaccination and Impact of Immunological Imprinting on Subsequent Vaccination
https://orcid.org/0000-0002-9199-1000
Kim Wooseob 12
1 Department of Microbiology, Korea University College of Medicine, Seoul 02841, Korea.
2 Vaccine Innovation Center, Korea University College of Medicine, Seoul 02841, Korea.
Correspondence to Wooseob Kim. Department of Microbiology, Korea University College of Medicine, 73 Goryeodae-ro, Seongbuk-gu, Seoul 02841, Korea. wooseob@korea.ac.kr
8 2024
25 6 2024
24 4 e2830 1 2024
04 4 2024
29 4 2024
Copyright © 2024. The Korean Association of Immunologists
2024
The Korean Association of Immunologists
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Vaccines are the most effective intervention currently available, offering protective immunity against targeted pathogens. The emergence of the coronavirus disease 2019 pandemic has prompted rapid development and deployment of lipid nanoparticle encapsulated, mRNA-based vaccines. While these vaccines have demonstrated remarkable immunogenicity, concerns persist regarding their ability to confer durable protective immunity to continuously evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. This review focuses on human B cell responses induced by SARS-CoV-2 mRNA vaccination, with particular emphasis on the crucial role of germinal center reactions in shaping enduring protective immunity. Additionally, we explored observations of immunological imprinting and dynamics of recalled pre-existing immunity following variants of concern-based booster vaccination. Insights from this review contribute to comprehensive understanding B cell responses to mRNA vaccination in humans, thereby refining vaccination strategies for optimal and sustained protection against evolving coronavirus variants.

B-Lymphocytes
Vaccination
SARS-COV-2
Memory B cell
Germinal center
==== Body
pmcINTRODUCTION

Over the course of several decades, a multitude of infectious disease have persisted as significant threat to human well-being, constituting a considerable burden on public health. Vaccination is widely recognized as the most effective intervention to confer protective immunity against infectious diseases. Once protective immunity is achieved through vaccination, exposure to vaccine-matched virus will trigger a rapid and robust immune response. Vaccination proactively exposes our immune system to targeted pathogen Ags, thereby engendering the formation of immunological memory and significantly minimizing the occurrence of severe cases and fatalities.

The onset of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a substantial number of infections and fatalities with considerable societal and economic losses. To address this crisis, mRNA-based vaccines were developed, initially by Pfizer-BioNTech and Moderna, and administered at an unprecedented speed to millions of people worldwide. Compared to traditional vaccines composing of protein Ags, mRNA-based vaccines are composed of mRNA strands encapsulated in lipid nanoparticles. Initially authorized COVID-19 vaccines were designed to encode surface spike proteins of SARS-CoV-2, eliciting immune responses directed against them. Spike protein plays a pivotal role in facilitating entry of the virus into host cells by interacting with human angiotensin-converting enzyme 2 (1). In addition to mRNA-based vaccines, other distinct vaccine platforms were also developed, including adenovirus vector-based vaccines (AstraZeneca’s ChAdOx1, Johnson & Johnson-Janssen’s Ad26.COV2.S), adjuvanted protein vaccines (Novavax’s NVX-CoV2373), and inactivated virus vaccines (Sinopharm’s Covilo, Sinovac’s CoronaVac). Several study comparing B cell and Ab response to diverse vaccines in humans suggested that mRNA-based vaccines induce exceptional short-term neutralizing Ab response and formation of memory B cells (MBCs) (234). Although mRNA vaccines have demonstrated notable immunogenicity with protection rates surpassing 90% (56), SARS-CoV-2 has undergone rapid evolution, leading to continuous emergence of divergent variants of concern (VOCs). In this context, uncertainties persist regarding the capacity of mRNA-based vaccine to induce durable protective immunity and the strategy for efficiently updating vaccine Ags to confront emerging variant strains.

This review focuses on B cell and Ab response observed in humans following administration of SARS-CoV-2 mRNA-based vaccines. Firstly, we specifically examined the B cell response model primarily developed from murine models. We then extended our discussion to incorporate recent findings in humans who received SARS-CoV-2 mRNA vaccines. Secondly, we discussed how B cell immune system would respond to booster vaccination. Contrast to in context of primary vaccination, where de novo response occurs against novel Ag, pre-existing immunity competes with naive B cells to contribute to immune responses in subsequent vaccination. To understand the impact of pre-existing immunity on immune response to additional vaccination, we discussed the phenomenon of immunological imprintings and findings from studies on human B cell response to variants-based vaccine.

MAIN 1: GERMINAL CENTER (GC) RESPONSE TO mRNA VACCINATION

Formation of immune memory through GC responses

Throughout history, the core objective of vaccination has been to induce durable protective immunity (7). The effectiveness of vaccination primarily relies on the generation and function of effector B-cell subsets including MBCs and long-lived plasma cells (LLPCs). These effector B-cell subsets mainly derive from GCs, which are as distinct microanatomical structures within follicles of secondary lymphoid organs (89). The forthcoming section will provide a comprehensive examination of fundamental mechanisms and dynamics of GC reactions in response to immunization. Myriad findings and mechanisms underlying GC reactions have been elucidated through murine models employing model Ag system. Our primary objective here is to initiate a discussion on these findings, drawing comparison with those observed in humans.

