Natural infection with SARS-CoV-2 induces a robust circulating memory B cell (Bmem) population, which remains stable in number at least 8 months post-infection despite the contraction of antibody levels after 1 month. Multiple vaccines have been developed to combat the virus. These include two new formulations, mRNA and adenoviral vector vaccines, which have varying efficacy rates, potentially related to their distinct capacities to induce humoral immune responses. The mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) elicit significantly higher serum IgG and neutralizing antibody levels than the adenoviral vector ChAdOx1 (AstraZeneca) and Ad26.COV2.S (Janssen) vaccines. However, all vaccines induce Spike- and RBD-specific Bmem, which are vital in providing long-lasting protection in the form of rapid recall responses to subsequent infections. Past and current SARS-CoV-2 variants of concern (VoC) have shown the capacity to escape antibody neutralization to varying degrees. A booster dose with an mRNA vaccine following primary vaccination restores antibody levels and improves the capacity of these antibodies and Bmem to bind viral variants, including the current VoC Omicron. Future experimental research will be essential to evaluate the durability of protection against VoC provided by each vaccine and to identify immune markers of protection to enable prognostication of people who are at risk of severe complications from COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is an ongoing global health threat with over 628 million cases and 6.5 million deaths as of November 2022 [1]. Genomic analysis suggests SARS-CoV-2 was initially transmitted from bats to humans through an intermediate species in a wet market in Wuhan, China, in late 2019 [2,3]. SARS-CoV-2 is a positive single-stranded RNA virus with four structural components: the Spike, Nucleocapsid, Envelope, and Membrane proteins (Figure 1) [4]. Cell entry and viral fusion are mediated by the receptor binding domain (RBD) in the S1 subunit of the Spike protein, which binds human angiotensin converting enzyme 2 (ACE2) (Figure 1) [5,6].

SARS-CoV-2 structural components and binding to human ACE2 receptor via the Spike RBD.

Figure 1.
SARS-CoV-2 structural components and binding to human ACE2 receptor via the Spike RBD.

The SARS-CoV-2 virus is composed of four main structural proteins: the Spike, Membrane, Envelope and Nucleocapsid. It carries a single-stranded RNA genome, which is encapsulated by a lipid envelope. The receptor-binding domain of the Spike protein binds to the human ACE2 receptor, allowing entry into host cells. ACE2, angiotensin converting enzyme 2; RBD, receptor-binding domain; ssRNA, single-stranded RNA. Created with BioRender.com.

Figure 1.
SARS-CoV-2 structural components and binding to human ACE2 receptor via the Spike RBD.

The SARS-CoV-2 virus is composed of four main structural proteins: the Spike, Membrane, Envelope and Nucleocapsid. It carries a single-stranded RNA genome, which is encapsulated by a lipid envelope. The receptor-binding domain of the Spike protein binds to the human ACE2 receptor, allowing entry into host cells. ACE2, angiotensin converting enzyme 2; RBD, receptor-binding domain; ssRNA, single-stranded RNA. Created with BioRender.com.

Close modal

Since the virus first spread to humans in December 2019, multiple variants have arisen including variants of concern (VoC) which are defined based on their capacity for increased transmissibility, infectivity, and disease severity, and decreased effectiveness of public health measures such as vaccination, or therapeutics (Table 1) [7,8]. Following initial emergence of the Alpha, Beta, Gamma, and Delta VoC, the current circulating VoC is Omicron. Omicron has multiple sublineages, of which the BA.1, BA.2, BA.4, and BA.5 are spreading globally. Omicron BA.5 is the dominant SARS-CoV-2 strain globally (as of November 2022), accounting for over 80% of sequences globally, having recently overtaken BA.2 [9,10].

Table 1
Current and previous SARS-CoV-2 VoC and their RBD mutations
WHO variant nameDates designated VoC (as of October 2022) [11]PANGO lineage code [11]Mutations in RBD (AA #319 to 541) [12]
Alpha December 18 2020 – March 9 2022 B.1.1.7 N501Y [13
Beta December 18 2020 – March 9 2022 B.1.351 K417N, E484K, and N501Y [14
Gamma January 11 2021 – March 9 2022 P.1 K417T, E484K, and N501Y [15
Delta May 11 2021 – June 7 2022 B.1.617.2 L452R, T478K [16
Omicron November 26 2021 – present B.1.1.529 Sublineage BA.1 G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H [9,17–19
BA.2 G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, and reversion to Wuhan G446 and G496 [17,18
BA.4/5 All BA.2 RBD mutations + L452R, F486V, and reversion to Wuhan Q493 [20
WHO variant nameDates designated VoC (as of October 2022) [11]PANGO lineage code [11]Mutations in RBD (AA #319 to 541) [12]
Alpha December 18 2020 – March 9 2022 B.1.1.7 N501Y [13
Beta December 18 2020 – March 9 2022 B.1.351 K417N, E484K, and N501Y [14
Gamma January 11 2021 – March 9 2022 P.1 K417T, E484K, and N501Y [15
Delta May 11 2021 – June 7 2022 B.1.617.2 L452R, T478K [16
Omicron November 26 2021 – present B.1.1.529 Sublineage BA.1 G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H [9,17–19
BA.2 G339D, S371F, S373P, S375F, T376A, D405N, R408S, K417N, N440K, S477N, T478K, E484A, Q493R, Q498R, N501Y, Y505H, and reversion to Wuhan G446 and G496 [17,18
BA.4/5 All BA.2 RBD mutations + L452R, F486V, and reversion to Wuhan Q493 [20

PANGO, Phylogenetic Assignment of Named Global Outbreak lineage; VoC, variant of concern; WHO, World Health Organization; RBD, receptor-binding domain.

Vaccines against SARS-CoV-2 are needed to combat outbreaks and control the pandemic. There has been global uptake of mRNA and adenoviral vector COVID-19 vaccines, which protect against severe disease and hospitalization [21,22]. However, the ability of these vaccines to induce durable humoral immune memory still needs to be established. This is important in the context of emerging VoC, as effective vaccines can help prevent viral variants from escaping immune protection and causing breakthrough infections, which are especially concerning for patients with underlying health conditions.

Within several days following a primary viral infection, relatively low-affinity antigen-specific antibodies are produced by short-lived plasmablasts [23,24]. Memory B cells (Bmem) and long-lived plasma cells (LLPCs) are generated later in the immune response, remaining in the body long after the initial infection producing high-affinity antibodies [25]. While LLPCs maintain serum antibody levels, Bmem are primed to rapidly differentiate and secrete antibody upon subsequent exposures to the virus, providing efficient protection against infection and disease.

Bmem differentiate from activated B cells through two distinct pathways, either extrafollicularly or through the germinal center (GC) response in the B-cell follicles of secondary lymphoid organs (Figure 2) [26]. GC reactions are driven by the presence of cognate antigen, which is delivered to the draining lymph node via the subcapsular sinus or by dendritic cells migrating from the site of infection [27,28]. Follicular dendritic cells (fDCs) present antigen to GC B cells by capturing it mainly in the form of immune complexes [29]. B cells can endocytose soluble antigen or capture bound antigen from the surface of fDCs, which they then process and present to follicular helper T(fh) cells in the GC. These T-B cell interactions drive B-cell proliferation and expression of activation-induced cytidine deaminase (AID), inducing somatic hypermutation (SHM) of Ig variable domains and class-switch recombination (CSR) of Ig constant regions [30]. SHM increases the affinity of the surface Ig to recognize antigen presented by fDCs, such that B cells with a low affinity for antigen are outcompeted resulting in a pool of high affinity B cells [31,32]. CSR involves genomic rearrangement to switch from expressing the IgM isotype to one of four IgG subclasses (IgG1, 2, 3 and 4), one of two IgA subclasses (IgA1 and 2), or the IgE isotype. The various antibody isotypes are distributed throughout the body to exhibit distinct effector functions required for tailored protective immunity [33].

The different pathways of the humoral immune response generate plasmablasts, Bmem, and LLPC.

Figure 2.
The different pathways of the humoral immune response generate plasmablasts, Bmem, and LLPC.

Following activation, B cells follow either the T-independent or dependent pathways, depending on the structure of their cognate antigen. (A) The T-independent response generates plasmablasts, IgM+IgD+CD27+ and IgA+CD27 Bmem. (B) The GC response is T-dependent and produces both LLPC and Bmem, which increase in CD27 expression and SHM levels upon re-entry. (C) The T-dependent extrafollicular response is GC-independent and generates short-lived plasmablasts which produce low-affinity antibody. Th, helper T cell; Tfh, follicular helper T cell; SHM, somatic hypermutation; GC, germinal center; fDC, follicular dendritic cell; LLPC, long-lived plasma cell. Based on information from [26,30,34–36]. Created with BioRender.com.

Figure 2.
The different pathways of the humoral immune response generate plasmablasts, Bmem, and LLPC.

Following activation, B cells follow either the T-independent or dependent pathways, depending on the structure of their cognate antigen. (A) The T-independent response generates plasmablasts, IgM+IgD+CD27+ and IgA+CD27 Bmem. (B) The GC response is T-dependent and produces both LLPC and Bmem, which increase in CD27 expression and SHM levels upon re-entry. (C) The T-dependent extrafollicular response is GC-independent and generates short-lived plasmablasts which produce low-affinity antibody. Th, helper T cell; Tfh, follicular helper T cell; SHM, somatic hypermutation; GC, germinal center; fDC, follicular dendritic cell; LLPC, long-lived plasma cell. Based on information from [26,30,34–36]. Created with BioRender.com.

Close modal

Recently activated B cells, which are antigen-experienced and proliferating, can be identified through the expression of CD71 [37]. Expression of CD20 distinguishes these cells from CD71+CD20- plasma cells. The activation marker CD71 is down-regulated on activated B cells after 3–4 weeks as they transition into quiescent Bmem [37].

After exiting the GC, Bmem circulate and are readily detectable in peripheral blood. A large number of circulating Bmem express CD27, which is a tumor necrosis factor receptor for CD70 [38,39]. On Bmem expressing IgA or IgE, this marker distinguishes GC-independent Bmem (CD27) from GC-derived Bmem (CD27+). On IgG+ Bmem, CD27 expression distinguishes cells derived from consecutive GC responses from the CD27 primary responses [34]. The CD27+IgG+ Bmem typically have higher levels of SHM and are more frequently switched to the distal IGHG genes (encoding IgG2 and IgG4) than the CD27IgG+ Bmem [34,40].

