Multiple antigen presenting system (MAPS): state of the art and potential applications

ABSTRACT

Introduction

Technological innovations have been instrumental in advancing vaccine design and protective benefit. Improvements in the safety, tolerability, and efficacy/effectiveness profiles have profoundly reduced vaccine-preventable global disease morbidity and mortality. Here we present an original vaccine platform, the Multiple Antigen Presenting System (MAPS), that relies on high-affinity interactions between a biotinylated polysaccharide (PS) and rhizavidin-fused pathogen-specific proteins. MAPS allows for flexible combinations of various PS and protein components.

Areas covered

This narrative review summarizes the underlying principles of MAPS and describes its applications for vaccine design against bacterial and viral pathogens in non-clinical and clinical settings.

Expert opinion

The utilization of high-affinity non-covalent biotin–rhizavidin interactions in MAPS allows for combining multiple PS and disease-specific protein antigens in a single vaccine. The modular design enables a simplified exchange of vaccine components. Published studies indicate that MAPS technology may support enhanced immunogenic breadth (covering more serotypes, inducing B- and T-cell responses) beyond that which may be elicited via PS- or protein-based conjugate vaccines. Importantly, a more detailed characterization of MAPS-based candidate vaccines is warranted, especially in clinical studies. It is anticipated that MAPS-based vaccines could be adapted and leveraged across numerous diseases of global public health importance.

Plain Language Summary

Existing conjugate vaccines, consisting of pathogen-derived polysaccharides (PSs) and carrier proteins unrelated to the target pathogen, have helped to significantly reduce morbidity and mortality of several bacterial diseases. However, the worldwide burden of infectious diseases targeted by conjugate vaccines is still high. This is mainly due to high pathogen diversity and ongoing evolution, and innovative approaches are needed to respond to these challenges. Multiple Antigen Presenting System (MAPS) is an original vaccine technology that relies on strong molecular interactions between biotin and rhizavidin. MAPS is highly adaptable, as different PS and protein components can be precisely combined and easily exchanged, with limited damage to immunogenic epitopes (PS and protein features recognized by the immune system). Unlike existing conjugate vaccines, MAPS complexes contain pathogen-specific proteins, able to elicit broad immune responses directed against the pathogen. To date, investigational MAPS-based vaccines have been evaluated in several non-clinical studies; one candidate pneumococcal vaccine has been evaluated in early phase clinical studies in healthy children and adults (including older adults). In these clinical studies, the MAPS-based vaccine candidate was well tolerated and induced robust immune responses. If the favorable profile of MAPS-based vaccines is confirmed in further studies, these vaccines could be used against infectious diseases associated with significant morbidity and mortality.

GRAPHICAL ABSTRACT

KEYWORDS:

• Bacterial vaccines
• biotin–rhizavidin interaction
• cell-mediated immunity
• glycocomplex
• MAPS
• multiple antigen presenting system
• pneumococcal vaccines
• polysaccharide-specific antibodies

1. Introduction

Estimated 3.5–5.0 million lives are saved worldwide every year as a consequence of vaccination. The success of vaccines at improving public health is a direct result of the seminal technological advances that have shaped vaccine development [1,2].

Most recently, mRNA and viral vector technologies have allowed for swift development and deployment of effective vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [3]; it is likely that similarly urgent innovations in vaccination may be needed in the future to combat emerging and new pathogens. Furthermore, there remains an opportunity for improvement across a wide range of long-established vaccines, regarding responses to vaccines (e.g. tolerability profiles, efficacy/effectiveness, extent, and duration of protection) as well as practical considerations (e.g. manufacturing, cold chain, stability, and distribution) [4–6].

The Multiple Antigen Presenting System (MAPS) is an innovative technology, with potential benefits across many vaccine-preventable diseases. MAPS combines pathogen-specific polysaccharide (PS) and protein components via a high-affinity non-covalent biotin–rhizavidin interaction [7]. This narrative review provides an overview of MAPS technology development, non-clinical and clinical evaluations to date, and discusses future applications and differentiated potential of MAPS.

2. Vaccines history and technology

The field of vaccinology has benefited from several key enhancements, including changes in the choice of immunogenic targets (e.g. from the whole pathogen to specific subunits, toxoids, polysaccharides, DNA, or mRNA), improved technologies for target identification (e.g. reverse vaccinology), strategies to improve vaccine immunogenicity (e.g. use of adjuvants) and enhance vaccination compliance and coverage (e.g. combination and multivalent vaccines) [1,6,8].

