Anti-Viral Vaccines

1. Anti-Viral Vaccines Sarah Pham Medicinal Chemistry March 27, 2008

2. Virus Basics • Viruses are intracellular parasites unable to survive without a living host • Non-living; do not follow Koch’s Postulates • They cannot reproduce or metabolize on their own because they lack the self-machinery to do so • Obligately replicate inside host cells using host metabolism • A single infectious virus particle is termed a virion that acts as the vehicle for transmission • All viruses consist of either double- or single-stranded DNA or RNA that is linear or circular (or fragmented)

3. Virus Basics • NucleicAcid: Viral DNA or RNA enclosed within the capsid that will be replicated within the host cell • Capsid: Made of proteins surrounding the nucleic acid of a virus. It is made of capsomer subunits that serve as a protective shield. It is also responsible for attachment and penetration of host cell. • Envelope: Some viruses’ capsids are enclosed by a protective envelope consisting of glycoproteins that comes from the host cell. It is used for cell recognition and attachment

4. Virus Basics

5. Vaccines [Background] • Vaccine comes from the Latin word “vacca” which pertains to “cows” • Based on the practice of variolation which was inoculating healthy individuals with weak forms of smallpox • 1st Vaccine (1796): Edward Jenner inoculated milkmaids with cowpox to confer protective immunity against smallpox. • 1st Attenuated Vaccine (1885): Louis Pasteur developed a vaccine to protect against rabies; vaccine is made from viable virus with reduced virulence (lower degree of pathogenicity).

6. Vaccines [Background] • Most damage to a cell is done too early before any clinical symptoms of disease appear. Treatment becomes difficult, therefore, prevention is preferred over post-exposure vaccines. • The Main Idea: Vaccines contain a weak form of a virus/microbe that is not pathogenic • Vaccines are used to protect a large number of people – fight against epidemics and pandemics. • Good vaccines elicit a secondary immune response that will eliminate the pathogen.

7. The Immune System & Response • Once vaccinated, the immune system takes a week and upwards to begin fighting off the organism. • Immunity is conferred once the immune system is “trained” to resist a certain disease a vaccine is developed for • Artificially Acquired Immunity is provided • Childhood vaccinations are highly encouraged against: • Measles, Mumps, Rubella, Polio, Hepatitis A & B, Diptheria, Pertussis, Tentanus, Chicken Pox, HIB, Rotavirus, Meningococcal disease, and Influenza.

9. The Immune System & Response • Macrophages: white blood cells that detect and engulf viral antigens; microbes are carried to lymphocytes • Within lymph nodes, T and B cells are activated • T cells: able to recognize virus infected cells early in infection period and release cytotoxins to destroy them • B cells: secrete antibodies that bind antigens on the virus surface. This coats the virus and prevents infection. B-cells can also recognize virus infected cells late in infection • Ideally, good vaccines evoke both T and B cells • Antibodies will activate macrophages to “eat” viral antigens

10. The Immune System & Response • Elimination of the disease will leave many T and B cells to convert into memory cells • Recovering from the infection leaves you with a supply of memory cells that will protect against future infection

11. Vaccine Types LIVE (ATTENUATED) VACCINES • consist of a live form of the virus that has been artificially weakened; select for mutants that will cause wild-type infection without onset of disease • Usually only takes 1 or 2 doses to confer life long immunity (childhood vaccines). • Must be careful of the small chance of reversion to a more virulent form • Elicit good immune response, inexpensive, but must be cautiously stored to maintain viability

12. Vaccine Types INACTIVATED VACCINES • Using heat, radiation or chemicals a virus is killed and is no longer infectious • WHY USE AN INACTIVATED VIRUS? • Attenuated strains have yet to be developed • Reversion to virulent forms is a high occurrence • Requires no refrigeration • The downside is that the immunogenicity is lowered and multiple doses will be required (i.e. booster shots) • Adjuvants: administered simultaneously to enhance immune response • Combination vaccines: DTP and MMR • More expensive to prepare

