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Commercial porcine circovirus type 2 vaccines: Efficacy and clinical application
The Veterinary Journal 194 (2012) 151–157
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The Veterinary Journal journal homepage: www.elsevier.com/locate/tvjl
Review
Commercial porcine circovirus type 2 vaccines: Efficacy and clinical application Chanhee Chae ⇑ Seoul National University, College of Veterinary Medicine, Department of Veterinary Pathology, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
a r t i c l e
i n f o
Article history: Accepted 24 June 2012
Keywords: Porcine circovirus type 2 Postweaning multisystemic wasting syndrome Porcine circovirus-associated disease Vaccine
a b s t r a c t Porcine circovirus type 2 (PCV2) is the one of the most economically important pathogens of pigs. After postweaning multisystemic wasting syndrome (PMWS) was first identified and reported in western Canada in 1991, it took 13 years for the first commercial PCV2 vaccine to be used under special licence in France and Germany in 2004. Along with PMWS, PCV2 is also associated with a number of diseases and syndromes, collectively referred to as porcine circovirus-associated disease (PCVAD). Currently, five commercial vaccines are available on the international market. Commercial PCV2 vaccines were initially developed to control PMWS, but they are now also used against other PCVAD. This review focuses on (1) the types of commercial vaccines; (2) the criteria of vaccine efficacy; (3) the clinical, virological, immunological and pathological efficacy of the vaccines; and (4) the use of PCV2 vaccines against different clinical manifestations of PCVAD. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction After postweaning multisystemic wasting syndrome (PMWS) was first identified and reported in western Canada in 1991 (Clark, 1996), it took 13 years for the first commercial porcine circovirus type 2 (PCV2) vaccine to be used under special licence in France and Germany in 2004 (Charreyre et al., 2005). Along with PMWS, PCV2 is also associated with a number of diseases and syndromes, collectively referred to as porcine circovirus-associated disease (PCVAD) (Chae, 2005; Segalés et al., 2005; Opriessnig et al., 2007). Before the introduction of the vaccine, the control of PCVAD was limited mainly to improving management strategies and controlling co-infections. Vaccination is now a major tool for the control of PCV2 infection. Commercial PCV2 vaccines were initially developed to control PMWS, but they are now also used against other PCVAD. Commercially available PCV2 vaccines differ in their antigen and adjuvant types, in the recommended animals for use (sow or piglet or both) and in the dosage (one or two doses). Many review articles have already been published on the pathological, immunological, and epidemiological aspects of PCVAD and PMWS (Chae, 2004, 2005; Opriessnig et al., 2007; Grau-Roma et al., 2008; Darwich and Mateus, 2012), but there has been less discussion of the efficacy of commercial PCV2 vaccines (Kekarainen et al., 2010; Beach and Meng, 2012). Over the last 5 years, the efficacy of five commercial PCV2 vaccines has been reported under experimental conditions (Fort et al., 2008, 2009b; Opriessnig et al., 2008, 2009, 2010; Shen et al., 2010b; Kim et al., 2011;
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Hemann et al., 2012) and in the field (Cline et al., 2008; Fachinger et al., 2008; Horlen et al., 2008; Kixmoller et al., 2008; Segalés et al., 2009; Pejsak et al., 2010; Kurmann et al., 2011; Lyoo et al., 2011; Martelli et al., 2011; Fraile et al., 2012). This review focuses on (1) the types of commercial vaccines; (2) the criteria of vaccine efficacy; (3) the clinical, virological, pathological and immunological efficacy of vaccines; and (4) the use of PCV2 vaccines against different clinical manifestations of PCVAD.
Commercial porcine circovirus type 2 vaccines Antigen type The commercial PCV2 vaccine (Circovac, Merial) was first introduced in 2006 and is based on the classical approach of an inactivated oil-adjuvanted vaccine. This PCV2 vaccine was originally licensed for breeding females only (dose 2 mL); later, it was approved for use in piglets at a reduced dosage (0.5 mL; Fraile et al., 2012). Subsequently, four additional commercial PCV2 vaccines licensed only for use in piglets were introduced to the international market. Three vaccines (Circoflex, Boehringer Ingelheim; Circumvent, Intervet/Merck; Porcillis PCV, Schering-Plough/Merck) are based on an open reading frame 2 (ORF2; capsid) protein expressed in the baculovirus system. ORF2 was chosen because it contains the main neutralising epitope and thus has potential to induce a protective immune response (Nawagitgul et al., 2002; Blanchard et al., 2003). The ORF2 sequence was inserted into a baculovirus expression system using an insect cell line derived from the ovaries of the armyworm Spodoptera frugiperda (SF+). After expression of
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ORF2 capsid protein, inactivation and purification, virus-like particles morphologically indistinguishable from PCV2 particles form (Fort et al., 2008). Circumvent and Porcillis PCV are different preparations of the same core vaccine and, except for the Republic of Korea, are not distributed in the same countries. Circumvent is available in North America, while Porcillis PCV is available in Europe. Another vaccine (Suvaxyn PCV2 One Dose, Pfizer Animal Health/Fort Dodge Animal Health) is based on a chimaeric PCV1/ 2 virus containing the genomic backbone of the non-pathogenic PCV1, with the ORF2 capsid gene replaced by that of PCV2 (Fenaux et al., 2004). In 2008, a chimaeric PCV1/2 isolate was incidentally identified by PCR in Canadian pig tissue homogenates (Gagnon et al., 2010). As a consequence, Pfizer Animal Health took the chimaeric PCV1/2 vaccine off the market to investigate the possibility that the isolate originated from the vaccine strain. In August 2011, a reformulated chimaeric PCV1/2 vaccine under a new brand name (Fostera PCV; Pfizer Animal Health) re-entered the market. All commercial PCV2 vaccines are based on the PCV2a genotype. Nevertheless, PCV2a-based vaccines are able to control PCV2b infection in pigs through cross-protection (Fort et al., 2008; Opriessnig et al., 2009). This cross-protection is significant in the field because PCV2b is the predominant genotype isolated in pigs with PCVAD worldwide (Patterson and Opriessnig, 2010). In addition, PCV2b may constitute a crucial factor in triggering the switch from PCV2 infection to PCVAD (Cheung et al., 2007; Lohse et al., 2008; Timmusk et al., 2008). Adjuvant type The currently available commercial PCV2 vaccines contain different adjuvants: Circoflex contains an aqueous polymer (carbomer); Circumvent and Porcillis PCV contain D1-a-tocopherol plus liquid paraffin (oil-in-water emulsion); Circovac contains light paraffin oil; and Fostera PCV contains sulpholipo-cyclodextrin in squalane-in-water (Table 1). Recommended administration to animals Sow vs. piglet vaccination Currently, only one commercial available PCV2 vaccine is licensed for sows and piglets, while the other four vaccines are licensed only for the direct induction of active immunity in piglets 3–4 weeks of age or older (Table 1). The principle of sow vaccination is to confer passive immunity to protect newborn piglets against exposure to PCV2 while they are highly susceptible. Vaccination of the sow is much less labour intensive than vaccination of piglets and can provide passive protection through increased levels of anti-PCV2 IgG antibodies in the colostrum; however, protection in the piglet is dependent upon the piglet’s access to sufficient amounts of colostrum during the initial 24–48 h after birth and the half-life of the passively acquired maternal antibodies. In
