WILL GENOMICS SPELL THE END OF VACCINES?

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By John C. S. Harding, DVM, MSc, Dipl ABVP (Swine Health Mgmt) Western College of Veterinary Medicine, University of Saskatchewan

During the last fifty years or so, disease control in the pork industry has evolved mainly relying on antimicrobials, vaccines, elimination (depopulation, repopulation, eradication, modified early weaning), and/or regional control depending on the diseases of concern and resources available. Looking forward, it is clear that antimicrobial usage, under increasing scrutiny for both metaphylactic and therapeutic uses will decline, whereas the use of vaccines will likely rise. Although killed and avirulent live vaccines represent the majority of products available to pork producers at present, they are likely to be augmented or replaced by novel vaccine technologies such as response-specific adjuvants, subunit, DNA or particle vaccines, and novel delivery strategies.That being said, it is unlikely that vaccines alone will deliver the health improvements needed to sustain the industry in future decades.

 

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Whereas antimicrobials and large-scale application of vaccines revolutionized human and livestock health in the 20th century, the application of genomics will revolutionize health care, including swine health, in the 21st. In terms of swine health, genomics involves the use of molecular technologies to identify genes or genomic regions that are associated with phenotypes with increased or decreased susceptibility to one or more diseases or conditions. The application of genomics has already had a positive impact on swine health, with notable examples including the discovery of the HAL-1843 mutation associated with porcine stress syndrome (PSS) in the early 1990's1 and the recessive FUT1 mutation associated with resistance to F18 E. coli diarrhea2 in ~2000. However, the remarkable decrease in the cost of sequencing and the completion of the human and other genome projects has recently enabled the genome wide investigations of complex and potentially polygenomic health traits.  Moreover, technologies are rapidly expanding to encompass related 'omic disciplines of transcriptomics, kinomics, epigenomics, and metabolomics. These tools will continue to be applied to improve swine productivity, health and welfare in the same way they are forging personalizing medicine for humans.

It is, however, also unlikely that genomics alone will solve all of the swine industry's disease challenges in the 21st century.  While it may be theoretically possible to develop lines of pigs with complete resistance to individual pathogens such as F18 E. coli2, and more recently PRRSV3, the time and resources needed to tackle all of the industry's important pathogens are enormous.  Similarly, in spite of recent genomic discoveries related to the susceptibility to PRRSV4, 5 and PCV26, decreasing pathogen susceptibility is equally difficult as variation in susceptibility is largely polygenic in nature, involving a large number of widely distributed genes, each accounting for a small proportion of the total variation.  An alternative approach, which up to now has had mixed results, may be to focus on improving disease resilience, that is, improving the animal's to respond to a pathogen in a way that minimizes the impact of the disease7. These inherent difficulties make it clear that genomic-based strategies targeted at improving swine health should be viewed as valuable tools in our toolbox, rather than silver bullets.

The complexity of host-pathogen interactions and modern swine production ecosystems necessitates integrated, multifaceted prevention and control strategies incorporating biosecurity, judicious antimicrobial intervention, vaccines, and increasingly, the 'omic technologies. Genomics will not spell the end of vaccines in human or animal health, but to be most effective, the two approaches must be integrated.  The important question is: "how can the application of genomics build on the successes of vaccinology to improve swine health?" I believe there are thee main ways.

  1. Application of genomics to select animals with a superior vaccinal immune response.

    The antibody and cell mediated immune response to vaccines varies widely even within homogeneous populations of animals. Take for example a standard two dose Mycoplasma hyopneumonia vaccine administered to a group of 100 animals at 4 and 7 weeks of age (Harding, unpublished).  Serum antibody (IgG) titres measured two weeks after booster vaccination varied widely, ranging from a low of 1:86 to a high of 1:19178 (mean 1317 ±3579).  Cell mediated responses, assessed by the number of interferon gamma secreting cells in peripheral blood were equally variable. While it can be argued that challenge experiments, rather than in vitro tests, are better indicators of protection following vaccination, there should be little debate that the immune response is variable and vaccine-induced protection never 100%. Hence, if genomics and other 'omic technologies (transcriptomics, kinomics, etc) could be used to select replacement gilts and boars which have more robust, balanced immune responses there will be better protection across the population and fewer vaccine failures.


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  2. Application of genomics to identify high-risk subpopulations which justify higher-end vaccine strategies and monitoring.

    By nature, the immune response varies resulting in individuals within a population having increased or decreased susceptibility to a given pathogen. The underlying mechanisms could be related to an increase or decrease in overall immune response, or a particular bias towards intracellular (Th1) or extracellular (Th2) immunity in an individual animal.  This natural variance within a population is further compounded by any biases or weaknesses in the immune response related to the breeds or genetic lines available in various regions around the world. In spite of this obvious heterogeneity within and between populations of breeding or feeding animals, the swine industry tends to vaccinate populations similarly, and conduct very little monitoring to ensure the target animals are adequately protected.  This is not particularly efficient. What if genomic-based tools could be used to identify subpopulations of animals that are at risk of a sub-optimal immune response following vaccination? As a minimum, the high-risk subpopulation could be more intensively monitored after vaccination, but preferably, a more intensive (higher end) vaccination strategy could be used in these animals. This would help ensure the high-risk subpopulation is adequately protected prior to exposure, regardless of any underlying weaknesses or biases in their individual immune response.