The initiation of B cell response to vaccination necessitates encounters between B cells and Ags (Fig. 1A). These encounters typically occur in secondary lymphoid tissues located near the injection site (10). In humans, vaccination is typically administered in the deltoid muscle of the upper arm, an area that primarily drains into the lateral axillary lymph node (1112). Human GC reactions to vaccination were observed in draining axillary lymph nodes for at least 6 months following mRNA vaccination (1314151617). In secondary lymphoid tissues, B cells that have encountered Ags will move to the interface of the B cell follicle and T cell zone, where they can interact with cognate CD4+ T cells (Fig. 1B) (18). Upon receiving survival and co-stimulatory signals from cognate CD4+ T cells, B cells will then migrate to the center of the follicle to initiate GC reactions. Active GC reactions consist of two distinguished regions: a lymphocyte-rich dark zone and a light zone where lymphocytes are distributed among a network of follicular dendritic cells (FDCs; Fig. 1D). While GC B cells can intensively proliferate and diversify B cell receptor (BCR) repertoire through somatic hypermutations (SHMs) in the dark zone, GC B cells compete each other to get limited survival signals from FDCs and follicular helper T cells in the light zone (19). As results of competition, GC B cells with high affinity BCR will undergo positive selection and then return to the dark zone to undergo further rounds of SHMs and proliferation. GC B cells exhibit bidirectional migration between the dark zone and light zone, enabling them to undergo iterative maturation cycles including BCR diversification and affinity-based positive selection. This dynamic progression culminates in enhanced affinity of GC B cells towards Ags (8).

Figure 1 Dynamics of GC reaction.

The left figure illustrates the lymph node structure with afferent lymph vessels, T cell area, and B cell follicle. The right figure depicts dynamics and outcomes of B cell response in GC. (A) Pathogens entering the draining lymph node are recognized by naive B cells or, if pre-existing immunity is present, memory B cells. (B) Upon encounter with Ag, B cells undergo initial activation and proliferation, migrating to B cell-T cell boundary to interact with cognate T cells. (C) This interaction leads cognate B cells either to differentiate into plasmablasts or to relocalize back to the follicle and undergo GC reaction. (D) GC B cell undergo proliferation and somatic hyper mutation in the dark zone before exiting to the light zone. In the light zone, GC B cells with high-affinity BCR for Ags undergo positive selection processes mediated by both FDC and follicular helper T cells. (E) An interactive cycle of GC reaction generates LLPCs and circulating memory B cells. (F) Upon re-exposure to antigenically related pathogen, memory B cells reengage in GC reaction to undergo further affinity maturation. Right table presents the summary of dynamics and characteristics observed within indicated B cell subsets following SARS-CoV-2 mRNA vaccination or infection in humans.

Another outcome of GC reactions is the generation of effector B cell such as MBCs and LLPCs (Fig. 1E). These two types of B cells play pivotal roles in sustaining long-term protective immunity. Their persistence directly influences the durability of vaccine efficacy. GC B cells with high-affinity BCR can undergo differentiation into LLPCs (2021). These terminally differentiated effector B cells specialize in sustained production of Abs targeting previously encountered Ags. The majority of LLPCs reside in tissues such as the bone marrow and serve as a first line of defense against pathogen reinfection by consistently supplying high-affinity Abs (222324). Simultaneously, MBCs are generated early during GC reaction. Accordingly, they exhibit low levels of SHMs (2021). They persist in circulation for extended durations. They are capable of re-entering GC reaction for additional rounds of affinity maturation upon secondary exposure, leading to the production of even higher-affinity Abs (2526). In the early phase of the pandemic, evidences indicating that SARS-CoV-2 infection and vaccination can induce re-engagement of pre-existing MBCs into GC reactions, concomitant with polyclonal Ab responses, have been reported. These observations suggest that pre-existing immunity to common cold coronaviruses (CCCoVs) can be stimulated following SARS-CoV-2 infection and vaccination, indicative of the potential for antigenic cross-reactivity between pre-existing immunity against CCCoVs and SARS-CoV-2 (2728). Notably, Turner et al. (17) have directly observed the presence of CCCoVs-reactive MBC clonal groups within GC reaction following SARS-CoV-2 mRNA vaccination. In this framework, MBCs and LLPCs collaborate in a division of labor to provide protection against reinfection by the original pathogen or related variants (2930). Specifically, MBCs could be primed to mount a rapid and specific immune response against pathogen infection not completely neutralized by LLPC-derived Abs.

Meanwhile, the initial interaction with cognate CD4+ T cells prior to entering GC reaction can induce extrafollicular differentiation of B cells towards short-lived plasmablasts (Fig. 1C) (31). In context of repeat exposure to antigenically related Ags such as annual seasonal influenza vaccination or SARS-CoV-2 booster vaccination, the majority of short-lived plasmablasts derive from recall responses of pre-exsiting MBC populations (2632). In humans, plasmablasts appear transiently in the blood approximately one wk after vaccination (3334). These plasmablasts can rapidly generate large amount of Abs, which can reach the maximum titer around one month after vaccination. Subsequently, Ab levels gradually decline to a plateau that is maintained by durable populations of LLPCs. This decline is primarily attributed to the intrinsically short life span of plasmablasts detectable for approximately a week after vaccination (1733). The frequency of short-lived plasmablast observed after vaccination correlates with both peak and plateau levels of vaccine-induced Ab titers, thereby providing a useful early indicator of vaccine responsiveness (35).

Induction of long-term protective B cell immunity by SARS-CoV-2 mRNA vaccination

This section discusses recent findings on human B cell responses following a primary SARS-CoV-2 mRNA vaccination. Clinical trials of Pfizer-BioNtech’s BNT162b2 vaccine and Moderna’s mRNA-1273 have demonstrated that a two-dose vaccination can elicit a robust Ab response in individuals without prior infection history (36). However, concerns regarding the durability of vaccine efficacy have been raised due to declining levels of Abs in the blood over time as well as the emergence of SARS-CoV-2 VOCs (37383940). It is important to note that a decrease in Ab level in the circulation is a typical characteristic of humoral immunity. It does not necessarily imply a loss of long-term protective immunity. Indeed, significant reduction in mortality rate among vaccinated individuals strongly suggests that vaccination can effectively establish protective immunity.

