Are Porcine Circovirus Diseases still important?

 

Porcine circovirus (PCV) type 2 (PCV2) was firstly characterized in 1998 as an agent systematically present within the lesions of a novel disease called postweaning multisystemic wasting syndrome (PMWS). The condition was described sporadically during early-middle 1990s in Canada. The name of PCV2 was used to differentiate it from an existing PCV that it was considered nonpathogenic for swine (subsequently named as PCV type 1, PCV1). Retrospective studies have shown that PCV2 was not a novel virus and PMWS was not a new disease. The virus has been detected as early as 1962 by PCR and the disease diagnostic criteria have been fulfilled in sick pigs from 1985 onwards. Moreover, phylogenetic and co-phylogenetic inference studies have suggested that PCV2 has been probably circulating in pigs for more than 100 years.

 

PMWS is clinically characterized by wasting and respiratory distress, although the scope of clinical signs can be very variable from farm to farm due to co-existing pathogens/diseases. Importantly, PMWS is considered a multifactorial disease in which PCV2 is the necessary but not sufficient infectious agent to trigger clinical signs. This aspect has been widely described in the literature, and it is probably the main reason for the almost impossibility to fulfil Koch’s postulates by using only PCV2 as inoculum. As many other multifactorial diseases, PMWS perfectly fulfils Evans’ postulates, which are a set of guidelines that take into account the infectious agent, the host and the spectrum of host responses in order to establish a relationship between causation and disease.

 

Besides PMWS, PCV2 has been linked to other pathological conditions, grouped together as porcine circovirus diseases (PCVDs). The most recently suggested terminology for different PCVDs is PCV2- systemic disease (PCV2-SD, to replace PMWS), PCV2-subclinical infection (PCV2-SI), PCV2- reproductive disease (PCV2-RD) and porcine dermatitis and nephropathy syndrome (PDNS). The last one is an immune-complex disease in which PCV2 is the suspected associated antigen; however, a scientific and unequivocal demonstration of this assumption is still lacking. Also, PCV2-respiratory and PCV2-enteric diseases have been suggested as specific entities linked to the virus. Recent data suggest that those conditions are probably part of the PCV2-SD scope.

 

The advent of vaccines against PCV2 by late 2000s available worldwide changed dramatically the clinical and pathological picture. Such devastating diseases were able to be controlled in a very significant way, to the point that in 2015 these vaccines are the most widely used ones in swine production. Therefore, PCVDs look like under control. The objective of this review is to critically discuss the current situation we are facing nowadays regarding PCV2 infections and some insights on its future.

 

 

The first available commercial PCV2 vaccines worldwide were in the France and Germany in 2004, and then in USA in 2006. The first official pan-European launch of a PCV2 vaccine was in 2007. This first product was an inactivated, adjuvanted vaccine (a classical vaccine manufacturing approach) to be used in sows/gilts. At that time, a number of producers and veterinarians felt that the vaccine reached the market too late; the disease was really important from 1997 onwards, especially until 2004-05, but not perceived so significant afterwards. However, problems associated to PCV2 infections were still present in a number of European farms. In fact, some veterinarians saw the novel vaccine as a potential opportunity to improve their production results. In 2008, most of the information coming from North-America indicated that piglet vaccination was more efficient to control PCV2-SD in the short term. Therefore, in some countries, like in Spain, a vaccine initially designed to be used in adult animals was mostly applied in piglets, and its use increased over time. Subsequently, in 2009, two more PCV2 vaccines were launched in the European market. Those two vaccines were licensed for their use in piglets and both were sub-unit products. Since then, the use of PCV2 vaccines has spread very significantly among producers, being nowadays the most used vaccine in pigs worldwide. In fact, in some countries like USA, Canada, Austria, Germany and others, almost all pigs reaching the slaughter have been vaccinated against this virus. Some years ago, the vaccine initially licensed for adult swine was also registered for its use in piglets. A fourth PCV2 vaccine has been very recently launched (inactivated vaccine based on a chimeric virus that contains the capsid gene of PCV2 inserted in the backbone of the porcine circovirus type 1 genome).