contrast, the principle underlying vaccination of piglets is to induce active immunity in piglets to protect against PCVAD. Maternally derived antibodies Ideally, PCV2 vaccination should be administered while residual maternally derived antibodies (MDA) are minimal and before pigs become naturally infected. Since almost 100% of sows are seropositive for PCV2 (Allan and Ellis, 2000), the majority of newborn piglets receive colostral antibodies from seropositive sows and have various levels of MDA. Therefore, piglets face potential interference from MDA at the time of vaccination. Whether the efficacy of vaccination in piglets can be affected by the presence of MDA is controversial. Interference with the efficacy of the PCV2 vaccine depends on the level of MDA at the time of vaccination. Animals with high immunoperoxidase monolayer assay (IPMA) titres (>10 log2) show interference with the development of the humoral immune response after vaccination, while piglets with low titres (<8 log2) do not (Fort et al., 2009b). These results are in agreement with a field study in which piglets with high IPMA titres (>10 log2) did not show elevated IPMA titres 21 days after vaccination (Fraile et al., 2012). Thus, the higher the MDA titres at the time of vaccination, the lower the subsequent anti-PCV2 IgG titre; however, this interference must be interpreted cautiously, since neutralising antibodies (NAs), but not anti-PCV2 IgG antibodies, are one of the key elements in protection against PMWS (Opriessnig et al., 2010). Experimental and field data indicate that PCV2 vaccines are not inhibited by MDA when efficacy is assessed in terms of the reduction of PCV2-associated lesions and viral load in the serum (Fort et al., 2008; Opriessnig et al., 2008, 2010; Martelli et al., 2011; Fraile et al., 2012). Hence, MDA interference does not significantly hamper vaccine efficacy (Fort et al., 2008; Opriessnig et al., 2008). PCV2 vaccines elicit PCV2-specific NAs and interferon-c-secreting cells (IFN-c-SCs), even in the presence of MDA (Fort et al., 2008, 2009a,b). These results suggest that levels of anti-PCV2 IgG antibodies at the time of vaccination in piglets do not have a major effect on the induction of protective humoral or cell-mediated immunity. Therefore, there is little value in measuring MDA for possible interference. It may be necessary to investigate interference and protection by measuring NAs. Comparison of sow and piglet vaccination Under field conditions, piglets that receive MDA passively from vaccinated sows showed improved pre-weaning average daily weight gains (ADWGs) compared to piglets actively immunised with PCV2. Under experimental conditions, 8-week-old piglets actively immunised with a PCV2 vaccine have lower PCV2 loads in the blood and lymphoid tissues than piglets that passively acquired MDA via sow vaccination in a PCV2 challenge model (Opriessnig et al., 2010; Pejsak et al., 2010). The duration of protective
Table 1 Commercial porcine circovirus type 2 vaccines available on the international market. Vaccine
Antigen
Adjuvant
Animals
Dosage
Administration
Web site
Circovac
Inactivated PCV2
Light paraffin oil
Sow
Two (2 mL)
www.merial.com
Circoflex Circumvent Porcillis PCV Fostera PCV
Capsid Capsid Capsid Inactivated chimaeric PCV1/2
Aqueous polymer D1-a-tocopherol + liquid paraffin D1-a-tocopherol + liquid paraffin Sulpholipo-cyclodextrin in squalane
Piglet Piglet Piglet Piglet Piglet
One (0.5 mL) One (1 mL) Two (2 mL) One (2 mL) One (2 mL)
5 and 2 weeks antepartum 3 weeks+ 2 weeks+ 3 weeks + 3 week interval 3 weeks+ 3 weeks+
www.boehringer-ingelheim.com www.merck-animal-health.com www.merck-animal-health.com www.animalhealth.pfizer.com
C. Chae / The Veterinary Journal 194 (2012) 151–157
immunity is approximately 12–13 weeks after the first immunisation (up to 15–16 weeks of age) under experimental and field conditions (Fachinger et al., 2008; Shen et al., 2010b). On the basis of these observations, sow vaccination may be beneficial in herds where newborn piglets are naturally infected with PCV2 at an early age. In contrast, vaccination of piglets may be beneficial in herds where PCV2 infection occurs between the late nursery and the early finisher phase. More pig practitioners and producers prefer to use piglet vaccination because MDA is unlikely to be protective in pigs that are infected in the late-nursery to early-finisher phase. In some countries, attempts have been made to vaccinate sows with the PCV2 subunit vaccine licensed for use in piglets in an attempt to save money or if sow vaccination is not available. Under experimental conditions, vaccination of sows with the piglet subunit PCV2 vaccine was not sufficient to induce passively acquired protective immunity in the offspring and did not completely prevent PCV2 infection compared to the vaccine licensed for use in sows and piglets (Opriessnig et al., 2010). Pig practitioners and producers are urged to use PCV2 vaccines only as licensed to optimise the efficacy of vaccination. Recommended administration dosage One-dose vs. two-dose vaccination With the exception of one subunit vaccine, piglet vaccines are administered in single doses (Table 1). One-dose vaccines have been used increasingly because of decreased labour costs, reduced stress to animals and a perception of decreased spread of other diseases, particularly porcine reproductive and respiratory syndrome virus (PRRSV) and PCV2 via injection needles (Otake et al., 2002; Patterson et al., 2011). One-dose vaccination can be employed and is less labour intensive; however, it is critical to follow the vaccination procedure to ensure that pigs are properly vaccinated. The one-dose vaccines for piglets (78% market share) are the most popular in Korea (Chae, 2005) and are likely to become more popular among pig producers worldwide. Efficacy of porcine circovirus type 2 vaccine Criteria of vaccine evaluation The lack of a consistent, precise and reproducible model of PMWS is one of the main obstacles to establishing clear parameters for the experimental evaluation of PCV2 vaccines. Parameters for vaccine efficacy based on the criteria for PMWS diagnosis include: (1) presence of clinical signs; (2) presence of characteristic microscopic lesions; and (3) presence of PCV2 within lesions (Chae, 2004). An additional criterion for the diagnosis of PMWS is the viral load in serum in association with clinical signs (Liu et al., 2000; Olvera et al., 2004; Opriessnig et al., 2009). These data suggested that quantification of PCV2 load could predict PCV2 infection status. In addition, reductions in PCV2 load in the blood coincide with the appearance of both NAs and IFN-c-SCs in PCV2-infected animals (Meerts et al., 2005, 2006; Fort et al., 2007, 2009a).
