Structural characteristics and corresponding advantages of FRPMM.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
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\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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The topology of FRPMM is depicted in Figure 1. As can be seen, it has a slotted rotor without any windings or PMs, and a stator with armature windings and PMs mounted on each stator teeth. First of all, the structural characteristics of FRPMMs and the corresponding performance advantages need to be explained:
FRPMMs are excited by PMs instead of the excitation windings, which are different with asynchronous motors and brushed DC motors. So, for FRPMMs, the rotor will not have copper losses, and the efficiency is relatively higher [1, 2].
The rotor of FRPMMs has no windings or permanent magnets, thus is suitable for high-speed operation and high-temperature operating conditions [3]. Moreover, the no excitation winding will keep away from the problems of friction noise and electric spark. So, FRPMMs are more reliable and require less maintenance [4, 5]. In addition, the rotor of FRPMMs is light in weight and has a small rotational inertia [6]; hence, the acceleration and deceleration response is faster.
The stator windings of FRPMMs are mostly concentrated windings, which are easy to manufacture. Moreover, the electromagnetic isolation of the concentrated windings is better than regular distributed windings, which means that if one winding has faults, the fault is not likely to spread to other windings, and thus the fault tolerance is good [7, 8]. In addition, the concentrated winding has a smaller winding factor, inductance, and a shorter electrical time constant than the distributed windings [9], and thus the dynamic response of concentrated winding is faster.
Compared to other stator-PM machines, that is, flux switching PM machines and doubly salient PM machines, FRPMMs have a simpler structure. The PMs of the flux switching PM machines and doubly salient PM machines are inserted into the stator core, which is not convenient for installation. In the flux switching PM machine, putting permanent magnets in the middle of the teeth will reduce the slot area and affect the output torque. In the doubly salient PM machine, placing PMs in the yoke will increase the volume of the motor and reduce the torque density. In the FRPMMs, the PMs are pasted on the inner surface of the stator teeth, thus eliminating the above problems [10].
Cross section of a FRPMM.
Finally, the structural characteristics and performance advantages of the flux-reverse motor can be summarized in Table 1.
No. | Structural characteristic | Advantages |
---|---|---|
1 | Use rare-earth PMs |
|
2 | No windings or PMs in the rotor |
|
3 | Often use concentrated windings |
|
4 | PMs attached to the stator teeth surface |
|
Structural characteristics and corresponding advantages of FRPMM.
It can be seen that the FRPMMs have many performance advantages, and these advantages can be utilized in different applications. First of all, the high efficiency, the large torque density, the rapid acceleration, and deceleration response make FRPMMs suitable for various high-speed rotation areas, such as electric vehicles [11, 12, 13], electric spindle [14], fans [15, 16], etc. Secondly, the number of rotor pole pairs is usually high, which is also suitable for low-speed areas, meanwhile its torque density is high at the low speeds, making FRPMMs suitable for various low-speed direct-drive occasions [17], for example wind power [18, 19, 20], direct drive servo system [21], wave power generation [22], etc. In addition, linear FRPMM has no PMs and copper windings in the secondary, which saves cost and is also very suitable for long rail transit linear motion applications [23, 24].
In most existing literatures, the design of FRPMMs is mainly based on the classical design method [25] with low accuracy or time-consuming finite element algorithm (FEA) [26]. Therefore, in this chapter, the specialized sizing equations for FRPMMs will be deduced and the analytical design method will be introduced, which can be directly employed in the initial design of FRPMMs and allows for fast calculations of machine dimensions.
This chapter is organized as follows. First, the structure and operation principles are introduced in Section 2. Then in Section 3, the magnetic circuit model is built and the sizing equations are analytically derived. After that, in Section 4, the influences of several key parameters (slot-pole combination, airgap radius, electric loading, and equivalent magnetic loading) in the sizing equation on the torque density are analyzed. Also, the effects of the airgap structural parameters on the pulsating torque, power factor, and PM demagnetization performances are investigated. Moreover, in Section 5, the geometric design of stator and rotor are introduced. And in Section 6, the design procedure is illustrated. Besides, to make the analytical design method more readable, a case study is presented and a FRPMM prototype is tested. Finally, conclusions are drawn in Section 7.
To clearly exhibit the operating principle, a three-phase FRPMM with two pole windings, six stator slots, and eight rotor teeth is cited as an example. The flux distributions at different rotor positions are illustrated in Figure 2. The magnetic flux field is excited only by the PMs, and the difference of each rotor movement is 11.25 mech. degrees (i.e., 1/4 rotor slot pitch). Taking flux linkage of phase A winding as an example, when the rotor position is 0 degree, the flux linkage is 0; when the rotor position is 11.25 mech. degree (90 elec. degree), the flux linkage reaches the positive maximum value; when the rotor position is 22.5 mech. degree (180 elec. degree), the flux linkage is 0; when the rotor position is 33.75 mech. degree (270 elec. degree), the flux linkage reaches the negative maximum value. Therefore, in the duration of one rotor slot pitch (360 elec. degrees), the winding flux linkage reverses the polarity, thus it is called “flux reversal machine.” Then, after obtaining the bipolar flux linkage, as shown in Figure 3, the winding can produce a bipolar back-electromagnetic motive force (EMF). If the armature windings are injected with currents having the same frequency and phase with the back-EMF, a steady torque can be yielded.
No-load flux lines of the FRPMM excited by the PMs: (a) rotor position =0 elec. degree; (b) rotor position =90 elec. degree; (c) rotor position =180 elec. degree; (d) rotor position =270 elec. degree.
Variation of flux linkage of phase a winding at different rotor positions.
In order to derive the sizing equation of FRPMMs, the magnetic circuit model should be built at first; then, based on the model, the analytical equations of airgap flux density, back-EMF, and torque will be deduced.
The equivalent magnetic circuit model can be plotted as Figure 4. At No.1 stator tooth, its magnetic field distribution corresponds to the position shown in Figure 2(b), that is, the rotor tooth is closer to the S-pole magnet. The S-pole magnetic generates two paths of magnetic flux, one is pole leakage flux Φpl, which goes through the adjacent N-pole magnet, the other is main flux Φm, which goes through the stator tooth, stator yoke, rotor tooth, and rotor yoke, thus can provide winding flux linkage and back-EMF. At No. 2 stator tooth, its magnetic field distribution corresponds to the position shown in Figure 2(c), that is, the rotor axis is at the same distance from the S-pole and N-pole magnets. Thus, at this time, the two magnets can only generate one magnetic flux path, that is, the pole leakage flux Φpl. At No. 3 stator tooth, its magnetic field distribution corresponds to the position shown in Figure 2(d), that is, the rotor tooth is closer to the N-pole magnet. The N-pole magnetic generates two paths of magnetic flux, one is pole leakage flux Φpl, which goes through the adjacent S-pole magnet, the other is main flux Φm, which goes through the stator tooth, stator yoke, rotor tooth, and rotor yoke, thus can provide winding flux linkage and back-EMF. It should be noted that the magnetic flux path of No. 1 stator tooth is just opposite to that of No. 3 stator tooth, so winding flux polarity in these two cases is just opposite to each other.
Equivalent magnetic model of FRPMMs.
As mentioned above, Figure 4 provides the magnetic circuit of FRPMMs, which can help analyze the flux distribution of FRPMMs at different rotor positions. However, the magnetic circuit requires the establishment of the whole FRPMM magnetic path, which is rather complex. Besides, the pole leakage flux, main flux, and the reluctance at each rotor positions should be calculated, which needs high workload. Therefore, a simplified magnetic circuit should be built. Observing Figure 2, it can be seen that a small rotor displacement brings a large rotation in stator flux field. This phenomenon is called as flux modulation effect, i.e. a high-pole slow-speed magnetic field becomes a low-pole high-speed magnetic field through the modulation effect of iron teeth. Therefore, the physical nature of FRPMM is indeed the flux modulation effect. The research of some flux modulation machines are usually based on the PM magnetic motive force (MMF)-airgap permeance model, such as the Vernier machine in [27]. So, this chapter will use this model to analyze FRPMMs.
In PM MMF-airgap permeance model, the no-load airgap flux density B(θs,θ) can be written as the product of PM MMF FPM(θs) and specific airgap permeance Λ(θs,θ):
where the definitions of angles θs and θ are shown in Figure 5. Then, the simplified magnetic circuit model can be given in Figure 6. Once knowing the PM MMF and airgap permeance, the no-load airgap flux density can be obtained. Then, the stator flux linkage λph(θ) can be deduced using winding function theory:
Definitions of different angles in FRPMM.
Simplified equivalent magnetic model of FRPMMs.
where N(θs) is the phase winding function. After that, the phase back-EMF Eph(t) and average torque Te can be calculated as:
where Iph is the peak value of phase current. Therefore, from Eqs. (1–4), it can be found that if the torque equation need to be calculated, the key is to obtain the equation of airgap flux density B(θs,θ), which is further determined by the PM MMF FPM(θs) and specific airgap permeance Λ(θs,θ). Therefore, in the next parts, the equations of the PM MMF FPM(θs) and specific airgap permeance Λ(θs,θ) will be deduced in detail.
As aforementioned, to derive the torque equation, the no-load airgap flux density B(θs,θ) should firstly be known, whose equation can be given as Eq. (1). Then, the next step is to derive the expressions of FPM(θs) and Λ(θs,θ). The PM MMF waveform excited by the magnets is shown in Figure 7, which can be given as:
Magnet MMF waveform.
where FC is:
Then, it can be written in Fourier series as follows:
where the magnitude Fi is
Then, the next step is to derive the specific airgap permeance Λ(θs,θ) in Eq. (1). Since the stator slotting effect has already been considered in Eqs. (5–8), the specific airgap permeance Λ(θs,θ) can be replaced by the airgap permeance with smoothed stator and slotted rotor Λr(θs,θ). The model of smoothed stator and slotted rotor is shown in Figure 8. Then, the Λr(θs,θ) can be expressed by:
Schematic of single-side salient structure on rotor.
