豚病会報

No.49

2006

15

Vaccination strategies for the control of circoviral diseases in pigs: PMWS and PCV2-associated PRDC



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Introduction
Post-weaning multisystemic wasting syndrome(PMWS) was first described in high health herds in1996 in Canada (Clark, 1997 (1); Harding and Clark,

1. Descriptions of PCV2-associated pathologies
and syndromes
1.1. Post-weaning Multi-systemic Wasting Syndrome(PMWS)

1997 (2)) and is now considered to be an important

PMWS is now well associated with PCV2 and has

emerging disease syndrome in the pig industry. It

become a major economic concern in all pig-produc-

was quickly associated with a newly discovered vi-

ing areas worldwide. In Asia, Europe or North Ameri-rus, Porcine Circovirus type 2 (PCV2) (Ellis et al., 1998

ca, PMWS occurs in both endemic and epidemic(3)).

forms (Allan and Ellis, 2000 (4); Ellis, 2004 (17) and Se-

Since then, PCV2 has been increasingly isolated

gales and Domingo, 2002 (18)). The presence offrom pigs affected with various other clinical manifes-

PMWS in Asia has been well documented (Ka-tations as PRDC (Porcine Respiratory Disease Com-washima et al 2003 (19)).

plex) (Allan and Ellis, 2000 (4); Harms et al., 2002 (5);PMWS is characterized by progressive growth re-

Kim et al., 2003 (6)), reproductive failures (Josephsontardation and wasting, enlargement of lymph nodes

and Charbonneau, 2001 (7); Ladekjaer-Mikkelsen et(especially the more easily visible inguinal lymphal., 2001 (8); Kim et al., 2004 (9); O'Connor et al., 2001

nodes), dyspnoea, diarrhoea and jaundice in pigs from

(10); West et al., 1999 (11)), PDNS (Porcine Dermatitis

about 6 to 12 weeks of age. Individual diagnosis is

and Nephropathy Syndrome) (Allan and Ellis, 2000

based on these clinical signs, associated with charac-(4); Gresham et al., 2001 (12); Meehan et al., 2001 (13);teristic histopathological lesions in lymphoid tissues

Thomson et al., 2001 (14); Ramos-Vara et al., 1997 (15)),(lymphocyte depletion together with histiocytic infil-

and liver disease, necrotizing lymphadenitis, granulo-

tration and/or inclusion bodies and/or giant cells),

matous enteritis or possibly exudative epidermitis

and detection of PCV2 in moderate to massive quan-(Chae, 2005 (16)).

tity within these lesions.The herd diagnosis is based

This article will review available data from natu-

on increase in mortality and wasting post weaning

rally acquired and experimentally induced diseases

compared with the historical level in the herd associ-to evaluate the involvement of PCV2 in various

ated with individual diagnosis established on necrop-

pathologies. In particular we will examine to what ex-sies of at least 5 pigs. (European Consortium

tend co-infections are necessary for the full expres-definition - Project No 513928 Sixth Frameworksion of PCV2-associated diseases. We will also assess

Programme - http:// www.pcvd.org ).

Ｒ
the efficacy of the vaccination with CIRCOVAC蕘
* in-

PCV2 is consistently isolated from PMWS field

cluded in more general vaccination regimens, in or-cases but the virus is found very often in association

der to prevent or minimize these syndromes.

with other known pathogenic viral or bacterial

Ｒ*CIRCOVAC蕘
is a registered trademark of Merial

in the United States, Japan and elsewhere.

agents as described in Asia in table I (Jeong et al.,2003 (20)).
In a US field case control study conducted to assess
the epidemiological association between PMWS and a16

Proc Jpn Pig Vet Soc No.49 2006
Table I: Pathogens mixed-infection detected with PCV2
Associated Pathogens
PRRSV, P. multocida, B. bronchiseptica
PRRSV, P. multocida
SIV, P. multocida
PRRSV
Pseudorabies virus
PEDV
PRCV
P. multocida
A. pleuropneumoniae
Total

No. of positive pigs /No. of pigs examined
1/52
1/52
1/52
23/52
4/52
3/52
1/52
6/52
2/52
42/52

Percentage
1.9
1.9
1.9
44.2
7.7
5.8
1.9
11.5
3.8
80.8

list of known viruses (PCV2, Porcine Respiratory anddyspnoea (Halbur, 1998 (50); Thacker, 2001 (51) andReproductive Syndrome virus (PRRSV), porcine par-Harms et al., 2002 (52)).

vovirus (PPV), porcine enterovirus types 1-3, Influ-

According to field data, pneumonia in pigs withenza viruses (SIV), porcine respiratory coronavirus,

PRDC is due to a combination of both viral and bacte-transmissible gastroenteritis virus, porcine endoge-

rial agents, such as PRRSV, PCV2, SIV, 
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nous retrovirus, porcine lymphotropic herpesvirus



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type 1 and bovine viral diarrhea virus) the strongest(Halbur, 1998 (50); Thacker, 2001 (51)). For in-association was found between PMWS and PCV2.

stance, a large retrospective study of 105 PRDC cases

The risk of contracting PMWS was much higher if

in Korea in 2003 (Kim et al., 2003 (6)), found 85 cases

the animal was concurrently infected with PCV2 andpositive for PCV2, 66 positive for PRRSV, 60 positive

PRRSV, suggesting that the development of PMWS

for PPV, and 14 positive for SIV with a majority of co-could be enhanced by cofactors (Pogranichniy et al.,infections. PCV2 and 

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was found2002 (24)).

in 38 cases, followed by PCV2 and 
in 33 cases.

  (), and 
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

PMWS has been reproduced in experimental pig

A similar picture was described in the US (Harms etmodels by both inoculation of PCV2 alone and in asso-

al. 2002 (5)). There is a marked increase in mortality

ciation with other agents. It has been possible to in-when single and multiple concurrent bacterial infec-

duce PMWS with PCV2 alone in various

tions occur (Done, 2002 (53); Harms et al., 2002 (5); Kim

experiments. However co-infections with both PCV2et al., 2003 (6); Thacker, 2001 (51)).

and PPV, or with PCV2 and PRRS , or with PCV2 andA particular case of pneumonia has been described



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
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 (
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
) generally induced

as proliferative necrotizing pneumonia (PNP) a term

more cases of PMWS. Those experimental co-infec-

coined to describe the specific histological features oftions consistently led to more severe clinical signs

a sub-acute to chronic pneumonia in swine. Original-and histopathological lesions, as well as increased

ly, this lesion was associated with SIV and then

PCV2 viral load (Allan et al., 2000 (47); DeJong et al.,PRRSV infection (Harms et al. 2002 (52); Morin et al.,2003 (48); Harms et al., 2001 (49)).

1990 (54); Rossow, 1998 (55); Larochelle et al., 1999(56)). But the consistent identification of PCV2 demon-

1.2. PCV2 and Porcine Respiratory Disease Complex

strated by in situ hybridization and immunohisto-(PRDC)

chemistry in PNP cases has led to the suggestion that

Porcine respiratory disease complex is a threat in

PCV2 could also be an important contributor to thisgrowing and finishing pigs from 16 to 22 weeks ofsyndrome. (Ellis et al., 1999 (57); Harms et al., 2002 (5)age. It is characterized by slow growth, decreased

Because the clinical signs of PRDC are variable andfeed efficiency, lethargy, anorexia, fever, cough, andits etiology can be multi-factorial, the presence of

豚病会報

No.49

2006

17

PCV2 DNA or antigen in lung tissues, together withplain the links with different associated diseases

a bronchointerstitial pneumonia including peribron-(Segales et al., 2004 (60)).

chial and peribronchiolar fibrosis are used as theIt was first proposed that initial PCV2 replication

main criteria for the diagnosis of PCV2-associated

was probably taking place in macrophages and

PRDC.

antigen-presenting cells of lymphoid tissues such as

In the laboratory, experimental evidence indicate

tonsils and regional lymph nodes (Clark, 1997 (61);that PCV2 and PRRS viruses can act synergistically

Rosell et al., 1999 (62)), or alternatively in Peyer's

and together induce more severe respiratory signs

patches (Rosell et al., 1999 (62); Royer et al., 2001 (63)),

and pulmonary lesions (Allan et al., 2000 (58)). Al-

because the virus is found consistently in those tis-though PCV2 might not increase the severity ofsues and in those cells. After infection and replication

PRRS lesions, PRRSV certainly potentiates the action

in resident mucosal macrophages and other antigen-of PCV2 (Allan et al., 2000 (58)). The bronchointersti-

presenting cells, PCV2 could be transported intracel-tial pneumonia produced by co-infection of PCV2 andlularly or migrate freely in lymph and/or blood. The

PRRSV is compatible with the typical lesions seen in

normal traffic of PCV2 infected cells to many tissues

field cases of PRDC (Drolet et al., 2003 (59)).

would contribute to the spread of viral infection to nu-

As well experimental co-infection studies withmerous organs (Rosell et al., 1999 (62)).