Immediately following the SARS-CoV-2 outbreak, immunological studies were initiated to examine the serological and cellular responses post symptom onset (PSO), and their durability in convalescence. Following natural SARS-CoV-2 infection, antibodies specific for a number of viral epitopes have been detected. The RBD contains major neutralization epitopes, as antibodies that target these directly compete with ACE2 for binding, inhibiting viral fusion and cell entry (Figure 1) [41–46]. Most monoclonal antibodies isolated from Bmem that bound the RBD were found to be neutralizing, while those that bound epitopes on other SARS-CoV-2 proteins were mainly non-neutralizing [47]. A minority of human monoclonal antibodies specific for the neighboring N-terminal domain of the Spike protein are neutralizing, potentially acting by limiting the conformational changes needed for viral fusion [48]. The Nucleocapsid protein is another major antibody target, but being located inside the viral particle (Figure 1), it is not a neutralizing target [42,49]. Thus, the Spike RBD-specific immune response will be the focus of this review.

In 95–100% of COVID-19 cases, SARS-CoV-2 Spike- and RBD-specific antibodies, predominantly of the IgG isotype, have been detected as early as the first week PSO [50–52]. RBD-specific antibodies peaked at 2–4 weeks PSO, followed by a significant decline (Figure 3) [41,44,45,50–53]. IgA and IgM levels decreased more rapidly than IgG, which remained detectable as late as 8 months PSO [41,43,52]. Neutralizing antibodies (NAb) against SARS-CoV-2 have been detected in 88% of COVID-19 cases, reaching peak levels at 1 month PSO followed by a decline [41,42,46,50,51,54]. An expansion of plasmablasts in peripheral blood following infection correlated with the peak in serum RBD-specific IgG [45,50,52]. Plasmablasts significantly decreased by 6 months PSO, signifying the resolution of acute infection and contraction of the antibody response (Figure 3) [44,55].

Kinetics of RBD-specific IgG, IgM, and IgA levels and plasmablast and Bmem numbers in SARS-CoV-2 convalescence.

Figure 3.
Kinetics of RBD-specific IgG, IgM, and IgA levels and plasmablast and Bmem numbers in SARS-CoV-2 convalescence.

RBD-specific IgG levels decline following a peak at 2–4 weeks PSO but remain at detectable levels, whereas IgA and IgM levels drop more rapidly. Plasmablasts decrease after reaching peak levels ∼2 weeks PSO. RBD-specific Bmem numbers significantly increase in the months following infection, remaining at stable levels at least 6–8 months PSO. PSO, post-symptom onset; Bmem, memory B cells; Abs, antibodies; RBD, receptor-binding domain. Drawn in the style of Röltgen and Boyd [35], based on information from [41,43,45,50–52]. Created with BioRender.com.

Figure 3.
Kinetics of RBD-specific IgG, IgM, and IgA levels and plasmablast and Bmem numbers in SARS-CoV-2 convalescence.

RBD-specific IgG levels decline following a peak at 2–4 weeks PSO but remain at detectable levels, whereas IgA and IgM levels drop more rapidly. Plasmablasts decrease after reaching peak levels ∼2 weeks PSO. RBD-specific Bmem numbers significantly increase in the months following infection, remaining at stable levels at least 6–8 months PSO. PSO, post-symptom onset; Bmem, memory B cells; Abs, antibodies; RBD, receptor-binding domain. Drawn in the style of Röltgen and Boyd [35], based on information from [41,43,45,50–52]. Created with BioRender.com.

Close modal

Up to 93% of SARS-CoV-2 convalescent individuals produced RBD-specific Bmem [41,56]. Numbers of Spike- and RBD-specific IgG+ Bmem increased over time and peaked ∼3–4 months PSO. In contrast with serum antibodies, Bmem numbers have not been shown to significantly decrease, remaining stable at 6–8 months PSO (Figure 3) [41,44,45,50,51,57]. Bmem isolated from infected individuals 3 months PSO produced RBD-specific antibodies with the capacity to potently neutralize viral entry [43,44,56]. Thus, natural infection elicits a Bmem population with the capacity to differentiate and secrete NAb to combat SARS-CoV-2 upon reinfection.

Between 1 and 6 months PSO, a shift from mainly activated, CD27+CD71+ Spike-specific B cells to mainly resting, CD27+CD71CD21+ Bmem has been observed [44]. Other studies have also shown an increase in frequencies of CD21+CD27+ SARS-CoV-2-specific Bmem between 1 and 3 months PSO, indicative of GC-dependent B-cell formation [42,43]. Molecular analysis of Ig variable regions from RBD-specific Bmem revealed a gradual increase in SHM levels up to 6 months PSO [43,44,57]. This observation of extended affinity maturation indicates persistent GC activity driving Bmem formation, and could be the basis of the improved neutralizing capacity and breadth of antibodies cloned from SARS-CoV-2-specific Bmem at 6 months PSO [44,57]. These ongoing GC responses are potentially driven by persistence of SARS-CoV-2 antigens, which have been detected in the intestinal epithelium at least 4 months post-infection [57]. In conclusion, an Ig-class-switched, durable Bmem population is generated in response to SARS-CoV-2 infection, with the potential to provide long-term immunity.

Vaccination triggers the capacity of the adaptive immune response to form antigen-specific immune memory by mimicking a primary pathogen exposure [58]. For SARS-CoV-2, the Spike protein was chosen as a major target, as antibodies against this surface protein have the capacity to neutralize the virus. The timing of the SARS-CoV-2 epidemic coincided with a new era in vaccine design, allowing induction of host cell production and presentation of Spike protein which ensures both humoral and cellular immune responses.

The two new vaccine designs employed for SARS-CoV-2 are mRNA vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), and adenoviral vector vaccines, predominantly ChAdOx1 (AstraZeneca) and Ad26.COV2.S (Janssen; Table 2). All vaccines are delivered in two-dose primary schedules except for Ad26.COV2.S, which is administered as a single dose. The mRNA vaccines both comprise mRNA transcripts for the proline-stabilized full-length Spike protein encapsulated in lipid nanoparticles (Figure 4) [59]. The mRNA is nucleoside-stabilized, meaning the RNA particles themselves are rendered non-immunogenic [60]. ChAdOx1 is a Y25 vector derived from a chimpanzee adenovirus, encapsulating dsDNA encoding the full-length Spike protein (Figure 4) [21]. Ad26.COV2.S has a similar design to ChAdOx1, except its Ad26 vector is derived from a human adenovirus, and the DNA encodes the proline-stabilized Spike protein form [61].

SARS-CoV2 mRNA and adenoviral vector vaccine designs.

Figure 4.
SARS-CoV2 mRNA and adenoviral vector vaccine designs.

Adenoviral vector vaccines such as ChAdOx1 or Ad26.COV2.S comprise adenoviral vectors encapsulating the SARS-CoV-2 Spike protein DNA. When the vector is internalized into the host cell, the DNA is inserted into the nucleus where it is transcribed into mRNA before being translated into the Spike protein. mRNA vaccines such as BNT162b2 or mRNA-1273 comprise lipid nanoparticles containing Spike protein mRNA, which are internalized by recipient cells where the mRNA in is simply translated in the cytoplasm. The full-length Spike protein generated from either vaccine type can then be (A) processed and presented in MHC Classes I and II, (B) expressed on the cell surface, or (C) secreted from the cells, where it becomes a target for the immune system. MHC, major histocompatibility complex. Based on information from [62]. Created with BioRender.com.

Figure 4.
SARS-CoV2 mRNA and adenoviral vector vaccine designs.

Adenoviral vector vaccines such as ChAdOx1 or Ad26.COV2.S comprise adenoviral vectors encapsulating the SARS-CoV-2 Spike protein DNA. When the vector is internalized into the host cell, the DNA is inserted into the nucleus where it is transcribed into mRNA before being translated into the Spike protein. mRNA vaccines such as BNT162b2 or mRNA-1273 comprise lipid nanoparticles containing Spike protein mRNA, which are internalized by recipient cells where the mRNA in is simply translated in the cytoplasm. The full-length Spike protein generated from either vaccine type can then be (A) processed and presented in MHC Classes I and II, (B) expressed on the cell surface, or (C) secreted from the cells, where it becomes a target for the immune system. MHC, major histocompatibility complex. Based on information from [62]. Created with BioRender.com.

Close modal
Table 2
Major COVID-19 vaccines and their effectiveness in protecting against symptomatic infection as reported by clinical trials
Vaccine nameCompanyVaccine type# doses in primary scheduleEncoded antigen [63]Efficacy against symptomatic infectionEfficacy against severe disease
Comirnaty (BNT162b2) Pfizer-BioNTech mRNA, lipid nanoparticle Proline-stabilized full-length Spike protein 95% [22,6492% [65
Spikevax (mRNA-1273) Moderna mRNA, lipid nanoparticle Proline-stabilized full-length Spike protein 94% [66100% [66
Vaxzevria (ChAdOx1) Oxford-AstraZeneca DNA, simian Y25 adenoviral vector Wild-type full-length Spike protein 70.4% [67,68100% [69
Jcovden (Ad26.COV2.S) [70Johnson & Johnson — Janssen DNA, human Ad26 adenoviral vector [61Proline-stabilized full-length Spike protein 67% [7185% [71,72
Vaccine nameCompanyVaccine type# doses in primary scheduleEncoded antigen [63]Efficacy against symptomatic infectionEfficacy against severe disease
Comirnaty (BNT162b2) Pfizer-BioNTech mRNA, lipid nanoparticle Proline-stabilized full-length Spike protein 95% [22,6492% [65
Spikevax (mRNA-1273) Moderna mRNA, lipid nanoparticle Proline-stabilized full-length Spike protein 94% [66100% [66
Vaxzevria (ChAdOx1) Oxford-AstraZeneca DNA, simian Y25 adenoviral vector Wild-type full-length Spike protein 70.4% [67,68100% [69
Jcovden (Ad26.COV2.S) [70Johnson & Johnson — Janssen DNA, human Ad26 adenoviral vector [61Proline-stabilized full-length Spike protein 67% [7185% [71,72

The mRNA and adenoviral vector vaccine particles are designed for rapid uptake by host cells, which use the RNA template for generation of Spike proteins. These proteins are processed in multiple ways to enable presentation to immune cells (Figure 4). There is evidence that the protein is presented on MHC Class I and II molecules, as both CD4+ and CD8+ T cells are generated in response to both vaccine types [62]. Additionally, host cells can express the full-length Spike protein on their surface or secrete it, where it becomes accessible to innate immune cells and B cells (Figure 4).

