Martínez‑Boixaderas et al. Porcine Health Management (2022) 8:11 https://doi.org/10.1186/s40813-022-00252-3 REVIEW Open Access Impact of maternally derived immunity on immune responses elicited by piglet early vaccination against the most common pathogens involved in porcine respiratory disease complex Núria Martínez‑Boixaderas1,2, Laura Garza‑Moreno2, Marina Sibila1,3,5 and Joaquim Segalés3,4,5* Abstract Background: Newborn piglets can trigger an elementary immune response, but the acquirement of specific anti‑ bodies and/or cellular immunity against pathogens before they get infected post-natally is paramount to preserve their health. This is especially important for the pathogens involved in porcine respiratory disease complex (PRDC) as they are widespread, fairly resistant at environment, and genetically variable; moreover, some of them can cause intrauterine/early life infections. Main body: Piglet protection can be achieved by either passive transfer of maternal derived immunity (MDI) and/ or actively through vaccination. However, vaccinating piglets in the presence of remaining MDI might interfere with vaccine efficacy. Hence, the purpose of this work is to critically review the putative interference that MDI may exert on vaccine efficacy against PRDC pathogens. This knowledge is crucial to design a proper vaccination schedule. Conclusion: MDI transferred from sows to offspring could potentially interfere with the development of an active humoral immune response. However, no conclusive interference has been shown regarding performance parameters based on the existing published literature. Keywords: Porcine respiratory disease complex (PRDC), Maternally derived immunity (MDI), Maternally derived antibodies (MDA), Vaccination, Interference, Piglet Background antigens in the last third of gestation [4–6]. These anti- Suidae species are characterized by a six-layered epithe- bodies are considered as part of the innate immune liochorial placenta [1] that, unless it is damaged during system [7] and are considered as “natural antibody rep- gestation [2] prevents leaking of large molecules like ertoire”. Although they might play a protective role for immunoglobulins from the sow to the foetuses [3]. How- the newborn pig [6], their response is weak [8] and little ever, foetuses can produce their own antibodies against is known about their specificity and affinity [9]. On the other hand, piglets are born with functional immune cells and extracellular components able to respond to infec- *Correspondence: joaquim.segales@irta.cat 3 OIE Collaborating Centre for the Research and Control of Emerging tions [10, 11]. However, due to limited or no external and Re-Emerging Swine Diseases in Europe (IRTA-CReSA), antigenic stimuli during foetal life, these components are 08193 Bellaterra, Catalonia, Spain Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/. The Creative Commons Public Domain Dedication waiver (http://​creat​iveco​ mmons.​org/​publi​cdoma​in/​zero/1.​0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Martínez‑Boixaderas et al. Porcine Health Management (2022) 8:11 Page 2 of 12 usually immature at birth. Therefore, neonates are not response. In this regard, two terms are used in the litera- fully immunologically competent. ture to refer to the persistence of such MDI: the dura- Since the complete adaptative protective immune tion of maternally derived antibodies (MDA) detected response of the piglet needs around four weeks to be by means of serological tests and the rate of MDA decay. established [12, 13], the protection of the newborn pig- The duration of MDA (Table 1) refers to the age of the let against infectious agents is dependent on the acquire- piglet at which their MDA levels fall below the limit of ment of maternally derived immunity (MDI) from detection of the test [16], whereas the rate of decay, also colostrum and milk [14]. called “half-life”, indicates the time required for a 50% The amount of MDI transferred from sows to their decrease in MDA levels [17]. This latter measure is a offspring is determined by the sow’s immunity level at constant value and would be the most appropriate one the time of parturition, the timing of colostrum intake to compare data among studies. However, the MDA and the volume of colostrum