Duration and robustness of GC reaction following vaccination are primary determinants of a long-term protective immunity (3841). As previously highlighted, GC responses within draining lymph nodes play a pivotal role in the establishment of long-term protective immunity by generating circulating MBCs and LLPCs. To evaluate the capacity of mRNA vaccines to elicit enduring protective immunity, it is imperative to investigate draining lymph nodes in humans. Despite challenges with respect to sample collection and analytical techniques, multiple studies analyzing immune responses within lymph nodes have been reported throughout the COVID-19 pandemic (1314151617). Ultrasound-guided fine needle aspiration enables sequential sampling of draining lymph nodes from multiple cohorts. This approach allows for a longitudinal examination of the dynamics and characteristics of human GC responses to mRNA vaccination. These studies have consistently reported a robust and persistent GC reaction in draining axillary lymph nodes. Substantial frequencies of spike-binding GC B cells have remained detectable for at least 29 wks after the primary two-dose mRNA vaccine series in 11 out of 15 individuals (16). Compared to seasonal quadrivalent inactivated influenza vaccine, where vaccine-binding GC B cells were detected for only 2 to 4 months post-vaccination in three of eight participants (26), mRNA vaccination appeared to elicit significantly more robust and durable GC responses. While extensive history of influenza virus exposure and the presence of pre-existing immune memory might complicate the comparison between GC responses to these vaccines in humans, this phenomenon can be attributed to immune-enhancing properties conferred by self-adjuvanting characteristics of lipid-nanoparticle encapsulated mRNA vaccine platform (424344) and prolonged duration of Ag dissemination in draining lymph nodes (1545). Röltgen et al. (15) have demonstrated that vaccine mRNA and spike proteins are still detectable in lymph nodes for up to 60 days post-vaccination. This suggests that GC persistence may indeed be contingent on Ag availability. Furthermore, it has been observed that FDCs exhibit a remarkable capacity of long-term retention of Ags, thereby contributing to sustained maintenance of GC response (4647).

Persistent GC reactions in draining lymph nodes lead to continual accumulation of SHMs on BCR sequences of vaccine-responding B cells (1648). Notably, a 3.5-fold increase in SHM frequency over six months was observed in GC B cells responding to the vaccine, indicating ongoing affinity maturation processes after vaccination. This sustained elevation in SHM frequencies ultimately culminated in the generation of affinity-matured MBCs in the blood and LLPCs in the bone marrow. Not only circulating MBCs and bone marrow-resident LLPCs are detectable after mRNA vaccination, but also their SHM frequency is progressively increased over time, concomitant with enhanced binding breadth and neutralization potency (164849505152).

In addition to SHM-mediated affinity maturation, GC B cells undergo Ig class switching. Akin to a natural infection (53), mRNA vaccination can induce notable transition over time in the proportion of isotypes expressed by GC B cells, shifting from IgG to IgA (1617). Consequently, class-switched MBCs are detectable after mRNA vaccination and the frequency of IgA-expressing MBCs is increased over time (50). Dimeric IgA, the main form of IgA, exhibits an improved ability to neutralize the virus compared to IgG. It may play a critical role in preventing reinfection within mucosal tissues (5455). Although it is uncertain whether SARS-CoV-2 vaccination can result in an increase of IgA level in mucosal tissues in human (56), intramuscular vaccination is known to result in a minimal mucosal IgA response and demonstrate reduced efficacy in mediating viral clearance at mucosal (5758). Furthermore, it is yet to be determined whether IgA+ GC B cell compartment induced by mRNA vaccination can lead to the formation of mucosal tissue-resident IgA+ MBCs and LLPCs. To address the limitation of intramuscular vaccination, the alternative routes such as intranasal or nebulization administration have been proposed (575960). In animal models, airway administration offers advantages over intramuscular delivery by inducing robust mucosal immunity, thereby preventing infection and onward transmission. Both the coronavirus vaccine roadmap (61) and Project NextGen (62) also underscored the importance of developing next generation vaccines and vaccination strategies to augment mucosal immunity.

MAIN 2: IMMUNOLOGICAL IMPRINTING ON SUBSEQUENT VACCINATION

Immunological imprinting by previous exposures to antigenically related pathogens

Administration of a two-dose primary vaccination can induce robust immune responses, leading to a substantial decrease in mortality rate. Nevertheless, the emergence of highly infectious variant viruses underscores the necessity for supplementary vaccine doses or the development of vaccines targeting variants (406364656667). It is necessary to approach additional vaccination as a distinct scenario from primary vaccination, particularly in terms of prior exposure history. In contrast to primary vaccination, which occurs in the absence of pre-existing immunity against SARS-CoV-2 viruses, administering additional doses against VOCs requires careful consideration of the impact of pre-existing immunity on subsequent immune response.

In 1960, Francis (68) conducted serological analyses of different age groups following influenza vaccination, revealing that Ab response to influenza strains encountered during childhood continued to dominate the overall anti-influenza virus Ab response throughout life. Even as an individual ages and elicits subsequent Ab responses against different strains, childhood-derived Abs can consistently maintain dominant levels over time. This phenomenon is known as “original antigenic sin” or, more recently, as “immunological imprinting.” The term “immunological imprinting” generically describes the impact of prior exposure history, such as viral infection or vaccination, on future patterns of Ab response upon re-exposure to antigenically related viruses (69). It reflects the back-boosting of pre-existing immunity, where immune memory established through prior exposures to an Ag is recalled to rapidly respond to re-exposure (Fig. 2). This phenomenon represents a fundamental immunological mechanism known as immune memory recall that underlies vaccine efficacy (70). When exposed to vaccine-matched pathogens, pre-existing MBCs formed by vaccination promptly can produce Abs to protect from severe infections (Fig. 2B). By leveraging this immunological feature, vaccinations can greatly reduce mortality rates caused by vaccine-matched viruses.

Figure 2 Recall of pre-existing immunity following exposure to homologous or heterologous Ags.