All four vaccines were demonstrated to be safe and effective at preventing symptomatic infection and hospitalization with COVID-19 in clinical trials, with a general tendency of mRNA vaccines to be slightly more effective than the adenoviral vector vaccines (Table 2). Following their roll-out, all vaccine formulations were found to greatly reduce the incidence of COVID-19 infection, severe disease outcomes, and death in the general population [73–76]. Immunizations with ChAdOx1 and Ad26.COV2.S have been linked to rare occurrences (1–2 per 100 000 vaccinees) of thrombosis with thrombocytopenia, resulting in hesitancy in their uptake and the recommendation to only use mRNA vaccines for booster immunizations [77–80].

Similar to natural infection, the COVID-19 vaccines BNT162b2, mRNA-1273, ChAdOx1, or Ad26.COV2.S predominantly elicit an IgG response [81–86]. After mRNA vaccination, Spike- and RBD-specific IgG and NAb have been found to peak within 1 month post-dose two (Figure 5), correlating with the peak of IgG+ plasmablasts [82,83,87,88]. Following a rapid decline in RBD-specific IgG and NAb levels, these then remained relatively stable between 3–6 months [82,83,87,88]. This decline in serum antibody levels correlated with a waning in protection against symptomatic infection [89]. However, the high level of mRNA vaccine protection from hospitalization and death has been shown to remain stable until at least 5 months post-dose two, suggesting that cellular immune memory rather than circulating antibody levels contribute to long-term protection against severe disease.

A single dose of ChAdOx1 or Ad26.COV2.S resulted in detectable serum NAb in 91–100% of recipients [21,90–92]. Spike-specific IgG peaked 2–4 weeks after one dose of ChAdOx1, followed by a contraction before the second dose, which boosted both IgG and NAb levels [21,84,93–95]. Similar to mRNA vaccination, RBD-specific IgG levels also declined between 1 and 6 months after Ad26.COV2.S vaccination, accompanied by a loss of detectable NAb in 39% of individuals by 6 months post-vaccination [96].

NAb and Spike-specific IgG levels elicited by both adenoviral vector vaccines, ChAcOx1 and Ad26.COV2.S, are significantly lower than those elicited by two doses of mRNA vaccines [85,93,95–98]. The diminished response to ChAdOx1 could be due to the lack of stabilizing proline mutations, which maintain the prefusion Spike conformation, which has been found to be more immunogenic [22,66,99–102].

After two doses of either mRNA vaccine, Spike-specific IgG+ Bmem have been detected in 90-100% of individuals [82,83]. The second dose boosted Bmem numbers and increased the frequency of high-affinity, isotype-switched Bmem [83]. Despite some variability in the detailed kinetics of Bmem after the second dose of an mRNA vaccine, Bmem frequencies measured 6 months after dose two stayed above post-dose one levels and were comparable to those formed after natural infection (Figure 5) [82,83]. Similarly, SARS-CoV-2-specific Bmem were detected in all individuals fully vaccinated with adenoviral vector vaccines [103]. In the 6 months following Ad26.COV2.S vaccination, RBD-specific Bmem increased in number; however, their absolute numbers and frequencies remained lower than those generated by mRNA vaccines [96]. While one dose of ChAdOx1 elicited detectable Spike-specific Bmem in only 53% of vaccinees, these numbers significantly expanded after the second dose and were detectable in all individuals [94]. Recipients of ChAdOx1 had lower frequencies of RBD-specific Bmem than mRNA vaccinees, but the affinity and neutralization activity of monoclonal antibodies isolated from these Bmem were similar between the two vaccine types [104].

Kinetics of the antigen-specific antibody and Bmem response to mRNA vaccines up to 6 months post-vaccination.

Figure 5.
Kinetics of the antigen-specific antibody and Bmem response to mRNA vaccines up to 6 months post-vaccination.

The Spike- and RBD-specific IgG response is boosted by each vaccine dose, and peaks 1 week post-dose two, before declining. RBD-specific Bmem increase in the months following vaccination and remain at stable levels at least 6 months post-dose one. Bmem are of a class-switched resting phenotype and increase in Ig affinity over time. RBD, receptor-binding domain; Bmem, memory B cells. Based on information from [82,83]. Created with BioRender.com.

Figure 5.
Kinetics of the antigen-specific antibody and Bmem response to mRNA vaccines up to 6 months post-vaccination.

The Spike- and RBD-specific IgG response is boosted by each vaccine dose, and peaks 1 week post-dose two, before declining. RBD-specific Bmem increase in the months following vaccination and remain at stable levels at least 6 months post-dose one. Bmem are of a class-switched resting phenotype and increase in Ig affinity over time. RBD, receptor-binding domain; Bmem, memory B cells. Based on information from [82,83]. Created with BioRender.com.

Close modal

One week after dose two of an mRNA vaccine, there was a reduction in the frequency of CD71+ Bmem, suggesting a shift to a resting memory population [82]. Following in vitro stimulation, these Spike-specific Bmem rapidly reactivated and produced neutralizing IgG, demonstrating their capacity to protect against secondary infections [82]. SARS-CoV-2-specific Tfh cells were produced after one mRNA vaccine dose, and their levels correlated with the neutralizing capacity of IgG [81,105]. This suggests that in response to mRNA vaccines, maturation of Bmem is supported by Tfh cells in GC reactions. Additionally, Spike-specific GC B cells were detected in draining lymph nodes as late as 3–4 months post-dose two, indicating sustained GC activity, similar to natural infection [44,87]. Further research is required into the phenotype, kinetics, and durability of the Bmem response generated by both adenoviral vector vaccines, to inform the extent of protective memory conferred by each vaccine.

While all four mRNA and adenoviral vector vaccines elicited strong antibody and Bmem responses against the parental Wuhan SARS-CoV-2 strain, NAb levels against previous and current VoC were reduced [15,106,107]. This reduction in reactivity to variants compared with Wuhan mostly resulted from mutations in the Spike RBD (Table 1) [108–110]. Continued close monitoring of vaccine effectiveness against emerging variants is essential, as viral escape from the immune response can lead to increases in severe disease incidence from breakthrough infections.

Past VoC have evaded the humoral immune response elicited by vaccines to varying degrees (Figure 6). Following two doses of either BNT162b2 or ChAdOx1, most studies reported a 2–3-fold lower NAb titer against the Alpha variant than to the original Wuhan strain [109,111]. In contrast, NAb levels generated by BNT162b2 or ChAdOx1to the Beta variant were 6–7-fold lower than to Wuhan [96,106,107,112]. The escape from neutralization by these variants can be partially explained by RBD mutations that reduce recognition by NAb such as N501Y shared by Alpha, Beta, and Gamma, which has been linked to increased Spike affinity for ACE2, and K417N/T and E484K in Beta (Table 1) [107,109,110,113–115]. Despite having a similar RBD sequence to Beta except for the substitution at position 417 (K417T), NAb titers against the Gamma variant have been found to be only 2–6-fold lower than those against Wuhan after two doses of an mRNA vaccine [108,109,116]. The difference in NAb titers against Beta and Gamma can be attributed to differences in their Spike protein sequences outside of the RBD, including in the N-terminal domain which has been shown to contain NAb targets [117,118].

Relative escape of SARS-CoV-2 VoC from neutralization by sera from recipients of two mRNA vaccine doses.

Figure 6.
Relative escape of SARS-CoV-2 VoC from neutralization by sera from recipients of two mRNA vaccine doses.

Each of the five main past and present VoC escape neutralization by vaccine-elicited sera to varying degrees. NAb titers against Alpha are, on average, 2.75 times lower compared with those against Wuhan [106,119–122], those against Beta are 6.74-fold [106,109,112,119,120,122,123], those against Gamma are 3.43-fold [109,120,124], those against Delta are 3.76-fold [106,119–123], and those against Omicron are 56.50-fold lower [107,119,123,125]. Values are presented as mean fold change compared with Wuhan, error bars represent the range of the referenced studies. Total number of serum samples from pooled publications indicated. NAb, neutralizing antibodies; RBD, receptor-binding domain; VoC, variants of concern.

Figure 6.
Relative escape of SARS-CoV-2 VoC from neutralization by sera from recipients of two mRNA vaccine doses.

Each of the five main past and present VoC escape neutralization by vaccine-elicited sera to varying degrees. NAb titers against Alpha are, on average, 2.75 times lower compared with those against Wuhan [106,119–122], those against Beta are 6.74-fold [106,109,112,119,120,122,123], those against Gamma are 3.43-fold [109,120,124], those against Delta are 3.76-fold [106,119–123], and those against Omicron are 56.50-fold lower [107,119,123,125]. Values are presented as mean fold change compared with Wuhan, error bars represent the range of the referenced studies. Total number of serum samples from pooled publications indicated. NAb, neutralizing antibodies; RBD, receptor-binding domain; VoC, variants of concern.

Close modal

The Delta variant was the dominant strain globally in late 2021 before the emergence of Omicron [11]. The RBD mutations in Delta, L452R and T478K, increase its affinity for ACE2, while reducing serum antibody binding [109]. One dose of either BNT162b2 or ChAdOx1 failed to induce serum NAb titers against Delta in ∼90% of individuals [15,106]. A second dose improved NAb levels against Delta, although these remained 2.5–6-fold lower than against Wuhan [15,106,109] (Figure 6). A study in Singapore showed no correlation between NAb levels and the incidence of breakthrough Delta infection [126]. However, higher RBD-specific Bmem levels correlated with a reduced likelihood of being infected, suggesting these are an accurate marker of protection against VoC [126]. Six months after two mRNA vaccine doses, more than 50% of all RBD-specific Bmem recognized the Alpha, Beta, and Delta variants, demonstrating that the capacity of Bmem to bind VoC was higher than that of the NAb response [82].

The original Omicron strain, BA.1, carries 15 RBD mutations, including: N501Y, shared by all past VoC; K417N, shared with Beta; and T478K, shared with Delta (Table 1) [11,17,20,118]. The BA.2 sublineage has 16 RBD mutations, with six differences from the sequence of BA.1 [20,118]. BA.4 and BA.5 carry 17 RBD mutations, and only differ from each other outside the Spike protein. These two variants share all BA.2 RBD mutations except for Q493R, while having acquired L452R and F486V [20,118].

The emergence of Omicron subvariants has led to greater rates of reinfections, breakthrough infections in vaccinated individuals, and community transmission than Delta and other ancestral variants [127–129]. One suggested mechanism behind these increased infection rates is the dramatically increased capacity of Omicron to replicate in the bronchi [130,131]. However, Omicron is detected less in the lower lung parenchyma, which could explain the reduced disease severity from infections with this variant [130,131]. The increased transmissibility of Omicron can be linked to a reduction in the protection provided by primary schedule vaccination. All Omicron sublineages significantly escape neutralization in recipients of mRNA and adenoviral vector vaccines, likely due to the large number of mutations these variants carry in their Spike and RBD (Table 1) [17,108]. Multiple studies reported that most double-vaccinated individuals have no detectable Omicron-reactive NAb, with levels being 20–120-fold lower against BA.1 than Wuhan [108,119,123,125,132–134] (Figure 6). Both BA.4 and BA.5 escaped neutralization from serum antibodies of BNT162b2 and Ad26.COV2.S recipients to a higher degree than BA.1 [135–137].