Vaccines against Streptococcus pneumoniae (pneumococcal vaccines) represent one clear example of technological innovations driving vaccine development [9–11]. Following initial development as inactivated whole-cell preparations, multivalent formulations containing pneumococcal capsular polysaccharides (CPSs) from up to 23 different serotypes were licensed. One 23-valent formulation (pneumococcal polysaccharide vaccine [PPSV23]) is still recommended in older adults aged ≥65 years and in certain populations at high risk for pneumococcal infection [12,13]. Nevertheless, the efficacy of the pure CPS vaccines against invasive pneumococcal disease is a matter of some controversy and, importantly, these vaccines are not reliably immunogenic in children under 2 years, in whom the burden of pneumococcal disease is particularly high [10,11].

Introduction of pneumococcal conjugate vaccines (PCVs), in which the CPS is covalently linked to a carrier protein that is not related to the targeted disease (i.e. disease-unrelated carrier protein), enabled the production of memory B cells via activation of T helper 2 (Th2) cells in immunized individuals [10,11,14,15] and significantly reduced the worldwide burden of invasive pneumococcal disease [16]. Unlike the pure CPS formulations, PCVs were found to induce T-cell-dependent and persistent PS-specific antibody responses also in young children and mediate extensive protection through herd immunity [11]. Currently licensed PCV formulations contain CPS from up to 20 serotypes [17–22]. Similar conjugation technology has been applied to vaccines (licensed and/or investigational) against a number of other pathogens, such as Neisseria meningitidis (meningococcus), Salmonella enterica Typhi and Paratyphi, Haemophilus influenzae type B, group B Streptococcus, and Shigella [15]. For example, for PCVs, a common feature of conjugate vaccines against the listed bacteria is induction of T-cell-mediated anti-PS antibody responses [15,23,24].

While conjugation technology can improve vaccine immunogenicity, few limitations remain. In the case of pneumococcal vaccines, the number of serotypes that can be included without deleterious impact on the immunogenicity profile is limited. One of the mechanisms hypothesized to underlie this limitation is carrier-induced epitopic suppression, leading to a decreased immune response with every increase in valency [11,25]. Furthermore, the inclusion of serotype-specific CPS in conjugate vaccines does not always confer protection; in current PCV formulations, the serotype 3 PS component has not had a demonstrable impact on rates of invasive disease caused by this serotype [17,26]. Conjugate vaccines have also been associated with serotype replacement, whereby the prevalence of serotypes that are not included in the vaccine formulation has increased [25]. After the introduction of PCV13 (a 13-valent PCV), a significant rise in invasive pneumococcal disease caused by non-vaccine serotype strains was observed in children in North America and Europe [10]. Serotype replacement is also an issue among (older) adults, who have been found to be colonized by a wider variety of disease-causing pneumococcal serotypes than children [10]. One hypothesis to explain the observed serotype replacement is that removing vaccine-targeted serotypes from the population opens a niche for non-vaccine-targeted serotypes [25]. With over 100 currently known pneumococcal serotypes [10], of which any can increase in prevalence, it is difficult to predict how vaccines may influence serotype replacement and which epidemiological shifts may occur. The effectiveness of the recently licensed 15- and 20-valent PCV formulations at reducing the pneumococcal disease burden remains to be determined. Finally, manufacturing of conjugate vaccines can be complex, especially for multivalent vaccines, where the multi-step conjugation reactions may affect a vaccine’s immunogenic potential [11,27].

Beyond pneumococcal vaccines, other potential limitations of current vaccination approaches include sub-optimal efficacy in specific populations (e.g. infants, older adults, immunocompromized individuals, and persons with underlying medical conditions), lack of universal protection against pathogens with inherent diversity, and limited duration of protection. Furthermore, key considerations such as ensuring health equity (i.e. availability across ethnicities and geographical regions) must also be tackled [5,28,29].

Vaccines for established and new pathogens continue to be evaluated to bring new or improved solutions. Strategies include but are not limited to novel viral vectors [30–33], updated mRNA technologies [34,35], novel adjuvants/adjuvant systems [36], bioconjugation [37–39] and Generalized Modules for Membrane Antigens (GMMA) [40–42]. The development of new vaccines is supported by ongoing advances in the fields of structural biology, reverse vaccinology, synthetic biology, and more recently, artificial intelligence and machine learning. For the purposes of this review, we will focus on MAPS.