PCV2 and demonstrated that can raise

However, while this scheme was indeed confirmed

the amount and prolong the presence of PCV2 anti-

as a general picture for the dissemination of the vi-

gen, increase the incidence of PMWS in pigs, increaserus, it has been demonstrated that PCV2 does not

the severity of PCV2-associated lymphoid lesions,

usually replicate in macrophages and antigen-present-

and also the intensity of PCV2-associated lunging cells (Vincent et al., 2005 (64)). In fact cells of thelesions. A synergetic effect of respiratory associatedmacrophage lineage do phagocytize and store huge

symptoms can be clearly seen as 1/9 of 



in-

amounts of PCV2 for very long time which explains

fected animals and 2/8 of PCV2 infected animals had

why the virus can be found in those cells. In vitro

necrotizing bronchiolitis while 7/9 of the dually in-tests demonstrate a rapid uptake of the virus and per-fected animals were presenting this symptom

sistence of antigen and infectious virus for prolonged(Opriessnig et al., 2004 (46)).

periods of time in dendritic cells. PCV2 survives
there in infectious form by avoiding the cellular deg-

1.3. PCV2 in other syndromes and diseases
PCV2 has also been associated mainly in field studies with reproductive failures alone or associatedradative machinery and replication in dendritic cells
will be at best extremely limited (Mc Cullough et al.,2003 (65)).

with enteritis, with diarrheas and granulomatous en-

When parenchymal cells are eventually infected in

teritis, with liver disease, with exudative epidermitis,the lungs, liver, kidneys, heart and other organs thewith neurological signs and with Porcine Dermatitis

transition to a full blown PMWS occurs. At this stage

and Nephropathy Syndrome (PDNS). The particular

PCV2 can actively replicate in endothelial or epithe-role of PCV2 and/or the other pathogens involved inlial cells and tremendous amount of virus can be de-these syndromes will have to be explored in thetected in the organs. This would support the idea

future.

that the tissue and cellular tropism of PCV2 expand
as PMWS develops (Krakowka et al., 2003 (66)), but

2. The pathogenic mechanisms of disease in
PCV2 infections and possibility of enhancementby co-infections

how such a shift takes place is still unclear although
we know it is linked to immune stimulation.
On the other hand, it has been demonstrated re-Different mechanisms have been proposed to de-cently that PCV2 does have a profound impact on

scribe the pathogenicity of PCV2 infections and ex-

some categories of dendritic cells and can impair

18

Proc Jpn Pig Vet Soc No.49 2006

their functions to an extent that stops immune de-these tissues. (Darwich et al., 2002 (72); Nielsen et al.,fenses and leads to immune pathologies and anergy.

2003. (73)).

At this point, any secondary pathogen will have an

Apoptosis has been proposed to account for loss ofopen access to the pig system (Mc Cullough et al.,

B and T lymphocytes in PMWS-affected pigs which

2003 (65)).

could account for disruption in cytokine signaling

We will now review the direct effect of PCV2 on(Shibahara et al., 2000 (74)) but this mechanism has

the immune system and possible synergistic effect

not been definitively demonstrated in all studies (Kra-with various triggers and secondary pathogens.

kowka et al., 2003 (66)).
The damage to the immune system of PCV2-in-

2.1. PCV2 infection produces immune suppression

fected and PMWS-affected pigs can then naturally

The signs of immune suppression in PCV2 infec-

lead to impaired immune responses and opportunis-

tions range from the cellular and microscopical leveltic infections are a final evidence of the immune sup-to the clinical level.

pression caused by PCV2 infection. For instance, aPMWS is characterized by widespread granuloma-

low prevalence (approximately 5%) of pulmonary in-tous inflammation, multinucleated giant cells, andfection with  was documented invariable numbers of intracytoplasmic basophilic viral

the early cases of PMWS in Western Canada (Ellis etinclusion bodies within infiltrating histiocytes andal., 1998 (75)). Another example is the inability ofmacrophages. In fact the hallmark histologic lesion of

PMWS pigs to produce or sustain neutralizing anti-

PMWS is multifocal to diffuse mixed angiocentric

body responses (Charreyre et al., 2000 (76); Meerts et

granulomatous inflammation. This unusual lesion isal., 2006 (77)).

unlike what is ordinarily associated with a viral infection and is sufficiently characteristic to be considered

2.2 Triggering factors leading from PCV2 infection todiagnostic for PMWS. Histiocytic infiltration is also

more severe clinical diseases

one of the initial events during PCV2 infection, and co-Experimentally PMWS has been obtained more

incides with macroscopic lymphadenopathy. Moreconsistently when PCV2-infected piglets are also im-

chronic cases tend to show less severe lymphocyte

mune stimulated by injections of an antigen emulsi-

depletion with less pronounced

fied in an oil-based macrophage-targeted adjuvant. In

histiocytic/multinucleate giant cell infiltration (Kra-fact activation of the immune system is the pivotal

kowka et al., 2003 (66); Allan et al., 1999 (32); Choi andevent that can induce the shift to PCV2 infected to-Chae, 1999 (67); Choi et al., 2000 (68); Ellis et al., 1999

wards full blown disease (Allan et al., 1999 (78); Allan(57); Kennedy et al., 2000 (33); Kim et al., 2002 (69); Kra-

et al., 2000 (58); Choi and Chae, 2000 (79); Ellis et al.,kowka et al., 2000 (27); Clark, 1997 (61); Rosell et al.,1999 (80); Kennedy et al., 2000 (33); Kim et al., 2003 (81);1999 (62); Quintana et al., 2001 (70)).

Krakowka et al., 2000 (27); Krakowka et al., 2001 (82)).

PCV2 antigen was also found present in more ad-Studies demonstrated that vaccination with bacter-vanced necrotic lesions, suggesting that PCV2 anti-

ins commonly used in the USA (and 



bac-

gen can be associated with necrotizing lymphadenitis

terins) enhanced PCV2 replication and the severity of(Kim and Chae, 2005 (71)).

clinical signs and lesions found in PMWS. Early vacci-

In field or experimental studies, peripheral bloodnation, antigen-rich single shot regimens, oily adju-

mononuclear cells counts and histopathologicalvants, high PCV2 prevalence in the environment, andevaluations also revealed lymphocyte depletion in dif-

low maternal antibody status may lead to increased

ferent lymphoid organs and a change in the propor-

incidence and severity of PMWS. (Opriessnig et al.

tions of the different lymphocyte subsets. As the2003 (83); Hoogland et al. 2006 (84)).

level of PCV2 in lymphoid tissues increases, so does

As described earlier, PMWS has also been ob-

the depletion in both B- and T-cell-dependent areas oftained more consistently experimentally in co-infec-

豚病会報

No.49

2006

19

tion models, with PCV2 and PPV, PCV2 and PRRSV,

sponse away from a TH1 type, in which the macro-or PCV2 and 
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.

phages would be activated to destroy it, towards a

In one of those experimental studies, pigs infectedless effective TH2 response, (Thacker, 2001 (87)), thus

with PPV appeared to display elevated interleukine

inducing more immune stimulation that could favor

10 responses that could activate B cells therefore fa-

PCV2 uptake.

voring immune stimulation and PCV2 uptake. Detec-

Other pathogens like SIV and cause acute in-tion of IL10 was prolonged in dually infected pigs

flammation of the lungs (Thacker et al., 2006 (88)), and(Hasslung and al., 2005 (38)).

they could as well up-regulate and favor PCV2

Based on the replicative cycle of PCV2 which,multiplication.

much like PPV, requires or makes use of actively rep-

All those possibilities will interact with each otherlicating cells (Meehan et al., 1998 (85)), factors that in-of course in even more complex fashion in field situa-

duce the replication of potential target cells would

tions when all pathogens can be present together.

favor PCV2 replication and, by extension, viral loadand disease. Therefore, co-infecting agents like PPV

3. The influence of virus variationthat can cause death of various cells and lead to re-

PCV2 isolates from different clinical disease mani-

generation of damaged tissue may indirectly enhance

festations and different geographical locations havethe replication of PCV-2. Cytokines and other growth

been sequenced and are all highly homologous withfactors that affect cell division may also indirectly up-

more than 90-96% nucleotide identity between

regulate the replication of PCV2.

isolates. (Allan et al., 1998 (89); Ellis et al., 1998 (75);PRRSV targets and kills specifically pulmonary al-

Fenaux et al., 2000 (90) ; Hamel et al., 2000 (91); Mank-veolar macrophages (PAMs), a cell population thatertz et al., 2000 (92); Meehan et al., 1998 (93)). PCV2 dif-can phagocytize and store high amounts of poten-

fers significantly from the non virulent PCV1

tially pathogenic PCV2 virus for long periods of time

(roughly 62% homology) suggesting that PCV2 iso-

as we described earlier. Destruction of those cells

lates are all members of a single pathogenic virus

could lead to PCV2 release in large amounts in the

genotype (Hamel et al., 1998 (94); Tischer et al., 1974

lung. Because PRRSV infection is rather persistent in(95); Tischer et al., 1986 (96); Meehan et al., 1998 (93)).

pigs, bursts of PCV2 release could also occur repeat-

A number of studies have found minor differences

edly over time in chronically dually infected pigs.
Infection with induces the production of pro-in the respective PCV2 genomes (Choi et al., 2002 (97);
Farnham et al., 2003 (98); Meehan et al., 2001 (13);inflammatory cytokines that will produce

O'Connor et al., 2001 (10)) but at this time it remains

inflammation. Therefore it is logical to observe that

unclear what significance these minor differencesinfection will induce a bronchiolitis that is en-

may have. Sequence analysis of ORF1 and ORF2

hancing PCV2 respiratory pathogenesis, then raise

genes has revealed that the extent of nucleotide varia-

the amount and prolong the presence of PCV2-anti-tion is logically greater for the ORF2 than ORF1

gen, and increase the incidence of PMWS in pigs

(Fenaux et al., 2000 (90); Hamel et al., 2000 (91); Mank-(Opriessnig et al, 2004 (46)). Interestingly it has beenertz et al., 2000 (92)). The alterations in ORF2, whichshown recently in vitro that PCV2 infected PAMs

encodes for the major structural capsid protein (Na-are functionally altered and will not be able to control

wagitgul et al., 2000 (99)) may suggest a link between

very effectively secondary pathogens like capsid protein variation and pathogenicity of PCV2.