ingested [15]. Strengthen- decay is reported in few studies and significant variation ing sow herd immunity against specific diseases through is provided depending on the study; for example, MDA exposure and/or vaccination is a useful management tool half-life for Actinobacillus pleuropneumoniae was calcu- for ameliorating clinical effects in piglets and delaying lated as 11–15 days by Vigre et al. [18] and 28–42 days by infection until the piglet immune system is fully prepared Cruijsen et al. [19]. Therefore, the duration of MDA is the to respond [13]. most widely used parameter among published studies. The duration of MDI is rather variable among patho- Nevertheless, it is important to consider that the dura- gens. Under field conditions, it is usually measured con- tion of MDA is dependent on the initial concentration of sidering only one arm of the immune system, the humoral MDA and the threshold of the serologic test used [20]. Table 1 Duration of maternally derived antibodies (MDA) for each infectious agent included in this review Pathogen V/NV ­sowsa Study facilities Duration of MDA (in weeks) References SIV NV Experimental 7–8 [65] V Experimental 10 [23] V Experimental 9–14 [67] V Field 7–10 [69] V Experimental 10 [66] V Experimental 13–16 [68] PRRSV V Field 4 [79] NV Experimental 4–8 [77] U Field 6–10 [80] U Field 2–8 [81] U Field 6–8 [72] V Experimental 7–11 [71] V Experimental 7–8 [78] V Experimental 3–8 [82] PCV-2 NV Experimental 4–11 [93] U Experimental 4–11 [96] NV Field 10 [95] V Field 4–12 [60] V Field 7–12 [21] NV Experimental 8 [94] M. hyopneumoniae NV Field 4–9 [20] V Experimental 2–7 [109] A. pleuropneumoniae U Experimental 9–12 [19] NV Field 8–10 [122] NV Experimental 2–8 [18] NV Experimental 10 [123] NV Field 3–7 [124] a V, Vaccinated prior to farrowing; NV, No vaccinated prior to farrowing; U, Unknown Martínez‑Boixaderas et al. Porcine Health Management (2022) 8:11 Page 3 of 12 If the level of MDI wane before piglets’ immune sys- These authors hypothesized that antibody crossing might tem has reacted against a given pathogen, there is a non- be associated with small damage to the placental barrier protected timeframe or time-window where the piglet is during the gestational period. If this happens only with highly susceptible to infection. Therefore, the desirable PCV-2 antibodies or with any type of antibody is pres- scenario is to vaccinate piglets prior to natural infec- ently unknown. tion although it implies that vaccination is performed in Antibodies and immune cells are transferred from presence of MDI for most pathogens. Depending on the sow to piglet by the ingestion of colostrum and milk, levels of such MDI, a potential interference of vaccine and these can cross the intestinal barrier and reach the uptake may happen, jeopardizing vaccine seroconversion peripheral blood for a limited period. This way they can and efficacy [21–25]. reach lymphatic and non-lymphatic tissues including The objective of this review was to compile information mesenteric lymph nodes, and a variety of other tissues on how MDI can affect vaccine efficacy against the most such as the spleen, liver, lungs and the duodenum and common swine pathogens involved in porcine respiratory jejunum’s lamina propria and submucosal spaces [33, 38, disease complex (PRDC), namely Swine Influenza viruses 39]. Nevertheless, this absorption process differs slightly (SIV), Porcine reproductive and respiratory syndrome between antibodies and cells [13, 40]. virus (PRRSV), Porcine circovirus 2 (PCV-2), Myco- The peak of antibody transfer occurs immediately after plasma hyopneumoniae (M. hyopneumoniae) and Actino- birth. Therefore, it is critical to ensure piglet suckling bacillus pleuropneumoniae (A. pleuropneumoniae). for at least the first 6 h of life [40]. Acquired antibodies remain intact in the neonatal digestive tract due to low Maternally derived immunity (MDI) proteolytic activity, which is further reduced by sow Components of MDI colostrum trypsin inhibitor [41]. Antibodies (IgG but not Different antibody isotypes are present to varying pro- IgA or IgM) can pass through the intestinal mucosa even portions within colostrum and milk [26]. Immunoglobu- if the maternal source or donor species is different from lins G (IgG) and M (IgM) are the