MAPS is an innovative vaccine platform and represents an original approach for antigen presentation and delivery, with the potential to ensure robust and broad immune responses against different pathogens [7,43]. The ability of MAPS-based complexes to induce both humoral and cellular responses coupled with broader serotype coverage may be a promising advance in modern vaccine development [7,43].

3. MAPS technology

The MAPS approach relies on the formation of a macromolecular complex consisting of two components, joined by non-covalent affinity-based coupling: biotinylated PS and pathogen-specific proteins genetically fused to rhizavidin (from Rhizobium etli), an avidin-like biotin-binding moiety (see also Graphical Abstract) [7]. After mixing these two main components together, the MAPS complexes are isolated using standard purification techniques. Depending on the individual PS target, the diameter of MAPS complexes can range between 20 nm and several hundred nm [7].

The interaction between biotin and avidin moieties is mediated by the esterophilic heterocycle of biotin and biotin-binding sites on the avidin polymer. The small size of biotin, its ability to bind different molecules through its hydrophilic carboxylic acid chain, and the strength of its interaction with avidin have enabled varied use of the biotin-avidin coupling [44]. In MAPS-based vaccines, rhizavidin is used as biotin-binding moiety [7,45–52]. In contrast to tetrameric avidin and streptavidin, rhizavidin is a dimer containing a proline residue after a flexible GGSG stretch in its loop between β-strands 7 and 8, leading to its unique and high-affinity interaction with biotin [53]. The dissociation rate constant between D-biotin and rhizavidin was found to be significantly higher than those of avidin and streptavidin [53].

Some advantages of this system include ease of manufacturing, versatility, and flexibility to easily adapt to different pathogens or in response to changes in disease epidemiology, while theoretically also minimizing possible epitope damage by avoiding covalent bindings [7]. The MAPS platform lends itself to vaccine optimization, as the PS:protein ratio can be precisely controlled, and the protein components can be easily exchanged. Furthermore, by combining PS with pathogen-specific, conserved proteins instead of disease-unrelated carrier proteins, the breadth of the immune response induced by MAPS vaccines is increased, comprising multipronged antibody- and cell-mediated immune responses to both PS and protein antigens [7,43].

4. Non-clinical and clinical evaluation of MAPS-based vaccines

Investigational MAPS-based rhizavidin-containing vaccines have been evaluated in several non-clinical studies [7,43,45–47,49–52,54] and clinical trials [48], with a large body of results not yet described in peer reviewed publications [45,47,54]. Two clinical studies regarding the safety and immunogenicity of a pneumococcal investigational vaccine (one in adults, NCT04265911; one in toddlers from the United States, NCT04525599) are completed and results are being prepared for publication.

Immunization with MAPS-based vaccines was shown to induce robust anti-PS immunoglobulin G (IgG) production [7,46,47,51], high levels of opsonophagocytic activity (OPA) [7,48,51] and Th1/Th17 cellular immune responses in non-clinical and clinical study settings [7,48–50,52].

4.1. Evidence from non-clinical studies

An important aspect of MAPS is its ability to induce not only anti-PS antibodies but also anti-protein humoral (usually IgG) and cell-mediated (e.g. cytotoxic and Th1 and Th17) immune responses (Table 1). The elicited immune responses are thus broader than those generated using classical conjugation technology. It has also been recently demonstrated that the MAPS-induced anti-PS and anti-protein antibodies can provide synergistic immunogenic and protective effects [43,45].

Table 1. Overview of immune responses induced by MAPS-based vaccines in non-clinical studies, by disease area.