(Chang et al., 2006 (86)). Another interesting fact is

Modification of the major viral capsid may alter deter-

the possibility for Gram-negative bacterial compo-

minants involved in tissue tropism or virus-hostnents as LPS to induce PCV2 multiplication in PAMs

interactions. One study has suggested that the minor

where it was dormant before.

variation in the ORF2 of PCV2 may account for differ- infection will also direct the immune re-ences in tropism with respect to the host organism

20

Proc Jpn Pig Vet Soc No.49 2006

(Mankertz et al., 2000 (92)). Two other studies havepiglets against PCV2 infection for a limited period ofsuggested that PCV2 isolated from reproductive fail-time while maternal antibody decline. This is re-ure and PDNS may be phenotypically or genetically

flected in field conditions, where active seroconver-different from PCV2 associated with PMWS (Meehansion is reported from 5 to 15 weeks of age (Cotrell,

et al., 2001 (13); O'Connor et al., 2001 (10)). However1999 (109); Larochelle et al., 2003 (110); Segales andcomparison of various PCV2-isolates side by side inMorvan, 2004 (111)).

challenge experiments demonstrated no or limited

Several studies by different groups have demon-

differences (Hasslung et al, 2005 (38); Halbur andstrated that active antibodies are also protective

Opriessnig, 2006 (100)).

against PMWS (Blanchard et al., 2004 (112); Pogranich-Because other host factors such as age, health sta-niy et al., 2004 (113); Fenaux et al., 2004 (114)). There-tus, route of infection, co-infections or other stressors

fore a well-controlled natural infection with PCV2 will

can markedly influence the pathogenicity and clinicalinduce a natural protection against associatedmanifestations of PCV2 infections, it will be difficult

diseases.

to assess isolate variability in field situations. Furthermore, all of the characterized isolates of PCV2 associ-4.1. Description of two laboratory efficacy studies

ated with PMWS are antigenically similar to each

The objective of the first study was to demon-other using monoclonal and polyclonal antibodies (Al-strate the efficacy of an inactivated oil adjuvantedlan et al., 1999 (101)).

PCV2 vaccine (CIRCOVAC) in a PCV2 controlledenvironment. Specific serological responses in vacci-

4. Circovaccination of the pig herd

nated gilts and protection of their piglets after PCV2

A vaccination scheme for PCV2-associated dis-experimental challenge at 3-4 weeks of age wereeases that targeted gilts and sows and the passive

evaluated. The objective of the second study was totransfer of high levels of maternally derived antibod-

demonstrate the efficacy of this vaccine in piglets

ies to PCV2 in colostrum and milk has been proposedborn to vaccinated gilts in the field and brought back(Charreyre et al. 2004 (102)) based on the following

into a PCV2 controlled environment. Protection of theinformation:

piglets after PCV2 experimental challenge at about 4− PCV2 is very stable, hardy and abundant in the en-

weeks of age was evaluated.

vironment and eradication unlikely in most farms

Other studies demonstrated that the vaccine pre-− In PMWS-affected farms higher levels of PCV2 vi-

sented a good safety of use in pregnant animals

rus are found in the nurseries and post-weaning(Reynaud et al., 2004 (115 and 116)).

phases than in later stages of the pig life (Sibila et

In the first study, specific pathogen free gilts, spe-al. 2005 (103), Lopez-Soria et al., 2005 (104) Rose etcifically seronegative for PCV2 antibodies by ELISA

al., 2004 (105))

were allocated to two groups. One group of 11 gilts− Maternal antibodies to PCV2 were demonstrated

was vaccinated at minimal antigen content via the in-to be protective against PCV2 infection and devel-

tramuscular route 5 and 2 weeks pre-breeding and 2

opment of PMWS (Charreyre et al., 2002 (106); Tho-

weeks before farrowing. Another group of 12 gilts

mas et al., 2005 (107))

was not vaccinated. All the gilts were inseminated ar-− Abortion and premature farrowing were obtained

tificially at 10 months of age and 8 gilts becamein sows inoculated with PCV2 three weeks before

pregnant. Therefore a first group of 22 piglets born

farrowing, thus emphasizing the need to protect

to 4 vaccinated gilts and a second group of 22 piglets

the breeder herd in the gestational phase (Park etborn to 4 control gilts were challenged intra-nasallyal., 2005 (108)).

with PCV2 at 3 to 4 weeks of age.

However, vaccination of the breeder herd and pas-

PCV2 antibodies were measured at regular inter-sive transfer of PCV2 antibodies will only protect thevals in the blood of the gilts and piglets throughout

豚病会報

No.49

2006

21

Table III: Experimental inoculations with PCV2 alone or in combination to
obtain PMWS
Type pigs/ Reference
CDCD piglets
Ellis et al., 1999 (26)Krakowka et al., 2000 (27)

Age and challenge

Clinical outcome(no.affected/no. inoculated)

3 days PCV2 (Stoon)
1 day
PCV2 (Stoon)
PCV2 + PCV1
PCV2 + PPVNormal (0/6)
Normal (0/3))
Normal (0/4)
Wasting (4/4)

Pogranichniy et al., 2000(28)8 wks

Normal (0/5)

Krakowka et al., 2001(29)

1 day
PCV2 (OSU3)
PCV2 + immunostimulation

Normal (0/3)
Wasting (24/24)

Bolin et al., 2001 (30)

20-25 d PCV2 (688)

Wasting (6/23)

Harms et al., 2001 (31)3 wks

Wasting (5/19)
Wasting (17/17)

PCV2 (ISU 98-15237)

PCV2 (35358)
PCV2 (35358) + PRRSVConventional, colostrum-deprived piglets
Allan et al., 1999 (32)
1 day
PCV2 (Stoon)`
PCV2 (Stoon) + PPV(Kresse)

Wasting (1/4)
Wasting (5/5)

Kennedy et al., 2000 (33)

1 day

PCV2 (Stoon)
PCV2 (Stoon) + PPV(Kresse)

Wasting (1/4)
Wasting (5/5)

Allan et al., 2000 (34)

1 day

PCV2 (Stoon)
PCV2 (Stoon) + PPV(Kresse)

Normal (0/5)
Normal (0/13)

Allan et al., 2000 (35)

1 day

PCV2 (48285)
PCV2 (48285) + PRRSVNormal (0/3)
Normal (0/5)

Allan et al., 2002 (36)

3 daysPCV2 (SPCV2)
PCV2 (SPCV2) + PPVWasting (1/4)
Wasting (5/9)

Kim et al., 2003 (37)

28 days controls
PCV2 (Korea2) + PPVNormal (0/8)
Wasting (24/24)

Hasslung et al., 2005 (38)

3 daysNormal (0/7)
Wasting (1/10)
Wasting (2/7)
Wasting (3/8)

Conventional SPF
Magar et al., 2000 (39)

3-4 wks PCV2 (LHVA-V53)

Normal (0/11)

Larochelle et al., 2000 (40)7 mos

PCV2 (LHVA-V53)

Normal (0/4)

Ladekjaer-Mikkelsen , 2002(41)3 wks

PCV2 (OSU3)
PCV2 + immunostimulation)

Wasting (3/5)
Wasting (1/5)

Fenaux et al., 2002 (42)

4 wks

Cloned PCV2 40895

Normal (0/10)

Conventional
Balasch et al., 1999 (43)

8 wks

PCV2

Normal (0/8)

Albina et al., 2001 (44)5-9 wks PCV2

Wasting (4/55)

Rovira et al., 2002 (45)31-40 d PCV2
PCV2 + PRRSV(lot/91)

Normal (0/7)
Wasting (1/5)

Opriessnig et al., 2004 (46)

4-6 wks Myco hyo (4 w old)
PCV2 (6 w old)
Myco hyo + PCV2 (6 w old)

No PMWS (0/17)
No PMWS (0/17)
Wasting (4/17)

PCV2 + PPV
PCV2 1010 + PPV
PCV2 (Sweden) + PPV (swe)
PCV2 (Sweden) + PPV (den)Table 1
CDCD, Caesarean-derived, colostrum deprived; SPF, specific pathogen-free; IN, intranasal;
ON, oronasal; IT, intratracheal; IM, intramuscular; SQ, subcutaneous;

22

Proc Jpn Pig Vet Soc No.49 2006

the study. After challenge, clinical signs were moni-Sows enrolled in a field efficacy trial in a PMWS af-

tored for four weeks. PCV2 viral load in serum and infected farm were selected as source of piglets for the

faecal swabs was also estimated by quantitative PCR

second study.

