Porcine Reproductive and Respiratory Syndrome

Porcine Reproductive and Respiratory Syndrome: History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Infectious Diseases

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porcine reproductive and respiratory syndrome virus (PRRSV)
modified live virus (MLV) vaccine
attenuation
heterologous cross-protection
safety
reversion to virulence
recombination

1. Introduction

Porcine reproductive and respiratory syndrome (PRRS), characterized as reproductive failure in breeding pigs and respiratory distress in pigs of all age, is one of the costliest diseases disturbing the global swine industry [1,2]. It was initially reported as a “mystery” disease in the United States in the late 1980s and then outbreaks with similar clinical symptoms were also documented in Western European countries in 1991 [3,4]. Each type of PRRS virus (PRRSV), the causative agent, spread rapidly in its respective continent and eventually widely transmit to the most pig producing countries [2,5]. Subsequently, many virulent strains, quite distinct from early prototype strains, have been continually identified in the United States, China, and Eastern European counties [2,6,7]. Especially in 2006, an unparalleled, large-scale, atypical PRRS outbreak caused by the highly pathogenic variants was documented in China, later in Vietnam, and other Southeast Asian countries [8,9,10]. This event has reformed the concept of pathogenicity and the economic impact of PRRSV. Nowadays, PRRSV remains ongoing through the swine population globally [11].

PRRSV is an enveloped, single-stranded positive-sense RNA (+ssRNA) virus, belonging to the family Arteriviridae, genus Porartevirus [12,13]. There are two species PRRSV-1 (type 1) and PRRSV-2 (type 2), which only share approximately 60% nucleotide sequence identity, and they are recently classified as Betaarterivirus suid 1 and Betaarterivirus suid 2, respectively, in the genus Betaarterivirus (EC 51, Berlin, Germany) (https://talk.ictvonline.org/taxonomy/p/taxonomy-history?taxnode_id=20171832, accessed on 1 July 2019) [14,15,16]. Based on the phylogenic analysis of the ORF5 gene, PRRSV can be divided into at least nine distinct genetic lineages within type 2 virus, and 3 subtypes within type 1 virus [17,18]. A nearly worldwide epidemic has been sustained by a set of emerging and re-emerging strains, attributed to its high-frequency mutation (reported evolutionary rate of 4.7–9.8 × 10⁻²/site/year) and recombination [19,20,21]. As PRRSV continues to rapidly spread in pig-raising regions worldwide, and its prevalence in the herds remains high, PRRS prevention and control are still the top priorities for pig farms.

Since the first animal vaccination was documented in the year 1872, the vaccine has been widely used for preventing and controlling infectious disease in livestock [22]. As one of the main tools to improve animal health and to reduce/limit pathogens transmission, the vaccine is desired to increase the production of livestock in a cost-effective manner. In addition, vaccinations are also considered to play important roles in reducing antimicrobial use and avoiding the emergence of antimicrobial resistance, as well as improving animal welfares [23]. A modified live virus (MLV) vaccine, the first commercial PRRS vaccine, was launched in the United States in 1994 [24]. Then, the PRRS MLV vaccine has been widely used for almost three decades (Table 1), and it is the major commercial vaccine that can successfully induce a protective immune response against the homologous virus and help in reducing the clinical sign and virus shedding during the heterologous viruses infection. However, it fails to confer sterilizing immunity against various field viruses and cannot provide solid protection against heterologous field strains [1,11,24,25]. Since the PRRS MLV is a leaky vaccine that can prevent the development of disease symptoms, but do not protect against infection and the onwards transmission of pathogens. As well, as in the field virus, MLV can still replicate in a subset of monocyte-derived cells of the host and modulate the immune response, as well, it has the potential issues of reversion to virulence and recombination with field strains, its safety has significantly been concerned [26,27]. Considering that the development and commercialization process of a novel PRRS vaccine cannot always match the speed of mutation and recombination in field strains, the chance for a commercial vaccine to provide homologous protection is limited. Thus, in the field of veterinary practices and pig producers, there are some debates regarding if it is valuable or necessary to use the PRRS MLV, given its leaky characterization [28]. To provide insights on vaccination efforts and the safety of PRRS MLV, the recent advances and opinions on MLV attenuation, protection efficacy, and safety concerns, as well as next-generation vaccine design are reviewed here.