(A) Upon primary exposure to novel Ags, such as the two-dose SARS-CoV-2 primary vaccination, naive B cells actively participate in immune response, leading to establishment of memory B cell population. Memory B cells generally participate in subsequent immune response to antigenically related Ags. (B) Upon secondary exposure to homologous Ags, the majority of memory B cells induced by primary exposure predominantly are recalled, contributing to an enhanced Ab response against either homologous infection or vaccination. (C) However, on secondary exposure to heterologous Ags, breadth of following Ab response is confounded by pre-existing immunity, a mechanism known as immunological imprinting. A limited pool of memory B cells that are predominantly cross-reactive to heterologous Ags is recalled, resulting in comparatively restricted breadth of Ab response to either VOCs infection or vaccination. The extent of the detrimental effect from immunological imprinting correlates with the antigenic distance between primary and secondary Ags.

However, in context of infections caused by antigenically evolving viruses, cross-reactive pre-existing immunity is mostly recalled (Fig. 2C). In other words, recall response tends to focus on conserved epitopes shared between primary and re-exposure Ags (71). Mechanistically, unlike a primary vaccination, wherein naive B cells primarily participate in immune response responses, both naive B cells and circulating MBCs compete to recognize re-exposure Ags. The circulating MBCs have competitive advantage over naïve B cells not only due to GC-driven affinity maturation, but also due to intrinsically lower activation threshold (72), thereby restricting participants of naïve B cells. Consequently, the majority of recall response is directed towards shared epitopes, leading to diminished Ab diversity and rare occurrence of variant-specific B cell response. In such scenarios, immunological imprinting could potentially increase an individual’s susceptibility to infection when these shared epitopes acquire escaping mutations. To effectively prevent variant infections, additional vaccinations should be designed to stimulate the generation of de novo B cell responses that can specifically recognize the novel epitope unique to variants.

B cell response to VOCs-based booster vaccination

The ongoing evolution of SARS-CoV-2 viruses, characterized by mutations in the spike protein, has endangered the efficacy of the initial two-dose of primary vaccination, leading to recommendations for additional booster shots (6473). Multiple studies have suggested that administrating repeated doses of homologous boosters containing the ancestral Wuhan-hu-1 spike can substantially improve Ab responses against both the Wuhan-Hu-1 and VOCs (747576). Concurrently, vaccines based on VOCs’ spike proteins have been developed to more effectively address these continuously evolving viruses (7778798081). However, efforts to improve the effectiveness of vaccine by incorporating spike Ags from VOCs have encountered challenges due to the immunological imprinting induced by ancestral spike-based primary vaccination. A main concern is whether VOCs spike proteins-based vaccines can induce de novo Ab responses to VOC-specific, non-conserved epitopes.

Recent studies have compared immune responses in individuals who have received third doses of the monovalent Wuhan-Hu-1-based vaccine, a monovalent B.1.341 (Beta)-based vaccine (mRNA1273.351), a bivalent B.1.351/B.1.617.2 (Beta/Delta)-based vaccine (mRNA-1273.213), and an monovalent BA.1 (Omicron)-based vaccine (mRNA-1273.529) (3282). Alsoussi et al. (32) focused on participants without prior COVID-19 infection history who had completed a two-dose primary vaccination. The primary objective was to assess the exclusive impact of booster vaccination on immune response against VOCs, considering both quantitative and qualitative aspects. Vaccine spike-specific plasmablasts were detected in blood samples of all participants. Their maturation was confirmed through increased SHM frequencies in their Ig heavy chain variable region gene (IGHV). Interestingly, plasmablasts identified after the booster vaccination exhibited significantly higher mutation frequencies than those after the primary two-dose vaccination series. This suggests that these plasmablasts might have originated from MBCs that have undergone affinity maturation after completion of the primary vaccination series (3334). Meanwhile, administration of booster vaccination elicited a robust GC response specific to vaccine spike Ags in draining axillary lymph nodes, persisting for a minimum of eight wks post-vaccination. Consistent with B cell responses observed in conventional seasonal influenza vaccinations (26), it was observed that pre-existing MBCs participated and re-engaged in GC reactions after booster vaccination. The quantity of bone marrow-resident LLPCs was also notably increased following a booster vaccination. This phenomenon is a result of persistent GC reactions induced by the initial two vaccine doses combined with additional GC reactions induced by repeated Ag exposures from the booster vaccination.

Additionally, Alsoussi et al. (32) provides important insights regarding the extent and dynamics of immunological imprinting after VOCs-based vaccination. Even if any booster vaccines did not encode ancestral spike Ags, the majority of GC B cells and MBCs identified after bivalent beta/delta or monovalent omicron vaccination could recognize the ancestral spike protein. This implies that vaccine-responding B cells predominantly originate from pre-existing clonal lineage established by the primary vaccination. Given that the degree of immunological imprinting could be determined by the antigenic distance between prior and subsequent exposures (838485), a high antigenic similarity between beta/delta spike and ancestral spike might have contributed to highly cross-reactive responses. As shown in the case of monovalent omicron vaccine, where spike Ags were antigenically distant from the ancestral spike, MBCs specific to omicron spike Ag were definitely observed. These B cells appeared to originate from de novo responses as they recognized omicron-specific epitopes with low SHM mutation frequencies. The immunological imprinting induced by ancestral spike-based vaccination was also reflected in serological responses, which are outcomes of B cell responses to subsequent exposures. Individuals who have received two doses of primary vaccination and encountered omicron infection still exhibit low levels of omicron-specific Ab responses (868788). Moreover, a bivalent booster BA.1 (mRNA-1273.214) and a bivalent booster BA.4/BA.5 (mRNA-1273.222) demonstrated superior neutralizing activity to Wuhan-Hu-1 booster against Wuhan-Hu-1 as well as matched Omicron sublineages (8990). Collectively, the abundant presence of serum Ab titer and MBCs that can recognize the ancestral spike protein following subsequent exposures serves as evidence of immunological imprinting. This phenomenon indicates that B cell responses to previously encountered Ags can maintain dominance even after exposure to antigenically related other Ags. Accordingly, the WHO Technical Advisory Group on COVID-19 Vaccine Composition recommended using monovalent Omicron XBB.1.5-based immunogen instead of Wuhan-Hu-1-based immunogen for future booster vaccine formulations due to antigenic divergence and the potential for immunological imprinting (91). This recommendation is supported by recent experimental evidence indicating that repeated boosting with omicron spike Ags has been shown to alleviate immunological imprinting (92). Taken together, these findings offer support to the idea that vaccination strategies with appropriately designed Ags are necessary to counter immune imprinting and activate infrequent naive B cells targeting novel variant epitopes.