(Q-PCR). A complete necropsy assessment was car-A first group of 12 piglets was born on the farm toried out on all 44 piglets at slaughter and mesenteric

8 non-vaccinated sows. The second group of 10 pig-

lymph nodes were collected for PCV2 immunochemis-

lets was born on the farm to 7 sows that had beentry (IHC).

vaccinated once with CIRCOVAC at minimal antigen

Before challenge, vaccinated gilts had high, stable

content via the intramuscular route 2 weeks before

and homogeneous PCV2 antibody levels while thefarrowing. A third group of 11 SPF piglets was added

control gilts and their piglets remained seronegative.

to the study to monitor challenge. Piglets from the

Vaccination induced a seroconversion immediately af-

farm were brought into the challenge facility at about

ter the first injection and this was further boosted by

3 days of age at a convenient date depending on thethe third injection before farrowing. An efficient

herd management calendar. Therefore the 3 groups

transmission and persistence of maternal antibodies

of piglets were subsequently submitted to intra-nasal

following colostrum intake was demonstrated by the

PCV2 challenge on the same day but at somewhat dif-measurement of high and homogeneous antibody ti-

ferent ages: group 1 from control sows were 32 days

tres to PCV2 in serum from piglets born to vacci-of age, group 2 from vaccinated sows were 25 days ofnated gilts.

age and SPF pigs were 47 days of age.

After challenge, a strong seroconversion was ob-

Throughout the study, PCV2 antibodies in blood

served in piglets born to non-vaccinated gilts while

were evaluated in samples from the farm sows andthe level of antibodies in piglets born to vaccinatedfrom the piglets and PCV2 virus in faeces was evalu-

gilts continued to decrease.

ated in serial samples from the piglets. The follow-up

Although no classical PMWS cases was recorded

after challenge lasted four weeks. Clinical signs werein this experiment, clinical signs and growth impair-monitored and a complete necropsy evaluation wasment were observed after PCV2 challenge and thecarried out at the end. Mediastinal lymph nodes wereclinical scores were significantly higher in pigletscollected to evaluate PCV2 viral load by immuno-

born to non-vaccinated gilts (p = 0.015).

chemistry (IHC).

At necropsy, the lesion scores were significantly

Two weeks before farrowing, at the time of vacci-

lower in piglets born to vaccinated gilts than in pig-

nation, all sows were seropositive and had similarlets born to non-vaccinated gilts (p<0.00001) Addition-

PCV2 antibody titers. Two weeks after farrowing theally, the amount of PCV2 DNA in the serum of piglets

level of PCV2 antibody in the vaccinated sows had in-

the amount of PCV2 DNA in rectal swabs and the vi-

creased significantly (p < 0.005) and the levels of

ral load in mesenteric lymph nodes were also signifi-

PCV2 antibody in piglets from vaccinated sows werecantly lower in piglets born from vaccinated gilts (p =higher than the levels in piglets from non-vaccinated0.00002).

sows up to challenge (p = 0.01).

The inactivated vaccine proved to be highly immu-

During these first 3 to 5 weeks of age it appeared

nogenic as shown by the high and stable antibodies ti-that fewer piglets born from vaccinated sows ex-tres obtained in vaccinated gilts. Vaccination induced

creted less PCV2 in faeces than piglets born from non-a significant protection after virulent PCV2 challenge

vaccinated sows. This was correlated with a higher

in piglets born to vaccinated gilts. The results demon-level of maternal antibodies.

strated that vaccination with CIRCOVAC was benefi-

In this experiment, PCV2 challenge did not induce

cial in improving the piglet health and performances

severe clinical signs in any group. The challenge wasafter PCV2 challenge in a highly controlled

nonetheless validated because of the elevated clinicalenvironment.

score in the SPF group, of the strong seroconversion

豚病会報

No.49

2006

23

to PCV2 in this group, and of the PCV2 excretion inslaughter at market time for signs of PCV2 disease. A

faeces of all challenged piglets.

global comparison of all piglets born from vaccinatedPiglets born from non-vaccinated sows exhibited arise in PCV2 antibody levels after challenge, whileand from controls during an entire year was finallydone.

PCV2 serum antibodies continued to decay in piglets

When the experiment started, all dams on the 3born to vaccinated sows. The absence of a booster ef-

farms studied were seropositive with about 12% offect in that group after challenge can be linked to thethem being highly seropositive. Following vaccina-

good protection conferred by maternal antibodies

tion 56% of vaccinated sows were deemed highly se-

against subsequent PCV2 infections.

ropositive versus only 7% in the non-vaccinatedAt necropsy, the piglets born from vaccinatedgroups. Concurrently to the rise in PCV2 antibody

sows displayed significant reduced lesion scores thanlevel in the breeder herds in the 3 farms following

the piglets born from non-vaccinated and/or SPF

vaccination , PMWS cases decreased quickly fromsows (p = 0.0001). No gross lesion was noted in the

more than 5% when the farms were selected to 1.12%

mesenteric lymph nodes of piglets born from vacci-in pigs from non-vaccinated sows (n = 4,183 piglets)nated sows, while 70 to 80% of the piglets in the two

and 0.67% in pigs from vaccinated sows (n = 10,462

other groups had high to very high lesion scores (p =piglets) in about 18 months.

0.00043).

These results were confirmed in very large num-Those results demonstrated that the sow vaccina-

bers of animals, under temporary licenses for CIRCO-

tion with CIRCOVAC in field conditions was benefi-

VAC, in Germany and in France. During these trials,

cial in reducing the natural PCV2 circulation andabout 366,895 sows have been vaccinated. Adverse re-shedding in the first weeks of the piglet life, but also

actions have been very limited (1 local reaction per

in improving the piglet health and performances af-

4,300 doses, 1 abortion per 44,000 doses).

ter an additional experimental PCV2 challenge.

Some results of the German survey are presented
as example. They contain the results obtained for4.2. MERIAL field efficacy studies in France and Ger-

13,992 vaccinated sows from all geographical areas ofmany

Germany. The effects of vaccination with CIRCO-

Under field trial authorisation, a field efficacy study

VAC were mainly analyzed through the following

has been on-going in three PMWS-affected farms inparameters: mortality rates in suckling piglets, inFrance for more than 18 months. Two farms were or-weaners and in finishers, as well as medications or

ganized with 7 groups of about 35 sows farrowing

drugs use for prevention or cure in the farms.

every three weeks, and the third farm had 22 groupsof about 12 sows farrowing every week.

Mortality results are shown in table IV. Because ofsome late implementations of the vaccination in partGroups 1 and 2 out of 7 or groups 1, 3, 5, 7, 9 and 11of the farms, the full effect of vaccination had not yet

out of 22 were kept as control groups. The remaining

taken place in the herds when the analysis was done.

groups were vaccinated over time with one injection

However, the reduction of mortality was significantof the minimal dose of CIRCOVAC vaccine 3 weeks

in the three age groups, with a decrease of 5.3% in

before each farrowing time. The replacement gilts

the nursery stage and 3% in the fattening units.

were obtained from outside sources and vaccinated

These improvements represented a tremendous eco-

twice in quarantine before introduction in the herds

nomical benefit for the farms.

throughout the experiment. Therefore up to 70% of
the animals were vaccinated over time.

In summary, positive results have been observedwith a great reduction of losses and number of

Besides serological follow-up of the breeder herd,

wasted pigs, more homogeneous growth rates, and re-

all piglets born from groups 1 to 4 and groups 1 to 12

duction in the use of antibiotic treatments. Global

in two successive gestations were followed up until

mortality rates between weaning and the end of fat-

24

Proc Jpn Pig Vet Soc No.49 2006
Table IV: mortality rates in German survey (Results before and during
vaccination are significantly different in all groups, p<0.05)

Suckling piglets
Piglets in flatdecks
Fattening pigs

Before V
During V
Before V
During V
Before V
During V% mean losses
14.5
12.0
8.4
3.1
5.8
2.8

tening decreased by at least 50% in the vast majorityof the farms.

STD
5.1
4.1
7.6
2.4
3.4
1.5

Number of farms
33
34
34
31
23
18

pp. 201-203.
3 - Ellis et al., 1998. J. Ellis, L. Hassard, E. Clark, J.C.S.
Harding, G.M. Allan, P. Willson, J. Strokappe, K.

Conclusion

Martin, F. McNeilly, B.M. Meehan, D. Todd and

It is now confirmed from laboratory and field trials

D.M. Haines, Isolation of circovirus from lesions ofthat vaccination against PCV2 infection can provide

pigs with postweaning multisystemic wasting

protection against the development of PMWS signs.

syndrome. Can. Vet. J. 39 (1998), pp. 44-51.