			MAPS-based vaccine formulation
Category	Target pathogen	Animal model	Rhavi fusion proteins	Biotynilated PS	Evaluated immune responses	Reference
Bacterial	Streptococcus pneumoniae	Mouse (MAPS 1 and 2) Rabbit (MAPS 1)	MAPS 1: sp0435 MAPS 2: PdT, PsaA, SP0435, SP1458, SP1534	MAPS 1: PnCPS14 MAPS 2: CWPS	Anti-PS Ab Anti-protein Ab Cellular responses	[7]
	Staphylococcus aureus	Mouse	Hla, ClfA, ClfB, SdrD, IsdA, IsdB	PnCPS1	Anti-protein Ab Cellular responses	[52]
	Shigella flexneri, Shigella sonnei	Rabbit	IpaB, SseB, SP1500-SP0785	OSP from four Shigella serotypes (S. flexneri 2a, 3a, 6 and S. sonnei 53 G)	Anti-PS Ab Anti-protein Ab	[47]
	Salmonella enterica Typhi and Paratyphi A	Mouse (MAPS 1) Rabbit (MAPS 2–6) Guinea pig (MAPS 2–4)	MAPS 1: rEPA MAPS 2: CRM197 MAPS 3: rEPA MAPS 4–6: SP1500-SP0785	MAPS 1: Vi MAPS 2–4: Vi MAPS 5: OSP MAPS 6: Vi, OSP	Anti-PS Ab	[51]
	Salmonella enterica Typhimurium, Enteritidis, Typhi and Paratyphi A	Rabbit (MAPS 1–3)	MAPS 1: SseB MAPS 2: IpaB MAPS 3: SP1500-SP0785 MAPS 4 (bivalent): SseB MAPS 5 (tetravalent): SseB	MAPS 1–3: OSP MAPS 4 (bivalent): OSP from S. Typhimurium and S. Enteritidis MAPS 5 (tetravalent): OSP from S. Typhimurium, S. Enteritidis, S. Paratyphi A, Vi from S. Typhi	Anti-PS Ab Anti-protein Ab	[46]
	Mycobacterium tuberculosis	Mouse	MAPS 1: lipidated rhizavidin, ESAT6/CFP10, TB9.8/TB10.4, MPT64, MPT83 MAPS 2: lipidated rhizavidin, TB9.8/TB10.4-MPT83, ESAT6/CFP10-MPT64, MPT51	PnCPS1	Anti-protein Ab Cellular responses	[50]
Viral	SARS-CoV-2	Rabbit Cynomolgus macaque	S-RBD	PnCPS1	Anti-protein Ab Cellular responses	[49]

Ab, antibody; CFP10, culture filtrate protein 10; ClfA and ClfB, clumping factors A and B; CRM197, Cross-Reactive Material 197; CWPS, pneumococcal cell wall polysaccharide; ESAT6, early secretory antigenic target protein 6; Hla, α-hemolysin toxoid; IpaB, invasion plasmid antigen B; IsdA and IsdB, iron-regulated surface protein A and B; MAPS, Multiple Antigen Presenting System; MPT51, 64, and 83, mycobacterial lipoprotein 51, 64, and 83; OSP, O-specific polysaccharide; PnCPS, pneumococcal capsular polysaccharide (1, 3, and 14 refer to serotypes 1, 3, and 14); PdT, pneumolysoid; PS, polysaccharide; PsaA, pneumococcal surface adhesin A; rEPA, recombinant exotoxin A of Pseudomonas aeruginosa; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; SdrD, serine-aspartate repeat protein D; SP1500, 1458, 1534, 0435, and SP0785, surface proteins 1500, 1458, 1534, 0435, and 0785; S-RBD, receptor-binding domain of the SARS-CoV-2 spike (S) protein; SseB, serodominant secreted effector protein B; TB9.8 and 10.4, Mycobacterium tuberculosis low-molecular-mass culture filtrate antigens 9.8 and 10.4; Vi, virulence capsular polysaccharide of Salmonella.

4.1.1. MAPS-induced humoral immunity: anti-PS and anti-protein antibodies

PS-specific IgG titers and OPA levels were several fold higher in MAPS-immunized versus PCV13-immunized mice [7] in the initial non-clinical study of candidate pneumococcal MAPS-based vaccine formulations. The described anti-PS responses were shown to be dependent on cluster-of-differentiation-4-expressing (CD4⁺) T cells, as depletion of these cells nearly abolished production of PS-specific antibodies.

The protein components may aid the anti-CPS responses induced by MAPS vaccines and the likely mechanisms have recently been described [43] (Figure 1). Inclusion of a pathogen-specific protein in a MAPS vaccine results in greater natural boosting of the antibody response to the PS components of the vaccine when the host is subsequently exposed to the organism [43].

Figure 1. Schematic representation of MAPS-induced immune responses to polysaccharide and protein antigens (largely based on [43]).