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1.9–9.3% (Table 2). The reduction in the number of PCV2-positive pigs and in the viral load in vaccinated pigs is associated with improved ADWGs and reduced mortality (Fachinger et al., 2008; Kixmoller et al., 2008; Martelli et al., 2011). The different growth performance in several field trials by different PCV2 vaccines may not be due to the different efficacies of vaccines, but to different co-infections, feeding systems and quality, production systems and housing and environmental facilities. Virological efficacy Reduction of viraemia by porcine circovirus 2 vaccines Several studies have shown that PCV2 DNA levels in serum are higher in pigs with PMWS than in healthy, subclinically infected pigs (Rosell et al., 1999; Liu et al., 2000; Ladekjær-Mikkelsen et al., 2002). The PCV2 load in the blood, as quantified by real-time PCR, (<106, 106–107 and >107 DNA copies/mL), is used to categorise PCV2-infected pigs as subclinically infected, suspected and PCVADpositive, respectively (Liu et al., 2000; Olvera et al., 2004; Opriessnig et al., 2009). These categories are used in the evaluation of PCV2 vaccine efficacy under experimental and field conditions, but may vary from laboratory to laboratory based on standards used for quantification. Regardless of the vaccine used, PCV2 vaccines reduce the proportion of viraemic pigs and the viral load in blood and also shorten the duration of viraemia under experimental and field conditions (Table 3). Single dose vaccination with different vaccines reduced viraemia by 42.0–86.1% in pigs experimentally infected with PCV2 alone (Fort et al., 2009b; Opriessnig et al., 2010). Using all types of PCV2 vaccines and challenge models, none of the vaccinated pigs had a viral load >107 DNA copies/mL (Brunborg et al., 2004; Fort et al., 2009b; Opriessnig et al., 2009, 2010; Shen et al., 2010b). Therefore, a well-documented feature of PCV2 vaccination of piglets under field conditions is the ability to decrease both the proportion of viraemic pigs and the viral load in vaccinated animals compared to non-vaccinated animals (Cline et al., 2008; Fort et al., 2008; Horlen et al., 2008; Kixmoller et al., 2008; Opriessnig et al., 2010; Pejsak et al., 2010; Fraile et al., 2012). Reduction of shedding by porcine circovirus type 2 vaccines PCV2 may be spread in several ways, including the oronasal, intranasal and faecal routes (Harms et al., 2001; Shibata et al., 2003; Fort et al., 2008; Patterson et al., 2011). The nasal route may be more effective than either the faecal or the oral route (Patterson et al., 2011). Transmission through nasal secretions has been suggested as a potential mode of horizontal spread, increasing the risk of transmission to other pigs and increasing the amount of PCV2 circulating within the herd (Patterson et al., 2011). PCV2 vaccination reduces nasal and faecal shedding of PCV2 (Fort et al., 2008). Single-dose vaccination was able to reduce the PCV2 viral load in nasal secretions under experimental conditions (Fort et al., 2009b), as well as to reduce the PCV2 viral load in faecal shedding under field conditions (Fraile et al., 2012). These studies indicate that the PCV2 vaccine is a useful tool for the control of PCV2 infection on both individual animal and population scales. Immunological efficacy
Clinical efficacy Field studies are useful to evaluate productivity in response to PCV2 vaccination, i.e. improvements in ADWGs in addition to reductions in mortality. Regardless of the PCV2 vaccine used, one-dose vaccination of piglets improves ADWGs by 16–69 g/day from 3 to 19–26 weeks of age under field conditions (Table 2). In addition, one-dose vaccination of piglets decreases mortality by
Neutralising antibodies The absence or impaired production of PCV2-specific NAs is associated with the development of PMWS (Meerts et al., 2006; Fort et al., 2007). A decrease in viraemia coincides with an increase in NA titres in pigs inoculated with PCV2 (Fort et al., 2007). These observations suggest that NAs represent an important mechanism for viral clearance and recovery from infection. The presence of
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Table 2 Clinical evaluation of average daily weight gains (ADWGs) and mortality (%) in pigs vaccinated with commercial porcine circovirus type 2 vaccines under field conditions. Vaccines
ADWGs g/day (week of age)
Circovac Circoflex
10–20 (3-S a) 30 (3–26) 60 (3–24) 50 (3–22) 40 (3–26) NA 40 (3–24)
Porcillis PCV Suvaxyn a b
Mortality (%)
References
Vaccinates
Controls
3.8–6 3.5 NAb 1.92 8.0 9.3 NA
5.9–8 7.48 NA 7.76 16.03 16.9 NA
Fraile et al. (2012) Kixmoller et al. (2008) Lyoo et al. (2011) Cline et al. (2008) Martelli et al. (2011) Segalés et al. (2009) Lyoo et al. (2011)
ADWGs from 3 weeks of age to date of first batch shipment to slaughter. Data not available.
Table 3 Virological and pathological evaluation of commercial porcine circovirus type 2 vaccines under experimental conditions. Vaccine
Circovac Circoflex Porcillis PCV Suvaxyn Fostera PCV a
Reduction (%) at 21 days post-challenge
References
Viraemia
Proportion of viraemic pigs
Lymphoid lesion score
PCV2 antigen score
NA 57 100 73–100 NA
20 30–60 100 100 83.3
94.4 16.6–100 NAa 74.6–88.9 NA
100 75–100 100 100 100
Opriessnig et al. (2010) Opriessnig et al. (2009, 2010) ; Shen et al. (2010a) Fort et al. (2008, 2009b) Opriessnig et al. (2008, 2009); Shen et al. (2010a) Hemann et al. (2012)
Data not available.
NAs and decreased PCV2 replication is strongly correlated with the absence of clinical PCVAD under experimental conditions (Meerts et al., 2005, 2006) and in the field (Fort et al., 2007). Hence, NAs play a key role in protection against PMWS. There is no obvious correlation between anti-PCV2 IgG antibodies and NAs (Opriessnig et al., 2010). NAs are induced by commercial PCV2 vaccines (Fort et al., 2009b; Opriessnig et al., 2009, 2010). Among these products, a chimaeric PCV1/2 vaccine induced significantly higher NA titres compared to subunit vaccines (Opriessnig et al., 2009), but there was no significant difference in the NA titres between subunit and inactivated vaccines (Opriessnig et al., 2010). Although one-dose vaccination induced a neutralising immune response in most vaccinated pigs, the mean NA titres were lower than the levels resulting from two-dose vaccination (Fort et al., 2008, 2009b).
factors, whereas the specific PCV2-associated lesions are not observed in pigs experimentally challenged with PCV2 alone. Vaccination of pigs against PCV2 reduces the number of PMWSassociated microscopic lesions and the PCV2 load in lymphoid tissues compared to non-vaccinated animals (Table 3). A decreased PCV2 serum load and decreased PCV2 antigen are strongly correlated with low histopathological scores in the lymph nodes under experimental and field conditions (Segalés et al., 2009; Kim et al., 2011). These results suggest that PCV2 vaccines may reduce the PCV2 load in the serum and lymph nodes, resulting in fewer histological lesions.
Interferon-c-secreting cells IFN-c, which is produced by antigen-stimulated T cells, is a key immunoregulatory cytokine that controls the differentiation of naïve CD4 T cells into Th1 effectors and mediates cell-mediated immunity against viral infections. PCV2-specific IFN-c-SCs were detected in pigs subclinically infected with PCV2 between 14 and 21 days post-inoculation, coinciding with the decline in the blood viral load (Fort et al., 2009a). One-dose vaccination against PCV2 can induce PCV2-specific IFN-c-SCs 3 weeks after immunisation, the same levels being maintained for 6 weeks after immunisation (Martelli et al., 2011). Since the commercial PCV2 vaccine induces NAs and IFN-c-SCs specific for PCV2 (Fort et al., 2009b; Opriessnig et al., 2009, 2010; Martelli et al., 2011); cell-mediated immunity, together with NAs, is likely to contribute to PCV2 clearance.
Commercial PCV2 vaccines were initially developed to control PMWS and are efficacious against PMWS under field conditions (Cline et al., 2008; Fachinger et al., 2008; Horlen et al., 2008; Kixmoller et al., 2008; Segalés et al., 2009; Pejsak et al., 2010; Kurmann et al., 2011; Lyoo et al., 2011; Martelli et al., 2011; Fraile et al., 2012). Vaccination against PCV2 alone improves overall growth performance in herds with concomitant infections of PRRSV, porcine parvovirus (PPV) and Mycoplasma hyopneumoniae (Fachinger et al., 2008; Kixmoller et al., 2008; Segalés et al., 2009; Martelli et al., 2011). Vaccination in combination with good husbandry practices, such as optimising stocking density, all-in/all-out production systems and effective ventilation, can be used to control PMWS efficiently and maintain acceptable infection control.