CLOSING

The return to normalcy from COVID-19 pandemics is facilitated by innovative mRNA-based platform vaccines. This global health crisis offers a unique opportunity to examine the dynamics and outcomes of GC-driven de novo B cell response in humans and to investigate the role of immunological imprinting in subsequent B cell responses. Our exploration of B cell responses to SARS-CoV-2 mRNA vaccination revealed several key findings. First, the induction of enduring protective immunity is intricately linked to the formation and persistence of GC reactions within draining lymph nodes. It was demonstrated that the mRNA vaccine platform, with its self-adjuvanting lipid-nanoparticle encapsulated structure, could foster robust and prolonged GC reactions, surpassing responses observed with traditional influenza vaccines. These reactions give rise to MBCs and LLPCs, crucial components for sustaining long-term immunity. Second, the inherent flexibility of mRNA-based vaccines enables rapid adaptation and development of vaccines specifically tailored to VOCs. Numerous studies investigating B cell responses after VOCs-based vaccination have highlighted the potential of mRNA vaccine to overcome the detrimental effect of immunological imprinting. To achieve long-term control of COVID-19 and improve immune response to VOCs, sustained research efforts are imperative, including continuous refinement and design of future vaccine boosters to effectively stimulate optimal, durable, and broadly protective B cell responses against continuously evolving coronavirus variants. Based on the insights discussed here, future approaches to developing next-generation vaccines could benefit from targeting specific epitopes from the spike Ags of future variants, rather than utilizing the full-length spike Ag, to mitigate immunological imprinting. Additionally, to effectively prevent infection and reduce virus transmission, mucosal vaccination that induces protective immune responses in the airway would be highly advantageous.