1 MAPS complexes are bound and internalized by antigen-presenting cells, 2 which in turn process MAPS components and present the relevant epitopes to lymphocytes; 3A Both the polysaccharide- and protein-derived epitopes are presented to B cells, inducing B-cell activation and 3B presentation of epitopes to T cells; 3C Interaction of B cells with antigen-presenting and T cells leads to B-cell differentiation into memory and antibody-producing plasma cells; 4 and 5 Presentation of MAPS-derived protein epitopes by activated antigen-presenting cells (with secretion of various cytokines and chemokines) to CD4⁺ or CD8⁺ T cells leads to their differentiation into Th1, Th17 or cytotoxic CD8⁺ T cells. CD4⁺ and CD8⁺, cluster-of-differentiation-4- and -8-presenting; IFN-γ, interferon gamma; IL-17, interleukin-17 and 17A; MAPS, Multiple Antigen Presenting System; Th1 and Th17, T helper cells 1 and 17; TNF-α, tumor necrosis factor-alpha.

In addition to anti-PS responses, MAPS complexes evaluated in non-clinical studies were shown to induce IgG responses specific for protein antigens from Mycobacterium tuberculosis (Mtb) [7,50], pneumococcus [7], Staphylococcus aureus [52], S. enterica serovars Typhimurium, Enteritidis, Typhi, and Paratyphi A [46,51], and SARS-CoV-2 spike protein [49]. Furthermore, when given at the equivalent amount of individual components, MAPS-based vaccines induced higher protein-specific responses than the uncoupled protein antigens [7,52]. Additionally, a study in non-human primates indicate that MAPS-induced antigen-specific antibodies may have distinct effector functionalities, since antibodies against the SARS-CoV-2 spike protein bound with high affinity to FCγRIIa and FCγRIIb in the presence of the spike protein or its receptor-binding domain [49]. The MAPS-induced antibodies promote phagocytic function in monocytes and neutrophils and antibody-dependent complement deposition [49].

4.1.2. MAPS-induced cellular immunity

Induction of CD4⁺ T cells producing interferon-gamma (IFN-γ) and interleukin-17A (IL-17A) was detected after immunization of mice with MAPS complexes containing Mtb proteins coupled to the pneumococcal CPS from serotype 3, but not with uncoupled Mtb proteins [7]. With the same PS backbone, the size of the MAPS complex was found to likely impact the level of induced cellular responses [7]. Induction of Th1 and Th17 responses, characterized by IFN-γ and IL-17A secretion upon stimulation of peripheral blood cells of immunized animals with the target protein antigens, was also detected in other studies, with different PS and protein antigen combinations used in the MAPS vaccines [49,50,52]. O’Hara et al. [50] found that mice immunized with an Mtb-targeting MAPS vaccine had increased total numbers of CD4⁺ and CD8⁺ T cells in peripheral blood and nasal tissues, but not in the lung or spleen [50]. Immunization with MAPS vaccines induced distinct CD4⁺ and CD8⁺ T-cell subpopulations. Specifically, in MAPS-immunized animals, CD4⁺ and/or CD8⁺ effector memory T cell levels were significantly increased in the systemic compartments (blood and spleen) and tissue-resident memory T cells in local tissues (nasal passages and lungs) [50]. MAPS-induced memory CD4⁺ splenic and lung T cells were specific to the target protein antigens. Upon ex vivo stimulation, the cells were found to produce IFN-γ (Th1 response), tumor necrosis factor-alpha (TNF-α) (Th1 response), IL-17A (Th17 response), or granzyme B (cytotoxic CD4⁺ T cells). A similar trend was detected for cytotoxic CD8⁺ responses, with IFN-γ or granzyme B production in the spleen, but only granzyme B in lung [50]. In another study investigating a MAPS-based vaccine targeting SARS-CoV-2 [49], antigen-specific T-cell responses, in terms of IFN-γ-producing T cells (CD4⁺ Th1, CD8⁺), TNF-α-producing CD8⁺ T cells, Th1 and Th17 cell frequencies, and IL-4-producing CD4⁺ T cells (Th2), were significantly higher in MAPS – than placebo-immunized macaques [49].