 

Under field conditions, all PCV2 commercial vaccines existing so far have been able to decrease percentages of mortality and number of runts in nursery and/or fattening/finishing pigs. More importantly, improvement of average daily gain (ADG, 10 to 40 g/day in vaccinated pigs compared to non-vaccinated controls), feed conversion rate and pig size/weight homogeneity as well as decreasing of co-infections and use of antibiotics have been the most significant benefits of PCV2 vaccination. Also, prevention of abortions and an increased fertility and reduction in returns to service of sows and gilts following the use of PCV2 sow vaccination have been described. Therefore, it seems that all commercial vaccines to date exert a very positive effect in those farms affected by PCV2 diseases.

 

An important current issue is the feasibility of PCV2 vaccines to improve productivity in farms not suffering from PCV2-SD outbreaks. To date, different field evidences indicate that such vaccines are able to improve productive parameters (ADG, percentage of runts, body condition and carcass weight) in PCV2 subclinical infection scenarios. These data allow speculating that if PCV2 vaccination counteracts the effects of the subclinical infection in cost-benefit terms, then, such vaccination would be justified in whatever situation in which PCV2 infection takes place, independently of overt disease occurrence or not. Moreover, if PCV2 is a ubiquitous virus, this means that the agent is virtually in all farms worldwide. Consequently, the systematic vaccination of all pigs against PCV2 would make sense. A practical aspect that would indirectly indicate such conclusion is the extensive use of vaccines in a number of countries as indicated above. Besides, it must be emphasized that effects of PCV2 vaccines on subclinical infection scenarios should be further studied and conveniently contrasted.

 

 

Vaccine summary of product characteristics (SPCs) states the indications, contraindications, adverse reactions, target species, dosage for each species, and route/s and method of administration. Therefore, practicalities on how, to whom and when to vaccinate against PCV2 are already given for each particular product.

 

To decide the corresponding vaccine schedule to apply in a particular farm, a number of aspects must be considered initially. A first level of decision is the convenience of vaccinating piglets or breeding stock, or both. Such decision level should include also the selection of the particular product to be applied, since there are a number of vaccines licensed for pigs, but only one specifically licensed for breeding stock. The following step depends on the first one, and includes the timing of vaccination. This latter issue is especially important when vaccinating piglets, since interference of maternally derived immunity (MDI) might exist with vaccine efficacy.

 

If the first decision level is to vaccinate sows, schedule might be primarily directed to prevent PCVDs of the offspring or, alternatively, to protect against PCV2-RD. In the first case, vaccination should take place at the end of gestation, as it is recommended by the single manufacturer of the PCV2 vaccine intended for sows. If the objective it to prevent PCV2-RD, vaccination might be applied before mating, being at the lactating period or at weaning for 1st parity or older sows, or during the acclimatization in gilts. Based on vaccine indications, this latter applicability should be considered offlabel, since licensing of these products were intended to control PCVDs in the growing-finishing pigs. In any case, the use of sow vaccination at the end of the gestation period in a repeated fashion in the farm also provides protection against PCV2-RD.

 

Alternatively, one may select piglet vaccination as the way to control PCVDs in the farm. It is nowadays known that control of PCV2-SD in affected farms is quicker if piglet instead of sow vaccination is used. The main reason is that the vaccine applied in pigs is able to elicit protective immune responses in the animal that subsequently suffer from the disease, therefore, having a positive effect in the very first vaccinated batch. Non-published field data indicate that sow vaccination helps controlling clinical disease in growing-finishing pigs, but needs 6 months to 1 year of continuous use of vaccine in sows to generate comparable effects to piglet vaccination in a single batch.

 

Finally, the third option is to vaccinate both sows and piglets. There are already reports on the benefits of this schedule at productive and virological levels. In this scenario is important to evaluate the putative interference of MDI upon PCV2 vaccine efficacy in piglets, since colostrum intake provides higher amounts of PCV2 antibodies. Within this scenario, an interesting point would be to analyze the benefit of leaving only one of the vaccine applications (sows or piglets) once the disease situation is under control. However, this strategy and its results have not been described in the literature yet.