A third mRNA vaccine dose, given to recipients of both mRNA and adenoviral vector primary vaccines, has been shown to increase protection against severe disease and death from SARS-CoV-2, including against Delta and Omicron [138–142]. This third dose booster may achieve protection in part by raising Spike- and RBD-specific IgG and NAb levels [116]. Notably, the third dose is reported to increase the neutralization capacity of serum antibody against BA.1 and BA.2 up to 100-fold, and against Delta up to 30-fold [108,119,125,143–145]. A third dose of BNT162b2 increased NAb against BA.4/5, but levels still remained at least 5-fold lower than against Wuhan [135–137]. These elevated serum NAb levels against VoC may be due to the Omicron-binding Bmem pool being reactivated by the third vaccine dose, inducing differentiation into antibody-secreting cells.

While the antibody response elicited by two doses of a COVID-19 vaccine is less effective against the Omicron sublineages, vaccine recipients still produce substantial frequencies of Bmem that recognize the VoC. A study using Spike and RBD probes to measure specific Bmem frequency by flow cytometry found similar frequencies of Bmem that bound Wuhan, Alpha, Delta, and Omicron BA.1 after two doses of BNT162b2, with a majority of Bmem being able to bind multiple variants [135]. A third dose or an infection with BA.1 increased variant-binding Bmem frequencies [135]. Another group found the proportion of resting Wuhan-specific IgG+ Bmem that bound Omicron BA.1 increased between 1- and 4–5-months post-dose two of BNT126b2 [146]. This demonstrates that Omicron-binding Bmem are generated following the primary dosing schedule of mRNA COVID-19 vaccines, mature over time, and are boosted by repeat exposures.

Higher levels of SHM were observed in the Ig genes of variant-binding Bmem than in those that only recognized the Wuhan strain [82,147]. Thus, the generation of higher-affinity Bmem through GC reactions may be advantageous for the recognition of VoC. This highlights a difference in the variant-binding capacity of the circulating antibody pool, produced by plasmablasts, and the resting Bmem population. A functional benefit that Bmem possess over terminally differentiated plasma cells, which have fixed specificity, is the capacity to evolve their antibody binding affinity and breadth [148,149]. This helps explain why COVID-19 vaccines elicit low plasma NAb levels against VoC, but higher frequencies of variant-specific Bmem. Similar Bmem analyses are still needed in the context of adenoviral vector vaccines, as well as further insights into the effectiveness of Bmem generated by either vaccine formulation against BA.2 and BA.4/5.

Effective vaccines that generate immune memory against SARS-CoV-2 and emerging variants are required to provide durable protection against severe COVID-19. Spike-specific IgG and NAb levels wane following both infection and a primary schedule of vaccination, suggesting serum antibodies are not the most robust marker of protection. In contrast, Bmem numbers are more stable months after infection or mRNA vaccination, indicating that this cellular marker of immune memory may be a better correlate of protection against severe disease with SARS-CoV-2. The kinetics of the Bmem response elicited by ChAdOx1 or Ad26.COV2.S have not been studied in detail. This research will still be insightful as although many countries are now delivering only mRNA booster doses, primary courses of adenoviral vector vaccines have been widely administered around the world.

Vaccine-elicited antibodies have a reduced neutralizing capacity against past and current VoC. Nevertheless, a third mRNA vaccine dose elevates antibody levels and increases the capacity of these antibodies to recognize variants. Variant-binding Bmem are elicited by mRNA vaccines; however, equivalent studies have not yet been performed in the context of ChAdOx1 or Ad26.COV2.S vaccination. Additionally, both serological and cellular measures of the immune response against Omicron BA.2 and BA.4/5 generated by all vaccine types requires more research. This will provide insight into the capacity of the current COVID-19 vaccines to induce humoral immune memory capable of long-term protection against severe breakthrough infections with VoC.

  • Natural infection and mRNA COVID-19 vaccination both elicit IgG-dominated antibody responses of similar magnitude, and robust resting Bmem populations. Adenoviral vector vaccines elicit lower serological responses, but insights into the Bmem response to this vaccine type are limited. Booster mRNA vaccines induce a rise in serum antibody levels and an expansion of Bmem, as well as the capacity of these to recognize VoC, regardless of the primary vaccine formulation.

  • While serum antibody levels induced by COVID-19 vaccines protect against infection, this effect rapidly wanes within 1–3 months. Vaccine-induced protection against severe disease lasts for at least 4–6 months and correlates better with the durability of immune memory cells than with the rapid contraction of the antibody response.

  • Quantitative and qualitative measurements of COVID-19 vaccine-induced humoral immune memory may provide immunological markers for protection from severe disease in vaccinated individuals. Future research is also required to expand the evidence base for the level of protection current Wuhan-based vaccines elicit against Omicron variants, and the need to update the vaccine strains to protect from infections with VoC.

M.C.v.Z. and R.O.H. are inventors on a patent application related to generation of fluorescently labeled antigen tetramers used for flow cytometric analysis of antigen-specific B cells. The other authors declare that there are no competing interests associated with the manuscript.

H.A.F. is supported by an Alfred Research Alliance Honours Scholarship, G.E.H. by a RTP Scholarship, M.C.v.Z. and R.O.H. by a National Health and Medical Research Council Ideas Grant: GNT2000773, an Australian MRFF Grant: MRF2016108, and an unrestricted grant from BD Biosciences.

Open access for this article was enabled by the participation of Monash University in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with CAUL.

M.C.v.Z. conceptualized the review and supervised H.A.F., H.A.F. wrote the original draft, G.E.H., E.S.J.E., and R.O.H. commented on and edited draft versions.