Clinical application of porcine circovirus type 2 vaccines Postweaning multisystemic wasting syndrome
Porcine respiratory disease complex Pathological efficacy The diagnosis of PMWS must include characteristic lesions in lymphoid tissues and detection of PCV2 antigen or DNA within these lesions. Hence, pathological evaluation with detection of PCV2 antigen within lesions is critical to evaluate the efficacy of PCV2 vaccines. Under field conditions, typical PMWS-associated lesions are induced in the presence of coinfections, as well as other
The pattern of PCVAD has changed over time, with respiratory signs becoming the predominant clinical signs in the field, while the incidence of PMWS has decreased due to vaccination. Therefore, porcine respiratory disease complex (PRDC) is likely to increase in frequency in the future. In contrast to PMWS, few studies have assessed the effects of PCV2 vaccination against PRDC. Vaccination against PCV2 alone can significantly improve overall
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growth performance (+18 g/day in ADWGs and 5.6 days to slaughter) of pigs with multi-factorial PRDC (coinfection with PCV2, PRRSV and M. hyopneumoniae) or late PRDC (16–20 weeks of age) (Fachinger et al., 2008). Since the introduction of a commercial PCV2 vaccine in Korea, PMWS has been diagnosed infrequently in piglets (6–8 weeks of age) and growers (8–14 weeks of age); however, PCV2 is increasingly diagnosed in association with PRDC in finishing pigs 16– 22 weeks of age (Chae, 2012). It is possible that vaccination has contributed to the disappearance of clinical PMWS, while allowing subclinical infection. Therefore, pigs subclinically infected with PCV2 may survive for long enough to be infected with common respiratory pathogens, such as M. hyopneumoniae and Pasteurella multocida. Hence, using PCV2 vaccines will be important in controlling PRDC. Seminal shedding of porcine circovirus type 2 in boars Boars can shed PCV2 continuously for extended periods without showing clinical signs or changes in semen quality parameters (McIntosh et al., 2006; Madson et al., 2008). Therefore, artificial insemination (AI) is a potential route of PCV2 transmission among pig herds (Madson et al., 2009d). Vaccination of boars against PCV2 reduces the duration and amount of shedding of PCV2 in semen (Seo et al., 2011) and PCV2-M. hyopneumoniae-coinfected boars (Opriessnig et al., 2011). Viraemia is associated with seminal shedding (Opriessnig et al., 2011; Seo et al., 2011). Vaccination against PCV2 in naturally infected boars can decrease the length of recurrent infection and decrease the duration of viral shedding in semen (Alberti et al., 2011). Vaccination has no dramatic effect on semen quality (Alberti et al., 2011). The reduction in PCV2 shedding is clinically meaningful because the PCV2 load in the semen plays a major role in the transmissibility of PCV2 (Madson et al., 2009d). Reproductive failure in sows Gilts and sows may be vaccinated to improve reproductive performance. Sow vaccination increased pre-weaning ADWGs and coincided with a 7% increase in the success of insemination (Pejsak et al., 2010). Considering that PCV2 can cross the placenta and infect fetuses in utero (Park et al., 2005), newborn piglets may develop PMWS in the postnatal period if they become infected with PPV or are injected with an immunostimulant (Ha et al., 2008). Approximately 33–40% of newborn and pre-suckling piglets from seropositive sows sampled in Korea and the USA were PCV2 viraemic (Shen et al., 2010a; Chae, 2012). A high prevalence of viraemia among newborn piglets may increase pre-weaning mortality. Hence, sow vaccination during pregnancy reduces the blood PCV2 load and the rate of transplacental infection (Madson et al., 2009b). PCV2 acquired during AI in naïve dams could cause PCV2-associated reproductive failure and fetal infection (Madson et al., 2009c). In an experimental study, vaccination did not protect fetuses against PCV2 infection via AI, but reduced the numbers of non-viable (dead and mummified) fetuses (Madson et al., 2009a). Hence, sow vaccination will help to control reproductive failure (Madson et al., 2009b). Conclusions PCV2 is associated with a number of diseases and syndromes collectively referred to as PCVAD. Commercial PCV2 vaccines were initially developed to control PMWS, but they are now also used against other PCVAD. Commercially available PCV2 vaccines differ in antigen and adjuvant type, as well in the recommended dosage
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and administration to animals. Nevertheless, all commercially available vaccines are highly efficacious against PCV2 infection based on the clinical, virological, immunological and pathological evaluation under experimental and field conditions. Conflict of interest statement The author of this paper has no financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. Acknowledgments The author’s research was supported by Technology Development Programme for Agriculture and Forestry, Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea. This research was also supported by contract research funds of the Research Institute for Veterinary Science (RIVS) from the College of Veterinary Medicine and by Brain Korea 21 Programme for Veterinary Science. I thank graduate students of the Seoul National University PCV2 research team, including Dr Hwi Won Seo, Dr Yeonsu Oh, Dr Kiwon Han, Dr Changhoon Park and Miss Yeji Yoon. References Alberti, K.A., Estienne, M.J., Meng, X.J., 2011. Effect of vaccination of boars against porcine circovirus type 2 on ejaculate characteristics, serum antibody titers, viremia, and semen virus shedding. Journal of Animal Science 89, 1581–1587. Allan, G.M., Ellis, J.A., 2000. Porcine circoviruses: A review. Journal of Veterinary Diagnostic Investigation 12, 3–14. Beach, N.M., Meng, X.J., 2012. Efficacy and future prospects of commercially available and experimental vaccines against porcine circovirus type 2 (PCV2). Virus Research 164, 33–42. Blanchard, P., Mahn, D., Cariolet, R., Keranflec’h, A., Baudouard, M.A., Cordioli, P., Albina, E., Jestin, A., 2003. Protection of swine against post-weaning multisystemic wasting syndrome (PMWS) by porcine circovirus type 2 (PCV2) protein. Vaccine 21, 4565–4575. Brunborg, I.M., Moldal, T., Jonassen, C.M., 2004. Quantitation of porcine circovirus type 2 isolated from serum/plasma and tissue samples of healthy pigs and pigs with postweaning multisystemic wasting syndrome using a TaqMan-based real-time PCR. Journal of Virological Methods 122, 171–178. Chae, C., 2004. Postweaning multisystemic wasting syndrome: a review of aetiology, diagnosis and pathology. The Veterinary Journal 168, 41–49. Chae, C., 2005. A review of porcine circovirus 2-associated syndromes and diseases. The Veterinary Journal 169, 326–336. Chae, C., 2012. Porcine circovirus type 2 and its associated disease in Korea. Virus Research 164, 107–113. Charreyre, C., Beseme, S., Brun, A., Bublot, M., Joisel, F., Lapostolle, B., Sierra, P., Vaganay, A., 2005. Vaccination strategies for the control of circoviral diseases in pigs. In: Proceedings of the European Society for Veterinary Virology International Conference on Animal Circoviruses and Associated Diseases, Queen’s University, Belfast, Northern Ireland, 11–13 September 2005, pp. 26– 30. Cheung, A.K., Lager, K.M., Kohutyuk, O.I., Vincent, A.L., Henry, S.C., Baker, R.B., Rowland, R.R., Dunham, A.G., 2007. Detection of two porcine circovirus type 2 genotypic groups in United States swine herds. Archives of Virology 152, 1035– 1044. Clark, T. 1996. Pathology of the postweaning multisystemic wasting syndrome of pigs. In: First Proceedings of the Western Canadian Association of Swine Practitioners, pp. 22–25. Cline, G., Wilt, V., Diaz, E., Edler, R., 2008. Efficacy of immunizing pigs against porcine circovirus type 2 at three or six weeks of age. Veterinary Record 163, 737–740. Darwich, L., Mateus, E., 2012. Immunology of porcine circovirus type 2 (PCV2). Virus Research 164, 61–67. Fachinger, V., Bischoff, R., Jedidia, S.B., Saalmuller, A., Elbers, K., 2008. The effect of vaccination against porcine circovirus type 2 in pigs suffering from porcine respiratory disease complex. Vaccine 26, 1488–1499. Fenaux, M., Opriessnig, T., Halbur, P.G., Elvinger, F., Meng, X.J., 2004. A chimeric porcine circovirus (PCV) with the immunogenic capsid gene of the pathogenic PCV type 2 (PCV2) cloned into the genomic backbone of the nonpathogenic PCV1 induces protective immunity against PCV2 infection in pigs. Journal of Virology 78, 6297–6303. Fort, M., Fernandes, L.T., Nofrarias, M., Diaz, I., Sibila, M., Pujols, J., Mateu, E., Segalés, J., 2009a. Development of cell-mediated immunity to porcine circovirus type 2 (PCV2) in Caesarean-derived, colostrum-deprived piglets. Veterinary Immunology and Immunopathology 129, 101–107.