Vaccination of the piglet is efficacious in controlled

4- Allan, G.M. and Ellis, J.A., 2000. Porcine circo-

laboratory conditions as long as maternal antibody

viruses: a review. Journal of Veterinary Diagnostic

levels are not too high. Vaccination of the breeder

Investigation 12, pp. 3-14.

herd including pregnant animals is safe and was

5- Harms, P.A., Halbur, P.G. and Sorden, S.D., 2002.

found efficacious in controlled laboratory conditions.

Three cases of porcine respiratory disease com-

This result has been confirmed in field conditions inplex associated with porcine circovirus type 2very large numbers of gilts and sows with a commer-

infection. Journal of Swine Health and Production

cial vaccine under temporary license that promoted

10, pp. 27-30.

an economically relevant level of protection against
clinical PMWS.
Although the efficacy of PCV2 vaccines in the protection against the development of other PCV2-associ-6- Kim, J., Chung, H.-K. and Chae, C., 2003. Associationof porcine circovirus 2 with porcine respiratory disease complex. The Veterinary Journal 166, pp. 251256

ated diseases and syndromes still needs to be

7- Josephson, G. and Charbonneau, G., 2001. Case re-evaluated, it is remarkable that field vaccination of

port of reproductive problems in a new startup

breeder herds against PCV2 did reduce total losses

operation. Journal of Swine Health and Production

significantly, up to the end of the pig life. This im-

9, pp. 258-259.

provement could be related to the deleterious, acute

8- Ladekjaer-Mikkelsen, A.-S., Nielsen, J., Storgaard,

and chronic immune suppression that uncheckedT., Botner, A., Allan, G. and McNeilly, F., 2001.

PCV2 infections can cause throughout the pig life,

Transplacental infections with PCV-2 associatedopening the door to other pathogens.

with reproductive failure in a gilt. Veterinary Record 148, pp. 759-760.

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32

Proc Jpn Pig Vet Soc No.49 2006
ワクチネーションによるブタサーコウイルス関連症（PMWS および PCV2 が関与する PRDC）のコントロール

始めにPMWS の特徴的な臨床所見は、約６〜１２週齢の豚の離乳後多臓器性発育不良症候群（PMWS）は、１９９６

進行性の発育遅延および削痩、リンパ節の腫脹（特に年、カナダの衛生レベルの高い農場で最初に報告され、そけいリンパ節は認めやすい外貌所見）、呼吸困難、下

現在、養豚産業での重要な新興性疾患となっている。

痢および黄疸である。PMWS の個体診断は、上記の臨（Clark, 1997 (1); Harding and Clark, 1997 (2)）最初の報

床症状に加えて、特徴的なリンパ組織における組織学

告後すぐに、PMWS には新たに見つかったブタサー的病変（組織球浸潤、封入体形成および巨細胞浸潤をコウイルス２型（PCV2）が関与することが明らかと伴うリンパ球減少、これらの病変は単独でも同時にもなった。（Ellis et al., 1998 (3)）PCV2 は、その後 PMWS

認められる）ならびに病変内における中程度から多量に留まらず、他の様々な疾患；PRDC（豚呼吸器複合の PCV2 の検出に基づく。群診断は、少なくとも５頭

感染症、Porcine Respiratory Disease Complex）、（Al-の解剖検査に基づく個体診断を合わせた、平時と比べ

lan and Ellis, 2000 (4); Harms et al., 2002 (5); Kim et al.,

た事故率と発育不良豚の上昇から判断する。（Euro-2003 (6)）異常産、（Josephson and Charbonneau, 2001

pean Consortium definition - Project No 513928 Sixth(7); Ladekjaer-Mikkelsen et al., 2001 (8); Kim et al.,Framework Programme - http:// www.pcvd.org ）．

2004 (9); O'Connor et al., 2001 (10); West et al., 1999

PCV2 は PMWS の野外症例から必ず検出されるが、(11)）PDNS、（豚皮膚炎腎症症候群、Porcine Derma-

表１のアジアでの報告のように他の病原ウイルスもしtitis and Nephropathy Syndrome）（Allan and Ellis,

く は 病 原 細 菌 と 同 時 に 検 出 さ れ る こ と が 多 い。

2000 (4); Gresham et al., 2001 (12); Meehan et al., 2001

（Jeong et al., 2003 (20)）(13); Thomson et al., 2001 (14); Ramos-Vara et al., 1997

米国での症例対照研究において、PMWS と既知の(15)）肝炎、壊死性リンパ節炎および肉芽腫性腸炎のウイルス（PCV2、PRRS ウイルス、ブタパルボウイル

症例から分離され、また、おそらく滲出性皮膚炎とのス（PPV）、ブタエンテロウイルス１−３型、ブタイ

関連（Chae, 2005 (16)）も推察されている。

ンフルエンザウイルス、ブタ呼吸器コロナウイルス、

ここでは、様々な病理学的機序における PCV2 の関TGE ウイルス、ブタ内因性レトロウイルス、ブタリン与を検討するために野外感染豚ならびに実験感染豚か

パ球向性ヘルペスウイルス１型および BVD ウイルス）

らの現在までのデータをレビューする。とりわけ、いの疫学的な関連性の強さを検討したところ、PCV2 とかにして共感染因子が PCV2 関連症の発症に関わり

PMWS との関連性が最も強かった。PMWS に罹患す合っているかを述べたい。また、PCV2 関連症を防御るリスクは、PCV2 と PRRS ウイルスが同時に感染しあるいは軽減化するために、その一般的な投薬計画をた場合に上昇し、PMWS 発症にはコーファクターにＲ
含めて CIRCOVAC蕘
* の有効性について評価したい。

よ る 増 悪 化 が 必 要 で あ る こ と が 推 測 さ れ た。（Po-

Ｒ*CIRCOVAC蕘
は米国、日本および各国でのメリアル社

granichniy et al., 2002 (24)）の登録商標。

PMWS は PCV2 単独接種ならびに他の感染因子による関与の両方の実験的再現モデルが報告されている。

１．PCV2 関連病変ならびに症候群の解説

い く つ か の 実 験 感 染 で は PCV2 単 独 接 種 に よ り

１．
１ 離乳後多臓器性発育不良症候群（PMWS）

PMWS を誘発することは可能であった。しかしながPMWS は PCV2 感染が強く関わり、世界中の豚養豚

ら、PCV2 と PPV、PCV2 と PRRS ウイルス、あるい地帯において主要な生産性阻害要因となっている。アは PCV2 と 





 

  
（



）の混合

ジア、ヨーロッパおよび北アメリカにおいて PMWS は感染が多くの実験で PMWS の発症頻度を上昇させた。

常在疾病（endemic form）あるいは流行病（epidemic

これらの実験感染に共通して、混合感染はより重篤なform）として発生している。
（Allan and Ellis, 2000 (4);

臨床症状ならびに組織学的病変形成を誘発し、またEllis, 2004 (17) and Segales and Domingo, 2002 (18)）ア

PCV2 量 を 上 昇 さ せ た。
（Allan et al., 2000 (47); De-

ジアにおける PMWS の発生についてはまとまった記Jong et al., 2003 (48); Harms et al., 2001 (49)）．

述がある。（Kawashima et al 2003 (19)）

豚病会報

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2006

１．
２ PCV2 と豚呼吸器複合感染症（PRDC）

33
よって形成される気管支間質性肺炎は、PRDC の野外

豚呼吸器複合感染症は、１６週から２２週齢の育成から典型病変と類似する。
（Drolet et al., 2003 (59)）同様に、肥育期に発生する疾病で、発育遅延、飼料効率の低下、

PCV2 と 
のの混合感染試験では が PCV2

元気消沈、食欲不振、発熱、咳および呼吸困難を特徴

抗原量の増加とその存在期間の延長、PMWS の発生と す る。
（Halbur, 1998 (50); Thacker, 2001 (51) and率の増加、PCV2 感染によるリンパ組織病変の重篤化

Harms et al., 2002 (52)）野外調査結果から、PRDC 罹と PCV2 感染による肺病変の重篤化をもたらした。両

患豚の肺炎は、ウイルスと細菌；例えば PRRS ウイル

微 生 物 に よ る 呼 吸 器 疾 患 の 相 乗 効 果 は 明 ら か で、ス、PCV ２、ブタインフルエンザウイルス（SIV）
、




単独感染で 1/9、PCV2 単独感染で 2/8 頭の豚が





, 













（）お よ び

壊死性細気管支炎が認められたのに対し、混合感染さ









 
 
の混合感染に起因する。
（Halbur,

せ た 7/9 頭 に 壊 死 性 細 気 管 支 炎 が 認 め ら れ た。

1998 (50); Thacker, 2001 (51)）一例をあげると、２００３年（Opriessnig et al., 2004 (46)）

韓国での PRDC 105 症例の後ろ向き調査では、（Kim
et al., 2003 (6)）８５症例が PCV2 陽性、６６症例が PRRS

１．
３ PCV2 が関連する他の症候群と病気

ウイルス陽性、６０症例が PPV 陽性、１４症例が SIV 陽

野外症例として、PCV2 は単独で異常産との関連が性であり、これらの症例の多くが混合感染であった。

報告されており、その他、腸炎、下痢と肉芽腫性腸炎、
肝

PCV2 と 







 
 