Abbreviations

BCR B cell receptor

CCCoV common cold coronaviruse

COVID-19 coronavirus disease 2019

FDC follicular dendritic cell

GC germinal center

LLPC long-lived plasma cell

MBC memory B cell

SARS-CoV-2 severe acute respiratory syndrome coronavirus 2

SHM somatic hypermutation

VOC variant of concern

Conflict of Interest: The author declares no potential conflicts of interest.
==== Refs
1 Lan J Ge J Yu J Shan S Zhou H Fan S Zhang Q Shi X Wang Q Zhang L Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor Nature 2020 581 215 220 32225176
2 Barouch DH COVID-19 vaccines - immunity, variants, boosters N Engl J Med 2022 387 1011 1020 36044620
3 Dashdorj NJ Wirz OF Röltgen K Haraguchi E Buzzanco AS 3rd Sibai M Wang H Miller JA Solis D Sahoo MK Direct comparison of antibody responses to four SARS-CoV-2 vaccines in Mongolia Cell Host Microbe 2021 29 1738 1743.e4 34861167
4 Zhang Z Mateus J Coelho CH Dan JM Moderbacher CR Gálvez RI Cortes FH Grifoni A Tarke A Chang J Humoral and cellular immune memory to four COVID-19 vaccines Cell 2022 185 2434 2451.e17 35764089
5 Baden LR El Sahly HM Essink B Kotloff K Frey S Novak R Diemert D Spector SA Rouphael N Creech CB Efficacy and safety of the mRNA-1273 SARS-CoV-2 Vaccine N Engl J Med 2021 384 403 416 33378609
6 Polack FP Thomas SJ Kitchin N Absalon J Gurtman A Lockhart S Perez JL Pérez Marc G Moreira ED Zerbini C Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine N Engl J Med 2020 383 2603 2615 33301246
7 Slifka MK Amanna I How advances in immunology provide insight into improving vaccine efficacy Vaccine 2014 32 2948 2957 24709587
8 Mesin L Ersching J Victora GD Germinal center B cell dynamics Immunity 2016 45 471 482 27653600
9 Berek C Berger A Apel M Maturation of the immune response in germinal centers Cell 1991 67 1121 1129 1760840
10 Cyster JG B cell follicles and antigen encounters of the third kind Nat Immunol 2010 11 989 996 20959804
11 Carati C Gannon B Piller N Anatomy and physiology in relation to compression of the upper limb and thorax J Lymphoedema 2010 5 58 67
12 Havenar-Daughton C Newton IG Zare SY Reiss SM Schwan B Suh MJ Hasteh F Levi G Crotty S Normal human lymph node T follicular helper cells and germinal center B cells accessed via fine needle aspirations J Immunol Methods 2020 479 112746 31958451
13 Lederer K Bettini E Parvathaneni K Painter MM Agarwal D Lundgreen KA Weirick M Muralidharan K Castaño D Goel RR Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals Cell 2022 185 1008 1024.e15 35202565
14 Mudd PA Minervina AA Pogorelyy MV Turner JS Kim W Kalaidina E Petersen J Schmitz AJ Lei T Haile A SARS-CoV-2 mRNA vaccination elicits a robust and persistent T follicular helper cell response in humans Cell 2022 185 603 613.e15 35026152
15 Röltgen K Nielsen SC Silva O Younes SF Zaslavsky M Costales C Yang F Wirz OF Solis D Hoh RA Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination Cell 2022 185 1025 1040.e14 35148837
16 Kim W Zhou JQ Horvath SC Schmitz AJ Sturtz AJ Lei T Liu Z Kalaidina E Thapa M Alsoussi WB Germinal centre-driven maturation of B cell response to mRNA vaccination Nature 2022 604 141 145 35168246
17 Turner JS O’Halloran JA Kalaidina E Kim W Schmitz AJ Zhou JQ Lei T Thapa M Chen RE Case JB SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses Nature 2021 596 109 113 34182569
18 Cyster JG Allen CD B cell responses: cell interaction dynamics and decisions Cell 2019 177 524 540 31002794
19 Young C Brink R The unique biology of germinal center B cells Immunity 2021 54 1652 1664 34380063
20 Phan TG Paus D Chan TD Turner ML Nutt SL Basten A Brink R High affinity germinal center B cells are actively selected into the plasma cell compartment J Exp Med 2006 203 2419 2424 17030950
21 Kräutler NJ Suan D Butt D Bourne K Hermes JR Chan TD Sundling C Kaplan W Schofield P Jackson J Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells J Exp Med 2017 214 1259 1267 28363897
22 Hammarlund E Thomas A Amanna IJ Holden LA Slayden OD Park B Gao L Slifka MK Plasma cell survival in the absence of B cell memory Nat Commun 2017 8 1781 29176567
23 Zehentmeier S Roth K Cseresnyes Z Sercan Ö Horn K Niesner RA Chang HD Radbruch A Hauser AE Static and dynamic components synergize to form a stable survival niche for bone marrow plasma cells Eur J Immunol 2014 44 2306 2317 24777940
24 Brynjolfsson SF Mohaddes M Kärrholm J Wick MJ Long-lived plasma cells in human bone marrow can be either CD19+ or CD19 Blood Adv 2017 1 835 838 29296727
25 Mesin L Schiepers A Ersching J Barbulescu A Cavazzoni CB Angelini A Okada T Kurosaki T Victora GD Restricted clonality and limited germinal center reentry characterize memory b cell reactivation by boosting Cell 2020 180 92 106.e11 31866068
26 Turner JS Zhou JQ Han J Schmitz AJ Rizk AA Alsoussi WB Lei T Amor M McIntire KM Meade P Human germinal centres engage memory and naive B cells after influenza vaccination Nature 2020 586 127 132 32866963
27 Ng KW Faulkner N Cornish GH Rosa A Harvey R Hussain S Ulferts R Earl C Wrobel AG Benton DJ Preexisting and de novo humoral immunity to SARS-CoV-2 in humans Science 2020 370 1339 1343 33159009
28 Murray SM Ansari AM Frater J Klenerman P Dunachie S Barnes E Ogbe A The impact of pre-existing cross-reactive immunity on SARS-CoV-2 infection and vaccine responses Nat Rev Immunol 2023 23 304 316 36539527
29 Purtha WE Tedder TF Johnson S Bhattacharya D Diamond MS Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants J Exp Med 2011 208 2599 2606 22162833
30 Pape KA Taylor JJ Maul RW Gearhart PJ Jenkins MK Different B Different B cell populations mediate early and late memory during an endogenous immune response Science 2011 331 1203 1207 21310965
31 Elsner RA Shlomchik MJ Germinal center and extrafollicular B cell responses in vaccination, immunity, and autoimmunity Immunity 2020 53 1136 1150 33326765