Table 1. Commercially available porcine reproductive and respiratory syndrome (PRRS) modified live virus (MLV) vaccines.

Vaccine	Parental Strain	Species/Type	Lineage	Producer/Developer
Ingelvac PRRSFLEX^® EU	94881	PRRSV-1	lineage 1	Boehringer Ingelheim
ReproCyc^® PRRS EU	94881	PRRSV-1	lineage 1	Boehringer Ingelheim
Pyrsvac-183^®	All-183	PRRSV-1	-	Syva
Unistrain^® PRRS	VP-046 BIS	PRRSV-1	lineage 1	Hipra
Amervac^® PRRS	VP-046	PRRSV-1	lineage 1	Hipra
Porcilis^® PRRS	DV	PRRSV-1	lineage 1	MSD Animal Health
Suvaxyn^® PRRS MLV	96V198	PRRSV-1	lineage 1	Zoetis
Prevacent^® PRRS	RFLP 184	PRRSV-2	lineage 1	Elanco
Ingelvac PRRS^® MLV	VR-2332	PRRSV-2	lineage 5	Boehringer Ingelheim
R98	R98	PRRSV-2	lineage 5	Nanjing Agricultural University
PRIME PAC^® PRRS+	Neb-1	PRRSV-2	lineage 7	MSD Animal Health
Ingelvac PRRS^® ATP	JA-142	PRRSV-2	lineage 8	Boehringer Ingelheim
JXA1-R	JXA1	PRRSV-2	lineage 8	Chinese Center for Animal Disease Control and Prevention
GDr180	GD	PRRSV-2	lineage 8	China Institute of Veterinary Drug Control
CH-1R	CH-1a	PRRSV-2	lineage 8	Harbin Veterinary Research Institute, CAAS
HuN4-F112	HuN4	PRRSV-2	lineage 8	Harbin Veterinary Research Institute, CAAS
TJM-F92	TJ	PRRSV-2	lineage 8	Institute of Special Animal and Plant Sciences, CAAS
Fostera^® PRRS	P129	PRRSV-2	lineage 8	Zoetis
PRRSV-PC	PC *	PRRSV-2	lineage 8	China National Pharmaceutical Group

Note: * A chimeric virus between the classical malicious PTK strain of PRRSV and HP-PRRSV strain, constructed by reverse genetic operation.

2. Protection Efficacy of PRRS MLV

2.1. Protective Mechanism

PRRSV infects a subset of monocyte-derived cells with CD163 expression, such as primary pulmonary alveolar macrophages (PAMs) and pulmonary intravascular macrophages (PIMs), where the virus replication can cause dysfunction or even cell death by necrosis and apoptosis [45]. Meanwhile, PRRSV markedly suppresses the innate immune response and induces inflammatory injury by a variety of mechanisms. As well, PRRSV can cross the maternal-fetal interface (MFI) in the pregnant sow to infect fetuses, leading to reproductive failures [46]. Attenuated PRRSVs infect pigs and cause milder illnesses compared with the virulent wild-type counterparts from which they are derived. Meanwhile, they amplify the amount of antigen available for inducing an immune response in pigs. Since the replication of PRRS MLV mimics that of wild-type virus, the host immune response resembles what occurs after a viral natural infection. However, this is not observed in either inactivated or subunit vaccines [47].