4.1.3. Protective capacity of MAPS-based vaccines

MAPS-immunized animals were protected against invasive disease and/or death compared to placebo-immunized animals in infection challenges in several studies [45,49,51,52]. Cieslewicz et al. [49] showed that the SARS-CoV-2 mRNA is more quickly and efficiently cleared from nasal and broncho-alveolar tissues in macaques immunized with a spike-protein-based MAPS vaccine compared to placebo [49]. Two of the most detailed characterizations of MAPS-induced protective responses were reported in studies focusing on S. aureus and Mtb [50,52]. Interestingly, in a S. aureus study, MAPS-induced protection was mediated by various immune mechanisms depending on the infection route (i.e. intravenous or subcutaneous injection, intranasal inoculation) [52]. Humoral responses were found to mediate protection against bacteremia and, together with cellular responses, to protect the animals against dermonecrosis, while cellular responses were both essential and sufficient for protection against skin abscesses and gastrointestinal (GI) colonization [52]. Either IFN-γ or IL-17A secretion (induced by MAPS vaccination) is sufficient for protection against skin abscesses, while both cytokines are required for optimal protection against GI colonization. Similar importance of joint IFN-γ- and IL-17A-driven responses was noted in an Mtb study, where a MAPS-based vaccine (containing several Mtb proteins [full-length or fragments]: ESAT6, CFP10, TB9.8, TB10.4, MPT64, MPT83, and MPT51) effectively lowered bacterial load in the lung and spleen in an Mtb infection challenge [50]. The mechanism of MAPS-mediated protection observed in the same study was likely multifaceted: broad cellular responses (including Th1, Th17, cytotoxic CD4⁺ and CD8⁺ cells, gamma delta T [γδT] and natural killer T [NKT] cells), tissue-resident memory T cells in nasal passages and lung tissues, and balanced secretion of IFN-γ and IL-17A. Furthermore, the co-administration of the MAPS-based Mtb vaccine with Bacille Calmette-Guérin boosted cellular immunity to Mtb antigens and improved bacterial clearance (especially from the lungs) beyond the levels of either vaccine alone [50].

Another study investigated the protective capacity of pneumococcal MAPS-based vaccines, specifically the synergistic effect of antibodies against CPS and pathogen-specific proteins, in a lethal sepsis model in mice [45]. Mice were challenged with a pneumococcal strain of serotype 3, against which PCV13 vaccines in humans are not effective [45]. If mice were immunized with sera from rabbits immunized with PCV13- or MAPS-based vaccine (containing CPS3, CP1, and a detoxified pneumolysin mutant SPP2), the latter group had a significantly higher median survival rate after a highly lethal infection challenge with a strain of serotype 3. These data strongly suggest a synergistic effect of pneumolysin- and CPS3-specific antibodies in mediating protection against serotype 3 pneumococcal infection [45].

Taken together, the above non-clinical studies illustrate the importance of the multifaceted MAPS-induced immune responses in conferring optimal protection against disease-associated morbidity and/or mortality in animal models.

4.2. Clinical evaluation of MAPS-based vaccines

4.2.1. MAPS-induced humoral immunity: anti-PS and anti-protein antibodies

The first clinical study of a pneumococcal MAPS-based vaccine indicated a similar profile of humoral responses in adults (aged 18–64 and 65–85 years) as observed in non-clinical studies [48]. At 30 days post-immunization with the investigational MAPS-based (AFX3772) and PCV13 control vaccine, anti-PS IgG geometric mean concentrations (GMCs) were comparable for shared serotypes and significantly higher for AFX3772-unique serotypes after AFX3772 versus PCV13 immunization [48]. Antibody OPA levels follow a similar trend as anti-PS IgG GMCs for most serotypes [48]. Moreover, the GMCs of IgG titer against sp1500 + sp0785 (the two pneumococcal proteins included in the MAPS vaccine) increased several folds over baseline at 1-month post-immunization with the AFX3772, but not with the control PCV13 vaccine [48].

4.2.2. MAPS-induced cellular immunity

The findings of a clinical study of the candidate pneumococcal AFX3772 vaccine are consistent with the described non-clinical T-cell data [48]. Upon ex vivo stimulation of peripheral blood mononuclear cells from the participants of this study with the purified antigenic fusion proteins, the Th17 responses (i.e. Th17 cell frequencies, IL-17 and IL-22 production) were significantly greater for individuals who received AFX3772 (at the highest dose group) versus PCV13 recipients at Day 30 [48]. Based on its composition and described immunogenicity findings, the investigational AFX3772 vaccine has the potential to induce multipronged immune responses to both pneumococcal PS and proteins, thereby providing better protection against different vaccine and possibly non-vaccine pneumococcal serotypes.

