Modified-live vaccines ‘by far’ most effective tool for combatting PRRS
This is one of eight reports that appears in a special edition
of Pig Health Today, “Framing the Future of PRRS.”
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Modified-live vaccines (MLVs) are “by far” the most effective tool the industry currently has to control porcine reproductive and respiratory syndrome virus (PRRSV), said Jay Calvert, PhD, research director, Global Biologicals Research, Zoetis.
One of the key advantages of MLVs is their ability to mimic natural infections. They induce robust protection against reinfection with the same (homologous) PRRSV or closely related strains. The result can be “sterilizing immunity,” which is demonstrated by the absence of detectible viremia and/or a lack of an increase in antibody titer.1,2,3
MLVs are also self-adjuvanting. They stimulate a cell-mediated immune response in addition to antibodies, and only one intramuscular injection is needed to provide lifetime protection in feeder pigs. This is in contrast to killed (inactivated) vaccines, which require an adjuvant to induce immunity and usually require two doses.
There are limitations, however, the scientist emphasized. All current MLVs for PRRSV are potentially prone to residual virulence in naïve herds, particularly in naïve thirdtrimester pregnant sows. Vaccination also results in seroconversion, which can complicate PRRSV surveillance.
It’s also possible for MLVs to persist and spread to non-vaccinates, though not reliably enough to yield solid herd immunity. In addition, recombination may occur between vaccine and field strains, he said.
‘GOOD NEWS, BAD NEWS’
Calvert reported “good news” and “bad news” regarding cross protection with MLVs for PRRSV. Most if not all PRRSV vaccines can provide partial, though statistically significant, cross protection against very divergent PRRSV strains.4,5 However, the degree of protection drops off rapidly as the degree of genetic relatedness between the vaccine strain and challenge strain decreases from 100% identity (homologous challenge).
He considers genetic relatedness one of several predictors of whether a vaccine is going to protect well against a known challenge virus. However, “just how much relatedness is needed is a matter of debate and depends on where you live.”
In the specific case of the US, the four licensed PRRSV MLVs are nearly equidistant genetically from the most common field strains. Any small differences in ORF5 sequence homology between a field isolate and particular vaccine viruses are irrelevant because they are swamped out by non-genetic factors, and because ORF5 only represents less than 4% of the viral genome, Calvert said.
Most live PRRSV vaccines are attenuated, which means the virulence of a field strain is reduced, and they become “modified live,” which makes them safe to use as vaccines. The attenuation process requires passing the field strain numerous times in a cell-culture system. Periodically, the virus is checked for both safety — the attenuation of disease — and efficacy.
At lower passages, the virus may be efficacious, but it’s still not safe enough and needs more passages. If there are too many passages, it may be safe but no longer efficacious. When the virus is shown to be safe and efficacious, it becomes a vaccine candidate, he continued.
Calvert provided some basic knowledge necessary for understanding the attenuation of PRRSV vaccines. In pigs, the primary cells that PRRS viruses infect are macrophages. These are also the only cells that express a protein known as CD163, which is the primary receptor for all PRRS viruses. The CD163 PRRS receptor was discovered by Zoetis scientists in 2004.
Nearly all live, commercial PRRSV vaccines are field viruses attenuated by repeated passages on the MA-104 monkey kidney cell line, because this was the only cell line that would support the growth of a PRRS virus. However, it expresses a monkey version of CD163.
“By forcing the virus to learn how to grow on monkey cells, the PRRS virus forgets how to grow on pig macrophages. When you put it back into the pig (vaccination), it takes time and several generations of viral replication to learn how to adapt and grow on pig macrophages again. The attenuation is transient, and if you put the re-isolated vaccine virus into a naïve pig, it has different growth characteristics from the virus that’s in the vaccine bottle,” Calvert said.
An exception is Fostera® PRRS, a modified-live PRRSV vaccine developed by Zoetis that’s produced with a unique attenuation method based on breakthrough research. A field isolate known as P129 was attenuated by repeated passage on recombinant non-monkey cell lines. The CD163 that’s expressed is the pig version. The virus replicates well in the pig straight out of the bottle, and the attenuation is not transient, he said.
The result is a vaccine with improved safety and efficacy in very young (pre-weaning) pigs and is why the Fostera PRRS vaccine was the first of its kind to be labeled for use in piglets as young as 1 day of age. This allows time for immunity to begin developing before weaning. The vaccine has a 6-month duration of immunity against respiratory disease and provides broad cross protection.
Although MLVs have limitations, Calvert said he believes they are the best option for PRRSV control and expects incremental improvements in these vaccines.
OTHER PRRSV VACCINE TYPES
Killed PRRSV vaccines are safe but, compared to MLVs, have poor efficacy in addition to their need for an adjuvant and multiple doses. Better adjuvants may improve them in the future, he said.
Recombinant live vaccines likewise have drawbacks. For instance, they have the potential for broadening cross protection, but so far, only modest improvements have been seen and may come at the expense of specific protection.
Calvert also reviewed several types of experimental PRRSV vaccines. Examples are subunit protein vaccines, which have issues similar to killed vaccines, and DNA vaccines, which are expensive to make and difficult to license.
Experimental vectored vaccines are similar to the DNA vaccines, but questions remain about which proteins from which strains to use, and poly-epitope vaccines need better adjuvants for cross protection, he said.
1 Diaz I, et al. Characterization of homologous and heterologous adaptive immune responses in porcine reproductive and respiratory syndrome virus infection. Vet Res. 2012 Apr 19;43:30. doi: 10.1186/1297-9716-43-30.
2 Batista L, Pijoan C, Dee S, Olin M, Molitor T, Joo HS, Xiao Z, Murtaugh M. Virological and immunological responses to porcine reproductive and respiratory syndrome virus in a large population of gilts. Can J Vet Res. 2004;68:267-273.
3 Rahe MC, Murtaugh MP. Mechanisms of Adaptive Immunity to Porcine Reproductive and Respiratory Syndrome Virus. Dixon L, Graham S, eds. Viruses. 2017;9(6):148. doi:10.3390/v9060148.
4 Charoenchanikran P, et al. Efficacy of Fostera PRRS modified live virus (MLV) vaccination strategy against a Thai highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) infection. Trop Anim Health Prod. 2016;48:1351-1359.
5 Choi K, et al. Comparison of commercial type 1 and type 2 PRRSV vaccines against heterologous dual challenge. Vet Rec. 2016;178:291.