ACE2

angiotensin-converting enzyme 2

Bmem

memory B cell

COVID-19

Coronavirus disease 2019

CSR

class-switch recombination

fDC

follicular dendritic cell

GC

germinal center

LLPC

long-lived plasma cell

NAb

neutralizing antibody

PANGO

Phylogenetic Assignment of Named Global Outbreak lineage

PSO

post-symptom onset

RBD

receptor binding domain

SARS-CoV-2

severe acute respiratory syndrome coronavirus-2

SHM

somatic hypermutation

Tfh

follicular helper T cell

VoC

Variant of concern

WHO

World Health Organization

1
World Health Organisation. WHO Coronavirus (COVID-19) Dashboard 2022. Available from
: https://covid19.who.int/
2
Holmes
,
E.C.
,
Goldstein
,
S.A.
,
Rasmussen
,
A.L.
,
Robertson
,
D.L.
,
Crits-Christoph
,
A.
,
Wertheim
,
J.O.
et al. (
2021
)
The origins of SARS-CoV-2: a critical review
.
Cell
184
,
4848
4856
3
Zhou
,
H.
,
Ji
,
J.
,
Chen
,
X.
,
Bi
,
Y.
,
Li
,
J.
,
Wang
,
Q.
et al. (
2021
)
Identification of novel bat coronaviruses sheds light on the evolutionary origins of SARS-CoV-2 and related viruses
.
Cell
184
,
4380
91.e14
4
Tortorici
,
M.A.
and
Veesler
,
D.
(
2019
)
Structural insights into coronavirus entry
.
Adv. Virus Res.
105
,
93
116
5
Yi
,
C.
,
Sun
,
X.
,
Ye
,
J.
,
Ding
,
L.
,
Liu
,
M.
,
Yang
,
Z.
et al. (
2020
)
Key residues of the receptor binding motif in the spike protein of SARS-CoV-2 that interact with ACE2 and neutralizing antibodies
.
Cell. Mol. Immunol.
17
,
621
630
6
Jiang
,
S.
,
Hillyer
,
C.
and
Du
,
L.
(
2020
)
Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses
.
Trends Immunol.
41
,
355
359
7
Steinhauer
,
D.A.
,
Domingo
,
E.
and
Holland
,
J.J.
(
1992
)
Lack of evidence for proofreading mechanisms associated with an RNA virus polymerase
.
Gene
122
,
281
288
8
Centres for Disease Control and Prevention. SARS-CoV-2 Variant Classifications and Definitions 2021 [updated December 1, 2021]. Available from
: https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-classifications.html
9
Nextstrain. Genomic epidemiology of SARS-CoV-2 with global subsampling 2022. Available from
: https://nextstrain.org/ncov/open/global
10
World Health Organisation. Weekly epidemiological update on COVID-19–24 August 2022 2022 [updated 24 August 2022]. Available from
: https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---24-august-2022
11
World Health Organisation. Tracking SARS-CoV-2 variants 2022 [updated 29 March 2022]. Available from
: https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/
12
Lan
,
J.
,
Ge
,
J.
,
Yu
,
J.
,
Shan
,
S.
,
Zhou
,
H.
,
Fan
,
S.
et al. (
2020
)
Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor
.
Nature
581
,
215
220
13
Davies
,
N.G.
,
Abbott
,
S.
,
Barnard Rosanna
,
C.
,
Jarvis Christopher
,
I.
,
Kucharski Adam
,
J.
,
Munday James
,
D.
et al. (
2021
)
Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England
.
Science
372
,
eabg3055
14
Tegally
,
H.
,
Wilkinson
,
E.
,
Giovanetti
,
M.
,
Iranzadeh
,
A.
,
Fonseca
,
V.
,
Giandhari
,
J.
et al. (
2021
)
Detection of a SARS-CoV-2 variant of concern in South Africa
.
Nature
592
,
438
443
15
Planas
,
D.
,
Veyer
,
D.
,
Baidaliuk
,
A.
,
Staropoli
,
I.
,
Guivel-Benhassine
,
F.
,
Rajah
,
M.M.
et al. (
2021
)
Reduced sensitivity of SARS-CoV-2 variant delta to antibody neutralization
.
Nature
596
,
276
280
16
Shiehzadegan
,
S.
,
Alaghemand
,
N.
,
Fox
,
M.
and
Venketaraman
,
V.
(
2021
)
Analysis of the delta variant B.1.617.2 COVID-19
.
Clin. Pract.
11
,
778
784
17
Coronavirus Antiviral & Resistance Database. SARS-CoV-2 Variants Genome Viewer: Stanford University; 2022 [updated 11 February 2022]. Available from
: https://covdb.stanford.edu/page/mutation-viewer/#omicron
18
European Centre for Disease Prevention and Control. SARS-CoV-2 variants of concern 2022 [updated March 24 2022]. Available from
: https://www.ecdc.europa.eu/en/covid-19/variants-concern
19
He
,
X.
,
Hong
,
W.
,
Pan
,
X.
,
Lu
,
G.
and
Wei
,
X.
(
2021
)
SARS-CoV-2 omicron variant: characteristics and prevention
.
MedComm
2
,
838
845
20
outbreak.info. Lineage Comparison 2022; SARS-CoV-2 (hCoV-19) Mutation Reports]. Available from
: https://outbreak.info/compare-lineages?pango=Omicron&gene
21
Folegatti
,
P.M.
,
Ewer
,
K.J.
,
Aley
,
P.K.
,
Angus
,
B.
,
Becker
,
S.
,
Belij-Rammerstorfer
,
S.
et al. (
2020
)
Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial
.
Lancet
396
,
467
478
22
Polack
,
F.P.
,
Thomas
,
S.J.
,
Kitchin
,
N.
,
Absalon
,
J.
,
Gurtman
,
A.
,
Lockhart
,
S.
et al. (
2020
)
Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine
.
N. Engl. J. Med.
383
,
2603
2615
23
Smith
,
K.G.
,
Hewitson
,
T.D.
,
Nossal
,
G.J.
and
Tarlinton
,
D.M.
(
1996
)
The phenotype and fate of the antibody-forming cells of the splenic foci
.
Eur. J. Immunol.
26
,
444
448
24
MacLennan
,
I.C.M.
,
Toellner
,
K.-M.
,
Cunningham
,
A.F.
,
Serre
,
K.
,
Sze
,
D.M.Y.
,
Zúñiga
,
E.
et al. (
2003
)
Extrafollicular antibody responses
.
Immunol. Rev.
194
,
8
18
25
Slifka
,
M.K.
,
Antia
,
R.
,
Whitmire
,
J.K.
and
Ahmed
,
R.
(
1998
)
Humoral immunity due to long-lived plasma cells
.
Immunity
8
,
363
372
26
Berkowska
,
M.A.
,
Driessen
,
G.J.
,
Bikos
,
V.
,
Grosserichter-Wagener
,
C.
,
Stamatopoulos
,
K.
,
Cerutti
,
A.
et al. (
2011
)
Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways
.
Blood
118
,
2150
2158
27
Stebegg
,
M.
,
Kumar
,
S.D.
,
Silva-Cayetano
,
A.
,
Fonseca
,
V.R.
,
Linterman
,
M.A.
and
Graca
,
L.
(
2018
)
Regulation of the germinal center response
.
Front. Immunol.
9
,
2469
28
Carrasco
,
Y.R.
and
Batista
,
F.D.
(
2007
)
B cells acquire particulate antigen in a macrophage-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node
.
Immunity
27
,
160
171
29
Gonzalez
,
S.F.
,
Lukacs-Kornek
,
V.
,
Kuligowski
,
M.P.
,
Pitcher
,
L.A.
,
Degn
,
S.E.
,
Turley
,
S.J.
et al. (
2010
)
Complement-Dependent transport of antigen into B cell follicles
.
J. Immunol.
185
,
2659
30
Viant
,
C.
,
Wirthmiller
,
T.
,
ElTanbouly
,
M.A.
,
Chen
,
S.T.
,
Cipolla
,
M.
,
Ramos
,
V.
et al. (
2021
)
Germinal center-dependent and -independent memory B cells produced throughout the immune response
.
J. Exp. Med.
218
,
e20202489
31
Muramatsu
,
M.
,
Kinoshita
,
K.
,
Fagarasan
,
S.
,
Yamada
,
S.
,
Shinkai
,
Y.
and
Honjo
,
T.
(
2000
)
Class switch recombination and hypermutation require activation-Induced cytidine deaminase (AID), a potential RNA editing enzyme
.
Cell
102
,
553
563
32
Gitlin
,
A.D.
,
Shulman
,
Z.
and
Nussenzweig
,
M.C.
(
2014
)
Clonal selection in the germinal centre by regulated proliferation and hypermutation
.
Nature
509
,
637
640
33
Julkunen
,
I.
,
Hovi
,
T.
,
Seppälä
,
I.
and
Mäkelä
,
O.
(
1985
)
Immunoglobulin G subclass antibody responses in influenza A and parainfluenza type 1 virus infections
.
Clin. Exp. Immunol.
60
,
130
138
34
de Jong
,
B.G.
,
IJspeert
,
H.
,
Marques
,
L.
,
van der Burg
,
M.
,
van Dongen
,
J.J.
,
Loos
,
B.G.
et al. (
2017
)
Human IgG2- and IgG4-expressing memory B cells display enhanced molecular and phenotypic signs of maturity and accumulate with age
.
Immunol. Cell Biol.
95
,
744
752
35
Röltgen
,
K.
and
Boyd
,
S.D.
(
2021
)
Antibody and B cell responses to SARS-CoV-2 infection and vaccination
.
Cell Host Microbe
29
,
1063
1075
36
Good-Jacobson
,
K.L.
and
Tarlinton
,
D.M.
(
2012
)
Multiple routes to B-cell memory
.
Int. Immunol.
24
,
403
408
37
Ellebedy
,
A.H.
,
Jackson
,
K.J.
,
Kissick
,
H.T.
,
Nakaya
,
H.I.
,
Davis
,
C.W.
,
Roskin
,
K.M.
et al. (
2016
)
Defining antigen-specific plasmablast and memory B cell subsets in human blood after viral infection or vaccination
.
Nat. Immunol.
17
,
1226
1234
38
Lens
,
S.M.A.
,
Keehnen
,
R.M.J.
,
van Oers
,
M.H.J.
,
van Lier
,
R.A.W.
,
Pals
,
S.T.
and
Koopman
,
G.
(
1996
)
Identification of a novel subpopulation of germinal center B cells characterized by expression of IgD and CD70
.
Eur. J. Immunol.
26
,
1007
1011
39
Agematsu
,
K.
,
Nagumo
,
H.
,
Yang
,
F.-C.
,
Nakazawa
,
T.
,
Fukushima
,
K.
,
Ito
,
S.
et al. (
1997
)
B cell subpopulations separated by CD27 and crucial collaboration of CD27+ B cells and helper T cells in immunoglobulin production
