Anti-Viral Vaccines

Sarah Pham

Medicinal Chemistry

March 27, 2008

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)

Virus Basics

• Nucleic Acid: 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

Virus Basics

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).

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.

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.

• 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

The Immune System & Response

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

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

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

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

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

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

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

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

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

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.

References

1. Vaccineinformation.org – Vaccine information for the public and health professionals2. Wolfe R, Sharp L (2002). "Anti-vaccinationists past and present". BMJ 325 (7361): 430–2.3. Bonhoeffer J, Heininger U (2007). "Adverse events following immunization: perception and evidence". Curr Opin

Infect Dis 20 (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 plan9. Cdc.org – Center for Disease Control website10. 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.