32 Alsoussi WB Malladi SK Zhou JQ Liu Z Ying B Kim W Schmitz AJ Lei T Horvath SC Sturtz AJ SARS-CoV-2 Omicron boosting induces de novo B cell response in humans Nature 2023 617 592 598 37011668
33 Wrammert J Smith K Miller J Langley WA Kokko K Larsen C Zheng NY Mays I Garman L Helms C Rapid cloning of high-affinity human monoclonal antibodies against influenza virus Nature 2008 453 667 671 18449194
34 Ellebedy AH Jackson KJ Kissick HT Nakaya HI Davis CW Roskin KM McElroy AK Oshansky CM Elbein R Thomas S Defining antigen-specific plasmablast and memory B cell subsets in human blood after viral infection or vaccination Nat Immunol 2016 17 1226 1234 27525369
35 Kardava L Rachmaninoff N Lau WW Buckner CM Trihemasava K Blazkova J Lopes de Assis F Wang W Zhang X Wang Y Early human B cell signatures of the primary antibody response to mRNA vaccination Proc Natl Acad Sci U S A 2022 119 e2204607119 35759653
36 Bok K Sitar S Graham BS Mascola JR Accelerated COVID-19 vaccine development: milestones, lessons, and prospects Immunity 2021 54 1636 1651 34348117
37 Jung J Kim JY Kwon JS Yun SC Kim SH Comparison of waning immunity between booster vaccination and 2-dose vaccination with BNT162b2 Immune Netw 2022 22 e31 36081526
38 Laidlaw BJ Ellebedy AH The germinal centre B cell response to SARS-CoV-2 Nat Rev Immunol 2022 22 7 18 34873279
39 Sette A Crotty S Adaptive immunity to SARS-CoV-2 and COVID-19 Cell 2021 184 861 880 33497610
40 Krause PR Fleming TR Longini IM Peto R Briand S Heymann DL Beral V Snape MD Rees H Ropero AM SARS-CoV-2 variants and vaccines N Engl J Med 2021 385 179 186 34161052
41 Victora GD Nussenzweig MC Germinal centers Annu Rev Immunol 2012 30 429 457 22224772
42 Alameh MG Tombácz I Bettini E Lederer K Sittplangkoon C Wilmore JR Gaudette BT Soliman OY Pine M Hicks P Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses Immunity 2021 54 2877 2892.e7 34852217
43 Li C Lee A Grigoryan L Arunachalam PS Scott MK Trisal M Wimmers F Sanyal M Weidenbacher PA Feng Y Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine Nat Immunol 2022 23 543 555 35288714
44 Tahtinen S Tong AJ Himmels P Oh J Paler-Martinez A Kim L Wichner S Oei Y McCarron MJ Freund EC IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines Nat Immunol 2022 23 532 542 35332327
45 Hassett KJ Rajlic IL Bahl K White R Cowens K Jacquinet E Burke KE mRNA vaccine trafficking and resulting protein expression after intramuscular administration Mol Ther Nucleic Acids 2023 35 102083 38161733
46 Martínez-Riaño A Wang S Boeing S Minoughan S Casal A Spillane KM Ludewig B Tolar P Long-term retention of antigens in germinal centers is controlled by the spatial organization of the follicular dendritic cell network Nat Immunol 2023 24 1281 1294 37443283
47 Pikor NB Mörbe U Lütge M Gil-Cruz C Perez-Shibayama C Novkovic M Cheng HW Nombela-Arrieta C Nagasawa T Linterman MA Remodeling of light and dark zone follicular dendritic cells governs germinal center responses Nat Immunol 2020 21 649 659 32424359
48 Cho A Muecksch F Schaefer-Babajew D Wang Z Finkin S Gaebler C Ramos V Cipolla M Mendoza P Agudelo M Anti-SARS-CoV-2 receptor-binding domain antibody evolution after mRNA vaccination Nature 2021 600 517 522 34619745
49 Sokal A Barba-Spaeth G Fernández I Broketa M Azzaoui I de La Selle A Vandenberghe A Fourati S Roeser A Meola A mRNA vaccination of naive and COVID-19-recovered individuals elicits potent memory B cells that recognize SARS-CoV-2 variants Immunity 2021 54 2893 2907.e5 34614412
50 Goel RR Painter MM Apostolidis SA Mathew D Meng W Rosenfeld AM Lundgreen KA Reynaldi A Khoury DS Pattekar A mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern Science 2021 374 abm0829 34648302
51 Pape KA Dileepan T Kabage AJ Kozysa D Batres R Evert C Matson M Lopez S Krueger PD Graiziger C High-affinity memory B cells induced by SARS-CoV-2 infection produce more plasmablasts and atypical memory B cells than those primed by mRNA vaccines Cell Reports 2021 37 109823 34610291
52 Tong P Gautam A Windsor IW Travers M Chen Y Garcia N Whiteman NB McKay LG Storm N Malsick LE Memory B cell repertoire for recognition of evolving SARS-CoV-2 spike Cell 2021 184 4969 4980.e15 34332650
53 Sterlin D Mathian A Miyara M Mohr A Anna F Claër L Quentric P Fadlallah J Devilliers H Ghillani P IgA dominates the early neutralizing antibody response to SARS-CoV-2 Sci Transl Med 2021 13 eabd2223 33288662
54 Corthésy B Multi-faceted functions of secretory IgA at mucosal surfaces Front Immunol 2013 4 185 23874333
55 Wang Z Lorenzi JC Muecksch F Finkin S Viant C Gaebler C Cipolla M Hoffmann HH Oliveira TY Oren DA Enhanced SARS-CoV-2 neutralization by dimeric IgA Sci Transl Med 2021 13 eabf1555 33288661
56 Sheikh-Mohamed S Sanders EC Gommerman JL Tal MC Guardians of the oral and nasopharyngeal galaxy: IgA and protection against SARS-CoV-2 infection Immunol Rev 2022 309 75 85 35815463
57 Hassan AO Kafai NM Dmitriev IP Fox JM Smith BK Harvey IB Chen RE Winkler ES Wessel AW Case JB A single-dose intranasal ChAd vaccine protects upper and lower respiratory tracts against SARS-CoV-2 Cell 2020 183 169 184.e13 32931734
58 Carr EJ Dowgier G Greenwood D Herman LS Hobbs A Ragno M Stevenson-Leggett P Gahir J Townsley H Harvey R SARS-CoV-2 mucosal neutralising immunity after vaccination Lancet Infect Dis 2024 24 e4 e5
59 McMahan K Wegmann F Aid M Sciacca M Liu J Hachmann NP Miller J Jacob-Dolan C Powers O Hope D Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques Nature 2024 626 385 391 38096903
60 Waltz E How nasal-spray vaccines could change the pandemic Nature 2022 609 240 242 36068305
61 Moore KA Leighton T Ostrowsky JT Anderson CJ Danila RN Ulrich AK Lackritz EM Mehr AJ Baric RS Baylor NW A research and development (R&D) roadmap for broadly protective coronavirus vaccines: a pandemic preparedness strategy Vaccine 2023 41 2101 2112 36870874
62 Becerra X Jha A Project NextGen - defeating SARS-CoV-2 and preparing for the next pandemic N Engl J Med 2023 389 773 775 37494477