most common isotypes the own mother (for example, newborn pigs have been in colostrum, whereas immunoglobulin A (IgA) is the proven to absorb cow antibodies [15]). This absorption most common one in milk [27]. Colostrum and milk also can be done by two transcytosis mechanisms to penetrate contain large numbers of cells that may vary depending the intestinal barrier: non-specific endocytosis or anti- on the mammary gland’s developmental stage and the body specific neonatal Fc-receptors [42–45]. The ability sow’s physiologic and immunologic status [28]. Many of to absorb MDA by the proximal to the distal part of the them are leukocytes, such as neutrophils, other granu- small intestine lasts only for a short period of time. Spe- locytes, and mostly antigen-experienced lymphoid cells cifically, Murata & Namioka [46] concluded that duode- [29–32] that participate in the cell-mediated immune num uptake stops 2 h after birth, while the jejunum’s and (CMI) response. In addition, there are also other com- ileum uptake stop 48 and 72 h after birth, respectively. ponents that are thought to play an immunomodula- This post-natal loss of absorption capability is known as tory role, such as the antibacterial protein lactoferrin, “gut closure”. Finally, within 9 days of birth, the mucosal lysozyme and cytokines [33, 34]. epithelium is completely replaced by intestinal epithelial cells incapable of transcytosis [47, 48]. Colostral IgG are MDI transfer detectable in the neonatal circulatory system from 48 h The newborn systemic and mucosal immune systems are after birth onwards [49, 50]. immature, with limited peripheral lymphoid cells, under- In contrast, transference of colostral cells needs a developed lymph nodes, rudimentary jejunal Peyer’s minimum period of suckling from 12 to 20 h, and the patches and a low number of effector and memory absorption is accomplished through the intercellular T-lymphocytes [11, 35, 36]. As indicated above, the new- space between the epithelial cells of intestinal mucosa born piglet does not receive neither produce antibodies [38]. Years ago it was considered that only maternally- against a specific pathogen during gestation, unless a derived cells from the biological mother could pass the potential intrauterine infection or damage of placenta- intestinal mucosa of piglets [38, 39]. This assumption was tion occurs during the immunocompetence period (from supported by Bandrick et al. [40] who reported no evi- around 70–80 days of gestation onwards) [37]. In such dence of immune cell reactivity in cross-fostered animals eventuality, the animal would be delivered already with just after birth. Therefore, animals fostered by a substi- antibodies against the specific pathogen. Noteworthy, tute dam could be deficient in CMI [40]. In contrast, new one report suggested PCV-2 antibody placental barrier research has shown that piglets may absorb immune cells leakage from sow to fetus, mainly in those cases from transferred by colostrum independently if they originate which the sows had very high levels of antibody titers [2]. from their biological mother or from another sow [29]. Martínez‑Boixaderas et al. Porcine Health Management (2022) 8:11 Page 4 of 12 Estimation of MDI transferred to the piglet by dams’ and development [15]. Importantly, this concept is parameters mainly considered with intramuscularly (and probably The most used technique to measure MDA levels in intradermally) applied vaccines that generate systemic mammary secretions [26, 51–53] and/or antibodies in and, eventually, mucosal immune responses. However, serum of sows and piglets [54] is the enzyme-linked the degree of potential vaccine efficacy interference due immunosorbent assay (ELISA). Occasionally, this tech- to MDA with vaccines delivered through mucosal sur- nique (commercial or in-house methods) has been also faces remains unknown [58]. used to monitor the presence and quantity of immuno- In the presence of high levels of systemic antibody globulins in other sample types like oral fluids [55, 56]. titres at the time of intramuscular vaccination, the most Alternatively, monitoring CMI is also feasible but mainly typical interference effect is a reduced or lack of sero- restricted to research purposes because the techniques conversion [59–61]. However, the