The coefficients of the airgap permeance function Λ0r and Λ1r in Eq. (9) can be obtained using the conformal mapping method [28, 29]:
where bo is the rotor slot opening width and t is the rotor slot pitch, as shown in Figure 8. Combining Eq. (1), Eqs. (5–13), the no-load airgap flux density B(θs,θ) can be finally calculated as:
where the magnitude Bi is
As can be seen in Eq. (14), the number of pole pairs in the air gap flux density is iZs/2 ± Zr, i = 1,3,5… Then, in order to make the flux density induce EMF in the armature windings, the pole pair number of the armature windings P should be equal to iZs/2 ± Zr, i = 1,3,5… Besides, for three phase symmetry, the winding pole pair number must also meet the following requirement:
All in all, the slot-pole combination of three-phase FRPMMs is ruled by the following equation:
where min means to select the minimum number of these qualified harmonic orders so as to obtain a maximal pole ratio of FRPMMs. Therefore, the feasible slot-pole combinations can be summarized as Table 2. Non-overlapping windings (i.e., concentrated windings) are usually used in FRPMMs because of the higher fault tolerance and easier manufacture than regular overlapping windings. However, some FRPMMs are suggested to employ overlapping windings in order to have a larger winding factor and thus a higher torque density. Therefore, both winding factors, that is, kwn (using non-overlapping winding) and kwr (using overlapping winding) are calculated for each FRPMM so as to see the difference of using different winding types.
Zs | Zr | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 10 | 11 | 12 | 13 | 14 | 15 | 16 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
6 | P | 1 | 1 | 2 | 2 | 1 | 1 | 2 | 2 | 1 | 1 | ||||
SPP | 1 | 1 | 0.5 | 0.5 | 1 | 1 | 0.5 | 0.5 | 1 | 1 | |||||
PR | 2 | 4 | 2.5 | 3.5 | 8 | 10 | 5.5 | 6.5 | 14 | 16 | |||||
kwn | 0.5 | 0.5 | 0.866 | 0.866 | 0.5 | 0.5 | 0.866 | 0.866 | 0.5 | 0.5 | |||||
kwr | 1 | 1 | 0.866 | 0.866 | 1 | 1 | 0.866 | 0.866 | 1 | 1 | |||||
12 | P | 4 | 2 | 1 | 1 | 2 | 4 | 5 | 5 | 4 | 2 | ||||
SPP | 0.5 | 1 | 2 | 2 | 1 | 0.5 | 0.4 | 0.4 | 0.5 | 1 | |||||
PR | 0.5 | 2 | 5 | 7 | 4 | 2.5 | 2.2 | 2.6 | 3.5 | 8 | |||||
kwn | 0.866 | 0.5 | 0.25 | 0.25 | 0.5 | 0.866 | 0.933 | 0.933 | 0.866 | 0.5 | |||||
kwr | 0.866 | 1 | 0.966 | 0.966 | 1 | 0.866 | 0.933 | 0.933 | 0.866 | 1 | |||||
18 | P | 7 | 6 | 5 | 4 | 3 | 2 | 1 | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
SPP | 3/7 | 0.5 | 0.6 | 0.75 | 1 | 1.5 | 3 | 3 | 1.5 | 1 | 0.75 | 0.6 | 0.5 | 3/7 | |
PR | 2/7 | 0.5 | 0.8 | 1.25 | 2 | 3.5 | 8 | 10 | 5.5 | 4 | 3.25 | 2.8 | 2.5 | 16/7 | |
kwn | 0.902 | 0.866 | 0.735 | 0.617 | 0.5 | 0.492 | 0.167 | 0.167 | 0.492 | 0.5 | 0.617 | 0.735 | 0.866 | 0.902 | |
kwr | 0.902 | 0.866 | 0.945 | 0.945 | 1 | 0.945 | 0.96 | 0.96 | 0.945 | 1 | 0.945 | 0.945 | 0.866 | 0.902 | |
PS: | Non-overlapping winding is recommended. | Other: Overlapping winding is recommended. |
Slot-pole combinations of three-phase FRPMM.
kwn and kwr are fundamental winding factors calculated based on non-overlapping winding type and recommended winding types, respectively.
Once the stator winding pole pair is selected, the stator flux linkage can be deduced using winding function theory, just as mentioned in Eq. (2). The winding function N(θs) in Eq. (2) can be written as:
where Ni is the ith harmonics of the winding function and kwi is the winding factor of the ith harmonics. As can be seen in Eq. (17), the pole pair number is iZs/2 ± Zr (i = 1,3,5…). So, the sum or difference of any two pole pair harmonics Pi1 and Pi2 is a multiple of stator slot number, that is,
Therefore, all the flux density harmonics are tooth harmonics of each other, that is, they have the same absolute values of winding factors, and their absolute winding factor equals the fundamental winding factor kw1:
Then, combining Eq. (2), Eq. (3), Eqs. (18–21), the back-EMF can be finally obtained as:
where
Since the reluctance torque of FRPMM is negligible, the electromagnetic torque under id = 0 control can be expressed as Eq. (4). Then, combining Eq. (4) and Eq. (22), the average torque Te is able to be calculated as:
So far, the general torque equation has been obtained as Eq. (24), but in this equation, some parameters such as Bi, Iph cannot be determined in the initial design stage of FRPMMs, so it is desirable that Eq. (24) can be transformed to a combination of several basic parameters, such as electric loading, magnetic loading, which can be easily determined in the initial design stage.
As known for electrical machines, the electric loading Ae can be written as:
Then, the equivalent magnetic loading of three-phase FRPMM Bm is defined as:
So, the torque expression in Eq. (24) can be rewritten as:
Thus, the rotor volume Vr, which equals πlstkr2g, can be obtained:
and then the airgap radius rg and the stack length lstk can be derived as:
where klr is the aspect ratio, equals to the ratio of rg to lstk. It can be found in Eq. (27) that the key parameters affecting the torque density are the airgap radius rg, stack length lstk, winding factor kw, rotor slot number Zr, electric loading Ae, and equivalent magnetic loading Bm, among which the stack length lstk can be determined by the volume requirement, and winding factor kw is approximate to 1. So, the remaining parameters rg, Zr, Ae, Bm should be determined at the initial stage of the design process. Thus, the influences of the above key parameters on important performances, such as average torque, pulsating torque, power factor, PM demagnetization performance, will be investigated in the following parts.
As aforementioned, the rotor slot number Zr is one of key parameters that should be determined in the first design stage. How to determine the rotor slot number is a question. In this part, the influence of Zr on the torque performance will be investigated, giving instruction on how to select Zr. The parameters of the FRPMM models are listed in Table 3. These parameters are kept the same for the FRPMMs in order to have a reasonable comparison of their torque performance. That is to say, the airgap radius rg, stack length lstk, and electric loading Ae are the same.
Parameter | Value | Parameter | Value |
---|---|---|---|
Stator outer diameter | 170 mm | Stator inner diameter | 105 m |
Stator slot opening ratio | 0.25 | Remanent permeability | 1.065 |
Stack length | 100 mm | PM thickness | 2.5 mm |
Series turns per phase | 80 | Airgap length | 0.5 mm |
Rotor slot opening ratio | 0.65 | Rated current | 5.3A |
Rated speed | 600 rpm | Magnet remanence | 1.21 T |
Parameters of the three-phase FRPMM models.
Figure 9 shows the influence of rotor slot number on the output torque when non-overlapping windings and recommended windings are used respectively. For Figure 9(a), when non-overlapping windings are adopted, the average torque is mainly related to the product of winding factor and rotor slot number, that is, kw*Zr*Bm. Since the machine volume and PM usage are kept the same, the equivalent magnet loading Bm is mainly determined by the pole ratio (PR). So, the variation trend of torque is similar to that of kw*Zr*PR. It can be seen that the torque achieves the maximum value when the rotor slot number is 8, 14, and 21 for 6 stator slots, 12 stator slots, and 18 stator slots, respectively. When the recommend windings are used, which means that the winding factor are maximized, the main factor that affects the torque is the Zr*PR. As shown in Table 2, the variation of PR is irregular, hence the variation of torque with rotor slot number is irregular. As can be seen, for recommended winding types, the torque achieves the maximal value when the rotor slot number is 8, 10 and 17 for 6 stator slots, 12 stator slots, and 18 stator slots, respectively.
Effect of combinations of stator slots and rotor slots on torque: (a) non-overlapping windings; (b) recommended windings.
As shown in Eq. (27), the airgap radius rg is also very important for the output torque. Figure 10 investigates the effect of optimal rotor slot number Zr at different rg. For 6, 12, 18 stator slots, their rotor slot numbers are selected as 8, 14, and 21, respectively. Moreover, non-overlapping windings are used in these models because non-overlapping winding is simple and has the same end winding length. It can be seen that when the airgap radius is small, the optimal rotor slot number is small. This is because when the airgap radius is small, the leakage flux between adjacent rotor teeth occupies a large percent, so the optimal rotor slot number should be small to reduce the leakage flux as much as possible. When the airgap radius gets larger and larger, the leakage flux decreases gradually. Hence, the optimal rotor slot number increases.
Effect of rg on optimal Zr when split ratio is 0.6.
Then, keeping the stator outer diameter as a constant, that is, 170 mm, the effects of airgap radius of average torque are analyzed in Figure 11. It indicates that when the airgap radius increases, the output torque goes up. This is because the torque is proportional to the square of airgap radius. The larger the airgap radius, the higher the torque. However, the torque is not only influenced by the airgap radius, but also the electric loading Ae. With the increase of airgap radius, the inner diameter of the stator increases, and thus the slot area decreases, leading to the decrease of winding turns per slot and the electric loading. Therefore, as the airgap radius keeps increasing, the output torque decreases afterwards.
Effect of rg on torque when stator outer diameter is 170 mm.
In addition to the rotor slot number Zr, airgap radius rg, the rest of key parameters affecting the torque in Eq. (27) are the electric loading Ae and the equivalent magnetic loading Bm. Figure 12 analyzes the influence of Ae and Bm on the average torque at different stator slot number. For these models, the airgap radius is fixed as 55 mm and their rotor slot number is chosen as their corresponding optimal value. Also, non-overlapping windings are adopted. As can be seen, the output torque increases with the electric loading. This reason is very simple, that is, a larger current, a higher torque. But for the equivalent magnetic loading, the variation trend of torque does not monotonically increase with the equivalent magnetic loading. This is due to the saturation effect of the iron core. Moreover, it can be seen that the knee point of the equivalent magnet loading increases with the stator slot number. Since the winding pole pair of the 18-stator-slot FRPMM is 6, which is larger than 1-winding-pole-pair of the 6-stator-slot and 4-winding-pole-pair of the 12-stator-slot FRPMM, the stator iron of the 18-stator-slot FRPMM is less likely to saturate than the others.