Generally, vaccine-elicited protection relies on the vaccine-induced memory B and T cells. During the PRRSV infection, memory B cells against viral structural and nonstructural proteins are confirmed to be present before viremia is cleared [48]. Even though memory B cells appear to be quite abundant, it has been regarded that there was no anamnestic response to the viral challenge [49]. In the previous studies, almost all challenges were performed before the initial infection of MLV has been completely resolved. In these cases, the protective effect could be due to an ongoing immunity response from the first exposure, before the sterilizing immunity is established. Recently, Rahe et al. created a PRRSV nsp7-specific B cell tetramer to facilitate the detection of PRRSV-specific memory B cells in the lymphoid tissues through a long-term vaccination-challenge study and found that the PRRSV-specific memory B cell response is long-lived in the blood after vaccination and they can be boosted during a live virus re-exposure [50,51,52]. However, it is still too early to conclude whether protection is entirely dependent on PRRSV-specific memory lymphocytes or not.

For many cases of the virus, neutralizing antibodies (NAs) play a key role in protecting from viral infections [53,54,55]. However, for PRRSV, the protection from antibody-mediated neutralization is not very clear, due to the conflicting data from various studies. In the years just after PRRSV identification, the antibodies against PRRSV were initially thought of as an ineffective component of the PRRSV-protective immune response or even deleterious due to the antibody-dependent enhancement (ADE) concerns [56,57]. Generally, the PRRSV NAs in primary infection mainly appear at 28 or 35 day post-infection (dpi), when viremia has been already resolved. Several monoclonal antibodies (mAbs) targeting antigenic regions corresponding to the putative “major NA epitope” have been found to possess less activity [58]. Moreover, it has been demonstrated that M-GP5 ectodomain-specific antibodies purified from the PRRSV-neutralizing serum could bind to the virus but had no neutralization capability, suggesting that the antibodies binding to ectodomain alone are not sufficient to ensure a complete neutralization of PRRSV [59]. In addition, GP3 but not GP5 and M, is regarded as the major target of NA from sera of PRRSV-1 Lelystad virus infected-pigs [60]. This might be reasonable, as GP2, GP3, and GP4 have been confirmed to form a multi-protein complex that binds to the key receptor CD163, playing an important role in PRRSV infectivity [61,62,63]. In addition, once PRRSV ends its first-round infection into the cells, it can utilize nanotubes and exosomes for intercellular spread, resisting to antibody neutralization [64,65]. One more concern is about the NA testing process. Usually, NA titers of most sera are tested on MARC-145 cells, which is not the real host target cell. Our recent study has found that sera with a high NA titer even around 1:96, tested on MARC-145 cells, cannot completely block the PRRSV infectivity in any dilution when parallelly tested on PAMs [66]. This further indicates that the serum with NA titer tested on MARC-145 cells, might not be guaranteed to have the same level of neutralization capability in vivo. In contrast, some other studies have reported that the passive transfer of homologous neutralizing antibodies was shown to prevent reproductive failure and viral transmission to neonatal piglets [67]. In addition, NA titer has been considered as the best predictor of level and duration of viremia [68]. Meanwhile, high titers of broadly neutralizing activity in naturally infected pigs can provide cross-protection against heterologous PRRSV, which correlated with the clearance of the virus from the circulation and tissues [69,70,71]. Thus, the NAs might help reduce PRRSV infection, but cannot completely block the infection, implying that PRRSV might use some strategies to antagonize and escape it. Future studies are still needed to explore the possible mechanism.