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Review
Commercial porcine circovirus type 2 vaccines: Efficacy and clinical application Chanhee Chae ⇑ Seoul National University, College of Veterinary Medicine, Department of Veterinary Pathology, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea
a r t i c l e
i n f o
Article history: Accepted 24 June 2012
Keywords: Porcine circovirus type 2 Postweaning multisystemic wasting syndrome Porcine circovirus-associated disease Vaccine
a b s t r a c t Porcine circovirus type 2 (PCV2) is the one of the most economically important pathogens of pigs. After postweaning multisystemic wasting syndrome (PMWS) was first identified and reported in western Canada in 1991, it took 13 years for the first commercial PCV2 vaccine to be used under special licence in France and Germany in 2004. Along with PMWS, PCV2 is also associated with a number of diseases and syndromes, collectively referred to as porcine circovirus-associated disease (PCVAD). Currently, five commercial vaccines are available on the international market. Commercial PCV2 vaccines were initially developed to control PMWS, but they are now also used against other PCVAD. This review focuses on (1) the types of commercial vaccines; (2) the criteria of vaccine efficacy; (3) the clinical, virological, immunological and pathological efficacy of the vaccines; and (4) the use of PCV2 vaccines against different clinical manifestations of PCVAD. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction After postweaning multisystemic wasting syndrome (PMWS) was first identified and reported in western Canada in 1991 (Clark, 1996), it took 13 years for the first commercial porcine circovirus type 2 (PCV2) vaccine to be used under special licence in France and Germany in 2004 (Charreyre et al., 2005). Along with PMWS, PCV2 is also associated with a number of diseases and syndromes, collectively referred to as porcine circovirus-associated disease (PCVAD) (Chae, 2005; Segalés et al., 2005; Opriessnig et al., 2007). Before the introduction of the vaccine, the control of PCVAD was limited mainly to improving management strategies and controlling co-infections. Vaccination is now a major tool for the control of PCV2 infection. Commercial PCV2 vaccines were initially developed to control PMWS, but they are now also used against other PCVAD. Commercially available PCV2 vaccines differ in their antigen and adjuvant types, in the recommended animals for use (sow or piglet or both) and in the dosage (one or two doses). Many review articles have already been published on the pathological, immunological, and epidemiological aspects of PCVAD and PMWS (Chae, 2004, 2005; Opriessnig et al., 2007; Grau-Roma et al., 2008; Darwich and Mateus, 2012), but there has been less discussion of the efficacy of commercial PCV2 vaccines (Kekarainen et al., 2010; Beach and Meng, 2012). Over the last 5 years, the efficacy of five commercial PCV2 vaccines has been reported under experimental conditions (Fort et al., 2008, 2009b; Opriessnig et al., 2008, 2009, 2010; Shen et al., 2010b; Kim et al., 2011;
⇑ Tel.: +82 2 8801277. E-mail address: [email protected] 1090-0233/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tvjl.2012.06.031
Hemann et al., 2012) and in the field (Cline et al., 2008; Fachinger et al., 2008; Horlen et al., 2008; Kixmoller et al., 2008; Segalés et al., 2009; Pejsak et al., 2010; Kurmann et al., 2011; Lyoo et al., 2011; Martelli et al., 2011; Fraile et al., 2012). This review focuses on (1) the types of commercial vaccines; (2) the criteria of vaccine efficacy; (3) the clinical, virological, pathological and immunological efficacy of vaccines; and (4) the use of PCV2 vaccines against different clinical manifestations of PCVAD.
Commercial porcine circovirus type 2 vaccines Antigen type The commercial PCV2 vaccine (Circovac, Merial) was first introduced in 2006 and is based on the classical approach of an inactivated oil-adjuvanted vaccine. This PCV2 vaccine was originally licensed for breeding females only (dose 2 mL); later, it was approved for use in piglets at a reduced dosage (0.5 mL; Fraile et al., 2012). Subsequently, four additional commercial PCV2 vaccines licensed only for use in piglets were introduced to the international market. Three vaccines (Circoflex, Boehringer Ingelheim; Circumvent, Intervet/Merck; Porcillis PCV, Schering-Plough/Merck) are based on an open reading frame 2 (ORF2; capsid) protein expressed in the baculovirus system. ORF2 was chosen because it contains the main neutralising epitope and thus has potential to induce a protective immune response (Nawagitgul et al., 2002; Blanchard et al., 2003). The ORF2 sequence was inserted into a baculovirus expression system using an insect cell line derived from the ovaries of the armyworm Spodoptera frugiperda (SF+). After expression of
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ORF2 capsid protein, inactivation and purification, virus-like particles morphologically indistinguishable from PCV2 particles form (Fort et al., 2008). Circumvent and Porcillis PCV are different preparations of the same core vaccine and, except for the Republic of Korea, are not distributed in the same countries. Circumvent is available in North America, while Porcillis PCV is available in Europe. Another vaccine (Suvaxyn PCV2 One Dose, Pfizer Animal Health/Fort Dodge Animal Health) is based on a chimaeric PCV1/ 2 virus containing the genomic backbone of the non-pathogenic PCV1, with the ORF2 capsid gene replaced by that of PCV2 (Fenaux et al., 2004). In 2008, a chimaeric PCV1/2 isolate was incidentally identified by PCR in Canadian pig tissue homogenates (Gagnon et al., 2010). As a consequence, Pfizer Animal Health took the chimaeric PCV1/2 vaccine off the market to investigate the possibility that the isolate originated from the vaccine strain. In August 2011, a reformulated chimaeric PCV1/2 vaccine under a new brand name (Fostera PCV; Pfizer Animal Health) re-entered the market. All commercial PCV2 vaccines are based on the PCV2a genotype. Nevertheless, PCV2a-based vaccines are able to control PCV2b infection in pigs through cross-protection (Fort et al., 2008; Opriessnig et al., 2009). This cross-protection is significant in the field because PCV2b is the predominant genotype isolated in pigs with PCVAD worldwide (Patterson and Opriessnig, 2010). In addition, PCV2b may constitute a crucial factor in triggering the switch from PCV2 infection to PCVAD (Cheung et al., 2007; Lohse et al., 2008; Timmusk et al., 2008). Adjuvant type The currently available commercial PCV2 vaccines contain different adjuvants: Circoflex contains an aqueous polymer (carbomer); Circumvent and Porcillis PCV contain D1-a-tocopherol plus liquid paraffin (oil-in-water emulsion); Circovac contains light paraffin oil; and Fostera PCV contains sulpholipo-cyclodextrin in squalane-in-water (Table 1). Recommended administration to animals Sow vs. piglet vaccination Currently, only one commercial available PCV2 vaccine is licensed for sows and piglets, while the other four vaccines are licensed only for the direct induction of active immunity in piglets 3–4 weeks of age or older (Table 1). The principle of sow vaccination is to confer passive immunity to protect newborn piglets against exposure to PCV2 while they are highly susceptible. Vaccination of the sow is much less labour intensive than vaccination of piglets and can provide passive protection through increased levels of anti-PCV2 IgG antibodies in the colostrum; however, protection in the piglet is dependent upon the piglet’s access to sufficient amounts of colostrum during the initial 24–48 h after birth and the half-life of the passively acquired maternal antibodies. In