Effect of equivalent magnetic loading and electric loading on torque: (a) Zs = 6; (b) Zs = 12; (c) Zs = 18.
Apart from the torque density, pulsating torque is also very important because a large pulsating torque will increase the vibration and noise of machines. Figure 13 shows the cogging torque and ripple torque waveforms of 13-, 14-, 16-, 17-, and 19-rotor-slot FRPMMs. The stator slot number of these models is all chosen as 12. For the rated torque, we can see in Figure 13(b) that the 14-rotor-slot FRPMM yields the largest among the five models. As for the pulsating torque, we can see that the cogging torque and ripple torque of 16-rotor-slot FRPMM are the largest, and that of 19-rotor-slot FRPMM is the least. This phenomenon is related to the least common multiple of stator slot number and rotor slot number. The larger least common multiple, the lower pulsating torque. The least common multiples of the 13-, 14-, 16-, 17-, and 19-rotor-slot FRPMMs are 156, 84, 48, 204, and 228, respectively. Therefore, the 19-rotor-slot FRPMM exhibit the lowest cogging torque and ripple torque. However, attentions should be paid to use odd rotor number because it will cause other problems such as eccentricity stress. Figure 14 compares the radial stress of the five FRPMM models. It can be seen that for the even rotor slot number FRPMMs, that is, 14 and 16 rotor slots, the stress harmonics only have even orders, which will not lead to eccentricity. However, for the odd rotor slot number FRPMMs, that is, 13, 17, and 19 rotor slots, there are many odd stress harmonics. Since the first-order harmonic is dominant for the eccentricity, the 13-rotor-slot FRPMM has a large eccentricity stress. Therefore, 13-rotor-slot is not recommended. The first-order stress harmonic for 17 and 19 rotor slots are very small, so their eccentricity can be neglected.
Effect of slot-pole combination on pulsating torque performances: (a) cogging torque waveforms (%); (b) rated torque waveforms.
Radial stress analysis of the FRPMMs: (a) 13-rotor-slot; (b) 14-rotor-slot; (c) 16-rotor-slot; (d) 17-rotor-slot; (e) 19-rotor-slot.
The influences of split ratio and PM thickness on cogging torque and ripple torque of FRPMMs are also analyzed in Figure 15. This figure is plotted based on the 14-rotor-slot, which is chosen because it has the largest torque density and a relatively low pulsating torque, as shown in Figure 13. It can be found in Figure 15(a) that the cogging torque increases with the PM thickness and the split ratio. When the PM thickness increases, the airgap flux density increases, and thus the interaction between the PMs and slot-teeth becomes greater, which leads to a higher cogging torque. As the split ratio increases, the airgap radius increases, hence the cogging torque increases with the split ratio [30]. As for the ripple torque, the ripple torque has the maximum value when the split ratio is around 0.66. This is because the ripple torque is not only related to the slot structure but also influenced by the electric loading. As aforementioned, the pulsating torque resulting from the slot structure is increased with the split ratio. However, as the split ratio increases, the slot area is reduced and the electric loading gets smaller and smaller, so the ripple torque resulting from the electric loading becomes lower. Considering these two impacts, the ripple torque has a maximal value when the split ratio changes.
Effect of split ratio and PM thickness on pulsating torque performances: (a) cogging torque (%); (b) ripple torque (%).
As we know, the airgap structure is significant for the pulsating torque because the pulsating torque results from the interaction between the two sides of the airgap, that is, stator and rotor. Therefore, this chapter also analyzes the influences of stator slot opening ratio and rotor slot opening ratio on cogging torque and ripple torque. Here, the stator/rotor slot opening ratio is defined as the ratio of stator/rotor slot opening width to the stator/rotor slot pitch. Figure 16 shows the variation of cogging torque and ripple torque with the two slot opening ratios. It can be seen that the cogging torque increases with the stator slot opening ratio. The reason is that a larger stator slot opening ratio reduces the PM width and the smoothness of PM MMF, thus the changing of the PM MMF along the tangential direction increases the cogging torque. As for the rotor slot opening ratio, which simultaneously influences all the harmonic contents of the airgap permeance, it has great and nonlinear impact on the pulsating torque. Since the pulsating torque results from the interaction of multi permeance harmonics, the variation of pulsating torque changes nonlinearly with the rotor slot opening ratio. It can be seen in Figure 16 that the optimal cogging torque and ripple torque can be achieved when the stator slot opening ratio and rotor slot opening ratio are around 0.25 and 0.7, respectively.
Effect of stator slot opening ratio and rotor slot opening ratio on pulsating torque: (a) cogging torque (%); (b) ripple torque (%).
Since the power factor of FRPMMs is usually low, which is around 0.4–0.7, meanwhile a low power factor will increase the converter capacity and cost, the influences of key parameters on the power factor should be also analyzed to achieve a relatively high power factor. The power factor can be given as:
where Is is the winding current, Ls is the synchronous inductance (because the saliency ratio is approximate to 1, Ld ≈ Lq), and ψm is the PM flux linkage. Then, the effect of stator inner diameter on power factor is shown in Figure 17. Here, the stator outer diameter is kept as 124 mm, and the airgap length is fixed as 0.5 mm. It can be found that with the increase of stator inner diameter, the power factor increases continuously. The reason is that with the increase of stator inner diameter, the slot area decreases, so the winding turns per phase decreases, thus leading to the reduction of the synchronous inductance Ls. The lower Ls, the higher power factor, as shown in Eq. (31). Apart from the stator inner diameter, another important parameter affecting the power factor is the PM thickness hm. Figure 18 investigates the variation of power factor with respect to the PM thickness. It indicates that the power factor initially increases with the PM thickness but then decreases. The reason is explained as follows. As the PM thickness increases, the PM flux linkage ψm becomes larger, so the power factor increases. However, the synchronous inductance Ls also increases with the PM thickness, which leads to the reduction of power factor afterwards. Therefore, there is an optimal PM thickness for a maximum achievable power factor.
Effect of stator inner diameter/airgap length on power factor.
Effect of PM thickness/airgap length on power factor.
Another important parameter that influences the airgap structure is the slot opening ratio. Hence, Figures 19 and 20 analyzes the effect of stator slot opening ratio and rotor slot opening ratio on pulsating torque performances, respectively. It can be seen in Figure 19 that the maximum power factor can be obtained when the stator slot opening ratio is approximately to 0.3. The explanation is as follows. When the stator slot opening ratio is too small, the slot leakage flux between the stator tips is large, thus the main flux is reduced, and the back-EMF is lowered, resulting in smaller back-EMF. And when the stator slot opening ratio is too large, the PM width will be narrower. Although the slot leakage flux is reduced, the main flux is not high due to the narrower PMs, thus the back-EMF is lowered. Therefore, the stator slot opening ratio cannot be too small or too large, that is, there is an optimal value for the stator slot opening ratio.
Effect of stator slot opening ratio on power factor.
Effect of rotor slot opening ratio on power factor.
Then, the influences of rotor slot opening ratio on power factor can be seen in Figure 20. It indicates that when the rotor slot opening ratio is around 0.7, the power factor reaches the maximal value. This is because the power factor is mainly influenced by the back-EMF. When the rotor slot opening ratio increases, the effective airgap length becomes smaller, thus the main flux is increased and the back-EMF is improved. As a result, the power factor is increased. When the rotor slot opening ratio keeps increasing, the flux modulation effect of the rotor teeth becomes weaker and weaker, thus the smaller modulated flux, and the lower back-EMF. Therefore, there is also an optimal value for rotor slot opening ratio when a high power factor is demanded.
For PM machines, PM demagnetization performances are very important because it is highly related to the safe operation and machine reliability. Therefore, the PM demagnetization performances of FRPMMs should be analyzed in this chapter. Since the magnetic properties of PM materials are sensitive to temperature, and the temperature coefficient of NdFeB magnet is as high as −0.126%K−1. When the current of FRPMMs is large, the winding heating can easily affect the PMs attached to the stator teeth surface, causing the decrease of PM magnetic performances. On the other hand, when the winding current is large, the demagnetizing effect of the armature field is enhanced, and thus the PMs have the possibility to be demagnetized. Therefore, it is of great importance to investigate the PM demagnetization performances of FRPMMs at different conditions.
Figure 21 shows the demagnetization curve of the magnets. The upper half is a straight line, and lower half under the knee point Bknee is a curved line. When the FRPMM works on the straight line (such as point P1), the return line coincides with the demagnetization curve, and the magnetic performance of the magnets will not be lost. However, when the armature equivalent MMF Ha´ is too large at load condition, or the knee point is too high, the working point Bknee is moved to P2. At this time, the recovery line does not coincide with the original demagnetization line, thus the intersection of the B-axis changes from Br to Br1, causing the irreversible demagnetization. Then, the PM properties and machine performances will no longer return to the original. So, the PM flux density should be examined in order to check the risk of irreversible demagnetization. As we know, the PM flux density is determined by the design parameters such as electric loading Ae, PM thickness hm, rotor slot opening ratio, etc. So, in this chapter, the effects of electric loading Ae, PM thickness hm, rotor slot opening ratio bo/t on PM demagnetization performances of FRPMMs will be studied. For instance, the PM material is selected as N38SH, and knee point of the PM flux density at 100°C is 0.35 T.
PM demagnetization curve.
Figure 22 shows the PM flux density of a 12-stator-slot/14-rotor-slot FRPMM when the electric loading Ae is 1600A/cm, the PM thickness hm is 3 mm, rotor slot opening ratio bo/t is 0.65. It can be seen that the PM flux density distribution varies with the rotor position. When the rotor position is 140°, the PM does not demagnetize, while at 0° and 340°, the PM will demagnetize. Hence, in the following analysis, the PM flux density at the most severe moment of demagnetization is selected.
PM demagnetization at different rotor positions: (a) rotor position = 0°; (b) rotor position = 140°; (c) rotor position = 340°.