Cell-mediated immunity (CMI) and innate immunity are believed to be the major protective mechanism against PRRSV infection [72,73,74,75,76,77]. However, cellular immune response in PRRSV-infected pigs is still poorly understood due to the difficulty of expanding antigen-specific T-cell populations in vitro and the deficiency of tools and reagents to examine antigen-specific responses in vitro or in vivo. Most evaluation on the CMI response was only based on interferon-γ (IFN-γ) ELISPOT or qPCR to test the level of IFN-γ after using PRRSV to stimulate the PBMCs, which were collected from the vaccinated pigs. However, the significance is uncertain, as the specific source of IFN-γ is difficult to further identify. The innate immune response to a PRRSV-1 vaccine (Porcilis^® PRRS, MSD) in the first 72 h post-vaccination (hpv) has been investigated through comparing of the PBMC transcriptome profiles at 6, 24, and 72 hpv, between vaccinated and unvaccinated pigs. The results showed that the MAP kinase activity, TRIF-dependent toll-like receptor signaling pathway, T-cell differentiation, and apoptosis were positively regulated, meanwhile, JAK-STAT pathway and regulation, TRAF6-mediated induction of NF-kB and MAPK, the NLRP3 inflammasome, endocytosis, and interferon signaling were downregulated during the early stage of PRRSV vaccination [78,79]. However, the detailed “cross-talk” among infected macrophages and B/T cells, related to the activation of the humoral and cellular immunity, has not been well investigated yet. Thus, the basic research on the mechanism of immune protection is the prerequisite for further improving the cross-protection efficacy of the PRRS MLV vaccine, especially against the heterologous strains.

Pigs are susceptible to PRRSV by direct or indirect exposure, via intranasal, oral, intrauterine, vaginal, and intramuscular routes [80,81]. Once an outbreak occurs, PRRSV tends to circulate within pig herds indefinitely. PRRSV-persistent pigs and the continually induced-susceptible animals can drive endemicity. Vaccination is usually considered as a relatively safer route to reach “herd immunity” [82]. To evaluate vaccine-afforded protection, vaccine trials routinely assess the efficacy at the individual level through immunological, virological, and pathological parameters. For an individual pig, the main objective of vaccination is to protect the animal from the infection and to lessen the clinical symptoms, thereby improving the health level of vaccinated pigs. While at the population level, the efficacy cannot be only evaluated in virological terms [83]. In epidemiological terms, the goal of vaccination is to decrease or even stop viral transmission within a swine farm and reduce infection-related economic losses [80,84,85]. On one side, the PRRS MLV vaccination can reduce the susceptibility of injected pigs, and on the other side, it also decreases the contagiousness of the individuals, by shortening the shedding period and reducing the viral load. Even the heterologous vaccination can decrease the duration of viremia and viral load, resulting in the reduced viral shedding. Several studies have assessed the R0 value of PRRSV transmission in the vaccinated and naïve pigs in the vaccination-challenge trials. For example, in two early studies, PRRSV-1 MLV vaccination could significantly reduce the R0 value (2.78 to 0.53 and 5.42 to 0.30, respectively), when inoculated with PRRSV-1 field strains with 93.4% or 92.7% of nucleotide similarity with the MLV, respectively [84,86]. In another study, an estimate of R0 for the vaccinated contact group was approximately 5.0, one half of that observed for the unvaccinated contact group (mode R0 = 10) [87]. Given the pig ages, MLV and inoculated virus were diverse, different models resulted in different R0 values. However, these results consistently suggest that even when a leaky vaccine cannot completely prevent pigs from heterologous infection, it can still have beneficial impacts on the transmission dynamics, contributing to the reduced R0 value in a pig herd.

2.2. Homologous Protection

Presently, it is a relative consensus that PRRS MLV has the highest protective efficacy against the genetically homologous virus, compared with commercially available KV or other kinds of vaccines under development. Numerous publications have described the protective efficacy of MLV under experimental or field condition, around the United States, Europe, and Asia [88,89,90,91]. At the individual level, the efficacy of PRRS MLV is generally described as protective against both reproductive failure and respiratory disorders, providing multiple benefits including but not limited to the reduction of clinical signs, lessened macroscopic and microscopic lung lesion and viremia, shortened viral shedding period and reduced secondary bacterial infection [30,92,93,94]. Reports in a gilts vaccination and late pregnant term challenge study have shown that MLV vaccination can improve the reproductive performance in sows and piglet health and overall viability, compared with unvaccinated sows [95,96,97].