key issue would be if used (for example, enzyme-linked immunosorbent spot this interference in seroconversion translates into lower [ELISPOT]) are labour-intensive, hard to read and rarely vaccine effectiveness. The most widely used method of commercialized. measuring vaccination effectiveness in terms of produc- However, the results obtained from measuring anti- tive parameters is the calculation of average daily weight body levels in the dam are not effective as a tool for esti- gain (ADWG) [62]. mating MDI transferred later through colostrum and Nowadays, piglets are usually vaccinated against several milk [40]. This is mainly because MDI levels in piglets pathogens at early ages. The most common infectious depend on how effective the colostrum and milk intakes agents involved in PRDC for which piglet vaccines have are in terms of quantity and timing. been developed are detailed in Table 2, including cur- rent data on potential interference with vaccine efficacy. Early life vaccination of piglets Importantly, while interference with vaccine efficacy is Different vaccination strategies are used to immunize often analyzed by comparing experimental vaccinated the populations of swine production (breeding animals, groups with different antibody titres, it may also be stud- piglets, or both). The vaccination approach will be deter- ied by comparing vaccinated groups of various ages. mined by the pathogenesis and epidemiology of each pathogen. Understanding the infection dynamics and Swine influenza viruses herd immunological status for each infectious agent will Swine influenza viruses (SIV), generally of type A, are be critical to determine the best vaccination strategy. the causal agents of swine influenza and a major cause of Early piglet vaccination might imply that piglets still acute respiratory disease outbreaks in pigs. Nowadays, have MDI. Therefore, a potential interference between different subtypes of SIV as H1N1, H1N2, H3N2, and residual immunity of maternal origin and the vaccine pandemic H1N1 virus are co-circulating worldwide [63]. antigen uptake needs to be considered. Piglet MDI may Their infection can display different clinical forms, rang- come from natural infection, vaccination or both sce- ing from an acute outbreak to an endemic subclinical sce- narios (natural infection and vaccination). In the latter nario [64]. Although the epizootic presentation is more case, and especially if sows are vaccinated by late gesta- aggressive, the endemic one is more common within tion, the amount of measurable MDA transferred can be herds. The virus is spread primarily through direct con- very high, increasing the risk of interference. Neverthe- tact with infectious oronasal secretions [63]. In this sce- less, vaccinating sows and piglets in the appropriate tim- nario, newborn piglets that do not receive MDI are at a ing may yield the best results in terms of herd protection high risk of showing clinical signs. and productivity. Some studies describing the MDA duration against SIV reported a steadily decline until the age of 10 weeks [23, Effect of MDA on the seroconversion and efficacy 65], with an average waning period of 7–8,5 weeks [65]. of the most used vaccines in the pig industry However, other investigations have reported that MDA in for pathogens involved in PRDC piglets coming from vaccinated sows could persist up to Vaccine efficacy interference by MDA is defined as the 2–4 months of age under both experimental [66–68] and ability of residual antibodies transferred to piglets by field [69] conditions. colostrum and/or milk to block or delay the active immu- Currently, the main strategy for controlling SIV infec- nization of the piglet [57]. This interference involves a tion is vaccination. Nevertheless, in the presence of high number of possible mechanisms, including the neutrali- MDA levels, previous studies reported interference of zation of the immunizing antigen [57], the masking of B early piglet vaccination in terms of reduced post-vacci- cell epitopes, and/or the down-regulation of neonatal Ig nation humoral response [23, 67] and worse respiratory synthesis by means of the inhibition of B cell maturation clinical signs [23, 68]. Interestingly, Kitikoon et al. [23] Martínez‑Boixaderas et al. Porcine Health