4.2.3. Safety profiles of MAPS-based vaccines

Both the published [48] and unpublished [48] phase 1–2 clinical data indicate an acceptable safety profile of the 24-valent investigational AFX3772 vaccine. In a phase 2 study in older adults (aged 65–85 years), the overall frequencies of administration-site and systemic AEs were comparable after AFX3772 or PCV13 administration in PCV13-naive participants [48]. Tenderness and pain were the most frequent administration-site AEs, while fatigue, headache, and myalgia were the most frequently reported systemic AEs. Frequencies of all AEs tended to be highest for the highest-dose AFX3772 formulation (5 μg of each PS), but the difference versus PCV13 was not statistically significant. There was no clear correlation between the vaccine dosage and the frequencies of treatment-emergent AEs, and no vaccine-related serious AEs were reported [48].

5. Conclusions

Despite major advances in vaccine technology, further developments are needed to enhance vaccine immunogenicity and effectiveness and to design vaccines that convey protection against evolving and emerging pathogens. The non-clinical and clinical data on MAPS-based vaccines suggest the broad applicability of MAPS and distinct functionalities of induced immune responses.

To date, the MAPS technology has been successfully evaluated in non-clinical studies across several bacterial targets, including S. pneumoniae, S. aureus, M. tuberculosis, Group B Streptococcus, Shigella, Salmonella, and a viral target, SARS-CoV-2. The initial phase 1/2 clinical trial of an investigational pneumococcal vaccine AFX3772 confirmed the non-clinical immunogenicity findings. Induction of specific T-cell responses, especially Th1 and Th17, together with antibody-mediated immunity is an important feature of MAPS-based vaccines, as these multifaceted responses may provide protection against a wider variety of pathogens compared to traditional conjugate vaccines. Further clinical studies are warranted to better characterize the AFX3772 and evaluate other MAPS-based vaccine candidates in human participants. Favorable outcomes of these clinical studies will be key to confirm the utility of MAPS for necessary innovations in modern vaccinology.

6. Expert opinion

MAPS technology is unique in that it leverages a well-known biotin–rhizavidin interaction to create novel, versatile, and adaptable antigen-presenting systems able to induce multifaceted immune responses. The process of generating MAPS complexes is now well established and can be tailored to various existing and emerging pathogens.

Several studies have indicated that MAPS-induced immunity is broad, characterized both by humoral (e.g. PS- and protein-specific IgG) and cellular (e.g. Th1, Th17, cytotoxic CD4⁺ and CD8⁺ T cells, γδT, and NKT cells) responses, owing largely to the inclusion of pathogen-specific proteins in MAPS complexes. In the sphere of pneumococcal vaccines, MAPS technology may help circumvent the issue of serotype replacement, by inducing serotype-specific and serotype-independent immune responses. Furthermore, MAPS may be a valuable approach when broad immune responses are required to enhance protection against the target disease. The modular and flexible natures of MAPS may be utilized to dissect mechanisms of protective immunity and help determine correlates of protection for diseases with complex pathogenesis.

Further research should focus on the following aspects: to evaluate and improve the use of MAPS system on the smaller PS and/or synthetic oligosaccharides; to study the underlying molecular mechanism as how MAPS-based vaccines may elicit different types of cellular responses; to explore the possibility of engineering a stable, monomeric rhizavidin derivative that could adapt fusion with protein antigens that oligomerize. Furthermore, not all protein antigens may tolerate a fusion with rhizavidin (e.g. steric hindrances, suboptimal epitope presentation, and loss of physiological activity). Thus, it is important to assess in which cases and how MAPS-based formulations may be limited concerning the choice of antigenic targets. In addition, the feasibility of the MAPS technology for other pathogens and the optimal approach for each (e.g. number and type of PS and protein components, valency, choice and addition of adjuvants for more challenging pathogens, and administration route) need to be evaluated. Existing and future vaccine candidates will also need to be evaluated in at-risk populations, such as infants, older adults and frail populations, individuals who may be immunocompromized due to disease and/or therapy, and people with underlying comorbidities and/or medical conditions. Furthermore, it is important to determine both vaccine efficacy and the real-world safety and effectiveness of MAPS-based vaccines.

The true impact of MAPS-generated multifaceted immune profiles on clinical outcomes will have to be evaluated for different pathogens and in specific populations. This will be particularly important to determine the long-term safety profile and persistence of MAPS-induced immune responses and the corresponding needs for revaccination.