Indeed, there is no fixed “cutoff value” for genetic similarity to classify the “homologous” or “heterologous” strains, the efficacy of homologous protection conferred by PRRS MLV is difficult to be predicted by sequence comparison, especially only based on the sequence of GP5. For example, the Chinese HP-PRRSV-derived MLV such as JXA1-R (P80), HuN4-F112, and TJM-F92 were all described to protect piglets from the lethal challenge of homologous strains, showing no obvious body temperature increase nor other clinical signs throughout the experiment [98,99,100,101,102]. This high protection efficacy could also be observed in the field during the initial years of the HP-PRRSV pandemic. In contrast, another study has reported that Lelystad-like MLV only provides partial protection against the field isolate of the same cluster, suggesting that the degree of genetic homology of ORF5 between the MLV vaccine and challenge isolate is not a good predictor for vaccine efficacy [103]. This is reasonable, as there is no evidence to support that the GP5 encoded by ORF5 is the only protection-related viral protein.

2.3. Heterologous Cross-Protection

PRRSV is well characterized by its mutability, which continually leads to the generation of novel variants, frequently causing an outbreak or re-outbreak in PRRS-stable herds, in which pigs have been previously vaccinated or acclimatized [1,24,104]. Lack of providing satisfied heterologous cross-protection against the rapidly evolving virus is the obvious deficiency for most PRRS vaccines, not only for MLV. At the individual level, MLV vaccination usually cannot induce sterilizing immunity to completely block the infection of heterologous strains [75,104,105,106,107]. However, many experimental vaccination-challenge trials or field studies have indicated that PRRSV vaccination can provide partial protection against heterologous strains, shown as delaying the onset of viremia, reducing the duration of viral shedding and significantly decreasing viral load throughout infection, not showing severe clinical signs as unvaccinated animals [75,97,106,108,109,110,111,112,113,114].

To investigate the cross-protection efficacy of commercially available PRRSV-1 and PRRSV-2 MLV against each type of virus, serial vaccination-challenge studies in growing pigs and pregnant gilts were carried out by Chae’s group. The clinical signs including body temperature, respiratory scores, viremia, viral shedding, macroscopic and microscopic lung lesion scores, PRRSV-antigen distribution in interstitial pneumonia, and productive performance such as duration of pregnancy, the ratio of stillborn, and numbers of weaning pigs, together with PRRSV-specific IFN-γ secreting cells in PBMC were all evaluated and compared among two types of MLV-vaccinated groups and unvaccinated groups. Generally, their results indicated that PRRSV-2 MLV was capable of providing partial heterologous cross-protection against the PRRSV-1 virus, but PRRSV-1 MLV was ineffective against PRRSV-2. Importantly, they also found that either PRRSV-1 or PRRSV-2 -specific IFN-γ-secreting cells in the PRRSV-2 MLV-vaccinated group were higher than the PRRSV-1 MLV-vaccinated group, which was regarded to attribute to unidirectional cross-protection between PRRSV-1 and PRRSV-2 [101,110,111,112].

