Manipulation of the Immune Response Vaccination April 11, 2008 Dr. Conrad

Vaccination Concept that the IR can be specifically manipulated so that the memory adaptive response will prevent a specific disease. Name comes from vaccinia – the virus family that caused smallpox. Countless lives have been saved as a result of vaccination.

On the 14th of May 1796 a milkmaid, Sarah Nelmes, came to Jenner with cowpox. He devised a brave and dangerous experiment. He passed on the disease to James Phipps - his gardener's son - by scratching his skin with infected metal. (vaccination). When James had recovered from the cowpox, Jenner tried to give him smallpox. James failed to contract the disease.

Smallpox Vaccination Give disease intentionally – lower lethality but still problematic. Related mild disease – cowpox – shares antigens and gives protection.

Vaccine Strategies Few pathogens have a mild “cousin” which can be used like cowpox. Most viral vaccines today –. Killed by heat or irradiation. Inactivated. Attenuated (best) – done by passage in non-human hosts. Subunit vaccines – using coat protein important for infectivity. HbsAg.

Attenuated virus example --

Reasons for Viral Vaccine Failures Virus may directly attack immune system – HIV best example. Rapid mutation – change coats – HIV/influenza. Multiple strains – rhino virus. Latency period – herpes/HIV.

Bacterial Vaccines… For whole bacteria – again attenuated strain is the best, but rarely available. Bacille Calmette Guérin (BCG) for TB. S. typhi – typhoid fever – mutant strain that lacks LPS necessary for pathogenicity.

Bacterial Vaccines… Toxin vaccination – probably the most common type of vaccine in use today. DPT vaccine gives protection against diptheria, tetanus and whooping couph (killed pertussis or engineered component vaccine). Generally toxoid, rather than toxin, is used as the vaccine. Antigenicity is preserved, but no longer toxic.

Bacterial Vaccines… Subunit vaccines – e.g. Purified capsular polysaccharides – good efficacy in adults. Variety is to attach to a protein carrier – then is effective at all ages. Conjugate vaccines

Increase in disease associated with decrease use of vaccine (Data from UK).

Adjuvants Complete Freund’s adjuvant (CFA) mineral oil with heat killed mycobacteria – very strong inflammatory response. Aluminum hydroxide (alum) – approved for use in humans – gives th2 direction. ISCOMs – immune stimulatory complexes – lipid carriers with minimal toxicity – gets antigen into cytoplasm to induce CTL.

Route of Vaccination Injection Scarification Nasal or oral route – Better mimic of infection Less traumatic

Vacccination As an Inadvertant Cause of Disease Attenuated vaccine. “Back mutates” to reacquire pathogenicity – polio vaccine rate is 3/106. Give killed vaccine first – then attenuated. Immune compromised individuals – not able to handle even the attenuated pathogen. As disease incidence comes down – resistance to vaccination goes up. Fear of side effects replaces fear of disease. DTaP.

Correlation Between Disease Prevalence and Need for Vaccine WHO declaration that smallpox was eliminated. Concept of “herd immunity.” Smallpox vaccination no longer recommended. Herd immunity is also lost. Concern for safety can be misplaced.

Reasons for Lack of Vaccines… Most of the diseases which are recalcitrant are chronic diseases – whereas successful vaccines are against acute diseases. Chronic pathogens cannot be eliminated by IR without assistance. Pathogens frequently subvert the IR. Vaccines must stimulate a different IR than disease itself – more difficult. Why ?

New Vaccine Strategies Complete genome for pathogens is or will be soon available. Subunit vaccines from cloned components of pathogen. Incorporation into adjuvants so that good response is obtained. Stimulate T cell (esp CTL) response – current vaccines are primarily Ab response.

New Vaccine Strategies Interesting new approach is to use DNA from pathogen. Bacterial DNA stimulates inflammation due to non-methylated CpG motifs – we have a “toll” receptor for this DNA which promotes inflammation. Generate “appropriate” response – Th1 instead of Th2, best example. Use IL-12 in vaccine

Summary Vaccination is the “big success” story of immunology – has given increased quality and quantity of life. Approach needs to be refined so as to work with the chronic pathogens that currently cause the most health problems in our society. WITH TIME – THIS WILL BE SUCCESSFUL!