の混合感染症例が３８症例、疾患、滲出性皮膚炎、神経症状あるいは皮膚炎腎症症

次いで PCV2 と 
が３３症例であった。類似の調査

候群（PDNS）との関連が指摘されている。これらの結果は、米国でも報告されている。
（Harms et al. 2002

疾患の PCV2 の役割あるいは混合感染する病原体につ(5)）PRDC では、もし１種類あるいは複数種の２次的いては、将来、調査の必要があるだろう。

な細菌感染が起これば、死亡率は急上昇する。
（Done,
2002 (53); Harms et al., 2002 (5); Kim et al., 2003 (6);Thacker, 2001 (51)）

２．PCV2 感染の病理発症メカニズムと混合感染による増悪化作用

肺炎の特殊な症例は増殖性壊死性肺炎（prolifera-

PCV2 感染の病理発生については多様なメカニズム

tive necrotizing pneumonia (PNP)）で、特徴的な組織が提起され、それが異なる PCV2 関連疾患に結びつく病変を示す亜急性から慢性肺炎として名付けられた。

と説明されている。（Segales et al., 2004 (60)）当初、

元来 PNP は SIV 感染、次いで PRRS ウイルス感染とPCV2 の宿主体内での最初の複製は扁桃や局所リンパ関 連 す る と 報 告 さ れ た。
（Harms et al. 2002 (52);

節（Clark, 1997 (61); Rosell et al., 1999 (62)）、あるいはMorin et al., 1990 (54); Rossow, 1998 (55); Larochelle et

パイエル板（Rosell et al., 1999 (62); Royer et al., 2001

al., 1999 (56)）
hybridization あるいは免疫組織化(63)）のようなリンパ組織中のマクロファージや抗原学的染色法による PNP 症例での一貫した PCV2 の検提示細胞で起こると推測された。これらのリンパ組織

出から、PCV2 は PNP の重要な因子であると推測され中や上記の細胞中にウイルスが一貫して見つかることている。（Ellis et al., 1999 (57); Harms et al., 2002 (5)）

か ら の 推 測 で あ っ た。PCV2 は 粘 膜 局 所 の マ ク ロ

PRDC の臨床症状は様々で、その原因は複数にまたがファージや抗原提示細胞に感染・複製した後、細胞とると考えられるが、上記手法による肺組織での PCV2

ともに、ないしは細胞から離れてリンパ流や血流にDNA や抗原検出は、気管支周囲あるいは細気管支周囲

乗って移動すると考えられた。この多くの組織につなの線維化を伴う気管支間質性肺炎とともに、PCV2 ががる体内運搬経路に PCV2 感染細胞が乗ることによっ関連する PRDC の主要な診断指標として用いられてて、様々な器官にウイルス感染が拡がることが考えらいる。

れたのである。しかしながら、この考えは PCV2 の全実験室レベルでは、PCV2 と PRRS ウイルスは相乗身への主な拡散手段として支持されたものの、PCV2

してより重篤な呼吸器症状と肺病変を現すことが証明

はマクロファージや抗原提示細胞では通常は複製しなされている。（Allan et al., 2000 (58)）PCV2 は PRRS ウ

いことが明らかにされた。（Vincent et al., 2005 (64)）

イルスの病変は重篤化しないが、PRRS ウイルスは

要するに、単球／マクロファージ系細胞は PCV2 を貪

PCV2 感染を増強するのは確かなようである。（Allan

食し、長期間、大量のウイルスを保持することから、

et al., 2000 (58)）PCV2 と PRRS ウイルスの混合感染にこれらの細胞で容易にウイルスが検出されると思われ34

Proc Jpn Pig Vet Soc No.49 2006

る。





の試験結果から、樹状細胞ではウイルスの2005 (71)）．野外調査ならびに実験感染での末梢血単急速な取り込みと細胞内で長期間にわたって抗原と感

核球細胞数ならびに組織病理所見から、様々なリンパ染ウイルスが持続することが明らかにされた。PCV2

組織においてリンパ球減少やリンパ球サブセットの割は細胞内分解機構を避けることによって感染力を保っ合の変化が起こることが示された。リンパ組織におけて細胞内に持続し、樹状細胞内での複製はあっても限る PCV2 量が増加するのに伴い、リンパ組織中のＢリン

定されていた。（Mc Cullough et al., 2003 (65)）肺、肝パ球とＴリンパ球領域のリンパ球が消失する。
（Dar-

臓、腎臓、心臓や他の臓器における実質細胞が最終的

wich et al., 2002 (72); Nielsen et al., 2003. (73)）．ア ポに感染すると PMWS 状態へ推移する。このステージ

トーシスは PMWS 罹患豚のＢならびにＴ細胞減少の原では、内皮細胞や上皮細胞で活発にウイルスが複製し、因となり、それにはサイトカインのシグナル伝達の混

爆発的な数のウイルスがこれらの臓器で検出される。

乱があると提起されたが、（Shibahara et al., 2000 (74)）

組織や細胞への親和性が拡大し、PMWS が発症する

このメカニズムは全ての研究で確かめられたわけではと考えられている。（Krakowka et al., 2003 (66)）免疫ない。
（Krakowka et al., 2003 (66)）
PCV2 感染豚ならび刺激と関連していると思われるが、いかにしてその変に PMWS 罹患豚では免疫系障害により免疫応答が阻位が起こるかについては、まだわかっていない。一方、害され、日和見感染症が PCV2 感染によって誘発されPCV2 は樹状細胞に深刻な影響を与え、その機能を傷る最終像となる。例えば、低罹患率（約５％）の 

害して免疫防御を停止させて免疫病やアネルギー（活









 

感染が西カナダの PMWS の初期の症例

動停止）へ導く可能性があることが最近、報告された。

で報告されている。
（Ellis et al., 1998 (75)）．別の例は、

この事実は、あらゆる２次的病原体が豚の生体内に容PMWS 罹患豚の中和抗体応答の産生や持続の不全で易に侵入し易くなる説明となる。
（Mc Cullough et al.,ある。（Charreyre et al., 2000 (76); Meerts et al., 2006

2003 (65)）次は免疫システムに対する PCV2 の直接作

(77)）
．

用と様々なトリッガーや２次的病原体との可能性のある相乗作用についてレビューする。

２．
２ PCV2 感染を重篤化に向かわせるトリッガー

２．
１ PCV2 感染は免疫抑制を導く

ジュバント乳化抗原で刺激することにより、PMWS

実験的に PCV2 感染豚を油性マクロファージ標的ア
PCV2 感染の免疫抑制の事象は、細胞ならびに顕微の発症が高まる。免疫刺激は PCV2 感染を PMWS 状

鏡 レ ベ ル か ら 臨 床 レ ベ ル ま で 幅 広 く 認 め ら れ る。

態に転換させうる極めて重要な因子であることが報告

PMWS の病変は、全身性の肉芽腫性炎症、多核巨細胞された。（Allan et al., 1999 (78); Allan et al., 2000 (58);の浸潤および浸潤した組織球やマクロファージ内にChoi and Chae, 2000 (79); Ellis et al., 1999 (80); Ken-

様々な数で形成される細胞質内好塩基性ウイルス封入

nedy et al., 2000 (33); Kim et al., 2003 (81); Krakowka et

体を特徴とする。とりわけ、PMWS の最も特徴的な

al., 2000 (27); Krakowka et al., 2001 (82)）

組織病変は、多発性からびまん性に認められる血管周米国で通常使用されているバクテリンを用いたワク

囲性の肉芽腫性の炎症である。この特異な病変は通常

チネーション（と バクテリン）は PCV2 ののウイルス感染による病変とは異なっており、PMWS

複製を促し、PMWS の臨床症状と病変を増悪化させの診断に有用である。組織球浸潤は PCV2 感染初期病

ることが報告された。若齢期のワクチネーション、抗変のひとつで、肉眼的にはリンパ節腫脹として認めら原量の多いワンショットでの投薬法、オイルアジュバ

れる。慢性期には重篤なリンパ球減少や明瞭な組織

ント、環境中の高い PCV2 浸潤および低い移行抗体レ

球・多核巨細胞浸潤は認めがたくなる。
（Krakowka

ベルは PMWS の発生率や増悪化を促す可能性がある。

et al., 2003 (66); Allan et al., 1999 (32); Choi and Chae,（Opriessnig et al. 2003 (83); Hoogland et al. 2006 (84)）

1999 (67); Choi et al., 2000 (68); Ellis et al., 1999 (57);

前記したように、PMWS は、PCV2 と PPV、PCV2

Kennedy et al., 2000 (33); Kim et al., 2002 (69); Kra-と PRRS ウイルスおよび PCV2 と 
の混合感染モ

kowka et al., 2000 (27); Clark, 1997 (61); Rosell et al.,

デルで再現されている。ひとつの実験モデルにおいて、1999 (62); Quintana et al., 2001 (70)）．PCV2 抗原は進行

PPV 感染豚ではインターロイキン１０が上昇することした壊死病変に多量に認められることから、壊死性リによりＢ細胞を活性化し、免疫刺激と PCV2 の取り込み

ンパ節炎との関連が推測されている（Kim and Chae,を促すことが示唆された。また、インターロイキン１
０

豚病会報

No.49

2006

35

の検出が混合感染豚では延長していた。（Hasslungとが明らかとなった。（Allan et al., 1998 (89); Ellis etand al., 2005 (38)）PPV に類似して、PCV2 もまた活発

al., 1998 (75); Fenaux et al., 2000 (90) ; Hamel et al.,に分裂している細胞が必要もしくは利用する複製サイ

2000 (91); Mankertz et al., 2000 (92); Meehan et al.,

クルを有するので、（Meehan et al., 1998 (85)）
ウイルス1998 (93)）PCV2 は非病原性の PCV1 との相同性が約に親和性のある細胞の分裂を誘発する因子は、PCV2