Figure 23 studies the magnetic flux density distribution in the PMs under different electric loadings. It can be found that the larger electric loading Ae, the smaller minimum flux density. This is because the larger electric loading, the higher armature MMF Ha´, and the more left operating point P2, so the lower flux density in the magnets. When the electric loading Ae is 1400A/cm, the PM irreversible demagnetization just occurs. In addition, it can be seen that the entire magnetic flux density map is skewed to the right. This is because the N-pole magnet is intercepted in this analysis, and there is an S-pole magnet next to the N-pole magnet. There is PM pole leakage flux between the S-pole magnet (negative axis) and the N-pole magnet (positive axis), so the magnetic flux density around the 0 position is lower, and away from the 0 position, the magnetic flux density gradually rises.
Influence of Ae on PM demagnetization.
Figure 24 analyzes the effect of PM thickness hm on the PM demagnetization performances. At this time, the electric loading is chosen as 800 A/cm, and the rotor slot opening ratio is selected as 0.65. It can be seen in Figure 24 that when the PM thickness hm is less than 2.5 mm, the irreversible demagnetization will happen, while when the PM thickness hm is larger than 2.5 mm, the irreversible demagnetization will not. In this model, the airgap length is 0.5 mm. Therefore, in the design stage, the PM thickness should be better to set as five times or more the airgap length. Considering the back-EMF, it is claimed in [3] that when the PM thickness is about three times the airgap length, the back-EMF will reach the maximum. But considering both back-EMF and PM demagnetization risk, it is safer to set the PM thickness as about five times airgap length.
Influence of hm on PM demagnetization.
Figure 25 shows the influences of rotor slot opening ratio bo/t on the flux density distribution inside the PMs. At this time, the electric loading is chosen as 800 A/cm, and the PM thickness is selected as five times the airgap length, that is, 3 mm. The larger rotor slot opening ratio, the narrower rotor teeth, thus the more saturated rotor teeth, and the smaller magnetic reluctance. As shown in Figure 20, when the magnetic gets smaller, the more left operating point P2, and thus the lower PM flux density. It can be seen in Figure 25 that when the rotor slot opening ratio bo/t is 0.9, the irreversible PM demagnetization just occurs. In Ref. [28], it is claimed that the maximum back-EMF can be achieved when the rotor slot opening ratio bo/t is around 0.6. So, during the design process, the optimal rotor slot opening ratio can be directly applied without consideration of the PM demagnetization risk.
Influence of bo/t on PM demagnetization.
The geometrical parameters of stator and rotor are shown in Figure 26. The no-load flux of each winding pole could be calculated as:
Geometry of stator and rotor.
where λw is the winding pitch. If full-pitch winding is adopted, the winding pitch is able to be written as:
Then, the no-load flux of each winding pole ϕm in Eq. (32) could change to:
Defining the average flux density at the stator yoke as By, the stator yoke thickness hy can therefore be deduced as:
Similarly, defining the average flux density at the middle of stator tooth as Bt, the stator tooth width is able to be worked out:
Moreover, in order to simultaneously maintain a relatively large torque density as well as reduce the risk of PM demagnetization, the PM thickness is recommended to be:
where g is the airgap length. Since the optimal torque density is often obtained when the slot opening ratio is approximate to 0.25 [28], the stator slot opening width wo could be written as:
Then, next step is to calculate the stator outer radius ro. Firstly, the total slot area of all the stator slots Aslot can be written based on the winding electric loading Ae and the current density Je:
where Sfg is the slot fill factor. Meanwhile, the total slot area of all the stator slots Aslot can be also derived out using the structural parameters:
Combining the Eqs. (39) and (40), the slot depth hs can be determined. Then, the stator outer radius ro can be given as:
Defining the average flux density of each rotor yoke and middle of rotor tooth as Bry, and Brt, respectively, the rotor yoke thickness hry and rotor tooth width wrt are able to be achieved using the similar derivation procedure as Eq. (35) and Eq. (36). Finally, the hry and wrt are given as:
Then, the rotor slot depth hrs is determined as:
Based on the analytical equations and the investigations of key performances in the former parts, a quick and accurate analytical design of a FRPMM can be realized by following these procedures (as depicted in Figure 27):
Based on the performance investigations in Figures 9–24, the initial design values, including combination of stator slot and rotor slot number, electric loading, equivalent magnetic loading, airgap length, materials of active parts, etc. can be firstly selected.
Then, assuming an appropriate aspect ratio klr, the airgap radius rg, and the stack length lstk can be worked out using Eqs. (29) and (30).
Based on Eqs. (32–44), the detailed geometric parameters of the stator core and the rotor core are able to be obtained. Therefore, the stator outer diameter ro and machine total length lo can be finally determined.
After that, check if the stator outer diameter and the machine total length satisfy the required design specifications. If so, proceed to the FEA verifications of machine performances. If not, reset the initial values such as combination of stator slot and rotor slot number, electric loading, equivalent magnetic loading, etc.
Conducting FEA simulations, the electromagnetic performances such as back-EMF, average torque, pulsating torque, power factor, efficiency, etc. can be obtained. Check if all the performances satisfy the design specifications. If not, adjust the design parameters in the former steps and iterate the design flow until every output meets the requirement.
Finally, it is the result output.
Design flow of FRPMM.
In order show the effectiveness of the introduced analytical method, a FRPMM is designed based on the method. Table 4 shows the specifications of the FRPMM, which mainly includes the rated torque, machine volume, cooling method, rated power, and speed. According to the rated torque, a design margin of 5% is suggested so as to make sure the torque output. Therefore, the requirement of the torque is 8.4 Nm for this design. Then, the combination of stator slots and rotor slots is determined in the first place. This combination is selected due to its high torque density and low pulsating torque, as shown in Figure 13. Then, since the cooling method is natural cooling, the electric loading and the equivalent magnetic loading are chosen as 300A/cm and 0.2 T, respectively. After that, based on the output torque value 8.4 Nm and Eq. (29), the airgap radius is determined as 38.5 mm. Furthermore, assuming the yoke flux density of stator core and rotor core as 1.0 T, and the teeth flux density of stator core and rotor core as 1.2 T, the detailed geometric parameters can all be determined. At last, the stator outer diameter is worked out as 124 mm, which is less than the requirement 130 mm. So far, this design is effective. Table 5 summarizes the design parameters of the FRPMM. Finally, in order to verify the accuracy of the proposed analytical design method, the FEA model is built, and the simulated performances are compared to the analytical designed values. It can be seen in Table 6 that the FEA simulated results match well with the analytical method. More importantly, the simulated performance output satisfies the design specifications. Therefore, this analytical design is successful.
Parameter | Value | Parameter | Value |
---|---|---|---|
Rated torque | 8 Nm | Rated speed | 300 rpm |
Rotor inner diameter | 32 mm | PM material | N38SH |
Stator outer diameter | 130 mm | Stack length | 120 mm |
Airgap length | 0.6 mm | Iron material | 50WW470 |
Cooling method | Natural cooling | Rated power | 0.25 kW |
Design specifications of a three-phase FRPMM.
Parameter | Value | Parameter | Value | |
---|---|---|---|---|
Stator | Outer diameter | 124 mm | Inner diameter | 79 mm |
Turns per phase | 300 | Teeth width | 11.5 mm | |
Slot number | 12 | Yoke thickness | 6 mm | |
Slot depth | 13.5 mm | Yoke flux density | 1.0 T | |
Winding pole pair | 1 | Teeth flux density | 1.1 T | |
Magnet | PM thickness | 3 mm | Magnet width | 7.8 mm |
Rotor | Outer diameter | 77.8 mm | Slot depth | 10.4 mm |
Teeth flux density | 1.2 T | Yoke thickness | 12.5 mm | |
Inner diameter | 32 mm | Yoke flux density | 1.0 T | |
Teeth width | 4 mm | Slot number | 17 |
Design parameters of the FRPMM using the design method.
Parameter | Analytical design method | FEA |
---|---|---|
PM flux linkage | 1.43 Wb | 1.35 Wb |
Back-EMF | 44.8 V | 42.4 V |
Torque | 8.4 Nm | 7.97 Nm |
Results comparison of the design method and 2D FEA.
To verify the calculated results by the analytical method and FEA, the FRPMM prototype has been built. Its major parameters are listed in Table 4. The structure and test bed of the prototype are shown in Figures 28 and 29, respectively.
12-slot/17-pole FRPMM prototype: (a) stator; (b) rotor.
Test bed of the FRPMM prototype.
Figure 30 compares the phase back-EMF waveform and spectrum at 300 rpm. It can be seen that the back-EMF waveforms are very sinusoidal. This is because the total harmonic distortion (THD) of FEA and experiments are only 1.26% and 2.63%, respectively. The sinusoidal back-EMF is inherent without any special design techniques such as skewing or pole shaping. Then, Figure 31 shows the FEA simulated and experimental results of average torque at different winding current values. In addition, the analytical design value is also plotted as the blue triangle. It indicates that the simulated, analytical and experimental results have reached good agreements. Finally, Table 7 compares the electromagnetic performances by FEA and experiments. Thus, the feasibility of the analytical design method can be seen.
Back-EMF waveforms at rated speed 300 rpm: (a) waveform; (b) FFT analysis.
Output torque vs. phase current.
Parameter | FEA | Experiment |
---|---|---|
Average torque at rated current | 7.97 Nm | 7.24 Nm |
Torque per weight | 0.66 Nm/kg | 0.60 Nm/kg |
Phase back-EMF magnitude at 300 rpm | 42.4 V | 41.2 V |
THD of the phase back-EMF at 300 rpm | 1.26% | 2.63% |
Total losses | 99.5 W | 116.7 W |
Efficiency | 60.3% | 57.3% |
Power factor | 0.756 | 0.746 |
Result comparison of FEA and experiment of the FRPMM prototype.
The design of FRPMMs is usually based on time-stepping FEA, which are accurate but time-consuming. To save the design time meanwhile maintain the accuracy, this chapter proposes an analytical design method of FRPMMs. First, the sizing equation is derived, and then the dimensional parameters of stator and rotor are calculated. Finally, based on the above equations, an analytical design procedure is established. Moreover, in order to help to choose the initial design parameters in the sizing equation, including number of stator slots and rotor slots, airgap radius, electrical loading, and equivalent magnetic loading, their effects on the average torque, cogging torque, torque ripple, and power factor are investigated, providing reliable guidance for designers. At last, in order to make the introduced design methodology easier to understand, a FRPMM is designed and tested.
