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When the problem of PMWS arose, discussions about the central involvement of PCV-2 in the disease were constant until vaccines emerged and their effectiveness removed all doubt. When PCV-3 emerged, the situation was practically the opposite: everyone assumed that it must cause some kind of pathology.
PCV-3 was discovered in 2015-2016 as a result of massive sequencing using metagenomics, a very powerful tool that allows us to obtain genome sequences of different microorganisms without preexisting knowledge about their sequence. In light of a series of PDNS cases, reproductive problems, myocarditis and after ruling out the presence of the main pathogens that could be involved, such as PRRSv and PCV-2, it was decided to perform metagenomic analysis, which is when this new circovirus was discovered. What we don't know is how long this virus has been present in the pig population. In fact, we and other research groups have conducted retrospective studies with stored serum samples and found that PCV-3 was already present since at least the 1990s. But since it was detected in the oldest available samples, it is likely that this virus was circulating in the pig population even earlier.
PCV-2 was also a ubiquitous virus that was detected in sera, from samples taken well before it began to cause clinical disease.
There has not been any change in pathogenicity with PCV-2, or at least not that we know. The virus does indeed evolve and change, but since porcine circovirus associated disease is a multifactorial disease, its presence depends on the concomitant presence of other factors. Therefore, the fact that we identified a new disease in the 1990s is attributed much more to the co-factors than to the virus itself. With PCV-3 we do not know its impact and we do not have a differential disease that can be attributed to it, as we saw in the 1990s. On the other hand, unlike PCV-2, the variability of PCV-3 is significantly lower. With PCV-2 we are talking about a divergence level of 10%; but all sequences of PCV-3, except two isolated sequences found in China with higher divergence, are extremely similar, with a degree of similarity of almost 98%.
There is a working group trying to establish if different PCV-3 genotypes can be considered. Although things may change, today we could only mention one genotype, and at most two if we consider those 2 sequences detected just once in China in 2006. Currently there is a considerable volume of PCV-3 sequences in the GeneBank, but we must take into account that 80% of the sequences come from China and we do not know if this reflects the level of representativeness in other regions.
"Associated with vs. causative of..."
In relation to PCV-3, most of the cases described are referred to as "PCV3-associated disease", that should be differentiated from " PCV-3 as a causative agent". The fact that a microorganism is detected in the context of a clinical problem does not necessarily indicate that it is causing the problem. Studies have been conducted where the presence of PCV-3 was assessed in cases sent to the laboratory due to digestive and respiratory problems and also in healthy animals, and the frequency of PCV-3 was practically the same in all three situations. We cannot forget that this virus is practically ubiquitous.
PCV-3 has been associated with a multitude of symptoms, and I personally do not see any "causative relation" in the vast majority of them. Where we are finding more evidence, currently, is in their role in certain reproductive cases, but we must also consider the frequency of the problem. If we look at the severity and extent when the PMWS problems started, it is something that we do not see now in relation to reproductive problems and PCV-3.
PCV-3 and reproductive problems
Although it seems difficult to find a clear biological effect between PCV-3 and the presence of digestive or respiratory problems, there could be reproductive problems associated with PCV-3. At ESPHM 2019, Susanna Williamson from the United Kingdom, presented a clinical case where there were stillbirths, piglets with deformities, and systemic inflammation, in particular vasculitis, with the presence of high levels of PCV-3 detected by PCR. We received samples from that clinical case so that we could perform an in-situ hybridization to locate the virus in the tissues. To our surprise, the amount of PCV-3 present in tissues was extremely high, comparable to the amounts of PCV-2 we used to find in clinical cases of PMWS. I therefore believe that PCV-3 is indeed a pathogen, which can probably cause reproductive problems, but the key question is how frequently is PCV-3 a problem? At present we do not have that evidence of frequency; this same British laboratory that sent us the samples has only recorded two similar cases in the last four years. So we could say that PCV-3 apparently has the capacity to produce lesions associated with reproductive problems, but it seems that the incidence of the disease it causes is very low. With this information we can only conclude that we do not really know the relevance of PCV-3 yet as a pathogen.
Can we expect cross-protection PCV-3 with PCV-2 vaccines?
We have to take into account that, although they have somewhat similar structures, the degree of genetic divergence between PCV-2 and PCV-3 is 60%, therefore they are very different. I wouldn't expect any cross-protection. We drew from the premise that, at present, we do not have isolates of PCV-3, so we have not been able to perform pathogenesis studies or serological techniques so that diagnostic techniques are limited to PCR and sequencing. All this makes it difficult to reach any conclusions on an experimental basis.
Will PCV-3 be a challenge in the future?
Today gaining a better understanding of how PCV-3 works is important, but as long as it is not perceived as a problem, it will not be considered a scientific priority. My conclusion is that PCV-3 is apparently capable of causing reproductive disease but that we do not have information about its relevance, which is essential.
I believe that, in the world of porcine circoviruses and with the continued excellent vaccine performance against PCV-2, if we think about medium-term challenges it is important to understand how, when, why, and to what extent PCV-3 is capable of producing disease.