.
Eur. J. Immunol.
27
,
2073
2079
40
Berkowska
,
M.A.
,
Schickel
,
J.-N.
,
Grosserichter-Wagener
,
C.
,
de Ridder
,
D.
,
Ng
,
Y.S.
,
van Dongen
,
J.J.M.
et al. (
2015
)
Circulating human CD27-IgA+ memory B cells recognize bacteria with polyreactive Igs
.
J. Immunol.
195
,
1417
1426
41
Sherina
,
N.
,
Piralla
,
A.
,
Du
,
L.
,
Wan
,
H.
,
Kumagai-Braesch
,
M.
,
Andréll
,
J.
et al. (
2021
)
Persistence of SARS-CoV-2-specific B and T-cell responses in convalescent COVID-19 patients 6–8 months after the infection
.
Med. (N Y)
2
,
281
95.e4
42
Wheatley
,
A.K.
,
Juno
,
J.A.
,
Wang
,
J.J.
,
Selva
,
K.J.
,
Reynaldi
,
A.
,
Tan
,
H.-X.
et al. (
2021
)
Evolution of immune responses to SARS-CoV-2 in mild-moderate COVID-19
.
Nat. Commun.
12
,
1162
43
Rodda
,
L.B.
,
Netland
,
J.
,
Shehata
,
L.
,
Pruner
,
K.B.
,
Morawski
,
P.A.
,
Thouvenel
,
C.D.
et al. (
2021
)
Functional SARS-CoV-2-Specific immune memory persists after mild COVID-19
.
Cell
184
,
169
83.e17
44
Sokal
,
A.
,
Chappert
,
P.
,
Barba-Spaeth
,
G.
,
Roeser
,
A.
,
Fourati
,
S.
,
Azzaoui
,
I.
et al. (
2021
)
Maturation and persistence of the anti-SARS-CoV-2 memory B cell response
.
Cell
184
,
1201
13.e14
45
Vaisman-Mentesh
,
A.
,
Dror
,
Y.
,
Tur-Kaspa
,
R.
,
Markovitch
,
D.
,
Kournos
,
T.
,
Dicker
,
D.
et al. (
2020
)
SARS-CoV-2 specific memory B cells frequency in recovered patient remains stable while antibodies decay over time
.
medRxiv
46
Suthar
,
M.S.
,
Zimmerman
,
M.G.
,
Kauffman
,
R.C.
,
Mantus
,
G.
,
Linderman
,
S.L.
,
Hudson
,
W.H.
et al. (
2020
)
Rapid generation of neutralizing antibody responses in COVID-19 patients
.
Cell Rep. Med.
1
,
100040
47
Stamper
,
C.
,
Dugan
,
H.
,
Li
,
L.
,
Asby
,
N.
,
Halfmann
,
P.
,
Guthmiller
,
J.
et al. (
2020
)
Distinct B cell subsets give rise to antigen-specific antibody responses against SARS-CoV-2
.
Res. Sq.
,
rs.3.rs-80476
48
Suryadevara
,
N.
,
Shrihari
,
S.
,
Gilchuk
,
P.
,
VanBlargan
,
L.A.
,
Binshtein
,
E.
,
Zost
,
S.J.
et al. (
2021
)
Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein
.
Cell
184
,
2316
31.e15
49
DiMuzio
,
J.M.
,
Heimbach
,
B.C.
,
Howanski
,
R.J.
,
Dowling
,
J.P.
,
Patel
,
N.B.
,
Henriquez
,
N.
et al. (
2021
)
Unbiased interrogation of memory B cells from convalescent COVID-19 patients reveals a broad antiviral humoral response targeting SARS-CoV-2 antigens beyond the spike protein
.
Vaccine X
8
,
100098
50
Hartley
,
G.E.
,
Edwards
,
E.S.J.
,
Aui
,
P.M.
,
Varese
,
N.
,
Stojanovic
,
S.
,
McMahon
,
J.
et al. (
2020
)
Rapid generation of durable B cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 and convalescence
.
Sci. Immunol.
5
,
eabf8891
51
Dan
,
J.M.
,
Mateus
,
J.
,
Kato
,
Y.
,
Hastie
,
K.M.
,
Yu
,
E.D.
,
Faliti
,
C.E.
et al. (
2021
)
Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection
.
Science
371
,
eabf4063
52
Seow
,
J.
,
Graham
,
C.
,
Merrick
,
B.
,
Acors
,
S.
,
Pickering
,
S.
,
Steel
,
K.J.A.
et al. (
2020
)
Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans
.
Nat. Microbiol.
5
,
1598
1607
53
Wajnberg
,
A.
,
Amanat
,
F.
,
Firpo
,
A.
,
Altman
,
D.R.
,
Bailey
,
M.J.
,
Mansour
,
M.
et al. (
2020
)
Robust neutralizing antibodies to SARS-CoV-2 infection persist for months
.
Science
370
,
1227
1230
54
Yu
,
J.
,
Tostanoski
,
L.H.
,
Peter
,
L.
,
Mercado
,
N.B.
,
McMahan
,
K.
,
Mahrokhian
,
S.H.
et al. (
2020
)
DNA vaccine protection against SARS-CoV-2 in rhesus macaques
.
Science
369
,
806
811
55
Shuwa
,
H.A.
,
Shaw
,
T.N.
,
Knight
,
S.B.
,
Wemyss
,
K.
,
McClure
,
F.A.
,
Pearmain
,
L.
et al. (
2021
)
Alterations in T and B cell function persist in convalescent COVID-19 patients
.
Med (N Y)
2
,
720
35.e4
56
Abayasingam
,
A.
,
Balachandran
,
H.
,
Agapiou
,
D.
,
Hammoud
,
M.
,
Rodrigo
,
C.
,
Keoshkerian
,
E.
et al. (
2021
)
Long-term persistence of RBD(+) memory B cells encoding neutralizing antibodies in SARS-CoV-2 infection
.
Cell Rep. Med.
2
,
100228
57
Gaebler
,
C.
,
Wang
,
Z.
,
Lorenzi
,
J.C.C.
,
Muecksch
,
F.
,
Finkin
,
S.
,
Tokuyama
,
M.
et al. (
2021
)
Evolution of antibody immunity to SARS-CoV-2
.
Nature
591
,
639
644
58
Dai
,
L.
and
Gao
,
G.F.
(
2021
)
Viral targets for vaccines against COVID-19
.
Nat. Rev. Immunol.
21
,
73
82
59
Walsh
,
E.E.
,
Frenck
,
R.W.
,
Falsey
,
A.R.
,
Kitchin
,
N.
,
Absalon
,
J.
,
Gurtman
,
A.
et al. (
2020
)
Safety and immunogenicity of Two RNA-Based COVID-19 vaccine candidates
.
N. Engl. J. Med.
383
,
2439
2450
60
Karikó
,
K.
,
Muramatsu
,
H.
,
Welsh
,
F.A.
,
Ludwig
,
J.
,
Kato
,
H.
,
Akira
,
S.
et al. (
2008
)
Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability
.
Mol. Ther.
16
,
1833
1840
61
Bos
,
R.
,
Rutten
,
L.
,
van der Lubbe
,
J.E.M.
,
Bakkers
,
M.J.G.
,
Hardenberg
,
G.
,
Wegmann
,
F.
et al. (
2020
)
Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 spike immunogen induces potent humoral and cellular immune responses
.
npj Vaccines
5
,
91
62
Rijkers
,
G.T.
,
Weterings
,
N.
,
Obregon-Henao
,
A.
,
Lepolder
,
M.
,
Dutt
,
T.S.
,
van Overveld
,
F.J.
et al. (
2021
)
Antigen presentation of mRNA-based and virus-Vectored SARS-CoV-2 vaccines
.
Vaccines
9
,
848
63
Mendonça
,
S.A.
,
Lorincz
,
R.
,
Boucher
,
P.
and
Curiel
,
D.T.
(
2021
)
Adenoviral vector vaccine platforms in the SARS-CoV-2 pandemic
.
npj Vaccines
6
,
97
64
Dagan
,
N.
,
Barda
,
N.
,
Kepten
,
E.
,
Miron
,
O.
,
Perchik
,
S.
,
Katz
,
M.A.
et al. (
2021
)
BNT162b2 mRNA COVID-19 vaccine in a nationwide mass vaccination setting
.
N. Engl. J. Med.
384
,
1412
1423
66
Baden
,
L.R.
,
El Sahly
,
H.M.
,
Essink
,
B.
,
Kotloff
,
K.
,
Frey
,
S.
,
Novak
,
R.
et al. (
2020
)
Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine
.
N. Engl. J. Med.
384
,
403
416
67
Voysey
,
M.
,
Clemens
,
S.A.C.
,
Madhi
,
S.A.
,
Weckx
,
L.Y.
,
Folegatti
,
P.M.
,
Aley
,
P.K.
et al. (
2021
)
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK
.
Lancet
397
,
99
111
68
Vasileiou
,
E.
,
Simpson
,
C.R.
,
Shi
,
T.
,
Kerr
,
S.
,
Agrawal
,
U.
,
Akbari
,
A.
et al. (
2021
)
Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study
.
Lancet (London, England)
397
,
1646
1657
69
Voysey
,
M.
,
Costa Clemens
,
S.A.
,
Madhi
,
S.A.
,
Weckx
,
L.Y.
,
Folegatti
,
P.M.
,
Aley
,
P.K.
et al. (
2021
)
Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials
.
Lancet
397
,
881
891
70
European Medicines Agency. Jcovden (previously COVID-19 vaccine Janssen) 2022. Available from
: https://www.ema.europa.eu/en/medicines/human/EPAR/jcovden-previously-covid-19-vaccine-janssen
71
Sadoff
,
J.
,
Gray
,
G.
,
Vandebosch
,
A.
,
Cárdenas
,
V.
,
Shukarev
,
G.
,
Grinsztejn
,
B.
et al. (
2021
)
Safety and efficacy of single-dose Ad26.COV2.S vaccine against COVID-19
.
N. Engl. J. Med.
384
,
2187
2201
72
Johnson & Johnson. Johnson & Johnson Announces Single-Shot Janssen COVID-19 Vaccine Candidate Met Primary Endpoints in Interim Analysis of its Phase 3 ENSEMBLE Trial 2021. Available from
: https://www.prnewswire.com/news-releases/johnson--johnson-announces-single-shot-janssen-covid-19-vaccine-candidate-met-primary-endpoints-in-interim-analysis-of-its-phase-3-ensemble-trial-301218035.html
73
Haas
,
E.J.
,
Angulo
,
F.J.
,
McLaughlin
,
J.M.
,
Anis
,
E.
,
Singer
,
S.R.
,
Khan
,
F.
et al. (
2021
)
Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data
.
Lancet
397
,
1819
1829
74
Tang
,
F.
,
Hammel
,
I.S.
,
Andrew
,
M.K.
and
Ruiz
,
J.G.
(
2022
)
COVID-19 mRNA vaccine effectiveness against hospitalisation and death in veterans according to frailty status during the SARS-CoV-2 delta (B.1.617.2) variant surge in the USA: a retrospective cohort study
.
Lancet Healthy Longev.
3
,
e589
e598
75
Macchia
,
A.
,
Ferrante
,
D.
,
Angeleri
,
P.
,
Biscayart
,
C.
,
Mariani
,
J.
,
Esteban
,
S.
et al. (
2021
)
Evaluation of a COVID-19 vaccine campaign and SARS-CoV-2 infection and mortality Among adults aged 60 years And older in a middle-income country
.
JAMA Netw. Open.
4
,
e2130800
76
Suthar
,
A.B.
,
Wang
,
J.
,
Seffren
,
V.
,
Wiegand
,
R.E.
,
Griffing
,
S.
and
Zell
,
E.
(
2022
)
Public health impact of COVID-19 vaccines in the US: observational study
.
BMJ
377
,
e069317
77
Schultz
,
N.H.
,
Sørvoll
,
I.H.
,
Michelsen