This work was supported by National Natural Science Foundation of China (NSFC) under Project Number 51807076, and Alexander von Humboldt Foundation.
remanent flux density relative permeability of magnets effective airgap length considering PM thickness PM height along the magnetization direction stator slot opening ratio (=slot opening width/slot pitch) airgap length airgap radius number of series turns per phase number of stator winding pole pairs active stack length number of rotor teeth mechanical angular speed of rotor number of stator teeth slot per pole per phase angular position of rotor axis with respect to the axis of phase a particular position in the stator reference frame measured from the axis of phase a pole ratio (=rotor pole number/winding pole pair)
Pandemics and epidemics of infectious origin are large-scale outbreaks that can greatly increase morbidity and mortality globally or over a wide geographic area, respectively [1]. Pandemics have occurred throughout history and appear to be increasing in frequency in the last centuries. Noteworthy examples include the Black Death at the end of the Middle Ages, Spanish flu in 1918, the 2014 West Africa Ebola epidemic or the current COVID-19 pandemic. The direct impact of pandemics on health can be dramatic. These large outbreaks can disproportionally affect younger or active workers, but vulnerable populations such as the elderly are at a particular high-risk. Pandemics can cause acute, short-term as well as longer-term damage to economic growth due to public health efforts, health system expenditures, and aid to affected sectors. Evidence suggests that epidemics and pandemics can have significant social and political consequences too, by debilitating institutions, amplifying political tensions, stigmatizing minority populations, or encouraging sharp differences between social classes [2].
Outbreaks by respiratory ribonucleic acid (RNA) viruses such as influenza or coronaviruses entail the principal threat due to their ease of spreading among humans, their potential severity and recurrence. However, other RNA viruses such as flaviviruses (Zika) or filoviruses (Ebola) must be taken into consideration due to a great overall burden of morbidity and mortality [3]. Antiviral drugs can help mitigate a viral outbreak by reducing the disease in infected patients or their infectiousness. While these drugs can be very successful against some viruses (e.g. hepatitis C virus [HCV]) [4], they are not universally effective as exemplified in the current SARS-CoV-2 pandemic [5]. Nowadays, having effective vaccines may be the only tool to reduce susceptibility to infection and thus, prevent the rate of virus spread [2].
Vaccination has dramatically decreased the burden of infectious diseases. Vaccines have saved hundreds of millions of lives over the years [6]. It has been estimated that approximately 103 million cases of childhood diseases were prevented in the United States through vaccination between 1924 and 2010 [7]. The eradication of smallpox in 1980 through vaccination is considered one of the crown accomplishments of medicine. Despite these achievements, effective vaccines have been developed against just over 30 pathogens among bacteria and viruses. There are many pathogens, including viruses such as human immunodeficiency virus (HIV) or respiratory syncytial virus (RSV), for which all efforts for vaccine development have failed so far. In addition, current available vaccines for worldwide important viral diseases like influenza are suboptimal, especially in the elderly, resulting in vulnerability among billions of at-risk populations [6]. On the other hand, having a new effective and safe vaccine in time to control highly contagious emerging viruses that cause epidemic or pandemic threats is an almost impossible task considering the timeframes for vaccine development. This includes preclinical and clinical research, its approval by the regulatory authorities, as well as its production and distribution [3].
Altogether, it has been postulated that one possibility of filling the gap between the appearance of a viral outbreak by an emerging pathogen and the availability of a specific vaccine is to take advantage of the heterologous protection of some existing vaccines, in order to increase the non-specific resistance of the host through trained immunity [8, 9].
Conventional (specific) anti-infectious vaccines are biological preparations containing live-attenuated or dead microorganisms, their antigens or nucleic acids encoding for them, designed for specific pathogens. The purpose of vaccination is to induce a long lasting adaptive immune response against key antigens able to confer host resistance for future encounters with the corresponding pathogen. Either the production of antibodies, generation of T helper/effector cells, or both, may play a critical role in such a resistance, which greatly depends on the type of pathogen, the route of entrance and the host-pathogen relationship (e.g., extracellular and/or intracellular) [10]. Successful vaccines are highly effective not only in inducing long-lasting immunity against disease-causing pathogens, but also in providing herd immunity to the community that substantially restricts the spread of infection [6].
Most of the vaccines available today have been developed empirically and used successfully long before their mechanism of action on the immune system was understood. Early protection is associated to induction of antigen-specific antibodies, being their quality (avidity, specificity, or neutralizing capacity) key factors for their efficacy. Long-term protection relies on the persistence of vaccine antibodies and availability of immune memory cells capable of rapid and effective reactivation with subsequent microbial exposure. On the other hand, T cells have a critical role in the induction of high affinity antibodies and immune memory. Furthermore, T cells have a direct role in protection conferred by some vaccines, including the tuberculosis Bacille Calmette-Guérin (BCG) vaccine [11].
Vaccines using whole pathogens have been classically classified as either live attenuated or inactivated (killed). Subunit vaccines contain just selected antigens (e.g., proteins, polysaccharides). Recently, due to a growing availability of bioinformatics and sequencing tools, there has been an increase interest on so-called “rational” vaccine design approaches for subunit vaccines, such as the reverse vaccinology [12]. In this regard, modern vaccines include recombinant proteins or nucleic acids [13]. Rather than administering the antigen itself, DNA and mRNA vaccines targeting dendritic cells (DCs) encode the antigen of interest that will be produced by the vaccinated host, representing a new era in vaccinology [14]. In fact, the first RNA vaccine licensed for humans in Western countries has been recently developed for SARS-CoV-2.
As commented before, a vaccine response is linked to the induction of T and B cell specific responses to the antigens contained in the vaccine. This requires lymphocyte activation, proliferation and differentiation on specialized lymphoid tissues (e.g lymph nodes), where antigen presenting cells, like DCs for T cells or follicular dendritic cells (FDCs) for B cells, are present. Mature DCs are recruited into the T cell areas of lymph nodes from the periphery, e.g., at the site of injection of the vaccine. DCs express pattern recognition receptors (PRR) that recognize evolutionary conserved pathogen-associated molecular patterns (PAMPs) that are not contained in self-antigens and are identified as “danger signals” [15]. When immature DCs are exposed to the vaccine-derived antigens at the site of vaccination, they uptake them and become activated [16]. This activation will lead to their maturation with the expression of homing receptors at their surface, triggering DC migration to the draining lymph node through afferent lymphatic vessels, where the activation of T and B lymphocytes will occur. Mature DCs process the up-taken antigens and present them to naïve T cells associated to molecules of the major histocompatibility complex (MHC) within the T cell areas of lymph nodes. On the other hand, unprocessed native antigens, either free or complexed with antibodies or complement, access the B cell areas of lymph nodes (lymphoid follicles) where they are captured by FDCs and displayed from their cell surface to the B cells. Antigen-specific B cells will rapidly proliferate forming a germinal center and differentiate into plasma cells producing low-affinity immunoglobulin (Ig) M antibodies. The B cells will then receive additional signals from activated T cells, undergoing isotype antibody switch from IgM to IgG or IgA and affinity maturation of the antibodies produced.
For a vaccine to be immunogenic enough, DC activation, that can be achieved by adjuvants, is essential. Live attenuated and inactivated whole-cell vaccines are considered “self-adjuvanted” as they naturally present sufficient PAMPs to activate innate immune cells, including DCs; thus, promoting a robust antigen-specific immune response. In contrast, subunit vaccines generally require different types of adjuvants to enhance and/or drive the immune response in the desired direction [15, 17].
Viral outbreaks appear when there is a sufficient number of susceptible individuals within a nearby population. Although susceptibility is a balance between host factors (high/low resistance) and pathogens (high/low virulence), in many cases it reflects a lack of prior contact with a given pathogen. In general, this is related to the emergence of new viruses or the lack of effective vaccines against known viruses. As pointed above, the development of effective vaccines is not an easy task against certain viruses. We are still lacking vaccines for some of the most lethal viral infections, including HIV and MERS-CoV, among others. These pathogens are difficult to tackle, as we do not fully understand their mechanisms to evade the immune system or how to elicit protective immunity against them [13]. However, encouraging progress is being made against these pathogens and there are currently several “pipeline vaccines” in development, such as RSV, universal influenza vaccine, and SARS-CoV-2 [18, 19, 20]. Apart of SARS-CoV-2 for obvious reasons in the current pandemic, there is an urgency to have a universal influenza vaccine that provides a broad and durable protection from influenza virus infection. Yet, the high level of antigenic diversity and variability, and antigenic drift in the surface antigens, enable these viruses to escape antibody-mediating neutralization [21]. On the other hand, there is a number of vaccines currently licensed, including the influenza A virus vaccine, that provide incomplete protection, especially in high-risk groups [22]. Mumps outbreaks observed in Ireland, United Kingdom and United States in vaccinated subjects with Measles Mumps Rubella (MMR) vaccine is another example [23]. Different factors have been postulated to contribute to mumps outbreak, including waning immunity and primary and secondary vaccine failure. Yet, their actual contribution is not fully understood [23].
Vaccine efficacy must consider different target populations as well. Adaptive immune response to vaccines may be limited in newborn and the elderly. Early in life, immune responses are dampened compared to adults [24, 25]. Neonates have underdeveloped germinal centers in lymph nodes and the spleen, and low expression of B cell receptors which in turn results in low levels of primary IgG responses to infections and vaccines [26]. As we age, our immune system undergoes age-related changes that lead to progressive deterioration of the innate and the adaptive immune responses, this is termed immunosenescence. The most common features of immunosenescence are short-lived memory responses, impaired response to new antigens, increased predisposition to autoimmune diseases and low-grade systemic inflammation (inflammaging) [27, 28]. Immunosenesence results in increased susceptibility to infections and deficient response to vaccination causing high hospitalization and mortality rates. For example, influenza vaccine efficiency has been reported to be 17–53% in the elderly, compared with the 70–90% efficacy in young adults [29]; and vaccination with Varicella zoster virus (VZV), also an important pathogen in elderly people, only partially prevents reactivation of herpes zoster [27].