The internal-type cross-protection was also widely investigated. Lager et al. have tested the efficacy of Inglevac PRRS^® MLV (from Boehringer Ingelheim, Ingelheim am Rhein, Germany) against Chinese and Vietnamese HP-PRRSV heterologous challenge in pigs, to demonstrate if this commercially available MLV in the United States could be used as an aid in the control of HP-PRRSV outbreaks. Their results indicated that vaccination decreased the duration of viremia and viral load, and shortened the time of high fever and reduced macroscopic lung lesions, compared with those of unvaccinated animals [101]. Similarly, after the United States-originated NADC30-like virus was identified to begin an epidemic in China, the cross-protection efficacy of commercially available vaccines against NADC30-like field strains was investigated by several research groups [107,115,116,117,118]. In our study, two commercial vaccines (JXA1-R and Inglevac PRRS^® MLV) and an attenuated low pathogenic strain HB-1/3.9-P40 were used to vaccinate pigs with the same dose as 2 × 10⁵ TCID₅₀, the data showed that vaccination in all three groups could not fully reduce the severe level of clinical signs and lung lesions caused by the NADC30-like virus. However, the Ingelvac PRRS^® MLV appeared to exert some beneficial effects on shortening the period of clinical fever and improving the growth performance of the challenged pigs [107]. The results of partial or limited cross-protection against the NADC30-like virus were also reported by other groups. The limited efficacy of cross-protection from commercial MLV vaccines against NADC30-like viruses might be an important reason that these viruses widely spread and became the predominant PRRSV strains in China [117,119,120,121]. Furthermore, the Fostera^® PRRS MLV from lineage 8 of PRRSV-2 is also confirmed to confer partial cross-protection against the heterologous challenge of a virulent PRRSV strain from lineage 3 [122]. To improve the heterologous protection efficacy, some immune boosters or regulators, such as quercetin and Quil A, which are regarded to be able to upgrade the mRNA expression of interferon and many other helpful cytokines, were orally taken or injected together with PRRS MLV. However, any significant improvement in heterologous cross-protection was not observed [123,124]. Some typical vaccination-challenge (homologous or/and heterologous) studies on different types of MLV are summarized in Table 2.

Table 2. Studies on evaluating cross-protection efficacy of commercial MLV vaccines

MLV	Challenge Virus	Species/Types (MLV/Challenge)	Homologous/Heterologous	Tested Animals	Parameters for Immune Response	Results and Reference
Porcilis^® PRRS	PR40/2014	PRRSV-1/PRRSV-1	Heterologous	Piglet	Ab and NAb	Triggered adaptive immunity against highly pathogenic strain, and reduced clinical indicators [125]
Amervac^® PRRS	KKU-PP2013	PRRSV-1/PRRSV-2	Heterologous	Piglet	Ab	A certain degree of protection against the PRRSV-2 challenge [126]
Amervac^® PRRS	01NP1	PRRSV-1/PRRSV-2	Heterologous	Piglet	Ab/IFN-α, IFN-β and IFN-γ	Upregulated IFN-α, IFN-β, and inflammatory cytokines and reduced PRRSV-2 viremia and number of viremic pigs [124]
Fostera^® PRRS	SNUVR090485	PRRSV-2/PRRSV-1	Heterologous	Piglet	Ab/IFN-γ secreting cells	Partial protection from the challenge of heterologous type 1 PRRSV and reduced viremia [111]
HuN4-F112	HuN4-F5	PRRSV-2/PRRSV-2	Homologous	Piglet	Ab and NAb	Protection from the lethal challenge [99]
Ingelvac PRRS^® MLV	VR-2332-P6, rJXwn06-P3, rSRV07-P3	PRRSV-2/PRRSV-2	Homologous/heterologous	Piglet	Ab	Partial protection against the homologous and heterologous PRRSV challenge [101]
JXA1-R	HV-PRRSV, NADC-20	PRRSV-2/PRRSV-2	Homologous/heterologous	Piglet	Ab and NAb/IFN-α and IFN-β	Protection from the challenge of HP-PRRSV or NADC-20, induced broadly neutralizing antibodies and enhanced pulmonary IFN-α/β production [90]
Ingelvac PRRS^® MLV	10186-614	PRRSV-2/PRRSV-2	Heterologous	Piglet	Ab	No prevention in viral shedding, reduced viral replication, and disease severity [127]
Ingelvac PRRS^® MLV/JXA1-R/(HB-1/3.9-P40)	CHsx1401(NADC30-like virus)	PRRSV-2/PRRSV-2	Heterologous	Piglet	Ab	Reduced clinical signs and lung lesions, shortening the period of clinical fever and improving the growth performance (Ingelvac PRRS^® MLV) [107]
PrimePac^® PRRS	dss	PRRSV-2/PRRSV-2	Heterologous	Piglet	Ab/Treg, IL-10, and IFN-γ	Partial protection against the Thai HP-PRRSV, based on body temperature, levels of viremia, and lung lesion [128]
Ingelvac PRRS^® MLV	1-4-4	PRRSV-2/PRRSV-2	Heterologous	Piglet	Ab and NAb/IFN-γ secreting cells (total lymphocytes, NK, CD4⁺, CD8⁺, and γδT cells)	No improvement in the efficiency of cross-protection (adjuvant M. vaccae WCL or CpG ODN), induced virus-specific T cell response (IM vaccination) [129]
Fostera^® PRRS	SNUVR090485	PRRSV-2/PRRSV-1	Heterologous	Gilt	Ab/IFN-γ secreting cells	Cross-protection against the PRRSV-1 challenge in late-term pregnant gilts, improved reproductive performance, and induced immunity lasting for 19 weeks at least [130]
Unistrain^® PRRS	SNUVR090485, SNUVR090851	PRRSV-1/(PRRSV-1 or PRRSV-2)	Heterologous	Gilt	Ab/IFN-γ secreting cells	Vaccinated pregnant sows with the PRRSV-1 MLV against PRRSV-1, but limited to PRRSV-2 in late-term pregnant gilts [95]
Ingelvac PRRS^® MLV	SNUVR090485, SNUVR100059	PRRSV-2/(PRRSV-1 or PRRSV-2)	Heterologous	Sow	Ab/IFN-γ secreting cells	Vaccinated pregnant sows with the PRRSV-2 MLV against PRRSV-2, but not to PRRSV-1 [131]
Unistrain^® PRRS/Fostera^® PRRS	SNUVR090485, SNUVR090851	(PRRSV-1 or PRRSV-2)/(PRRSV-1 + PRRSV-2)	Heterologous	Gilt	Ab/IFN-γ secreting cells	PRRSV-2 MLV vaccine is more efficacious than PRRSV-1 MLV against the dual heterologous challenge in gilts [132]