13. Vaccine Types SUBUNIT VACCINES • Vaccines only contain the antigens of a virus to stimulate an immune response • Usually safer than attenuated or inactivated vaccines • Chances of reversion are low • Subunits are recognized by antibodies • Finding the correct subunit or specific antigen/protein that antibodies will recognize is a much more complex process • Yields low success rates and effects, but has great potential

15. Vaccines – a method of prevention • Influenza • Nearly 40,000 deaths and 115,000 hospitalized yearly in US • Educated guess on most probable form of virus • Also comes in nasal spray of attenuated form • New vaccines must always be produced due to high antigenic variation • At risk individuals (elderly, immunodeficient) should be vaccinated

16. Vaccines – a method of prevention • HIV • Currently in use: subunit, recombinant, and DNA vaccines • Method: • Inhibit fusion to host cell • Inhibit reverse transcriptase • Stops any viral integration into host cells • Targets functional HIV viral proteins • Viral exit form host cell is stopped • HIV continuously mutates and recombines to escape effects of vaccine • It can also be transmitted as a free virus

17. Vaccines – a method of prevention • HPV – Human Papillomavirus • Genital HPV most common sexually transmitted infection in US • Cause of cervical cancer, genital warts, anal & penile cancer • By the age of 50, 80% of women will have contracted at least 1 strain of the virus • Fortunately, many strains can be cleared by immune system before symptoms occur • HPV vaccine is a preventative measure against initial infection

19. Vaccines – a method of prevention • HPV – Human Papillomavirus • Types 16 and 18 cause 70% of the cases of cervical cancer and types 6 and 11 cause 90% of genital warts • HPV Vaccine, Gardasil, protects against these strains • Pap smears are still recommended since there are over 100 HPV strains identified, many of which can also cause cancer

20. Vaccines – a source of controversy • Some health critics say vaccination benefits are exaggerated. Claim that vaccines are not solely responsible for reducing mortality rates of any one disease. • Opponents find that even vaccinated individuals still contract disease • Adverse effects (although RARE) can be worse than the naturally occurring disease • Vaccine schedules are not designed for multiple exposure to immunogens at young ages • Some diseases and conditions (leukemia, MS, SIDS) have increased with the use of vaccinations • Some vaccines contain mercury, formaldehyde, neomycin, and other toxic chemical components

21. Vaccines • BE SMART! • Vaccines still most effective preventative measure you can take to protect yourself from disease • Remains one of the most affordable methods • Not only are you protecting yourself, you are protecting everyone around you.

22. References 1. Vaccineinformation.org – Vaccine information for the public and health professionals 2. Wolfe R, Sharp L (2002). "Anti-vaccinationists past and present". BMJ325 (7361): 430–2. 3. Bonhoeffer J, Heininger U (2007). "Adverse events following immunization: perception and evidence". Curr Opin Infect Dis20 (3): 237–46. 4. Advanced Drug Delivery Reviews, 2004 (Vol. 56) (No. 10) 1367-1382 Morein, B., Hu KeFei, Abusugra, I 5. Immunization. MedlinePlus. U.S. National Library of Medicine (2007-12-27). 6. Plotkin, Stanley A. (2006). Mass Vaccination: Global Aspects - Progress and Obstacles (Current Topics in Microbiology & Immunology). Springer-Verlag Berlin and Heidelberg GmbH & Co. K. 7. Lombard M, Pastoret PP, Moulin AM (2007). "A brief history of vaccines and vaccination". Rev. - Off. Int. Epizoot.26 (1): 29–48. 8. Melinda Wharton. National Vaccine Advisory committee U.S.A. national vaccine plan 9. Cdc.org – Center for Disease Control website 10. Strathern, Paul (2005). A Brief History of Medicine. London: Robinson, p. 179. 11. Flint, S.J. Principles of Virology. 2nd edition. 2004. ASM Press: Washington D.C.