If the difficulties listed above are outlined for existing or developing vaccines, quickly obtaining an effective vaccine to urgently control a new virus outbreak is almost an impossible task in the short-term as pointed above. This is well exemplified by the SARS-CoV-2 vaccine race pushed by the devastating COVID-19, with more than 100 vaccine candidates in the running. It is considered that no less than 1 year will last the time until the first licensed vaccine can provide protection in the best scenario [30]. This, in spite of greatly shortening the usual clinical development time and regulatory obstacles for a new vaccine and, therefore, without knowing its true performance and/or safety in the medium term compared to other authorized vaccines [31].
It has become evident from epidemiological, clinical and experimental data that some conventional whole-cell vaccines, like BCG and others, also provide resistance to infectious diseases not related with the specific pathogen targeted by the vaccine [32, 33, 34]. Much of these non-specific “heterologous” effects appear to depend on the activation of innate immune cells by the PAMPs contained naturally in these vaccines [10], although other mechanisms such as cross-reactive epitopes between different pathogens could also account for this protection in some cases [35].
Immunological memory, understood as the ability to “remember” past encounters with pathogens, has been classically attributed to the adaptive branch of the immune system exclusively, by virtue of the antigen-driven clonal expansion of T and B lymphocytes and exemplified by the mechanism of conventional specific vaccines pointed above. However, the notion that innate immunity was unable to induce immunological memory has been challenged in recent years, particularly from studies in organisms that lack adaptive immunity, such as plants or invertebrates, as well as early studies in mice lacking the adaptive immune system [8, 36]. Altogether, the term ‘trained immunity’ was coined to define an innate immune memory that lead the innate immune system to an enhanced response to secondary challenges [37]. Importantly, trained immunity seems to be underlying the heterologous effects of an increasing number of vaccines [38, 39, 40].
What is trained immunity? - Trained immunity is defined as the memory of the innate immune system, where an encounter with a first stimulus (e.g. a microbial insult) results in a subsequent long-term adaptation and enhanced non-specific response by innate immune cells against a secondary challenge (the same or unrelated), thus providing non-specific, broad-spectrum, long-term protection in case of infection [8, 9, 37, 41].
Which cells can be trained? - Trained immunity properties have been defined for distinct cell subsets of the innate immune system [9, 42], including natural killer (NK) cells and innate lymphoid cells [43]. Of note, training of myeloid cells [42], particularly monocytes and macrophages [44, 45], and more recently DCs [46, 47] and hematopoietic stem cells [48], have been extensively studied. Finally, the acquisition of this immunological memory has also been demonstrated to a lesser extent for non-immune cells [49].
How to get trained? - A wide variety of stimuli can train innate immune cells, particularly when considering monocytes and macrophages [9, 50]. Among infectious agents, live microorganisms such as the tuberculosis vaccine BCG [51], Candida spp [52] or viruses [53, 54]; bacterial components, such as flagellin, lipopolysaccharide, muramyl dipeptide [55], fungal components as β-glucan [52] or even helminth products [56]. In general, microbial ligands engaging some PRR, like C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain-like receptors (NLRs) are well established training inducers, whereas those engaging toll-like receptors (TLRs) may have opposite effects depending on the TLR type and concentration [55, 57]. Intriguingly, not only infectious agents but also endogenous inducers and metabolites such as oxidized low-density lipoprotein or mevalonate can induce trained immunity [50].
What hallmarks define trained immunity? - In contrast to adaptive immune responses, epigenetic reprogramming of transcriptional pathways — rather than gene recombination — mediates trained immunity. This training phenomenon comprises three key hallmarks that occur at the intracellular level: increased cytokine production upon rechallenge, changes in the metabolism and epigenetic reprogramming [9, 58, 59], which eventually support increased protection upon infection.
Among those cytokines whose production is augmented after re-exposure in trained cells, proinflammatory molecules such as tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-1β and interferon γ (IFN-γ) are fairly constant [45, 52, 55, 60, 61]. Modulation of IL-10 varies between studies [45, 52, 56, 62, 63]. A noted shift from oxidative phosphorylation to aerobic glycolysis (Warburg effect) is the main change in cellular metabolism during the induction trained immunity [64]. Moreover, glutaminolysis, cholesterol synthesis and the tricarboxylic acid cycle are non-redundant pathways required for trained immunity to take place [64, 65]. Epigenetic reprogramming, mainly mediated by histone modifications, is one of the bases for the long-lasting effect of trained immunity [8, 66, 67, 68]. Immune pathway activation and changes in metabolism serve as basis for epigenetic rewiring [65]. As a result, epigenetic modifications have been found at the level of important promoters for the training process, which makes chromatin more accessible and conditions gene expression patterns of trained cells upon stimulation with a secondary challenge [69].
As a result of the whole process, enhanced, broad-spectrum, non-specific protection mediated by innate immune cells is found upon infection. This cross-protection has been observed for a wide range of human pathogens including fungi [51, 52], parasites [70, 71] and different bacterial infections [72, 73, 74, 75]. Importantly, induction of trained immunity has been proved to be effective against viral infections including yellow fever [76], influenza A virus [77] and others [78, 79]. In this line, the induction of this phenomenon has been also proposed as a tool for reducing susceptibility to emergent SARS-CoV-2 infection, as will be described at the end of the chapter [78, 80].
How long does trained immunity last? – Trained immunity phenotypes have been observed for months and up to one year after the training insult. This was initially controversial, as trained immunity properties had been attributed to short-lived myeloid cells such as monocytes or DCs [38]. In this regard, several studies have shown that modulation of bone marrow progenitors is also an integral component of trained immunity, supporting the long-lasting effect of this phenomenon [9, 81]. In this way, trained immunity inducers [82, 83, 84, 85] would be able to reprogram and induce expansion of hematopoietic progenitors with a particular bias to the myeloid lineage. Thus, bone marrow-derived mature cells would be also trained [86], showing improved clearance of infection [83].
Complementary to progenitor reprogramming, peripheral trained immunity induction would take place in tissue-resident cells [9]. This is especially relevant at the mucosal level, where cells encounter most of the infectious training inducers. Alveolar macrophage (AM) memory was demonstrated following viral infection [87, 88]. Training of these long-living cells led to increase antimicrobial properties, independently of systemic immunity [87, 89]. This local training of AM was further reproduced following respiratory mucosal administration of tuberculosis vaccine, being crucial for Mycobacterium tuberculosis clearance [90]. On the other hand, training of NK cells lead to long-lived, self-renewing, stable expanded cells with memory-like properties, both in an antigen-dependent or independent manner [91, 92, 93]. Finally, it was also reported that self-renewing long-living skin epithelial stem cells exhibited local trained immunity, providing faster wound healing in primed mice than in naïve mice [94, 95].
Non-specific effects of vaccines have been extensively studied and reported over the last decades. Although trained innate cells could partially account for these effects, involvement of adaptive immunity has also been suggested [96]. An adaptive immune mechanism of non-specific effects could be heterologous immunity; vaccine antigens can give rise to T cell cross-reactivity against other antigens that may confer some protection against unrelated pathogens [96, 97].
However, innate immune cells constitute the bridge between the intrusion of microbial threats and the activation of adaptive immunity. As said before, following sensing of pathogens by PRRs, activated innate immune cells secrete different factors and act as antigen-presenting cells (APCs) to initiate activation of adaptive immunity [98]. Thus, it would not be unexpected that trained innate immune cells, within their acquired enhanced properties, would be able to induce stronger adaptive immune responses [39]. In this regard, BCG vaccine, a well-known trained immunity inducer, has shown to enhance the antibody titer and alter heterologous T cell responses against a wide range of vaccines and unrelated infections [99, 100, 101]. In different experimental models, BCG-mediated protection against viral and Plasmodium infections was abrogated in the absence of T cells. In these models, BCG vaccination has been mainly associated with modulation of CD4+ T helper (Th) 1 responses. Similar observations have been found in different clinical studies [99]. Of note, BCG vaccinated human volunteers displayed a long-lasting heterologous Th1 and Th17 response upon stimulation with unrelated pathogens and TLR-ligands [38]. To some extent, similar observations have been found in other vaccines such as diphtheria-tetanus-pertussis (DTP) or measles vaccine [99].
As said before, trained immunity properties have been recently described also for DCs. As being the most professional APCs, they emerge as crucial bridge for potentiating adaptive immune responses. In this sense, DCs with high immunostimulatory properties that enhance adaptive immune responses via IL-1β release had been described [102]. More recently, programmed memory DCs have shown to increase Th1/Th17 immunity and confer protection during cryptococcosis [46]. Finally, different polybacterial preparations of whole-cell inactivated bacteria, have shown to prime DCs and induce enhanced Th1, Th17 and IL-10 T cell responses against related and unrelated stimuli [103, 104]. This capability of modulating heterologous T cell responses by APCs have been also described to suppress pathogenic T cell immunity in experimental models of autoimmune encephalomyelitis [56].
As noted above, a hallmark of trained innate immune cells is the enhancement of some effector functions leading to increased non-specific resistance against a variety of pathogens. In this regard, β-glucan-trained monocytes show enhanced candidacidal activity and efficiently inhibit the C. albicans outgrowth [52]. Production of reactive oxygen species (ROS) has shown to be also affected by the induction of training. Thus, BCG-trained monocytes [45], β-glucan-trained macrophages [105] or β-glucan-trained neutrophils [106] produced increased amount of ROS following different challenges. Finally, increased phagocytosis and production of microbicidal molecules have been observed in β-glucan-trained macrophages [70, 105]. Mechanisms underlying this enhanced effector function could be an intrinsic cell reprogramming as consequence of the training, as well as be supported increased expression of different PRRs and surface molecules [45, 60, 87]. Altogether, these enhanced effector responses could improve pathogen clearance by increasing host resistance.