 

The effect of MDI (measured as maternally derived antibodies, MDA) is significant, and may protect against PCV2 challenge and influence the humoral response developed after vaccination. A significant negative correlation between MDA at the day of vaccination and the increment of antibody titers to PCV2 4 weeks post vaccination has been demonstrated. In other words, the higher the antibody titer at vaccination (generally at weaning), the lower the degree of seroconversion 4 weeks later. Moreover, one study compared a protocol of both sow and piglet double vaccination, with application of the product in pigs at 3 and 7 weeks of age. Evident MDA interference with vaccine seroconversion was only observed in the 3-week-old piglet vaccination schedule. Based on these observations, optimal vaccination strategies must balance the advantage of delayed vaccination in case of high antibody titers at weaning age with the need to induce immunity prior to exposure to pathogens under field conditions. In consequence, a “vaccination window” has been proposed, defined as the range of antibody titers at which piglets should be vaccinated to minimize interference with MDA and, at the same time, ensure the development of protective immunity before PCV2 exposure.

 

This latter point is the one that should define the age at piglet vaccination. Product label indicates vaccination from 2-3 weeks of age onwards, although one vaccine is licensed for an earlier age if a double dosage is used. In fact, and taking into account that MDA interference with vaccine seroconversion has been demonstrated, the important point is to ascertain if this is paralleled with interference with vaccine efficacy. A first study indicated that efficacy is not jeopardized by MDA, with independence of antibody titres at vaccination. However, if such interference does exist, it is very likely that most of the pigs in a batch overcome MDI on a practical basis. In the worst case scenario, such putative interference would happen in the proportion of pigs with relatively high or very high antibody titres. Such proportion might be different from batch to batch. A very recent study concluded that PCV2 vaccination in the presence of high MDA levels is efficacious when used in 3-week old but not in 1-week old pigs. This paper indicated that PCV2 vaccine efficacy was independent of the level of MDA, since MDA titers of pigs vaccinated at both 1 and 3 weeks of age were apparently comparable. Anyway, when analyzing the data of this particular work, the pig group that performed better was the one vaccinated at 3 weeks of age in one of the studied farms, being the batch with the lower antibody titres. Therefore, an alternative interpretation of these results would suggest interference of vaccine efficacy by means of high, or probably very high, titres of MDA.

 

Overall, however, piglet vaccination around weaning should work in a majority of farms worldwide unless piglets have very high titres at the time of vaccination. Experience also tell that, in case of double sow and piglet vaccination, the last one will benefit of delaying some weeks its application in order to avoid interference with MDI.

 

 

PCV2 vaccines are currently the most sold preventive products in swine worldwide. Some countries are vaccinating almost if not all pigs that reach slaughter as indicated above, and this trend is increasing in other parts of the world. This situation is well understood, since vaccines are able to improve productive parameters (ADWG, percentage of runts, body condition and carcass weight) in PCV2-SI situations. The ubiquity of PCV2 may prompt, therefore, to further intensify vaccination in these countries in which the vaccination rate is still medium to low. At the very end, the return of inversion with this vaccine is one of the highest among available biological products.

 

Early reports of PCV2-SD already indicated an increased co-infection rate in affected pigs, probably due to the immunosuppressive nature of the disease. Concomitant infections included not only viruses, but bacteria and, to a lesser extent, parasites. Therefore, it is not surprising that, in Denmark, herds experiencing PCV2-SD had a usage of antimicrobials 37 and 19% higher before the outbreak in nursery pigs and finishers, respectively, compared to herds not experiencing the disease. Subsequently, it has been observed that vaccination against PCV2 does not only imply direct beneficial effects on pig productivity, but also contributes to reduction of antimicrobial use. This issue is and will be of special importance taking into account the antimicrobial use policies being implemented worldwide.

 

Although the initial tendency was mainly to vaccinate piglets, the number of vaccinated sows and gilts is increasing over time. Taking into account that combined vaccination of piglets and sows offer the best performance of animals, it is likely that a “continuous protection fashion” will gain ground in the future. Initial assessments point out that besides getting the best ADWG of pigs, vaccination of both pigs and sows is overall cost-effective.