Given the extensive genetic and antigenic variation of PRRSV, most situations in the field can be considered as a “heterologous challenge”, as the field strains are more or less different from the commercial vaccine strains. Thus, improving the heterologous or even providing broadened cross-protection is one of the major requirements for designing a perfect PRRS vaccine. However, the unclearness of the mechanism on immunological protection greatly hinders the progress of PRRS vaccine development.

3. Genetically Modified Live Virus Vaccine

Since the first RNA-launched infectious cDNA clone of the Lelystad virus, the PRRSV-1 prototype, was successfully constructed, more than 20 distinct PRRSV infectious clones have been generated [24]. With the platform of reverse genetic operation, it is possible to artificially edit the virus by point mutations, truncations, gene insertion or fragment swapping between different strains, to identify the virulence factors, cross-protection antigens, and other factors related to protective efficacy and vaccine safety, which will contribute to the development of PRRS vaccine. An informative table summarizing the knockouts and knockdowns of viral genes and their influence on the viruses was presented in a previous review [24]. Furthermore, various strategies have been documented based on the reverse genetic operation. In order to improve the heterologous protective efficacy, viral genes or clusters of genes from strains with different antigenic characterizations were swapped to create the chimeric viruses or the recombinant viruses carrying DNA shuffled fragments or the conserved fragment of sequence from multiple strains were constructed. In addition, codon pairs de-optimization was also used for rapid attenuation of the virus. As well, foreign fragment including B-cell epitope, protective antigen, and adjuvant cytokines were inserted into the genome of PRRSV to create a marker vaccine, multivalent vaccine or protective efficacy-improved vaccine. These novel strategies and approaches to develop the next generation of vaccines have been well-reviewed before [11,57].

This entry is adapted from the peer-reviewed paper 10.3390/vaccines9040362

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