On the other hand, a substantial part of the adaptive immune response is directed at recruiting other effector cells from the innate immune system to eventually resolve an infection. Both T helper and B responding cells release cytokines, antibodies, and other mediators that activate monocytes, macrophages, NK cells or neutrophils to clear extracellular and intracellular pathogens [107]. Multiple studies have demonstrated the importance of IFN-γ-mediated priming in the activation of macrophages [108, 109], produced by CD4+ Th1 and CD8+ T cells [107]. In this sense, it has been previously demonstrated that adaptive T cells render innate macrophage memory via IFN-γ-dependent priming [87, 89]. Furthermore, a deep crosstalk between Th17 and neutrophils have been widely demonstrated, via production of IL-17 and other related cytokines [110].
Taken into account the potential role of trained innate cells in both the induction of adaptive and effector responses, a notable amplification loop in the global immune response could be considered (Figure 1).
Effect of trained immunity on ongoing immune responses. Induction of trained immunity allows trained cells to enhance adaptive immune responses and vice versa, final effector functions of trained cells can be further potentiated by enhanced adaptive responses.
Based on trained immunity pillars, a next generation of anti-infectious vaccines has been postulated, coined as ‘Trained Immunity-based Vaccines’ (TIbVs). TIbVs would be conceived to confer a broad protection far beyond the antigens they contain. By proper targeting of innate immune cells to promote trained immunity, a TIbV may confer non-specific resistance to unrelated pathogens while trained immunity memory is still present, in addition to the specific response given by intrinsic antigens [39].
A bona fide TIbV would consist of two main components: the trained immunity inducer(s) and the specific antigen(s). The antigen(s) mission is to generate an adaptive (specific) immune response as any conventional vaccine. The trained immunity inducers aim to promote the training of innate immune cells. This innate immune training would confer non-specific resistance against unrelated pathogens for a window of time (months) plus an enhanced adaptive immune response to the antigens present in the vaccine itself or from other sources (e.g., coming from eventual infections or bystander pathogens) [39].
Two additional concepts arise under the TIbV umbrella: i) trained immunity-based immunostimulants (TIbIs) and ii) trained-immunity-based adjuvants (TIbAs). The former (TIbIs) would induce the training of innate immune cells, so they would be ready-to-act against upcoming infections conferring broad non-specific protection while trained immunity is present, still enhancing adaptive immune responses following any eventual natural infection. The latter (TIbAs) would enhance adaptive responses against specific antigens incorporated either to the trained inducers as in bona fide TIbVs, or in a separated but combined vaccine [39] (Figure 2).
Different possibilities of trained immunity-based vaccines (TIbVs). Under the umbrella of trained immunity-based vaccines (TIbVs) different possibilities exist depending on their design and purpose. Bona fide TIbVs are those containing both trained immunity inducers and antigens in the same vaccine as occurs in conventional vaccines with trained immunity inducing properties. These vaccines show heterologous protection in addition to the specific response to the target antigen. TIbIs are intended just to confer non-specific protection by means of trained immunity induction beyond the intrinsic antigens they may contain. TIbAs are intended to enhance the specific response of other vaccines that are administered later, once trained immunity has been induced, or specific antigens combined in the same vaccine as any other adjuvant.
Following the above features, the TIbV concept can be applied to existing anti-infectious vaccines composed of microorganisms that show heterologous protection ascribed to trained immunity.
During the last decades, robust epidemiological data has demonstrated the role of certain vaccines leading to protection against heterologous infection with a high impact on overall mortality in children [111, 112, 113]. This protection could not only be explained by protection achieved by the target disease. Studies on MMR vaccination in high-income settings have also evidenced a reduction in non-target infections, particularly in respiratory infections [114]. A limitation for most of these epidemiological studies is that they do not identify the agent (viral, bacterium or parasite) responsible for the infection. These heterologous effects of certain vaccines conferring non-specific protection for a quite long time are believed to be largely due to non-specific stimulation of the innate immune system. It is not yet clear whether this is a direct reflection of trained immunity induction (i.e., acting as TIbVs) in every case. The fact that most of these vaccines use live-attenuated microorganisms, i.e., self-replicating agents, may suggest that a continuous stimulation of innate immune cells is necessary to obtain protection and/or to achieve a proper trained immunity for this purpose.
The BCG-Denmark strain was tested in randomized-controlled trials (RCT) in infants who normally did not receive the BCG vaccine at birth. These studies carried out in Guinea-Bissau demonstrated that vaccination at birth was associated with lower neonatal mortality, especially due to neonatal sepsis, respiratory infections, and fever [111, 115]. In these lines, a meta-analysis commissioned by the WHO concluded that BCG administration during the first month of life reduces all-cause mortality by 30% [116]. In these studies authors did not discriminate the etiology of infection (bacterial vs. virus); therefore, a reduction in viral infections may explain, to some extent, this result. However, in two studied carried out in India in neonates with BCG-Russian strain no such effect was observed [117]; suggesting that different immunological effect of diverse BCG strains may account for these discrepancies. A study carried out in infants to assess the impact of BCG vaccination on the incidence of RSV infection suggested a possible protective role for BCG vaccination against acute lower respiratory tract infection [118]. Other clinical studies have provided evidence suggesting a protective role for BCG on secondary viral infections [79]. In this regard, the impact of BCG vaccination on viral infection in human healthy volunteers has been assessed using the live attenuated yellow fever vaccine (YFV) as a model of viral human infection [76]. BCG vaccination induced epigenetic reprogramming in human monocytes, and these modifications correlated with IL-1β upregulation and the reduction of viremia, all these features being the hallmarks of trained immunity [76].
Similar protective effect of BCG was observed in several studies in elderly people regarding respiratory tract infections. BCG vaccination in subjects of 60–75 years old once a month for three consecutive months resulted in reduction of acute upper respiratory tract infection, concomitant to significant increase in IFN-γ and IL-10 compared with those receiving placebo [119]. A recent randomized trial of BCG vaccination was carried out in elderly patients (age ≥ 65 years) returning home from hospital admission, these subjects are at high risk to develop infections. The BCG vaccination increased the time to first infection (primary outcome) and decreased the incidence of a new infection [120]. Besides, results demonstrated that BCG vaccination resulted in lower number of infections of all causes, especially respiratory tract infections of probable viral origin, although no discrimination was made between respiratory tract infections caused by bacteria or viruses.
BCG has also been shown to enhance the response to vaccines directed against viral infections [79]. A clinical study in healthy volunteers demonstrated that BCG administration prior to influenza vaccination increases antibody titers against the 2009 pandemic influenza A (H1N1) vaccine strain, concomitantly with an enhanced IFN-γ production to influenza antigens compared with the control group [121].
The cold-adapted, live attenuated influenza vaccine (CAIV) has been shown to provide non-specific cross-protection against RSV in an experimental model of infection [122].
In a randomized pilot study conducted in healthy volunteers receiving a trivalent influenza vaccine, cytokine responses against unrelated pathogens were observed [121]. During the 2003–2004 influenza A (H3N2) outbreak, an open-labeled, nonrandomized vaccine trial was carried out in children 5 to 18 years old. Subjects received either trivalent live attenuated or inactivated influenza vaccine. Live attenuated influenza vaccine but not trivalent inactivated vaccine was effective in children administered during influenza outbreak, despite the dominant circulating influenza virus was antigenically different from the vaccine strain [123].
Measles vaccine (MV) is among the live vaccines that have been shown to have beneficial effects reducing all-cause mortality [124]. Randomized clinical trials and observational studies from low-income countries have concluded that measles vaccination is associated with decreased overall mortality and morbidity [100]. However, a systematic review carried out by Higgins and colleagues has pointed out that most of these studies were considered at high risk of bias [116]. Nevertheless, MV seems to induce a transient suppressive effect on both the lymphoproliferative and innate response evaluated in peripheral blood mononuclear cells (PBMCs) from children, with slight increase in innate immune response, measured by non-specific cytokine production [100]. It has been reported that following measles vaccination, the ex vivo production of both innate (IL-6 and TNF-α) and adaptive (IFN-γ and IL-2) cytokines decreases for 2 weeks, but levels of IL-2, IL-6 and IFN-γ are increased at day 30 post vaccination compared with baseline [125]. Differences in males and females have been reported, where girls seem to receive stronger beneficial effects. In this regard, a study of MV-specific innate responses following MMR vaccination found higher TNFα, IL-6 and IFN-α secretion, cytokines associated to trained immunity, in adolescent girls than boys [126].
There are currently only three countries where polio remains endemic. Thus, polio-free, high income countries are introducing the use of the inactivated polio vaccine (IPV). However, there are still many countries that use the live-attenuated oral polio vaccine (OPV). Despite current WHO policy to replace OPV by IPV, there is epidemiological evidence that supports that replacing OPV by IPV might have an impact on overall mortality [96], since OPV has shown strong non-specific beneficial effects even in settings where the incidence of the targeted infection is low. In this regard, campaigns to eliminate polio in West Africa have been associated with lower child mortality rates [127].
As pointed above, most of the vaccines described so far showing non-specific heterologous effects contain live-attenuated microorganisms. Nevertheless, fully inactivated bacterial vaccines have also been described conferring protection against viral infections, and some of them for a fairly long period of time. Interestingly, these vaccines are mucosal preparations that are administered daily for long periods of time (weeks/months) rather than single, or seldom, doses used in live attenuated vaccines. Thus, it seems that the much longer administration of these inactivated mucosal vaccines resembles the effect achieved by live vaccines on heterologous protection associated to trained immunity (Figure 3).
Trained immunity window by self-replicating and inactivated TIbVs. Trained immunity-based vaccines (TIbVs) containing live-attenuated self-replicating microorganisms (e.g. BCG) may require fewer administrations to induce an adequate trained immunity window of sufficient intensity, quality and/or duration than vaccines with dead microorganisms. Fully-inactivated TIbVs can be enhanced to induce trained immunity with a multiple dose schedule (e.g. MV130).
These vaccines are used for the prevention of recurrent infections in susceptible subjects, mainly associated to the respiratory and urogenital tracts [128, 129, 130, 131, 132, 133, 134]. Since they target infections occurring in these tracts, their administration is generally through mucosal tissues to obtain a better mucosal response [135, 136].