Management (2022) 8:11 Page 5 of 12 Table 2 Interference of maternally derived antibodies (MDA) with vaccine efficacy in terms of serological and production parameters Pathogen Vaccination age (in weeks) Interference on antibody Interference on production References seroconversion (assay used)a parameters (parameters evaluated)b SIV 3 Yes (HI assay) NE [23] Different age groups Yes (HI assay) NE [67] 16 Yes (HI assay, ELISA) NE [68] PRRSV 3 Yes (ELISA, VNT) NE [71] 3&4 Yes (ELISA) NE [82] PCV-2 4 Yes (ELISA) No (ADWG) [96] 3 NE No (ADWG) [93] 3 Yes (IPMA, VNT) NE [17] 3 Yes (ELISA) NE [95] 3 Yes (IPMA) NE [97] 4 Yes (IPMA) No (ADWG) [98] Different age groups Yes (ELISA) Yes (ADWG) [99] 4 Yes (ELISA) NE [60] 3 Yes (ELISA) Only when S/P values at vac‑ [21] cination are extremelly high (ADWG) 2 NE No (ADWG, mortality) [100] M. hyopneumoniae 1&4 Yes (ELISA) No (ADWG, mortality) [115] 2 Yes (ELISA) NE [112] 1&4 Yes (NC) NE [114] 1 No (ELISA) NE [109] 1 No (ELISA) NE [111] 1 Yes (ELISA) NE [116] 1 Yes (ELISA) NE [113] A. pleuropneumoniae 6 Yes (ELISA) NE [128] 6 Yes (ELISA) NE [123] a “Yes” when the age and/or MDA of the animals of study are associated with reduced/retarded active antibody post-vaccinal response; “No” when the age and/or MDA of the animals of study are not attributed to a reduced/retarded active antibody post-vaccinal response; “NE” when serologic parameters are not evaluated. HI assay: Hemagglutination-inhibition assay; VNT: Virus neutralisation test; ELISA: Enzyme-linked immunosorbent assay; IPMA: Immunoperoxidase monlayer assay; NC: Not cited b NE Not evaluated; ADWG Average daily weight gain found that piglet vaccination gave better protection (less infection, as animals can remain contagious even after fever, lower viral shedding and reduced pneumonia) than clinical disease recovery [72, 73]. Since piglets can be MDA against SIV, raising doubts on the common prac- infected congenitally or very early in life [74], it is critical tice of immunizing sows to boost MDI. Information on to protect them as soon as possible after birth or also to the putative interference of MDA in vaccine efficacy in protect against intrauterine infections. terms of production parameters has not been assessed so Different studies showed that MDA has a significant far. protective effect against PRRSV infection in suckling piglets [75, 76], lasting between 2 and 11 weeks [71, 72, Porcine reproductive and respiratory syndrome virus 77–82]. In fact, the highest rates of PRRSV detection in (PRRSV) sera usually occur between 6 and 8 weeks of age, when Porcine reproductive and respiratory syndrome (PRRS) MDA have achieved lowest levels in many cases [71, is a common disease in pigs with one of the major eco- 72, 81]. Therefore, since high levels of MDI may offer a nomic impacts in porcine production worldwide [70]. strong protection to the piglets in the first few weeks of Its etiological agent is PRRSV, a virus that causes repro- life, one of the options is to protect the piglet through ductive problems in sows and respiratory disorders in dam vaccination [71]. However, piglets gradually lose pigs of all ages, as well as slower growth and mortality in passive immunity, resulting in a steady supply of PRRSV- growing pigs [71]. This virus can also cause a long-lasting susceptible piglets and allowing the virus to spread across Martínez‑Boixaderas et al. Porcine Health Management (2022) 8:11 Page 6 of 12 pig herds. Under this scenario, piglet vaccination may Haake et al. [99] concluded that, regardless the antibody strengthen the piglet’s own early humoral and cellular titre at vaccination, immunization at 1 week of age can immune responses [71]. result in lower production parameters than immunizing Since vaccination of sows and piglets is a common later (3 weeks of age). However, in this study, 1 week-old strategy for controlling PRRS, it is important to consider vaccinated piglets had higher antibody values than those the effect the MDI may have on developing an active vaccinated at 3 weeks of age. immune response after vaccination. In this regard, recent investigations have yielded contradictory results. Accord- Mycoplasma hyopneumoniae ing to Fablet et al. [71] and Renson et al. [82], piglets with Mycoplasma hyopneumoniae is the main aetiological high