contrast, the principle underlying vaccination of piglets is to induce active immunity in piglets to protect against PCVAD. Maternally derived antibodies Ideally, PCV2 vaccination should be administered while residual maternally derived antibodies (MDA) are minimal and before pigs become naturally infected. Since almost 100% of sows are seropositive for PCV2 (Allan and Ellis, 2000), the majority of newborn piglets receive colostral antibodies from seropositive sows and have various levels of MDA. Therefore, piglets face potential interference from MDA at the time of vaccination. Whether the efficacy of vaccination in piglets can be affected by the presence of MDA is controversial. Interference with the efficacy of the PCV2 vaccine depends on the level of MDA at the time of vaccination. Animals with high immunoperoxidase monolayer assay (IPMA) titres (>10 log2) show interference with the development of the humoral immune response after vaccination, while piglets with low titres (<8 log2) do not (Fort et al., 2009b). These results are in agreement with a field study in which piglets with high IPMA titres (>10 log2) did not show elevated IPMA titres 21 days after vaccination (Fraile et al., 2012). Thus, the higher the MDA titres at the time of vaccination, the lower the subsequent anti-PCV2 IgG titre; however, this interference must be interpreted cautiously, since neutralising antibodies (NAs), but not anti-PCV2 IgG antibodies, are one of the key elements in protection against PMWS (Opriessnig et al., 2010). Experimental and field data indicate that PCV2 vaccines are not inhibited by MDA when efficacy is assessed in terms of the reduction of PCV2-associated lesions and viral load in the serum (Fort et al., 2008; Opriessnig et al., 2008, 2010; Martelli et al., 2011; Fraile et al., 2012). Hence, MDA interference does not significantly hamper vaccine efficacy (Fort et al., 2008; Opriessnig et al., 2008). PCV2 vaccines elicit PCV2-specific NAs and interferon-c-secreting cells (IFN-c-SCs), even in the presence of MDA (Fort et al., 2008, 2009a,b). These results suggest that levels of anti-PCV2 IgG antibodies at the time of vaccination in piglets do not have a major effect on the induction of protective humoral or cell-mediated immunity. Therefore, there is little value in measuring MDA for possible interference. It may be necessary to investigate interference and protection by measuring NAs. Comparison of sow and piglet vaccination Under field conditions, piglets that receive MDA passively from vaccinated sows showed improved pre-weaning average daily weight gains (ADWGs) compared to piglets actively immunised with PCV2. Under experimental conditions, 8-week-old piglets actively immunised with a PCV2 vaccine have lower PCV2 loads in the blood and lymphoid tissues than piglets that passively acquired MDA via sow vaccination in a PCV2 challenge model (Opriessnig et al., 2010; Pejsak et al., 2010). The duration of protective
Table 1 Commercial porcine circovirus type 2 vaccines available on the international market. Vaccine
Antigen
Adjuvant
Animals
Dosage
Administration
Web site
Circovac
Inactivated PCV2
Light paraffin oil
Sow
Two (2 mL)
www.merial.com
Circoflex Circumvent Porcillis PCV Fostera PCV
Capsid Capsid Capsid Inactivated chimaeric PCV1/2
Aqueous polymer D1-a-tocopherol + liquid paraffin D1-a-tocopherol + liquid paraffin Sulpholipo-cyclodextrin in squalane
Piglet Piglet Piglet Piglet Piglet
One (0.5 mL) One (1 mL) Two (2 mL) One (2 mL) One (2 mL)
5 and 2 weeks antepartum 3 weeks+ 2 weeks+ 3 weeks + 3 week interval 3 weeks+ 3 weeks+
www.boehringer-ingelheim.com www.merck-animal-health.com www.merck-animal-health.com www.animalhealth.pfizer.com
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immunity is approximately 12–13 weeks after the first immunisation (up to 15–16 weeks of age) under experimental and field conditions (Fachinger et al., 2008; Shen et al., 2010b). On the basis of these observations, sow vaccination may be beneficial in herds where newborn piglets are naturally infected with PCV2 at an early age. In contrast, vaccination of piglets may be beneficial in herds where PCV2 infection occurs between the late nursery and the early finisher phase. More pig practitioners and producers prefer to use piglet vaccination because MDA is unlikely to be protective in pigs that are infected in the late-nursery to early-finisher phase. In some countries, attempts have been made to vaccinate sows with the PCV2 subunit vaccine licensed for use in piglets in an attempt to save money or if sow vaccination is not available. Under experimental conditions, vaccination of sows with the piglet subunit PCV2 vaccine was not sufficient to induce passively acquired protective immunity in the offspring and did not completely prevent PCV2 infection compared to the vaccine licensed for use in sows and piglets (Opriessnig et al., 2010). Pig practitioners and producers are urged to use PCV2 vaccines only as licensed to optimise the efficacy of vaccination. Recommended administration dosage One-dose vs. two-dose vaccination With the exception of one subunit vaccine, piglet vaccines are administered in single doses (Table 1). One-dose vaccines have been used increasingly because of decreased labour costs, reduced stress to animals and a perception of decreased spread of other diseases, particularly porcine reproductive and respiratory syndrome virus (PRRSV) and PCV2 via injection needles (Otake et al., 2002; Patterson et al., 2011). One-dose vaccination can be employed and is less labour intensive; however, it is critical to follow the vaccination procedure to ensure that pigs are properly vaccinated. The one-dose vaccines for piglets (78% market share) are the most popular in Korea (Chae, 2005) and are likely to become more popular among pig producers worldwide. Efficacy of porcine circovirus type 2 vaccine Criteria of vaccine evaluation The lack of a consistent, precise and reproducible model of PMWS is one of the main obstacles to establishing clear parameters for the experimental evaluation of PCV2 vaccines. Parameters for vaccine efficacy based on the criteria for PMWS diagnosis include: (1) presence of clinical signs; (2) presence of characteristic microscopic lesions; and (3) presence of PCV2 within lesions (Chae, 2004). An additional criterion for the diagnosis of PMWS is the viral load in serum in association with clinical signs (Liu et al., 2000; Olvera et al., 2004; Opriessnig et al., 2009). These data suggested that quantification of PCV2 load could predict PCV2 infection status. In addition, reductions in PCV2 load in the blood coincide with the appearance of both NAs and IFN-c-SCs in PCV2-infected animals (Meerts et al., 2005, 2006; Fort et al., 2007, 2009a).