MV130 is a sublingual vaccine used to prevent recurrent respiratory tract infections [128, 129] containing inactivated whole-cell bacteria that are common pathogens in the airways. Its ability immunomodulating DCs has been addressed experimentally in vitro and in vivo. MV130 triggers the release of cytokines ascribed to trained immunity in different setting, including TNF-α, IL-1β and IL-6 [103, 137, 138]. Sublingual immunization of mice with MV130 induces a systemic Th1/Th17 and IL-10 enhanced responses against unrelated antigens [103]. Similar enhancement was shown in patients treated with MV130 where an increased T cell response to flu antigens were described [128]. MV130 was successfully used in infants with recurrent wheezing, a condition triggered in most cases by viral infections. It is noteworthy that the protective effect was also shown 6 months after discontinuation of treatment, which points to a long-lasting effect that fits with the memory ascribed to trained immunity (Nieto et al., under review). In this regard, MV130 has been shown to induce trained immunity and to confer protection against experimental virus infections (Brandi et al., under review). Recent studies have assessed the clinical benefit of MV130 as a TIbV in the context of recurrent respiratory infections in vulnerable populations such as patients with different primary and secondary immunodeficiencies showing a reduced rate of respiratory infections [130, 139] (Ochoa-Grullón et al., in press).
Although not considered vaccines but immunostimulants, these bacterial preparations are, like MV130, used for the prevention of recurrent respiratory infections. OM-85, one of the best studied, is composed of chemically treated bacterial lysates for oral administration, acting through the gastro-intestinal mucosa. OM-85 has been shown to be effective in experimental viral infections [140] and in children with recurrent wheezing [141], a condition triggered by viruses as noted above. OM-85 stimulates the release of proinflammatory cytokines such as IL-1β, TNF-α and IL-6 by macrophages [142], typical of trained immunity induction, as well as Th1 cytokines including IFN-γ [143]. It is not known, however, the role of trained immunity in their mechanism of protection. A recent study conducted in infants, the observed protection against respiratory infections under OM-85 treatment stopped when treatment was discontinued [144], which may point against the memory ascribed to trained immunity.
The non-specific mechanism of TIbVs against widely differing pathogens associated to the induction of trained immunity can be exploited clinically. This makes TIbVs as a ready-to-act tool to tackle disease outbreaks from different angles where conventional specific vaccines have proven their limitations:
Newly emerging disease outbreaks, with no conventional vaccines available. Even in the presence of therapeutic options, vaccines are the best tool to prevent infections. However, even with worldwide efforts, getting a vaccine to the public takes time. In addition, side effects, dosing issues, and manufacturing problems can all cause delays [3]. Herein, using available TIbVs could mitigate the devastating consequences of emergent outbreaks by means of non-specific protection, until a suitable specific vaccine is available.
Newly emerging disease outbreaks, first coming vaccines with partial efficacy. Even if a vaccine gets available to the market, conventional strategies might raise some issues. The unpredictable identity of largely unknown emerging pathogens, the lack of appropriate experimental animal models, and the time for faster developing may give raise to an upcoming vaccine with no full efficacy [3]. On the other hand, limitations of current vaccines, such as mumps, also include a low efficacy resulting from an unacceptable drop in the immune response over time, requiring re-immunization [145]. In these contexts, the administration of a TIbV prior to the specific vaccine may enhance the response to the latter (111).
Re-emerging disease outbreaks, pathogens with high mutation rates and loss of vaccine efficacy. Mutations are the building blocks of evolution in any organism. Viruses are among the fastest evolving entities, especially RNA viruses such as influenza. Implications in conventional vaccine design are numerous, as a high mutation rate makes it hard to design a vaccine that is universally effective across many years. As a result, this makes a vaccine effective for shorter and raises the need for yearly vaccination programs [22, 146]. Since the underlying mechanism of TIbVs extend well beyond their nominal antigens and have a broad-spectrum of protection, TIbVs could overcome the troublesome of highly specific vaccines that promote antigen variant switching [147].
Disease outbreaks in vulnerable populations. During infectious disease outbreaks, vulnerable populations are usually disproportionately affected due to an interplay of immunological, epidemiological, and medical factors, which leads to sub-optimal or even under-vaccination [148]. This is well exemplified in the elderly population, where successful vaccination against important infectious pathogens which cause high morbidity and mortality represents a growing public health priority. Age-related immunosenescence and ‘inflammaging’ have been postulated as underlying mechanisms responsible for decreased response and high mortality, including during COVID-19 pandemic or influenza season [80, 149]. Therefore, more potent vaccines are needed. In this regard, the induction of trained immunity by the use of TIbVs is proposed to overcome the immune dysfunction found in these individuals [28]. Thus, elderly has been proposed as one of the groups to benefit from the use of TIbVs, including severe COVID-19 disease, with the aim of potentiating the immunogenicity of their vaccination [80]. Moreover, some types of immunodeficiencies or immunosuppression may benefit from TIbVs. These formulations, by means of tackling both branches of immunity, especially the innate compartment, may be an achievable alternative to reinforce protection or optimize immunogenicity of vaccination in this population [130, 139].
Altogether, harnessing the TIbV concept has been suggested as a crucial step in future vaccine development and implementation, because a wide range of clinical applications may benefit to some extent from their use [150].
Despite the tremendous financial and scientific effort invested to rapidly obtain a prophylactic vaccine against SARS-CoV-2, only the first one has been licensed in December 2020. Although this means less than a year since the declaration of the pandemic by the WHO, which is an unprecedented achievement, in the meantime, two pandemic waves of COVID-19 and more than 1.5 million deaths have been declared worldwide. Therefore, alternative strategies have been considered to fill the gap until a safe and effective vaccine is available. As noted earlier in this chapter, TIbVs can play an important role for this purpose by increasing host resistance to other pathogens, including viruses.
A bunch of recent studies have been published supporting the role of certain vaccines, including BCG, OPV and measles, as a possible successful strategy to reduce susceptibility and severity to SARS-CoV-2 through trained immunity induction [80, 151, 152]. Thus, clinical trials are currently being conducted to find out the contribution of trained immunity as a preventive tool in the context of COVID-19 pandemics [153]. In a prospective observational trial, 255 MMR vaccinated subjects were followed searching for COVID-19 cases, thirty-six presented COVID-19 but all with a remarkable mild course [154]. Recent studies have also suggested a potential benefit of influenza vaccine on the susceptibility and the outcome of certain infections including SARS-CoV-2. In this sense, a particular attention has been focused on a high-risk population, the elderly. In a study conducted in Italy, influenza vaccination in people aged 65 and over was associated with a reduced spread and a less severe clinical expression of COVID-19 [155].
Finally, in addition to the potential role of TIbV conferring resistance against SARS-CoV-2 infection, they can eventually be used to increase efficacy of specific anti-COVID-19 vaccines, when available, especially in vulnerable population. In this sense, implications of vaccination route and mucosal immunity have also been raised as a key aspect in the development of safe and effective prophylaxis interventions against SARS-CoV-2. Most formulations in development are parentally administered; only a few COVID-19 vaccine candidates are administered by mucosal routes. Still, studies indicate that even if mucosal immunization against coronavirus does not confer sterilizing immunity, the ability to induce anti-SARS-CoV-2 IgA responses in the airways may prevent virus spread to the lung and avoid respiratory distress [156]. In this regard, mucosal TIbVs could enhance the mucosal response of specific COVID-19 vaccines acting as TIbAs by combining them as pointed above in those especially vulnerable subjects.
Viral outbreaks can cause epidemics and pandemics if the route of transmission allows for the rapid virus spread. Given the ease of travel and the global exchange of potential transmitting agents, these situations will be increasingly frequent in the future. Preventing the spread of a virus outbreak caused by a highly contagious agent is not easy in the absence of effective therapies or preventive measures. Although the development of effective prophylactic vaccines specific for the threatening virus is the final goal when possible, this requires a minimum time of almost a year in the best possible scenario. Meanwhile, the consequences of the spread of a deadly virus can be devastating, as it is exemplified during the COVID-19 pandemic. This scenario may also take place in the case of re-emerging viruses tackled by partial efficacious vaccines. In such situations, harnessing the heterologous non-specific protection of some existing vaccines with a known safety track record is an interesting possibility. This protection may be critical for vulnerable subjects and/or for highly exposed individuals, like healthcare workers.
Non-specific protection of some vaccines is thought to be mainly dependent on their effect on the innate immune system. Increasing evidence gathered over the past few years points that innate immune cells show memory-like features when properly activated. This memory termed “trained immunity” has been associated with the non-specific protection of vaccines. The concept of “trained immunity-based vaccine” (TIbV) has been drawn to exploit the potential of trained immunity in designing novel vaccines or to redefine bacterial-derived preparations conferring broad protection against widely differing pathogens. As trained immunity may have implications on the adaptive immune response and vice-versa, its potential to provide enhanced immune responses is quite broad whether considering natural infections or following vaccination.
Taken advantage of the current COVID-19 pandemic, a number of clinical trials have been launched with putative TIbVs in order to address protection in highly exposed subjects. The results are eagerly expected as these initiatives may be considered as a proof-of-concept supporting their use in future epidemics/pandemics to fill the gap until a specific vaccine is available. Nevertheless, as trained immunity can be achieved by different inducers, it is unlikely to obtain the same degree of protection, duration, etc. for all of them, which may also depend on the biological behavior and the route of transmission of the threatening pathogen. As in most instances rapidly spreading viruses are airborne and primarily infect the mucosa of the airway tract, induction of trained immunity at the local mucosal level can confer a more adequate protection. This may be an opportunity for mucosal TIbVs as compared to those given parenterally.
Trained immunity may justify heterologous protection of vaccines, help to explain their underlying mechanisms, open avenues for next generation of vaccines, or be proposed to tackle outbreaks by new pathogens as described here. However, this is an emerging field that requires more clinical data before being a reality in the clinical practice; not only to be used against infectious outbreaks, but to fight against recurrent infections in vulnerable subjects for whom no effective vaccines are yet available.
JLS is the founder and CEO of Inmunotek SL, Spain, a pharmaceutical company that manufactures bacterial vaccines. LC and PS-L are employees of Inmunotek.
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\n\nWe have adopted the Protocol to increase the number of readers of our publications. All our Works are more widely accessible, with resulting benefits for scholars, researchers, students, libraries, universities and other academic institutions. Through this method of exposing metadata, IntechOpen enables citation indexes, scientific search engines, scholarly databases, and scientific literature collections to gather metadata from our repository and make our publications available to a broader academic audience.
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