MDA at vaccination had a hindered post-vaccina- agent of enzootic pneumonia [101, 102]. Under experi- tion immunological response for at least 4 weeks. In con- mental conditions, M. hyopneumoniae infection can last trast, Balasch et al. [78] and Jeong et al. [83] showed that for up to 240 days [103]. During that time, animals could vaccines can overcome maternal immunity and piglets still shed the pathogen in a slow and silent fashion, which as young as one day old can generate a partially protec- explains the M. hyopneumoniae endemic and chronic tive immune response. It may happen that different vac- behaviour on most farms. cines may have different ability to overcome MDI, but The prevalence of M. hyopneumoniae infection in pig- side-by-side comparisons in such regard have not been lets at weaning has been, in some studies, correlated performed. with the prevalence and severity of lung lesions in fat- Noteworthy, up to now, interference of MDI on PRRSV tening pigs [104, 105]. For this reason, reducing verti- vaccine efficacy in terms of productive parameters has cal transmission from dams to piglets during lactation not been studied. period is considered a critical point in M. hyopneumo- niae control. In consequence, sow vaccination strategies Porcine circovirus 2 (PCV‑2) have been proposed as a potential tool to reduce verti- Porcine circovirus 2 (PCV-2) is the primary aetiologic cal transmission and induce specific antibodies and CMI agent of porcine circovirus diseases (PCVDs) [84], in sow serum and colostrum. These components would which include the systemic disease (PCV-2-SD), the be, in turn, transferred to their suckling piglets and play a reproductive disease (PCV-2-RD), porcine dermatitis role in piglet protection [14, 29, 106–108]. MDA against and nephropathy syndrome (PDNS) and the subclinical M. hyopneumoniae wane approximately between 2 and infection (PCV-2-SI) [85–87]. Although PCV-2 is ubiq- 9 weeks [20, 109]. Moreover, piglet vaccination is the uitous in domestic swine and wild boar, pigs younger most common practice, and it usually takes place around than 4 weeks of age are very rarely affected by the disease weaning, within the 4 first weeks of life. Nevertheless, [88]. This suggest that certain levels of MDI prevent the some vaccines are licensed to be applied within the first development of PCV-2-SD in the offspring [89, 90]. How- week of life [110] and, consequently, such vaccination ever, early infections, including intrauterine infections, takes place in presence of MDI [111]. do occur in farms in presence or absence of subsequent The influence of MDI on piglet’s vaccination has not PCV-2-SD in late nursery or growing pigs [91, 92]. been fully elucidated. Whereas some studies reported MDA against PCV-2 is known to last between 4 and that the antibody response elicited by vaccination in face 12 weeks of age [21, 60, 93–96], and can be fostered by of MDI could be reduced or absent [112–115], some sow vaccination at mid-late gestation. Although a strong others do not describe it [109, 111, 116]. However, lack maternal immunization is crucial for the newborn pig- of seroconversion following vaccination has not been let protection against infection, when the piglet is vac- related to worse productive parameters of the piglet so cinated it may block the vaccine antigen. Indeed, high far [115]. MDA titres against PCV-2 have been shown to impair an active seroconversion after vaccination [17, 21, 60, Actinobacillus pleuropneumoniae 95–99]. However, production parameters such as ADWG Actinobacillus pleuropneumoniae is the aetiological did not appear to be jeopardized in similar scenarios [21, agent of porcine contagious pleuropneumonia. Virulent 93, 96, 98, 100], suggesting that interference with sero- serotypes of this bacteria can cause respiratory distress, conversion does not always imply a lack of protection. anorexia, and fever, with variable degrees of sever- Of note, Feng et al. [21] highlighted that extremely high ity depending on the clinical form: peracute, acute, or titres of MDA at vaccination may interfere with produc- subacute [117]. Death is frequent in peracute and acute tion parameters, although it was considered not eco- presentations. Subclinical infections can also take place nomically relevant in