６２％であることから、PCV2 は病原性をもつ単一の遺の複製を促し、ひいてはウイルス量の増大と発症につ伝 子 型 と 推 測 さ れ る。
（Hamel et al., 1998 (94);

ながる。それゆえ、様々な細胞を破壊し傷害された組

Tischer et al., 1974 (95); Tischer et al., 1986 (96); Mee-

織の再生を誘発する PPV のような共感染因子は、
間接

han et al., 1998 (93)）分離された PCV2 の塩基配列には的に PCV2 の複製を増強する可能性がある。サイトカ

マイナーな差違はあるが、（Choi et al., 2002 (97); Farn-

インや他の成長因子もまた、細胞分裂を促すことで、

ham et al., 2003 (98); Meehan et al., 2001 (13); O'Connor

間接的に PCV2 の複製を上昇させうる。

et al., 2001 (10)） 今のところ、このマイナーな違いに

PRRS ウイルスは肺胞マクロファージ（PAMs）にど の よ う な 意 義 が あ る か は 不 明 で あ る。ORF1 と特異的に感染し破壊する。前述したように単球／マクORF2 の塩基配列の分析から、塩基配列の変動の大きロファージ系細胞は、PCV2 を貪食し、長期間、細胞さは ORF1 に比べ ORF2 で大きいことが明らかとなっ

内で病原性を保っている多量のウイルスを貯蔵していた。
（Fenaux et al., 2000 (90); Hamel et al., 2000 (91);

るため、PAMs の破壊は、肺内に極めて多量の PCV2

Mankertz et al., 2000 (92)）主要な構造キャプシド蛋白を放出することにつながる。PRRS ウイルスの感染はをエンコードする ORF2（Nawagitgul et al., 2000 (99)）

豚体内でかなり長期にわたるため、慢性の混合感染豚の変化は、キャプシド蛋白のバリエーションと PCV2では、PCV2 の多量放出も長期にわたって繰り返し起の病原性とに関わるかも知れない。主要ウイルスキャ

こりうる。

プシドの修飾によって組織親和性ないしはウイルスー





感染は炎症性サイトカインの産生を誘導する。
それゆえ、
は細気管支炎を誘導して PCV2 の呼宿主の相互作用に関わる決定要素を変化させる可能性がある。ある報告では、PCV2 の ORF2 のマイナーな吸器病原性を亢進することは明白で、PCV2 抗原量の変化が宿主親和性の差違につながると推測している。

増大と局在の持続を促し、PMWS の発生率を増大さ（Mankertz et al., 2000 (92)）別の２つの報告では、異せる。（Opriessnig et al, 2004 (46)）興味深いことに、常産と PDNS から分離される PCV2 株は表現型や遺伝In vitro 試験で PCV2 感染 PAMs は機能的に変化し、子型が PMWS から分離される株とは異なる可能性を





のような２次感染病原体を効果的に抑圧できな推察している。
（Meehan et al., 2001 (13); O'Connor et

いことが、最近、報告された。
（Chang et al., 2006 (86)）

al., 2001 (10)）しかしながら、攻撃試験での PCV2 株の

さらに LPS のようなグラム陰性細菌の構成要素が不同時比較ではこの差違は無いかあっても限定的である。

活発であった PAMs 内での PCV2 の複製を誘導する興（Hasslung et al, 2005 (38); Halbur and Opriessnig,

味ある報告がなされた。また、
感染はマクロ2006 (100)） 日齢や健康状態等の宿主因子、感染経路、ファージを活性化しウイルス破壊が亢進する Th1 反共感染因子あるいは他のストレス因子は PCV2 感染の応 か ら、よ り 効 果 の 弱 い Th2 反 応 へ シ フ ト さ せ、

病原性と臨床症状発現を大きく左右するので、野外農（Thacker, 2001 (87)）PCV2 の取り込みを促進する可能場における分離株の病原性を検討することは困難であ性がある。他の SIV や は肺の急性炎症を惹起し、る。さらに PMWS に関連する全てのＰＣＶ２株はモノ（Thacker et al., 2006 (88)）炎症反応が亢進することでクロナール抗体やポリクロナール抗体の検討から抗原PCV2 の複製を促すかも知れない。全ての病原体が関的に類似している。
（Allan et al., 1999 (101)）

与するような野外の状況では、より複雑に上記のメカ
ニズムが相互作用しているであろう。

４．豚農場でのサーコウイルスワクチネーション
初乳やミルクを介した高いレベルの抗 PCV2 移行抗３．ウイルス株の差違による影響
異なる臨床症状を呈する豚や地理的に異なる地域か体付与による繁殖候補豚や母豚への PCV2 関連疾病のワクチネーションは、以下の情報によりその有効性がら分離された PCV2 株の塩基配列が比較され、すべて提起される。
（Charreyre et al. 2004 (102)）の PCV2 株間の相同性は９０−９６％以上と非常に高いこ

蘆 PCV2 は非常に安定しており、農場環境中に多量36Proc Jpn Pig Vet Soc No.49 2006に存在するため、多くの農場で撲滅は困難である。
蘆

母豚由来の２２頭の子豚で、第２群が４頭のワクチン非PMWS 発生農場では、肥育期に比べて哺育期や離接種母豚由来の２２頭で、おのおの３〜４週齢に PCV2

乳後の育成期の豚で多量の PCV2 が検出される。

が鼻腔内接種された。母豚ならびに子豚の血清中の（Sibila et al. 2005 (103), Lopez-Soria et al., 2005 (104)

PCV2 抗体は実験期間中、一定間隔で調べられた。攻Rose et al., 2004 (105)）

撃後、臨床症状を４週間観察した。血清中ならびに糞蘆蘆PCV2 に対する移行抗体は PCV2 感染と PMWS 発

中の PCV2 ウイルス量は定量 PCR 法（Q-PCR）で調症に対して防御効果があることがわかった。
（Char-

べられた。全４４頭の解剖検査が実施され、腸間膜リンreyre et al., 2002 (106); Thomas et al., 2005 (107)）

パ節が PCV2 を免疫組織化学的に検出するために採取

流産と早産が分娩３週前の母豚に PCV2 を接種すされた。攻撃前、ワクチン接種母豚は高く安定したることにより再現された、このため妊娠中の繁殖豚

PCV2 抗体価を保ったが、一方、ワクチン非接種群の群を防御する必要がある。
（Park et al., 2005 (108)）

母豚ならびにその子豚は抗体陰性であった。最初のワ

し か し な が ら、繁 殖 豚 群 の ワ ク チ ネ ー シ ョ ン とクチン接種後すぐに抗体の陽転が誘導され、分娩前のPCV2 抗体の受動免疫によっては、移行抗体が低下す

３回目の接種により一層の追加免疫がみられた。初乳るので、子豚の PCV2 感染に対する防御効果は限定的による移行抗体の十分な付与と持続は、ワクチン接種な期間に限られている。生後５〜１５週間に感染抗体の母豚から生まれた子豚の血清中 PCV2 抗体の高力価で上昇が起こる野外の状況からも受動免疫が限定的であ個体間のばらつきのない抗体価により確認された。攻ることが推察できる。（Cotrell, 1999 (109); Larochelle

撃後、顕著な抗体の陽転がワクチン非接種母豚由来の

et al., 2003 (110); Segales and Morvan, 2004 (111)）異な子豚に認められたが、ワクチン接種母豚群由来の子豚るグループにより感染抗体は PMWS 発症に対して防は 抗 体 価 の 減 少 が 続 い た。こ の 実 験 で は 典 型 的 な

御効果があることが報告された。それゆえ、よくコン

PMWS 症例は認められなかったものの、PCV2 攻撃後トロールされた PCV2 の自然感染は PCV2 関連疾患にに臨床症状と発育遅延が観察され、臨床スコアは、ワ対する自然防御誘導すると考えられる。

クチン非接種母豚由来の子豚が顕著に高値であった（p ＝ 0.015）。解剖時、病変スコアはワクチン接種母豚

４．
１ 実験室における２つの有効性試験

由来の子豚がワクチン非接種母豚由来の子豚に比べて最初の実験の目的は、PCV2 感染がコントロールさ有意に低い値であった（p ＜ 0.00001）。さらに血清中、れた環境下で不活化オイルアジュバンド PCV2 ワクチ

直腸スワッブおよび腸間膜リンパ節での PCV2 DNAン（CIRCOVAC）の有効性を調べることであった。ワ

量はワクチン接種母豚由来の子豚が有意に低い値でクチン接種された繁殖母豚の特異抗体の上昇と生まれあった（p ＝ 0.00002）。この不活化ワクチンはワクチ

た子豚の生後３−４週間での PCV2 攻撃試験による防ン接種された繁殖母豚が高く安定した抗体価を維持し御効果が評価された。２番目の試験の目的は、野外農たことから、高い免疫原性があることが立証された。