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  3. Novel niche-market vaccines designed for specific to populations based on their anticipated immune response phenotype.

    An alternative approach to selecting animals based on their immune response phenotype, is to create vaccines specific to a given animal population.  At first glance this may not be popular for animal health companies with established products and markets and would present a number of regulatory hurdles. However, it may be an easier approach than developing animal populations with homogeneous immune responses. With continued consolidation it is likely that there will only be a half dozen companies providing genetics to the global swine industry in the next several decades, similar to the poultry industry.  If breeding lines provided by some of those companies differ in terms of their immune response phenotype, there may be sufficient demand to justify the development of a unique product for a given genetic line(s) of pigs. If not by the major pharmaceutical companies, then by niche-market biotech companies producing unique products containing novel adjuvants, antigen load, formulation or antigens; depending on what works best in the intended line of pigs. Moreover, producers in the future may have sufficient justification to ask vaccine manufactures whether a specific vaccine has been developed and/or tested for efficacy in a given genetic line or breed. This may force vaccine manufacturers to more fully efficacy test products in several or all of the major genetic lines prior to licencing, to ensure the products are equally efficacious across various immune phenotypes.

 

In summary, we are fortunate to have many cost effective vaccines available for use in the global swine industry, and should applaud our industry partners for their efforts. That being said, disease control is more complex now that it once was for a multitude of reasons including large population sizes, globalization, dependency on pig transport, pathogen evolution and emergence. Vaccination programs of the future will require more innovative products, more sophisticated implementation, and more intensive monitoring strategies. It is also clear that advancements in the 'omic technologies will revolutionize health care in the next 30-50 years to levels beyond our present comprehension. As industry leaders, it is in our best interest to exploit the opportunity to integrate genomics with vaccinology to enhance swine health, as neither vaccination nor genomics alone will be sufficient to control the disease challenges of the future.  It is time to embrace the next wave: personalized medicine for pig populations.

 

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Disclosure and a final word: The previous is a personal view, which is in no way influenced by a company nor intended to promote a company. It is, however, meant to be thought- provoking, and may be controversial for some. My views are based on my experience working as a clinical veterinarian for production systems and a genetics company, and more recently as a researcher involved in a number of swine health/genomics projects. I would like to thank the many experts whom I have worked with in various capacities over the last 30 years, which have helped to foster the ideas presented today. 

References

1. Otsu K, Khanna VK, Archibald AL, Maclennan DH. Cosegregation of porcine malignant hyperthermia and a probable causal mutation in the skeletal-muscle ryanodine receptor gene in backcross families. Genomics. 1991;11:744-750.

2. Meijerink E, Neuenschwander S, Fries R, Dinter A, Bertschinger HU, Stranzinger G, Vogeli P. A DNA polymorphism influencing alpha(1,2)fucosyltransferase activity of the pig FUT1 enzyme determines susceptibility of small intestinal epithelium to Escherichia coli F18 adhesion. Immunogenetics. 2000;52:129-136.

3. Whitworth KM, Rowland RRR, Ewen CL, Trible BR, Kerrigan MA, Cino-Ozuna AG, Samuel MS, Lightner JE, McLaren DG, Mileham AJ, Wells KD, Prather RS. Gene-edited pigs are protected from porcine reproductive and respiratory syndrome virus. Nat. Biotechnol. 2016;34:20-22.

4. Boddicker N, Waide EH, Rowland RRR, Lunney JK, Garrick DJ, Reecy JM, Dekkers JCM. Evidence for a major QTL associated with host response to Porcine Reproductive and Respiratory Syndrome Virus challenge. J. Anim. Sci. 2012;90.

5. Koltes JE, Fritz-Waters E, Eisley CJ, Choi IS, Bao H, Kommadath A, Serao NVL, Boddicker NJ, Abrams SM, Schroyen M, Loyd H, Tuggle CK, Plastow GS, Guan L, Stothard P, Lunney JK, Liu P, Carpenter S, Rowland RRR, Dekkers JCM, Reecy JM. Identification of a putative quantitative trait nucleotide in guanylate binding protein 5 for host response to PRRS virus infection. BMC Genomics. 2015;16:(28May2015).

6. McKnite AM, Bundy JW, Moural TW, Tart JK, Johnson TP, Jobman EE, Barnes SY, Qiu JK, Peterson DA, Harris SP, Rothschild MF, Galeota JA, Johnson RK, Kachman SD, Ciobanu DC. Genomic analysis of the differential response to experimental infection with porcine circovirus 2b. Anim. Genet. 2014;45:205-214.

7. Plastow G. Solving health problems with genetics. Proc. London Swine Conference. London, Canada. April 1-2, 2015:84-89.