Despite the currently open questions regarding MAPS-based vaccines, we believe this is a promising technology for modern vaccine development. MAPS technology may offer immunological and practical solutions to many of the challenges in vaccinology. Should MAPS be successfully used for immunization against common pathogens, the relatively simple production and customizable design may lead to improved vaccine coverage in previously underserved or vulnerable populations. Applications of MAPS technology to other noninfectious disease areas may also be possible in the future. Finally, its adaptable design may support more rapid vaccine development in response to changes in disease epidemiology by age, ethnicity, and geographic location, and allow for tailored approaches to combat diseases (e.g. for targeting specific pneumococcal serotypes contributing to invasive pneumococcal disease) of public health consequences.

Article highlights

• Several aspects of infectious diseases, such as diverse mechanisms of pathogenesis, high diversity and evolution of etiological agents, serotype replacement, and emergence of new pathogens, call for development of novel and more effective vaccines.

• Multiple Antigen Presenting System (MAPS) is a unique vaccine platform that uses high-affinity biotin–rhizavidin interaction to combine polysaccharides and target-pathogen-specific proteins into macromolecular complexes.

• MAPS complexes are stable, precisely defined (controlled ratio of components), modular (components easily exchanged and combined), flexible (combination of components of different origin/property), and epitope-preserving (single-point attachment between polysaccharide and protein).

• In non-clinical studies, MAPS-based candidate vaccines against six bacterial and one viral target were able to induce broader (antibody- and cell-mediated) immune responses compared to licensed vaccines targeting the same pathogens or purified protein controls.

• In clinical studies, a 24-valent MAPS-based pneumococcal candidate vaccine (AFX3772) was shown to be well tolerated and induced robust immune responses in healthy adults (including older adults).

• Inclusion of conserved pathogen-specific proteins in MAPS complexes may potentiate the protection mediated by polysaccharide-specific immunity via eliciting serotype-independent and multifaceted humoral and cellular responses (e.g. helper T cells [Th]1 and Th17 and cytotoxic T cells).

• MAPS technology may provide a platform to support advanced vaccine development across various disease targets and overcome some inherent limitations of current technologies.

Abbreviations

AE, adverse event; CD4⁺ and CD8⁺, cluster-of-differentiation-4- and −8-expressing; CPS, capsular polysaccharide; γδT, gamma delta T cells; GI, gastrointestinal; GMC, geometric mean concentration; GMMA, Generalized Modules for Membrane Antigens; IFN-γ, interferon-gamma; IgG, immunoglobulin G; IL-17A, interleukin-17A; MAPS, Multiple Antigen Presenting System; Mtb, Mycobacterium tuberculosis; NKT, natural killer T cells; OPA, opsonophagocytic activity; PCV, pneumococcal conjugate vaccine; PPSV23, pneumococcal polysaccharide vaccine; PS, polysaccharide; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; Th1, Th2, and Th17, T helper cells 1, 2, and 17; TNF-α, tumor necrosis factor-alpha.

Declaration of interests

R Malley is a former employee of GSK and was an Affinivax board member and scientific founder at the time this manuscript was initiated. R Malley receives consulting fees from GSK as a consultant in the field of vaccines and discloses GSK support for attending meetings and/or travel and participation to the GSK Advisory board. F Zhang and YJ Lu received consulting fees from Affinivax and GSK as consultants. R Malley, F Zhang, and YJ Lu declare potential future payments and royalties as equity holders of Affinivax and named co-inventors of MAPS technology. R Malley, F Zhang, and YJ Lu have issued or pending patents on MAPS technology. S Sebastian has issued and pending patents on Multivalent Pneumococcal Vaccine. DO Willer has restricted share stock ownership in GSK. S Sebastian and DO Willer are employees of the GSK group of companies. None of the authors have any other financial or non-financial interests to declare. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors contributed substantially to the conception and design of the review article and interpreting the relevant literature and were involved in writing the review article and revised it for intellectual content. All authors contributed equally to manuscript development and have approved the final version of the manuscript.

Acknowledgments

The authors thank Akkodis Belgium for providing manuscript writing (Irena Zurnic Bönisch) and coordination support on behalf of GSK.

Additional information

Funding

This manuscript was funded by GlaxoSmithKline Biologicals SA.