場でのワクチン接種繁殖母豚から生まれた子豚を実験

このワクチネーションによりワクチン接種母豚由来の室に運び、そこで攻撃試験を行うことによりワクチン

子豚は病原性のある PCV2 の攻撃に対して著明な防除の有効性を調べることであった。この試験では生後約効果を示した。この結果から、CIRCOVAC によるワ

４週齢で PCV2 に攻撃され、その防御効果が評価されクチネーションは高度にコントロールされた環境下でた。この２つの試験以外にワクチンの妊娠豚に対するは、PCV2 攻撃後の豚の健康状態の改善に有効性があ

安 全 性 を 証 明 し た。
（Reynaud et al., 2004 (115 andることが示された。

116)）

２番目は野外効果試験で、PMWS 発生農場におけ最初の試験では、ELISA 検査による PCV2 抗体が陰る母豚から生まれた子豚が試験に用いられた。第１群性の SPF 繁殖母豚が２群に分けられた。１１頭の繁殖をこの農場の８頭のワクチン非接種母豚由来の子豚１
２

母豚グループには交配５および２週前、および分娩２頭とした。第２群をこの農場の分娩２週間前に最小限

週前に筋肉内に最小限の抗原がワクチン接種された。

の抗原（CIRCOVAC）が筋肉内に一回接種された７頭

別の１２頭の繁殖母豚はワクチン非接種群であった。すの母豚由来の子豚１０頭とした。攻撃対照として、１１頭べての繁殖母豚は１０ヶ月齢で人工授精され８頭の母豚の SPF 豚が第３群として設けられた。この農場から、が妊娠した。それゆえ、第１群が４頭のワクチン接種

約３日齢の子豚が農場管理スケジュールに沿った日に

豚病会報

No.49

2006

実験感染施設に運び込まれた。それゆえ、これら３群

37
４．
２ メリアルによるフランスとドイツでの野外有効の豚は同じ日に PCV2 が鼻腔内接種されたが、いくぶ性試験

ん異なる接種日齢となった。すなわち、攻撃された日

野外試用承認のもと、
フランスの３つの PMWS 発生

齢は、第１群のワクチン非接種対照母豚由来の子豚は農場で１８ヶ月以上にわたる野外有効性試験が継続中

３
２日齢、第２群のワクチン接種母豚由来の子豚は２５日である。２農場では、３週ごとに分娩する１群約３
５頭

齢および第３群の攻撃対照の SPF 豚は４７日齢であっの母豚が７群、残り１農場では毎週分娩がある１群１２た。試験期間を通して、連続的に母豚ならびにその子

母豚の２２群が計画された。７群中の１ならびに２群、豚の血中 PCV2 抗体価、および子豚の糞中に検出され２
２群中１、３、５、７、９および１
１群がワクチン非接

る PCV2 ウイルスが調べられた。攻撃後４週間、臨床種群とした。残りの群には長期間にわたって分娩３週症状をモニターし、４週目に解剖検査された。解剖時、間前に CIRCOVAC の最小用量が１回ワクチン接種さ縦隔リンパ節が免疫組織化学的検査によるウイルス量れた。更新母豚は外部から導入され、試験期間中は導測定のために採取された。分娩２週間前、すなわちワ入前の検疫期間に２回ワクチン接種された。この接種

クチン接種日には、全ての母豚は類似した抗体価のにより試験期間中にワクチン接種された豚は母豚のPCV2 抗体を保有していた。ワクチン接種母豚の分娩７０％になった。繁殖豚群の血清学的な追跡調査以外に、後２週後の PCV2 抗体価は有意に上昇し（p ＜ 0.005）、

第１〜４群および１〜１
２群の連続２回の妊娠から生まワクチン接種母豚由来の子豚の PCV2 抗体価はワクチれた全ての子豚において PCV2 関連疾病の有無が出荷

ン非接種母豚由来の子豚に比べ、攻撃日まで有意に高まで調べられた。ワクチン接種ならびにワクチン非接値であった（p ＝ 0.01）。３〜５週齢の期間、糞中に小種母豚由来の全ての子豚の全期間に渡る大規模な比較量の PCV2 が検出される子豚の数は、ワクチン接種母試験が終了した。試験開始時、３つの農場の全ての母

豚由来の子豚群がワクチン非接種母豚由来の子豚群よ

豚は PCV2 抗体陽性で、その１２％に高い抗体価が認めり少なく、子豚の移行抗体の抗体価の高低と関連してられた。ワクチンネーション後、５６％のワクチン接種

いた。実験期間中、重篤な PMWS 症状を示す接種子豚母豚が高い抗体価を持つと判断されたのに対し、ワクはいずれの群にも認められなかった。しかしながら、

チン非接種母豚では７％のみであった。ワクチネー

SPF 豚群での臨床スコアの上昇と PCV2 抗体の顕著なション後の繁殖豚群での PCV2 抗体価の上昇に伴い、陽転ならびに全ての接種子豚の糞中への PCV2 の排泄PMWS 症例はこの１８ヶ月の期間に、
農場選択時の５％から、この攻撃試験の有効性は認められた。ワクチン

以上の発症率からワクチン非接種母豚由来の子豚

非接種母豚由来の子豚は攻撃後 PCV2 抗体価の上昇が（４，１８３頭）で１．
１２％、ワクチン接種母豚由来の子豚で認められたが、一方、ワクチン接種母豚由来の子豚で

（１
０，
４
６２）
０．
６７％と急激に減少した。以上の結果は、ドは抗体価の減少が続いた。ワクチン接種母豚由来の子

イツとフランスでの CIRCOVAC の暫定認可下の非常豚で攻撃後の PCV2 抗体価の上昇が認められないことに大規模な試験によっても確認された。試験期間中、は、移行抗体により付加された PCV2 感染に対する防

３
６
６，
８
９５頭の母豚がワクチン接種された。副作用報告

御効果に関連すると推察される。解剖時、ワクチン接は非常に限定されていた（４，
３
００ドーズのうち１つの局

種母豚由来の子豚では、ワクチン非接種母豚由来子豚

所反応と４
４，
０
００ドーズのうち１つの流産例）。ドイツならびに SPF 豚に比べ、肉眼病変スコアの顕著な減少でのいくつかの調査結果を例に挙げる。ドイツ全国にが認められた（p ＝ 0.0001）。全てのワクチン接種母豚

わたった１
３，
９
９２頭のワクチン接種母豚からの結果が含由来の子豚では腸間膜リンパ節に肉眼病変は認められまれている。CIRCOVAC のワクチネーションの有効なかったが、一方、他の２群の７０−８０％の子豚では高性は、主に以下のパラメーター；哺乳豚、離乳豚およ〜極めて高い病変スコアが認められた（p ＝ 0.00043）。

び肥育豚の死亡率ならびに農場での疾病防除に使用さ以上の結果により、野外農場での CIRCOVAC によるれた薬剤使用によって解析された。死亡率は表４に記

母豚ワクチネーションは農場内の PCV2 の循環や哺育載した。一部の農場でのワクチネーション実施の遅れ

豚のウイルス排泄の抑制に対し有効性があるばかりでから、解析時点ではワクチネーション効果の完全な判なく、PCV2 攻撃後の子豚の健康状態の改善に有効で定はまだである。しかしながら、哺乳豚で５．
３％、肥育

あった。

豚で３％と３つの肥育ステージでの死亡率の減少は顕著であった。これらの改善効果は農場に多大な利益を38

Proc Jpn Pig Vet Soc No.49 2006

もたらしている。結論として、死亡豚と削痩豚の発生

チネーションの有効性は、ワクチンが臨床的な PMWS

数の著明な減少、より均一な発育、および抗生物質使の防除に経済的に適切なレベルであることを確かめる

用の減少という肯定的な結果が得られた。離乳から出暫定認可のもとでの市販ワクチンを用いた繁殖母豚と荷までの全体の死亡率の減少は少なくとも、５０％の農妊娠母豚の大規模な野外有効性試験で立証された。他

場で認められた。

の PCV2 関 連 疾 病 や 症 候 群 に 対 す る 防 除 に お け る
PCV2 ワクチンの有効性に関してはさらに検討する必結論

要があるが、繁殖母豚への PCV2 に対するワクチネー

実験室内ならびに野外試験成績から、PCV2 感染にションは、出荷に至るまでの損耗を大幅に軽減するこ

対するワクチネーションは PMWS 発症を抑制する効とは注目に値する。この改善効果は、他の病原体の易果があることが立証された。子豚へのワクチネーショ

感染化につながる野放しの PCV2 感染によってもたらンは移行抗体レベルが高くない限りコントロールされされる長期にわたる有害で、急性ないしは慢性の免疫た実験室内レベルでは有効である。妊娠豚を含む繁殖抑制状態の改善と関連しているのであろう。

母豚のワクチネーションは安全でコントロールされた
実験室内レベルで有効であることが認められた。ワク（翻訳：川嶌健司

動衛研東北支所）