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1.9–9.3% (Table 2). The reduction in the number of PCV2-positive pigs and in the viral load in vaccinated pigs is associated with improved ADWGs and reduced mortality (Fachinger et al., 2008; Kixmoller et al., 2008; Martelli et al., 2011). The different growth performance in several field trials by different PCV2 vaccines may not be due to the different efficacies of vaccines, but to different co-infections, feeding systems and quality, production systems and housing and environmental facilities. Virological efficacy Reduction of viraemia by porcine circovirus 2 vaccines Several studies have shown that PCV2 DNA levels in serum are higher in pigs with PMWS than in healthy, subclinically infected pigs (Rosell et al., 1999; Liu et al., 2000; Ladekjær-Mikkelsen et al., 2002). The PCV2 load in the blood, as quantified by real-time PCR, (<106, 106–107 and >107 DNA copies/mL), is used to categorise PCV2-infected pigs as subclinically infected, suspected and PCVADpositive, respectively (Liu et al., 2000; Olvera et al., 2004; Opriessnig et al., 2009). These categories are used in the evaluation of PCV2 vaccine efficacy under experimental and field conditions, but may vary from laboratory to laboratory based on standards used for quantification. Regardless of the vaccine used, PCV2 vaccines reduce the proportion of viraemic pigs and the viral load in blood and also shorten the duration of viraemia under experimental and field conditions (Table 3). Single dose vaccination with different vaccines reduced viraemia by 42.0–86.1% in pigs experimentally infected with PCV2 alone (Fort et al., 2009b; Opriessnig et al., 2010). Using all types of PCV2 vaccines and challenge models, none of the vaccinated pigs had a viral load >107 DNA copies/mL (Brunborg et al., 2004; Fort et al., 2009b; Opriessnig et al., 2009, 2010; Shen et al., 2010b). Therefore, a well-documented feature of PCV2 vaccination of piglets under field conditions is the ability to decrease both the proportion of viraemic pigs and the viral load in vaccinated animals compared to non-vaccinated animals (Cline et al., 2008; Fort et al., 2008; Horlen et al., 2008; Kixmoller et al., 2008; Opriessnig et al., 2010; Pejsak et al., 2010; Fraile et al., 2012). Reduction of shedding by porcine circovirus type 2 vaccines PCV2 may be spread in several ways, including the oronasal, intranasal and faecal routes (Harms et al., 2001; Shibata et al., 2003; Fort et al., 2008; Patterson et al., 2011). The nasal route may be more effective than either the faecal or the oral route (Patterson et al., 2011). Transmission through nasal secretions has been suggested as a potential mode of horizontal spread, increasing the risk of transmission to other pigs and increasing the amount of PCV2 circulating within the herd (Patterson et al., 2011). PCV2 vaccination reduces nasal and faecal shedding of PCV2 (Fort et al., 2008). Single-dose vaccination was able to reduce the PCV2 viral load in nasal secretions under experimental conditions (Fort et al., 2009b), as well as to reduce the PCV2 viral load in faecal shedding under field conditions (Fraile et al., 2012). These studies indicate that the PCV2 vaccine is a useful tool for the control of PCV2 infection on both individual animal and population scales. Immunological efficacy
Clinical efficacy Field studies are useful to evaluate productivity in response to PCV2 vaccination, i.e. improvements in ADWGs in addition to reductions in mortality. Regardless of the PCV2 vaccine used, one-dose vaccination of piglets improves ADWGs by 16–69 g/day from 3 to 19–26 weeks of age under field conditions (Table 2). In addition, one-dose vaccination of piglets decreases mortality by
Neutralising antibodies The absence or impaired production of PCV2-specific NAs is associated with the development of PMWS (Meerts et al., 2006; Fort et al., 2007). A decrease in viraemia coincides with an increase in NA titres in pigs inoculated with PCV2 (Fort et al., 2007). These observations suggest that NAs represent an important mechanism for viral clearance and recovery from infection. The presence of
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Table 2 Clinical evaluation of average daily weight gains (ADWGs) and mortality (%) in pigs vaccinated with commercial porcine circovirus type 2 vaccines under field conditions. Vaccines
ADWGs g/day (week of age)
Circovac Circoflex
10–20 (3-S a) 30 (3–26) 60 (3–24) 50 (3–22) 40 (3–26) NA 40 (3–24)
Porcillis PCV Suvaxyn a b
Mortality (%)
References
Vaccinates
Controls
3.8–6 3.5 NAb 1.92 8.0 9.3 NA
5.9–8 7.48 NA 7.76 16.03 16.9 NA
Fraile et al. (2012) Kixmoller et al. (2008) Lyoo et al. (2011) Cline et al. (2008) Martelli et al. (2011) Segalés et al. (2009) Lyoo et al. (2011)
ADWGs from 3 weeks of age to date of first batch shipment to slaughter. Data not available.
Table 3 Virological and pathological evaluation of commercial porcine circovirus type 2 vaccines under experimental conditions. Vaccine
Circovac Circoflex Porcillis PCV Suvaxyn Fostera PCV a
Reduction (%) at 21 days post-challenge
References
Viraemia
Proportion of viraemic pigs
Lymphoid lesion score
PCV2 antigen score
NA 57 100 73–100 NA
20 30–60 100 100 83.3
94.4 16.6–100 NAa 74.6–88.9 NA
100 75–100 100 100 100
Opriessnig et al. (2010) Opriessnig et al. (2009, 2010) ; Shen et al. (2010a) Fort et al. (2008, 2009b) Opriessnig et al. (2008, 2009); Shen et al. (2010a) Hemann et al. (2012)
Data not available.
NAs and decreased PCV2 replication is strongly correlated with the absence of clinical PCVAD under experimental conditions (Meerts et al., 2005, 2006) and in the field (Fort et al., 2007). Hence, NAs play a key role in protection against PMWS. There is no obvious correlation between anti-PCV2 IgG antibodies and NAs (Opriessnig et al., 2010). NAs are induced by commercial PCV2 vaccines (Fort et al., 2009b; Opriessnig et al., 2009, 2010). Among these products, a chimaeric PCV1/2 vaccine induced significantly higher NA titres compared to subunit vaccines (Opriessnig et al., 2009), but there was no significant difference in the NA titres between subunit and inactivated vaccines (Opriessnig et al., 2010). Although one-dose vaccination induced a neutralising immune response in most vaccinated pigs, the mean NA titres were lower than the levels resulting from two-dose vaccination (Fort et al., 2008, 2009b).
factors, whereas the specific PCV2-associated lesions are not observed in pigs experimentally challenged with PCV2 alone. Vaccination of pigs against PCV2 reduces the number of PMWSassociated microscopic lesions and the PCV2 load in lymphoid tissues compared to non-vaccinated animals (Table 3). A decreased PCV2 serum load and decreased PCV2 antigen are strongly correlated with low histopathological scores in the lymph nodes under experimental and field conditions (Segalés et al., 2009; Kim et al., 2011). These results suggest that PCV2 vaccines may reduce the PCV2 load in the serum and lymph nodes, resulting in fewer histological lesions.
Interferon-c-secreting cells IFN-c, which is produced by antigen-stimulated T cells, is a key immunoregulatory cytokine that controls the differentiation of naïve CD4 T cells into Th1 effectors and mediates cell-mediated immunity against viral infections. PCV2-specific IFN-c-SCs were detected in pigs subclinically infected with PCV2 between 14 and 21 days post-inoculation, coinciding with the decline in the blood viral load (Fort et al., 2009a). One-dose vaccination against PCV2 can induce PCV2-specific IFN-c-SCs 3 weeks after immunisation, the same levels being maintained for 6 weeks after immunisation (Martelli et al., 2011). Since the commercial PCV2 vaccine induces NAs and IFN-c-SCs specific for PCV2 (Fort et al., 2009b; Opriessnig et al., 2009, 2010; Martelli et al., 2011); cell-mediated immunity, together with NAs, is likely to contribute to PCV2 clearance.
Commercial PCV2 vaccines were initially developed to control PMWS and are efficacious against PMWS under field conditions (Cline et al., 2008; Fachinger et al., 2008; Horlen et al., 2008; Kixmoller et al., 2008; Segalés et al., 2009; Pejsak et al., 2010; Kurmann et al., 2011; Lyoo et al., 2011; Martelli et al., 2011; Fraile et al., 2012). Vaccination against PCV2 alone improves overall growth performance in herds with concomitant infections of PRRSV, porcine parvovirus (PPV) and Mycoplasma hyopneumoniae (Fachinger et al., 2008; Kixmoller et al., 2008; Segalés et al., 2009; Martelli et al., 2011). Vaccination in combination with good husbandry practices, such as optimising stocking density, all-in/all-out production systems and effective ventilation, can be used to control PMWS efficiently and maintain acceptable infection control.
