Medical Officer of Health Medical Director, Travel Health and Tropical Medicine Services Winnipeg Regional Health Authority

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1 DNA Vaccines The Future of Travel Health Vaccines? Or Just a Bad Idea? Dr. Pierre J. Plourde Medical Officer of Health Medical Director, Travel Health and Tropical Medicine Services Winnipeg Regional Health Authority Professor Department of Community Health Sciences Department of Medical Microbiology and Infectious Diseases University of Manitoba

2 Conflict of Interest Statement Faculty Pierre Plourde M.D. FRCPC Relationships with commercial interests: Grants/Research Support: I wish Speakers Bureau/Honoraria: I wish Consulting Fees: I wish Other (s.a. major shareholder): I wish April 2018

3 Objectives Describe DNA vaccines and how they differ from traditional vaccines Explain how DNA vaccines are administered and how they work Describe advantages and disadvantages of DNA vaccines Conceptualize future applications of DNA vaccines

4 What is a DNA Vaccine? Vaccines contain primarily DNA coding for specific proteins (antigens) from a pathogen DNA injected into cells (muscle, dermal) Cells use the DNA to synthesize proteins (antigens) Proteins (antigens) processed by host cells, displayed on their surface, recognized as foreign, triggering immune responses

5 DNA vaccines have it all! From: J Int Med 2003;253:

6 Types of Vaccines Injectable influenza vaccine Yellow fever vaccine SPf66 malaria vaccine HBV vaccine Incompetent adenovirus type 5 HIV vaccine HIV, HPV, influenza, HBV, HCV, Zika virus, Ebola virus, MERS coronavirus, malaria, breast cancer, colorectal cancer, lymphoma, melanoma vaccines HPV vaccine Live recombinant salmonella HIV vaccine From: GenScript website

7 How a DNA Vaccine is made Figure out antigen against which neutralizing antibodies and/or CMI is elicited End product is extraction and purification of DNA plasmids Locate antigen producing gene Build a plasmid DNA including antigen producing gene Rapidly manufacture large amounts of new plasmid DNA with antigen producing gene (in yeast or bacteria) From: GenScript website

8 How a DNA Vaccine is delivered From: J Int Med 2003;253:

9 How a DNA Vaccine is delivered From: J Int Med 2003;253:

10 From: Human Vaccines & Immunotherapeutics 2013;9(10):

11 So What is Electroporation? From: Mol Biotechnol 2009;41:

12 From: Microbial Cell Factories 2005;4:26

13 Results Zika virus DNA vaccine (2016) Phase 1 study 40 US adults (Aug/Sept 2016) Fig 3B. Neutralizing Antibody Response (ID with EP at 0, 4, and 12 weeks) From: NEJM Oct 2017 DOI: /NEJMoa

14 Results Zika virus DNA vaccine (2016) Fig 5B. ZIKV Infection in IFNAR Mice Injected with Serum from Participants Week 14 serum drawn from volunteers after vaccination at 0, 4, and 12 weeks Control mice injected with saline 92% survival of mice injected with Week 14 serum; all mice injected with baseline serum or saline rapidly died From: NEJM Oct 2017 DOI: /NEJMoa

15 Injection Site Pain From: Human Vaccines & Immunotherapeutics 2013;9(10):

16 Figure 4. Immunogenicity at baseline and 4 weeks after last vaccination, measured by intracellular cytokine staining showing T-cell responses Phase 1 Zika virus DNA vaccine study 125 US adults (Aug/Sept 2016) Lancet

17 Results HIV DNA vaccine ( ) Phase 1 study 168 US adults (Oct 2007-May 2010) Figure 4. T-cell response rates for PENNVAX-B DNA vaccine plus interleukin-12 arms, comparing intramuscular (IM) delivery and IM delivery with electroporation (EP) at 0, 4 and 12 weeks From: J Infect Dis. 2013;208(5):

18 Results Avian Influenza A H5 DNA vaccine (2009) Fig 2 - H5 antibody responses Fig 3 - H5 HA CMI responses From: Vaccine. 2010;28:

19 New Approaches to Influenza Vaccines N Engl J Med 2010;33:

20 Recombinant DNA Approaches to Influenza Vaccines N Engl J Med 2010;33:

21 Results HPV cervical cancer therapeutic DNA vaccine (2012) Fig. 3 Robust HPV16/HPV18 E6/E7 specific T H 1-biased cellular immune responses after vaccination with VGX-3100 (IM with EP) at 0, 4, 12 weeks Phase 1 study 18 US women with high grade cervical dysplasia/cin2/3 From: Sci Transl Med. 2012;4:155ra138

22 Results HPV cervical cancer therapeutic DNA vaccine (2012) Phase 1 study 18 US women with high grade cervical dysplasia/cin2/3 Fig. 5 Strong memory T cell responses 24 weeks after vaccination with VGX-3100 delivered IM with EP at 0, 4, and 12 weeks From: Sci Transl Med. 2012;4:155ra138

23 Results HPV cervical cancer therapeutic DNA vaccine ( ) Phase 2b study in 167 women from US, Estonia, SA, India, Canada, Australia, Georgia with high grade cervical dysplasia/cin2/3 Fig. 2 Clinical Efficacy of HPV DNA vaccine delivered IM with EP at 0, 4, and 12 weeks From: Lancet. 2015;386:

24 Wide Range of DNA Vaccines From: Clin Infect Dis 2011;53:

25 Advantages of DNA over Traditional Vaccines DNA Vaccines Non-infectious (uses only the DNA from infectious organisms) Stimulates both humoral and cell mediated immunity Minimal storage requirements (no refrigeration needed; no cold chain) Traditional Vaccines Uses weakened/killed form of infectious organism (risk of reversion to pathogenic organism) Stimulates primarily humoral immunity Usually requires refrigeration (with cold chain challenges) Inexpensive to mass produce Expensive to mass produce Rapid timeline to mass production Many months to mass production

26 Where to from Here? Great potential for large scale production of efficacious DNA vaccines Synthetic DNA vaccines can be rapidly mass produced at relatively low cost But are there any risks of DNA vaccines?

27 Cautions Integration of DNA plasmid into host genome Insertional mutagenesis Chromosomal instability Turning ON oncogenes Turning OFF tumour suppressor genes Over expression of DNA plasmids Acute or chronic inflammatory responses Anti DNA antibodies Autoimmune diseases Antibiotic resistance genes in plasmids

28 Challenges Limited to protein immunogens (not useful for non-protein antigens such as bacterial polysaccharides) Uncertainty over long term immunity (how many priming doses needed and is there need for booster dosing?) Marketability of electroporation (or minielectrocution!) or biolistic bombardment (with a gene gun ) Infection control issues with electrodes

29 The Gene Gun The Helios Gene Gun is a new way for in vivo genetic immunization (DNA vaccination). This gun uses Biolistic particle bombardment where DNA-coated gold particles are loaded into the gun and you pull the trigger. A low pressure helium pulse delivers the DNA-coated gold particles into virtually any target cell or tissue.

30 Conclusions After over a decade, human DNA vaccines are still in their early phases There are currently no marketed human DNA vaccines But this just the beginning Stay tuned - DNA vaccines are going to be the vaccines of the future!

31 DNA Vaccines The Future of Travel Health Vaccines? Or Just a Bad Idea? Dr. Pierre J. Plourde Medical Officer of Health Medical Director, Travel Health and Tropical Medicine Services Winnipeg Regional Health Authority Professor Department of Community Health Sciences Department of Medical Microbiology and Infectious Diseases University of Manitoba