practical conditions as it is rare with several A. pleuropneumoniae serotypes [118]. to find such high MDA titres in the field. Alternatively, This bacterium cannot survive in the environment for Martínez‑Boixaderas et al. Porcine Health Management (2022) 8:11 Page 7 of 12 long periods of time [119]; therefore, transmission Discussion is mostly pig-to-pig via direct contact, both oral and Vaccination can be applied to sows, piglets or both nasal, and, to a lesser extent, via aerosols over short populations. Sow immunization prior to farrow- distances [120]. In addition, infected pigs that carry the ing enhances MDI transferred to offspring through bacterium silently contribute to the pathogen’s spread colostrum and milk. Piglet vaccination at early ages [121]. Therefore, a proportion of piglets are exposed to is directed to immunize them before they become the bacterium early in life, mainly during the suckling infected naturally. The optimal moment would be when period. Subsequently, when MDI wanes by end of the MDA levels are high enough to protect the piglet, but nursery period or during the growing phase, infection low enough to minimize the interference with vaccine is further spread [119]. antigen. That is why the third alternative, vaccinating MDA against A. pleuropneumoniae-specific can per- both collectives, is the one at a higher risk of interfer- sist from 2 to 12 weeks of age in the offspring [18, 19, ence with vaccine efficacy in the piglet. 122–124]. Vaccinating dams against A. pleuropneu- Several studies have assessed the amount and dura- moniae can be an effective method for improving the tion of MDA to properly ascertain the best timing herd serological status and, consequently, the amount to apply the vaccine to the piglet. However, the exact of acquired colostral antibodies in piglets [125]. Colos- duration of MDA for each pig or groups of pigs is vir- tral immunity protects piglets against sudden death or tually impossible to be assessed under field conditions, peracute outbreaks, but not against infection, as piglet since it is dependent on the sow’s serological status at infection with A. pleuropneumoniae can occur from farrowing and on the piglet colostrum intake. There- 10th day of life even in the presence of MDA [126]. fore, it is expectable to have high individual variability However, high levels of MDI against the pathogen are amongst sows and even within piglets from the same especially indicated for newborns as they remain sero- litter. positive for a longer period and enhances antibody The most likely situation is that piglets are vacci- response when they seroconvert due to natural infec- nated in the presence of an unknown level of MDA. tion [124]. Indeed, Krejci et al. [127] found that the This scenario would imply a potential risk of interfer- protection of the piglet could be even better if, in addi- ence between these antibodies and the vaccine antigen tion to having specific colostrum-derived antibodies, it intake. In this regard, it is worth noting that interfer- was pre-infected with low infection doses. ence might be assessed from two different perspec- Vaccine manufacturers recommend vaccination in tives: interference on seroconversion and interference late nursery and/or early fattening pigs for protection on vaccine efficacy in terms of production parameters against A. pleuropneumoniae [123]. However, vaccina- (mainly ADWG). Several studies on PRDC pathogens tion at those ages is a concern due to interference of reviewed in this work have shown that MDA may inter- MDA that may still be present. Tumamao et al. [128] fere with seroconversion, particularly when the titres found that vaccinating piglets against A. plueropneu- of systemic antibodies were high at the time of piglet moniae in the presence of low levels of MDA induces a vaccination. Therefore, it might be interesting in some significant antibody response, but no comparison with cases to wait for MDA declining and vaccinate piglets animals with high MDA levels was made in the same beyond 3–4 weeks of age, or even later. In contrast, study. On the other hand, Jirawattanapong et al. [123] when vaccine efficacy was also evaluated, the interfer- found no antibody response after vaccination of pigs in ence was shown in terms of seroconversion