 

Continuous surveillance for new PCV2 variants is paramount for a DNA virus that has evolutionary rates resembling those of RNA viruses. So far it seems that current vaccines based on PCV2a strains are able to cope with major circulating strains worldwide (PCV2a, PCV2b), including with the PCV2d (formerly known as mPCV2b), due to cross-reactivity among genotypes. However, limited existing data suggest that PCV2b vaccines might be even more efficient to counteract currently circulating viruses. Therefore, vaccine manufacturers should consider licensing products based on PCV2b (some countries already have them) or, alternatively, to develop polyvalent vaccines including two or more genotypes.

 

Elimination of PCV2 from a herd or a batch is feasible without vaccination. On the other hand, since viremia control is very efficient by means of PCV2 vaccination and that a double dose can prevent viremia in experimentally challenged pigs, it was hypothesized that a continuous, high vaccination pressure of piglets and sows might be able to control, and eventually eradicate, PCV2 infection in a farm. This hypothesis was recently tested and after one year of such mass vaccination program, PCV2 was undetectable by conventional PCR techniques and piglets reached slaughter sero-negative. Discontinuity of this vaccination program resulted in re-detection of the virus 4 months after. Evidence of infection after stopping the vaccination program might indicate either re-infection or that the virus was never cleared out from the farm, being the second hypothesis the most probably one. Although this was just a punctual study, it would be interesting to assess if the application of such control measure extended over an undetermined period of time in a local, regional or country basis would result in the eradication of PCV2 infection.

 

A still fairly naïve field of research is the PCV2-RD. Although there are consistent criteria to diagnose the reproductive disease by means of fetal analyses, there are still a number of gaps on the real effects of PCV2 on reproductive parameters as well as regarding the subclinical infection of the sow and fetuses. Vaccines allow preventing reproductive failure caused by PCV2, but the extent of their effects on general reproductive performance is still poorly known.

 

Novel research on PDNS is not really expected. The occasional occurrence of this disease and the complete lack of an experimental model make difficult to progress in the knowledge of its pathogenesis. The involvement of PCV2 antigen in this immune-complex disease has never been scientifically demonstrated, but field data indicate that farms that experienced PDNS together with PCV2-SD (they usually went together), the PDNS picture virtually disappeared after vaccination. If such effect is due to the control of PCV2 by itself or because of the general health improvement of the farm is not known.

 

The so-called “PCV2 vaccine failure” is also a matter of current and future concern. Such wording has been used when farmers and veterinarians did not get the expected results by means of PCV2 vaccination or when PCV2 diagnosis is fulfilled in already vaccinated piglets. However, the more in depth study of these potential failures has demonstrated that in most of the cases there are intrinsic situations that point out to a deficient management of the vaccination, rather than a problem with the specific use of the vaccine. Among these circumstances, the most usual ones imply: 1) too early vaccination (with too high levels of MDI), therefore, jeopardizing the vaccine intake, 2) too late vaccination, getting closer to the natural infection timing and not having the minimal time to elicit the corresponding protective response, 3) vaccination of sick pigs or pigs incubating a disease, and 4) lack of real vaccination when veterinarian thought that it was performed. Therefore, so far and to the autor knowledge, there is still not a well-documented case of unequivocal vaccine failure with PCV2. Although it has been speculated that PCV2d may escape protection elicited by commercial PCV2a based vaccines, experimental studies have demonstrated that this is not the case. 

 

 

In conclusion, last 8 years have been a continuous demonstration that PCV2 vaccination has been a great advance for the pig health worldwide, being probably one of the vaccines that veterinarians and farmers have perceived as more beneficial in the last 3 decades. Therefore, PCV2 vaccination is considered as fundamental to control clinical and non-clinical outcomes associated to this viral infection. Moreover, control and prevention of risk factors for PCV2-SD are still a “life insurance” for the correct performance of the vaccine and the farm and the farmer should not forget them. Importantly, and assuming everything is well managed in the farm (including vaccination against PCV2), farmers, veterinarians and scientists must continue being aware on what is going on under field conditions, applying good management practices at all levels and establish the proper diagnosis of a condition that may resemble PCVDs in vaccinated farms.