Clinical application of porcine circovirus type 2 vaccines Postweaning multisystemic wasting syndrome
Porcine respiratory disease complex Pathological efficacy The diagnosis of PMWS must include characteristic lesions in lymphoid tissues and detection of PCV2 antigen or DNA within these lesions. Hence, pathological evaluation with detection of PCV2 antigen within lesions is critical to evaluate the efficacy of PCV2 vaccines. Under field conditions, typical PMWS-associated lesions are induced in the presence of coinfections, as well as other
The pattern of PCVAD has changed over time, with respiratory signs becoming the predominant clinical signs in the field, while the incidence of PMWS has decreased due to vaccination. Therefore, porcine respiratory disease complex (PRDC) is likely to increase in frequency in the future. In contrast to PMWS, few studies have assessed the effects of PCV2 vaccination against PRDC. Vaccination against PCV2 alone can significantly improve overall
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growth performance (+18 g/day in ADWGs and 5.6 days to slaughter) of pigs with multi-factorial PRDC (coinfection with PCV2, PRRSV and M. hyopneumoniae) or late PRDC (16–20 weeks of age) (Fachinger et al., 2008). Since the introduction of a commercial PCV2 vaccine in Korea, PMWS has been diagnosed infrequently in piglets (6–8 weeks of age) and growers (8–14 weeks of age); however, PCV2 is increasingly diagnosed in association with PRDC in finishing pigs 16– 22 weeks of age (Chae, 2012). It is possible that vaccination has contributed to the disappearance of clinical PMWS, while allowing subclinical infection. Therefore, pigs subclinically infected with PCV2 may survive for long enough to be infected with common respiratory pathogens, such as M. hyopneumoniae and Pasteurella multocida. Hence, using PCV2 vaccines will be important in controlling PRDC. Seminal shedding of porcine circovirus type 2 in boars Boars can shed PCV2 continuously for extended periods without showing clinical signs or changes in semen quality parameters (McIntosh et al., 2006; Madson et al., 2008). Therefore, artificial insemination (AI) is a potential route of PCV2 transmission among pig herds (Madson et al., 2009d). Vaccination of boars against PCV2 reduces the duration and amount of shedding of PCV2 in semen (Seo et al., 2011) and PCV2-M. hyopneumoniae-coinfected boars (Opriessnig et al., 2011). Viraemia is associated with seminal shedding (Opriessnig et al., 2011; Seo et al., 2011). Vaccination against PCV2 in naturally infected boars can decrease the length of recurrent infection and decrease the duration of viral shedding in semen (Alberti et al., 2011). Vaccination has no dramatic effect on semen quality (Alberti et al., 2011). The reduction in PCV2 shedding is clinically meaningful because the PCV2 load in the semen plays a major role in the transmissibility of PCV2 (Madson et al., 2009d). Reproductive failure in sows Gilts and sows may be vaccinated to improve reproductive performance. Sow vaccination increased pre-weaning ADWGs and coincided with a 7% increase in the success of insemination (Pejsak et al., 2010). Considering that PCV2 can cross the placenta and infect fetuses in utero (Park et al., 2005), newborn piglets may develop PMWS in the postnatal period if they become infected with PPV or are injected with an immunostimulant (Ha et al., 2008). Approximately 33–40% of newborn and pre-suckling piglets from seropositive sows sampled in Korea and the USA were PCV2 viraemic (Shen et al., 2010a; Chae, 2012). A high prevalence of viraemia among newborn piglets may increase pre-weaning mortality. Hence, sow vaccination during pregnancy reduces the blood PCV2 load and the rate of transplacental infection (Madson et al., 2009b). PCV2 acquired during AI in naïve dams could cause PCV2-associated reproductive failure and fetal infection (Madson et al., 2009c). In an experimental study, vaccination did not protect fetuses against PCV2 infection via AI, but reduced the numbers of non-viable (dead and mummified) fetuses (Madson et al., 2009a). Hence, sow vaccination will help to control reproductive failure (Madson et al., 2009b). Conclusions PCV2 is associated with a number of diseases and syndromes collectively referred to as PCVAD. Commercial PCV2 vaccines were initially developed to control PMWS, but they are now also used against other PCVAD. Commercially available PCV2 vaccines differ in antigen and adjuvant type, as well in the recommended dosage
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and administration to animals. Nevertheless, all commercially available vaccines are highly efficacious against PCV2 infection based on the clinical, virological, immunological and pathological evaluation under experimental and field conditions. Conflict of interest statement The author of this paper has no financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. Acknowledgments The author’s research was supported by Technology Development Programme for Agriculture and Forestry, Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea. This research was also supported by contract research funds of the Research Institute for Veterinary Science (RIVS) from the College of Veterinary Medicine and by Brain Korea 21 Programme for Veterinary Science. I thank graduate students of the Seoul National University PCV2 research team, including Dr Hwi Won Seo, Dr Yeonsu Oh, Dr Kiwon Han, Dr Changhoon Park and Miss Yeji Yoon. References Alberti, K.A., Estienne, M.J., Meng, X.J., 2011. Effect of vaccination of boars against porcine circovirus type 2 on ejaculate characteristics, serum antibody titers, viremia, and semen virus shedding. Journal of Animal Science 89, 1581–1587. Allan, G.M., Ellis, J.A., 2000. Porcine circoviruses: A review. Journal of Veterinary Diagnostic Investigation 12, 3–14. Beach, N.M., Meng, X.J., 2012. Efficacy and future prospects of commercially available and experimental vaccines against porcine circovirus type 2 (PCV2). Virus Research 164, 33–42. Blanchard, P., Mahn, D., Cariolet, R., Keranflec’h, A., Baudouard, M.A., Cordioli, P., Albina, E., Jestin, A., 2003. Protection of swine against post-weaning multisystemic wasting syndrome (PMWS) by porcine circovirus type 2 (PCV2) protein. Vaccine 21, 4565–4575. Brunborg, I.M., Moldal, T., Jonassen, C.M., 2004. Quantitation of porcine circovirus type 2 isolated from serum/plasma and tissue samples of healthy pigs and pigs with postweaning multisystemic wasting syndrome using a TaqMan-based real-time PCR. Journal of Virological Methods 122, 171–178. Chae, C., 2004. Postweaning multisystemic wasting syndrome: a review of aetiology, diagnosis and pathology. The Veterinary Journal 168, 41–49. Chae, C., 2005. A review of porcine circovirus 2-associated syndromes and diseases. The Veterinary Journal 169, 326–336. Chae, C., 2012. Porcine circovirus type 2 and its associated disease in Korea. Virus Research 164, 107–113. Charreyre, C., Beseme, S., Brun, A., Bublot, M., Joisel, F., Lapostolle, B., Sierra, P., Vaganay, A., 2005. Vaccination strategies for the control of circoviral diseases in pigs. In: Proceedings of the European Society for Veterinary Virology International Conference on Animal Circoviruses and Associated Diseases, Queen’s University, Belfast, Northern Ireland, 11–13 September 2005, pp. 26– 30. Cheung, A.K., Lager, K.M., Kohutyuk, O.I., Vincent, A.L., Henry, S.C., Baker, R.B., Rowland, R.R., Dunham, A.G., 2007. Detection of two porcine circovirus type 2 genotypic groups in United States swine herds. Archives of Virology 152, 1035– 1044. Clark, T. 1996. Pathology of the postweaning multisystemic wasting syndrome of pigs. In: First Proceedings of the Western Canadian Association of Swine Practitioners, pp. 22–25. Cline, G., Wilt, V., Diaz, E., Edler, R., 2008. Efficacy of immunizing pigs against porcine circovirus type 2 at three or six weeks of age. Veterinary Record 163, 737–740. Darwich, L., Mateus, E., 2012. Immunology of porcine circovirus type 2 (PCV2). Virus Research 164, 61–67. Fachinger, V., Bischoff, R., Jedidia, S.B., Saalmuller, A., Elbers, K., 2008. The effect of vaccination against porcine circovirus type 2 in pigs suffering from porcine respiratory disease complex. Vaccine 26, 1488–1499. Fenaux, M., Opriessnig, T., Halbur, P.G., Elvinger, F., Meng, X.J., 2004. A chimeric porcine circovirus (PCV) with the immunogenic capsid gene of the pathogenic PCV type 2 (PCV2) cloned into the genomic backbone of the nonpathogenic PCV1 induces protective immunity against PCV2 infection in pigs. Journal of Virology 78, 6297–6303. Fort, M., Fernandes, L.T., Nofrarias, M., Diaz, I., Sibila, M., Pujols, J., Mateu, E., Segalés, J., 2009a. Development of cell-mediated immunity to porcine circovirus type 2 (PCV2) in Caesarean-derived, colostrum-deprived piglets. Veterinary Immunology and Immunopathology 129, 101–107.
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