,
A.E.
,
Munthe
,
L.A.
,
Lund-Johansen
,
F.
,
Ahlen
,
M.T.
et al. (
2021
)
Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination
.
N. Engl. J. Med.
384
,
2124
2130
78
Greinacher
,
A.
,
Thiele
,
T.
,
Warkentin
,
T.E.
,
Weisser
,
K.
,
Kyrle
,
P.A.
and
Eichinger
,
S.
(
2021
)
Thrombotic thrombocytopenia after ChAdOx1 nCov-19 vaccination
.
N. Engl. J. Med.
384
,
2092
2101
79
Simpson
,
C.R.
,
Shi
,
T.
,
Vasileiou
,
E.
,
Katikireddi
,
S.V.
,
Kerr
,
S.
,
Moore
,
E.
et al. (
2021
)
First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland
.
Nat. Med.
27
,
1290
1297
81
Goel
,
R.R.
,
Apostolidis
,
S.A.
,
Painter
,
M.M.
,
Mathew
,
D.
,
Pattekar
,
A.
,
Kuthuru
,
O.
et al. (
2021
)
Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals following mRNA vaccination
.
Sci. Immunol.
6
,
eabi6950
82
Goel
,
R.R.
,
Painter Mark
,
M.
,
Apostolidis Sokratis
,
A.
,
Mathew
,
D.
,
Meng
,
W.
,
Rosenfeld Aaron
,
M.
et al. (
2021
)
mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern
.
Science
374
,
abm0829
83
Piano Mortari
,
E.
,
Russo
,
C.
,
Vinci
,
M.R.
,
Terreri
,
S.
,
Fernandez Salinas
,
A.
,
Piccioni
,
L.
et al. (
2021
)
Highly specific memory B cells generation after the 2nd dose of BNT162b2 vaccine compensate for the decline of serum antibodies and absence of mucosal IgA
.
Cells
10
,
2541
84
Ewer
,
K.J.
,
Barrett
,
J.R.
,
Belij-Rammerstorfer
,
S.
,
Sharpe
,
H.
,
Makinson
,
R.
,
Morter
,
R.
et al. (
2021
)
T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial
.
Nat. Med.
27
,
270
278
85
Kang
,
Y.M.
,
Minn
,
D.
,
Lim
,
J.
,
Lee
,
K.-D.
,
Jo
,
D.H.
,
Choe
,
K.-W.
et al. (
2021
)
Comparison of antibody response elicited by ChAdOx1 and BNT162b2 COVID-19 vaccine
.
J. Korean Med. Sci.
36
,
e311
86
Sablerolles
,
R.S.G.
,
Rietdijk
,
W.J.R.
,
Goorhuis
,
A.
,
Postma
,
D.F.
,
Visser
,
L.G.
,
Geers
,
D.
et al. (
2022
)
Immunogenicity and reactogenicity of vaccine boosters after Ad26.COV2.S priming
.
N. Engl. J. Med.
386
,
951
963
87
Turner
,
J.S.
,
O'Halloran
,
J.A.
,
Kalaidina
,
E.
,
Kim
,
W.
,
Schmitz
,
A.J.
,
Zhou
,
J.Q.
et al. (
2021
)
SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses
.
Nature
596
,
109
113
88
Sokal
,
A.
,
Barba-Spaeth
,
G.
,
Fernández
,
I.
,
Broketa
,
M.
,
Azzaoui
,
I.
,
de La Selle
,
A.
et al. (
2021
)
mRNA vaccination of naive and COVID-19-recovered individuals elicits potent memory B cells that recognize SARS-CoV-2 variants
.
Immunity
54
,
2893
907.e5
89
Tartof
,
S.Y.
,
Slezak
,
J.M.
,
Fischer
,
H.
,
Hong
,
V.
,
Ackerson
,
B.K.
,
Ranasinghe
,
O.N.
et al. (
2021
)
Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study
.
Lancet
398
,
1407
1416
90
Ramasamy
,
M.N.
,
Minassian
,
A.M.
,
Ewer
,
K.J.
,
Flaxman
,
A.L.
,
Folegatti
,
P.M.
,
Owens
,
D.R.
et al. (
2020
)
Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial
.
Lancet
396
,
1979
1993
91
Barrett
,
J.R.
,
Belij-Rammerstorfer
,
S.
,
Dold
,
C.
,
Ewer
,
K.J.
,
Folegatti
,
P.M.
,
Gilbride
,
C.
et al. (
2021
)
Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses
.
Nat. Med.
27
,
279
288
92
Stephenson
,
K.E.
,
Le Gars
,
M.
,
Sadoff
,
J.
,
de Groot
,
A.M.
,
Heerwegh
,
D.
,
Truyers
,
C.
et al. (
2021
)
Immunogenicity of the Ad26.COV2.S vaccine for COVID-19
.
JAMA
325
,
1535
1544
93
Kim
,
J.Y.
,
Lim
,
S.Y.
,
Park
,
S.
,
Kwon
,
J.-S.
,
Bae
,
S.
,
Park
,
J.Y.
et al. (
2022
)
Immune responses to the ChAdOx1 nCoV-19 and BNT162b2 vaccines and to natural coronavirus disease 2019 infections over a 3-Month period
.
J. Infect. Dis.
225
,
777
784
94
Barros-Martins
,
J.
,
Hammerschmidt
,
S.I.
,
Cossmann
,
A.
,
Odak
,
I.
,
Stankov
,
M.V.
,
Morillas Ramos
,
G.
et al. (
2021
)
Immune responses against SARS-CoV-2 variants after heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination
.
Nat. Med.
27
,
1525
1529
95
Liu
,
X.
,
Shaw
,
R.H.
,
Stuart
,
A.S.V.
,
Greenland
,
M.
,
Aley
,
P.K.
,
Andrews
,
N.J.
et al. (
2021
)
Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial
.
Lancet
398
,
856
869
96
Cho
,
A.
,
Muecksch
,
F.
,
Wang
,
Z.
,
Tanfous
,
T.B.
,
Dasilva
,
J.
,
Raspe
,
R.
et al. (
2022
)
Antibody evolution to SARS-CoV-2 after single-dose Ad26.COV2.S vaccine
.
J. Exp. Med.
219
,
e20220732
97
Tenbusch
,
M.
,
Schumacher
,
S.
,
Vogel
,
E.
,
Priller
,
A.
,
Held
,
J.
,
Steininger
,
P.
et al. (
2021
)
Heterologous prime–boost vaccination with ChAdOx1 nCoV-19 and BNT162b2
.
Lancet Infect. Dis.
21
,
1212
1213
98
Collier
,
A.-Y.
,
Yu
,
J.
,
McMahan
,
K.
,
Liu
,
J.
,
Chandrashekar
,
A.
,
Maron
,
J.S.
et al. (
2021
)
Differential kinetics of immune responses elicited by COVID-19 vaccines
.
N. Engl. J. Med.
385
,
2010
2012
99
Coutard
,
B.
,
Valle
,
C.
,
de Lamballerie
,
X.
,
Canard
,
B.
,
Seidah
,
N.G.
and
Decroly
,
E.
(
2020
)
The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade
.
Antiviral Res.
176
,
104742
100
Kaku
,
C.I.
,
Champney
,
E.R.
,
Normark
,
J.
,
Garcia
,
M.
,
Johnson
,
C.E.
,
Ahlm
,
C.
et al. (
2022
)
Broad anti-SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 vaccination
.
Science
375
,
eabn2688
101
Wrapp
,
D.
,
Wang
,
N.
,
Corbett
,
K.S.
,
Goldsmith
,
J.A.
,
Hsieh
,
C.L.
,
Abiona
,
O.
et al. (
2020
)
Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
.
Science
367
,
1260
1263
102
Heinz
,
F.X.
and
Stiasny
,
K.
(
2021
)
Distinguishing features of current COVID-19 vaccines: knowns and unknowns of antigen presentation and modes of action
.
npj Vaccines
6
,
104
103
Zhang
,
Z.
,
Mateus
,
J.
,
Coelho
,
C.H.
,
Dan
,
J.M.
,
Moderbacher
,
C.R.
,
Gálvez
,
R.I.
et al. (
2022
)
Humoral and cellular immune memory to four COVID-19 vaccines
.
Cell
185
,
2434
51.e17
104
Wang
,
Z.
,
Muecksch
,
F.
,
Muenn
,
F.
,
Cho
,
A.
,
Zong
,
S.
,
Raspe
,
R.
et al. (
2022
)
Humoral immunity to SARS-CoV-2 elicited by combination COVID-19 vaccination regimens
.
J Exp Med.
219
,
e20220826
105
Painter
,
M.M.
,
Mathew
,
D.
,
Goel
,
R.R.
,
Apostolidis
,
S.A.
,
Pattekar
,
A.
,
Kuthuru
,
O.
et al. (
2021
)
Rapid induction of antigen-specific CD4+ T cells is associated with coordinated humoral and cellular immunity to SARS-CoV-2 mRNA vaccination
.
Immunity
54
,
2133
42.e3
106
Wall
,
E.C.
,
Wu
,
M.
,
Harvey
,
R.
,
Kelly
,
G.
,
Warchal
,
S.
,
Sawyer
,
C.
et al. (
2021
)
Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination
.
Lancet
397
,
2331
2333
107
Garcia-Beltran
,
W.F.
,
Lam
,
E.C.
,
St. Denis
,
K.
,
Nitido
,
A.D.
,
Garcia
,
Z.H.
,
Hauser
,
B.M.
et al. (
2021
)
Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity
.
Cell
184
,
2372
2383.e9
108
Garcia-Beltran WF
,
S.
,
Denis
,
K.J.
,
Hoelzemer
,
A.
,
Lam
,
E.C.
,
Nitido
,
A.D.
,
Sheehan
,
M.L.
et al. (
2022
)
mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 omicron variant
.
Cell
185
,
457
66.e4
109
Liu
,
C.
,
Ginn
,
H.M.
,
Dejnirattisai
,
W.
,
Supasa
,
P.
,
Wang
,
B.
,
Tuekprakhon
,
A.
et al. (
2021
)
Reduced neutralization of SARS-CoV-2 B.1.617 by vaccine and convalescent serum
.
Cell
184
,
4220
4236.e13
110
Jangra
,
S.
,
Ye
,
C.
,
Rathnasinghe
,
R.
,
Stadlbauer
,
D.
,
Krammer
,
F.
,
Simon
,
V.
et al. (
2021
)
SARS-CoV-2 spike E484K mutation reduces antibody neutralisation
.
Lancet Microbe
2
,
e283
e284
111
Supasa
,
P.
,
Zhou
,
D.
,
Dejnirattisai
,
W.
,
Liu
,
C.
,
Mentzer
,
A.J.
,
Ginn
,
H.M.
et al. (
2021
)
Reduced neutralization of SARS-CoV-2 B.1.1.7 variant by convalescent and vaccine sera
.
Cell
184
,
2201
2211.e7
112
Zhou
,
D.
,
Dejnirattisai
,
W.
,
Supasa
,
P.
,
Liu
,
C.
,
Mentzer
,
A.J.
,
Ginn
,
H.M.
et al. (
2021
)
Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera
.
Cell
184
,
2348
2361.e6
113
Wibmer
,
C.K.
,
Ayres
,
F.
,
Hermanus
,
T.
,
Madzivhandila
,
M.
,
Kgagudi
,
P.
,
Oosthuysen
,
B.
et al. (
2021
)
SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma
.
Nat. Med.
27
,
622
625
114
Yang
,
T.-J.
,
Yu
,
P.-Y.
,
Chang
,
Y.-C.
,
Liang
,
K.-H.
,
Tso
,
H.-C.
,
Ho
,
M.-R.
et al. (
2021
)
Effect of SARS-CoV-2 B.1.1.7 mutations on spike protein structure and function
.
Nat Struct Mol Biol
28
,
731
739
.
115
Wang
,
Z.
,
Schmidt
,
F.
,
Weisblum
,
Y.
,
Muecksch
,
F.
,
Barnes
,
C.O.
,
Finkin
,
S.
et al. (
2021
)
mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants
.
Nature
592
,
616
622
116
Chen
,
Y.
,
Tong
,
P.
,
Whiteman
,
N.
,
Moghaddam Ali
,
S.
,
Zarghami
,
M.
,
Zuiani
,
A.
et al. (
2022
)
Immune recall improves antibody durability and breadth to SARS-CoV-2 variants
.
Sci. Immunol.
0
,
eabp8328
117
Gavor
,
E.
,
Choong
,
Y.K.
,
Er
,
S.Y.
,
Sivaraman
,
H.
and
Sivaraman
,
J.
(
2020
)
Structural basis of SARS-CoV-2 and SARS-CoV antibody interactions
.
Trends Immunol.
41
,
1006
1022
118
Stanford University Coronavirus Antiviral & Resistance Database. SARS-CoV-2 Variants: Stanford University; 2022. Available from
: https://covdb.stanford.edu/page/mutation-viewer/#omicron
119
Gruell
,
H.
,
Vanshylla
,
K.
,
Tober-Lau
,
P.
,
Hillus
,
D.
,
Schommers
,
P.
,
Lehmann
,
C.
et al. (
2022
)
mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 omicron variant
.
Nat. Med.
28
,
477
480
120
Bekliz
,
M.
,
Adea
,
K.
,
Vetter
,
P.
,
Eberhardt
,
C.S.
,
Hosszu-Fellous
,
K.
,
Vu
,
D.-L.
et al. (
2022
)
Neutralization capacity of antibodies elicited through homologous or heterologous infection or vaccination against SARS-CoV-2 VOCs
.
Nat. Commun.
13
,
3840
121
Mlcochova
,
P.
,
Kemp
,
S.A.
,
Dhar
,
M.S.
,
Papa
,
G.
,
Meng
,
B.
,
Ferreira
,
I.A.T.M.
et al. (
2021
)
SARS-CoV-2 B.1.617.2 delta variant replication and immune evasion
.
Nature
599
,
114
119
122
Pegu
,
A.
,
O'Connell Sarah
,
E.
,
Schmidt Stephen
,
D.
,
O'Dell
,
S.
,
Talana Chloe
,
A.
,
Lai
,
L.
et al. (
2021
)
Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants
.
Science
373
,
1372
1377
123
Liu
,
J.
,
Chandrashekar
,
A.
,
Sellers
,
D.
,
Barrett
,
J.
,
Jacob-Dolan
,
C.
,
Lifton
,
M.
et al. (
2022
)
Vaccines elicit highly conserved cellular immunity to SARS-CoV-2 omicron
.
Nature
603
,
493
496
124
Furukawa
,
K.
,
Tjan
,
L.H.
,
Kurahashi
,
Y.
,
Sutandhio
,
S.
,
Nishimura
,
M.
,
Arii
,
J.
et al. (
2022
)
Assessment of neutralizing antibody response against SARS-CoV-2 variants after 2 to 3 doses of the BNT162b2 mRNA COVID-19 vaccine
.
JAMA Netw. Open
5
,
e2210780
125
Cheng
,
S.M.S.
,
Mok
,
C.K.P.
,
Leung
,
Y.W.Y.
,
Ng
,
S.S.
,
Chan
,
K.C.K.
,
Ko
,
F.W.
et al. (
2022
)
Neutralizing antibodies against the SARS-CoV-2 omicron variant BA.1 following homologous and heterologous CoronaVac or BNT162b2 vaccination
.
Nat. Med.
28
,
486
489
126
Tay
,
M.Z.
,
Rouers
,
A.
,
Fong
,
S.-W.
,
Goh
,
Y.S.
,
Chan
,
Y.-H.
,
Chang
,
Z.W.
et al. (
2022
)
Decreased memory B cell frequencies in COVID-19 delta variant vaccine breakthrough infection
.
EMBO Mol. Med.
14
,
e15227
127
Lyngse
,
F.P.
,
Mortensen
,
L.H.
,
Denwood
,
M.J.
,
Christiansen
,
L.E.
,
Møller
,
C.H.
,
Skov
,
R.L.
et al. (
2022
)
Household transmission of the SARS-CoV-2 omicron variant in Denmark
.
Nat. Commun.
13
,
5573
128
Pulliam
,
J.R.C.
,
van Schalkwyk
,
C.
,
Govender
,
N.
,
von Gottberg
,
A.
,
Cohen
,
C.
,
Groome
,
M.J.
et al. (
2022
)
Increased risk of SARS-CoV-2 reinfection associated with emergence of omicron in South Africa
.
Science
376
,
eabn4947
129
Eggink
,
D.
,
Andeweg
,
S.P.
,
Vennema
,
H.
,
van Maarseveen
,
N.
,
Vermaas
,
K.
,
Vlaemynck
,
B.
et al. (
2022
)
Increased risk of infection with SARS-CoV-2 omicron BA.1 compared with delta in vaccinated and previously infected individuals, The Netherlands, 22 November 2021 to 19 January 2022
.
Euro Surveill
27
,
2101196
130
Hui
,
K.P.Y.
,
Ho
,
J.C.W.
,
Cheung
,
M.
,
Ng
,
K.
,
Ching
,
R.H.H.
,
Lai
,
K.
et al. (
2022
)
SARS-CoV-2 omicron variant replication in human bronchus and lung ex vivo
.
Nature
603
,
715
720
131
Hui
,
K.P.Y.
,
Ng
,
K.-C.
,
Ho
,
J.C.W.
,
Yeung
,
H.-W.
,
Ching
,
R.H.H.
,
Gu
,
H.
et al. (
2022
)
Replication of SARS-CoV-2 omicron BA.2 variant in ex vivo cultures of the human upper and lower respiratory tract
.
eBioMedicine
83
,
104232
132
Cele
,
S.
,
Jackson
,
L.
,
Khoury
,
D.S.
,
Khan
,
K.
,
Moyo-Gwete
,
T.
,
Tegally
,
H.
et al. (
2022
)
Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization
.
Nature
602
,
654
656
133
Medigeshi
,
G.R.
,
Batra
,
G.
,
Murugesan
,
D.R.
,
Thiruvengadam
,
R.
,
Chattopadhyay
,
S.
,
Das
,
B.
et al. (
2022
)
Sub-optimal neutralisation of omicron (B.1.1.529) variant by antibodies induced by vaccine alone or SARS-CoV-2 infection plus vaccine (hybrid immunity) post 6-months
.
eBioMedicine
78
,
103938
134
Schmidt
,
F.
,
Muecksch
,
F.
,
Weisblum
,
Y.
,
Da Silva
,
J.
,
Bednarski
,
E.
,
Cho
,
A.
et al. (
2021
)
Plasma neutralization of the SARS-CoV-2 omicron variant
.
N. Engl. J. Med.
386
,
599
601
135
Quandt
,
J.
,
Muik
,
A.
,
Salisch
,
N.
,
Lui Bonny
,
G.
,
Lutz
,
S.
,
Krüger
,
K.
et al. (
2022
)
Omicron BA.1 breakthrough infection drives cross-variant neutralization and memory B cell formation against conserved epitopes
.
Sci. Immunol.
0
,
eabq2427
136
Khan
,
K.
,
Karim
,
F.
,
Ganga
,
Y.
,
Bernstein
,
M.
,
Jule
,
Z.
,
Reedoy
,
K.
et al. (
2022
)
Omicron BA.4/BA.5 escape neutralizing immunity elicited by BA.1 infection
.
Nat. Comm.
13
,
4686
137
Hachmann
,
N.P.
,
Miller
,
J.
,
Collier
,
A.-Y.
,
Ventura
,
J.D.
,
Yu
,
J.
,
Rowe
,
M.
et al. (
2022
)
Neutralization Escape by SARS-CoV-2 Omicron Subvariants BA.2.12.1, BA.4, and BA.5
.
N. Engl. J. Med.
387
,
86
88
138
Abu-Raddad
,
L.J.
,
Chemaitelly
,
H.
,
Ayoub
,
H.H.
,
AlMukdad
,
S.
,
Yassine
,
H.M.
,
Al-Khatib
,
H.A.
et al. (
2022
)
Effect of mRNA vaccine boosters against SARS-CoV-2 omicron infection in Qatar
.
N. Engl. J. Med.
386
,
1804
1816
139
Andrews
,
N.
,
Stowe
,
J.
,
Kirsebom
,
F.
,
Toffa
,
S.
,
Sachdeva
,
R.
,
Gower
,
C.
et al. (
2022
)
Effectiveness of COVID-19 booster vaccines against COVID-19-related symptoms, hospitalization and death in England
.
Nat. Med.
28
,
831
837
140
Barda
,
N.
,
Dagan
,
N.
,
Cohen
,
C.
,
Hernán
,
M.A.
,
Lipsitch
,
M.
,
Kohane
,
I.S.
et al. (
2021
)
Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study
.
Lancet
398
,
2093
2100
141
Andrews
,
N.
,
Stowe
,
J.
,
Kirsebom
,
F.
,
Toffa
,
S.
,
Rickeard
,
T.
,
Gallagher
,
E.
et al. (
2022
)
COVID-19 vaccine effectiveness against the omicron (B.1.1.529) variant
.
N. Engl. J. Med.
386
,
1532
1546
142
Gram
,
M.A.
,
Emborg
,
H.D.
,
Schelde
,
A.B.
,
Friis
,
N.U.
,
Nielsen
,
K.F.
,
Moustsen-Helms
,
I.R.
et al. (
2021
)
Vaccine effectiveness against SARS-CoV-2 infection or COVID-19 hospitalization with the Alpha, Delta, or Omicron SARS-CoV-2 variant: A nationwide Danish cohort study
.
PLoS Med.
19
,
e1003992
143
Nemet
,
I.
,
Kliker
,
L.
,
Lustig
,
Y.
,
Zuckerman
,
N.
,
Erster
,
O.
,
Cohen
,
C.
et al. (
2021
)
Third BNT162b2 vaccination neutralization of SARS-CoV-2 omicron infection
.
N. Engl. J. Med.
386
,
492
494
144
Evans
,
J.P.
,
Zeng
,
C.
,
Qu
,
P.
,
Faraone
,
J.
,
Zheng
,
Y.-M.
,
Carlin
,
C.
et al. (
2022
)
Neutralization of SARS-CoV-2 omicron sub-lineages BA.1, BA.1.1, and BA.2
.
Cell Host Microbe
30
,
1093
1102.e3
145
Yu
,
J.
,
Collier
,
A.-Y.
,
Rowe
,
M.
,
Mardas
,
F.
,
Ventura
,
J.D.
,
Wan
,
H.
et al. (
2022
)
Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 Variants
.
N Engl J Med.
386
,
1579
1580
146
Kotaki
,
R.
,
Adachi
,
Y.
,
Moriyama
,
S.
,
Onodera
,
T.
,
Fukushi
,
S.
,
Nagakura
,
T.
et al. (
2022
)
SARS-CoV-2 omicron-neutralizing memory B-cells are elicited by two doses of BNT162b2 mRNA vaccine
.
Sci. Immunol.
7
,
eabn8590
147
Wang
,
K.
,
Jia
,
Z.
,
Bao
,
L.
,
Wang
,
L.
,
Cao
,
L.
,
Chi
,
H.
et al. (
2022
)
Memory B cell repertoire from triple vaccinees against diverse SARS-CoV-2 variants
.
Nature
603
,
919
925
148
Purtha
,
W.E.
,
Tedder
,
T.F.
,
Johnson
,
S.
,
Bhattacharya
,
D.
and
Diamond
,
M.S.
(
2011
)
Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants
.
J. Exp. Med.
208
,
2599
2606
149
Turner
,
J.S.
,
Zhou
,
J.Q.
,
Han
,
J.
,
Schmitz
,
A.J.
,
Rizk
,
A.A.
,
Alsoussi
,
W.B.
et al. (
2020
)
Human germinal centres engage memory and naive B cells after influenza vaccination
.
Nature
586
,
127
132
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). Open access for this article was enabled by the participation of Monash University in an all-inclusive Read & Publish agreement with Portland Press and the Biochemical Society under a transformative agreement with CAUL.