elicited by presence of high MDA titres at 6 and 10 weeks of age. the immunization, but it was rarely translated in worse Therefore, it seems that vaccination against A. pleuro- productive parameters. However, it must be considered pneumoniae should not be used during the first weeks that lack of demonstrated commercial vaccine effective- of life to prevent an impairment of post-vaccinal anti- ness is unlikely to be published in the literature. Fur- body response [119]. thermore, it would be also worthy to investigate if the Notably, evident interference of MDI on A. pleuro- existence of antigen-specific CMI of maternal origin in pneumoniae vaccine effectiveness in terms of produc- the neonatal piglet can influence the development of tive parameters has not been found in published studies. vaccine-induced immunity, particularly in those cases However, all marketed products against this pathogen where the piglet is vaccinated very early [129]. indicate vaccination from 6 weeks of age onwards, which All in all, based on the existing literature, early piglet suggests vaccine efficacy interference if administered vaccination could be considered as an option to pro- to earlier ages still with MDI (European Medicines tect the piglet in terms of reduction of clinical signs and Agency—https://​ema.​europa.​eu). improving performance parameters, notwithstanding the potential serological interference issue. Martínez‑Boixaderas et al. Porcine Health Management (2022) 8:11 Page 8 of 12 Conclusion Immunology. 1998;95(4):595–603. https://​doi.​org/​10.​1046/J.​1365-​2567.​ 1998.​00641.X. According to the literature, MDA transferred from sows 4. Redman DR, Bohl EH, Ferguson LC. Porcine parvovirus: natural and to offspring could potentially interfere with the develop- experimental infections of the porcine fetus and prevalence in mature ment of an active humoral immune response when vac- swine. Infect Immun. 1974;10(4):718–23. https://​doi.​org/​10.​1128/​IAI.​ 10.4.​718-​723.​1974. cines are applied at the recommended age for most of 5. Redman DR, Bohl EH, Cross RF. Intrafetal inoculation of swine with the PRDC pathogens. However, no conclusive interfer- transmissible gastroenteritis virus. Am J Vet Res. 1978;39(6):907–11. ence has been shown regarding performance parameters 6. Sun J, Hayward C, Shinde R, Christenson R, Ford SP, Butler JE. Antibody repertoire development in fetal and neonatal piglets. I. Four VH genes based on the existing published literature. account for 80 percent of VH usage during 84 days of fetal life. J Immu‑ nol. 1998;161(9):5070–8. Acknowledgements 7. Ochsenbein AF, Zinkernagel RM. Natural antibodies and complement Núria Martínez is holder of an Industrial Doctorat grant from the Catalan link innate and acquired immunity. Immunol Today. 2000;21(12):624– Government (Spain), with the reference No. 2020 DI 59. 30. https://​doi.​org/​10.​1016/​S0167-​5699(00)​01754-0. 8. Butler JE, Sun J, Weber P, Ford SP, Rehakova Z, Sinkora J, Lager K. Authors’ contributions Antibody repertoire development in fetal and neonatal piglets. IV. Conceptualization, N.M., L.G.M., M.S., J.S.; writing—original draft preparation, Switch recombination, primarily in fetal thymus, occurs independent N.M.; writing—review and editing, L.G.M., M.S., J.S. All authors have read and of environmental antigen and is only weakly associated with repertoire agreed to the published version of the manuscript. diversification. J Immunol (Baltimore, Md: 1950). 2001;167(6):3239–49. https://​doi.​org/​10.​4049/​JIMMU​NOL.​167.6.​3239. Funding 9. Butler JE, Zhao Y, Sinkora M, Wertz N, Kacskovics I. Immunoglobulins, IRTA-CReSA funds are partially supported by the CERCA program from the antibody repertoire and B cell development. Dev Comp Immunol. Generalitat de Catalunya. 2009;33(3):321–33. https://​doi.​org/​10.​1016/J.​DCI.​2008.​06.​015. 10. Šinkora M, Sun J, Šinkorová J, Christenson RK, Ford SP, Butler JE. Availability of data and materials Antibody repertoire development in fetal and neonatal piglets. VI. B All data used in this review work has been obtained from public scientific cell lymphogenesis occurs at multiple sites with differences in the databases, available elsewhere. frequency of in-frame rearrangements. 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