63 Wang Z Schmidt F Weisblum Y Muecksch F Barnes CO Finkin S Schaefer-Babajew D Cipolla M Gaebler C Lieberman JA mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants Nature 2021 592 616 622 33567448
64 Andrews N Stowe J Kirsebom F Toffa S Rickeard T Gallagher E Gower C Kall M Groves N O’Connell AM COVID-19 vaccine effectiveness against the Omicron (B.1.1.529) variant N Engl J Med 2022 386 1532 1546 35249272
65 Kuhlmann C Mayer CK Claassen M Maponga T Burgers WA Keeton R Riou C Sutherland AD Suliman T Shaw ML Breakthrough infections with SARS-CoV-2 omicron despite mRNA vaccine booster dose Lancet 2022 399 625 626 35063123
66 Schmidt F Muecksch F Weisblum Y Da Silva J Bednarski E Cho A Wang Z Gaebler C Caskey M Nussenzweig MC Plasma neutralization of the SARS-CoV-2 Omicron variant N Engl J Med 2022 386 599 601 35030645
67 Cele S Jackson L Khoury DS Khan K Moyo-Gwete T Tegally H San JE Cromer D Scheepers C Amoako DG Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization Nature 2022 602 654 656 35016196
68 Francis T On the doctrine of original antigenic sin Proc Am Philos Soc 1960 104 572 578
69 Henry C Palm AE Krammer F Wilson PC From original antigenic sin to the universal influenza virus vaccine Trends Immunol 2018 39 70 79 28867526
70 Koutsakos M Ellebedy AH Immunological imprinting: understanding COVID-19 Immunity 2023 56 909 913 37105169
71 Cobey S Hensley SE Immune history and influenza virus susceptibility Curr Opin Virol 2017 22 105 111 28088686
72 Good KL Avery DT Tangye SG Resting human memory B cells are intrinsically programmed for enhanced survival and responsiveness to diverse stimuli compared to naive B cells J Immunol 2009 182 890 901 19124732
73 Lucas C Vogels CB Yildirim I Rothman JE Lu P Monteiro V Gehlhausen JR Campbell M Silva J Tabachnikova A Impact of circulating SARS-CoV-2 variants on mRNA vaccine-induced immunity Nature 2021 600 523 529 34634791
74 Muecksch F Wang Z Cho A Gaebler C Ben Tanfous T DaSilva J Bednarski E Ramos V Zong S Johnson B Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA boost Nature 2022 607 128 134 35447027
75 Goel RR Painter MM Lundgreen KA Apostolidis SA Baxter AE Giles JR Mathew D Pattekar A Reynaldi A Khoury DS Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine Cell 2022 185 1875 1887.e8 35523182
76 Arunachalam PS Lai L Samaha H Feng Y Hu M Hui HS Wali B Ellis M Davis-Gardner ME Huerta C Durability of immune responses to mRNA booster vaccination against COVID-19 J Clin Invest 2023 133 e167955 36951954
77 Choi A Koch M Wu K Chu L Ma L Hill A Nunna N Huang W Oestreicher J Colpitts T Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis Nat Med 2021 27 2025 2031 34526698
78 Zhang NN Zhang RR Zhang YF Ji K Xiong XC Qin QS Gao P Lu XS Zhou HY Song HF Rapid development of an updated mRNA vaccine against the SARS-CoV-2 Omicron variant Cell Res 2022 32 401 403 35165421
79 Scheaffer SM Lee D Whitener B Ying B Wu K Liang CY Jani H Martin P Amato NJ Avena LE Bivalent SARS-CoV-2 mRNA vaccines increase breadth of neutralization and protect against the BA.5 Omicron variant in mice Nat Med 2023 29 247 257 36265510
80 Collier AY Miller J Hachmann NP McMahan K Liu J Bondzie EA Gallup L Rowe M Schonberg E Thai S Immunogenicity of BA.5 bivalent mRNA vaccine boosters N Engl J Med 2023 388 565 567 36630611
81 Nham E Kim J Lee J Park H Kim J Lee S Choi J Kim KT Yoon JG Hwang SY Low neutralizing activities to the omicron subvariants BN.1 and XBB.1.5 of sera from the individuals vaccinated with a BA.4/5-containing bivalent mRNA vaccine Immune Netw 2023 23 e43 38188597
82 Chu L Vrbicky K Montefiori D Huang W Nestorova B Chang Y Carfi A Edwards DK Oestreicher J Legault H Immune response to SARS-CoV-2 after a booster of mRNA-1273: an open-label phase 2 trial Nat Med 2022 28 1042 1049 35241844
83 Schiepers A van ’t Wout MF Greaney AJ Zang T Muramatsu H Lin PJ Tam YK Mesin L Starr TN Bieniasz PD Molecular fate-mapping of serum antibody responses to repeat immunization Nature 2023 615 482 489 36646114
84 Smith DJ Forrest S Ackley DH Perelson AS Variable efficacy of repeated annual influenza vaccination Proc Natl Acad Sci U S A 1999 96 14001 14006 10570188
85 Huang CQ Vishwanath S Carnell GW Chan AC Heeney JL Immune imprinting and next-generation coronavirus vaccines Nat Microbiol 2023 8 1971 1985 37932355
86 Addetia A Piccoli L Case JB Park YJ Beltramello M Guarino B Dang H de Melo GD Pinto D Sprouse K Neutralization, effector function and immune imprinting of Omicron variants Nature 2023 621 592 601 37648855
87 Hoffmann M Behrens GM Arora P Kempf A Nehlmeier I Cossmann A Manthey L Dopfer-Jablonka A Pöhlmann S Effect of hybrid immunity and bivalent booster vaccination on omicron sublineage neutralisation Lancet Infect Dis 2023 23 25 28 36480944
88 Tortorici MA Addetia A Seo AJ Brown J Sprouse K Logue J Clark E Franko N Chu H Veesler D Persistent immune imprinting occurs after vaccination with the COVID-19 XBB.1.5 mRNA booster in humans Immunity 2024 57 904 911.e4 38490197
89 Chalkias S Whatley JL Eder F Essink B Khetan S Bradley P Brosz A McGhee N Tomassini JE Chen X Original SARS-CoV-2 monovalent and Omicron BA.4/BA.5 bivalent COVID-19 mRNA vaccines: phase 2/3 trial interim results Nat Med 2023 29 2325 2333 37653342
90 Chalkias S Harper C Vrbicky K Walsh SR Essink B Brosz A McGhee N Tomassini JE Chen X Chang Y A bivalent omicron-containing booster vaccine against COVID-19 N Engl J Med 2022 387 1279 1291 36112399
91 World Health Organization Statement on the antigen composition of COVID-19 vaccines [Internet] accessed on 4 April 2024 Available at https://www.who.int/news/item/13-12-2023-statement-on-the-antigen-composition-of-covid-19-vaccines
92 Yisimayi A Song W Wang J Jian F Yu Y Chen X Xu Y Yang S Niu X Xiao T Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting Nature 2024 625 148 156 37993710
