Session 27: Vaccines

Patricia Fitzgerald-BocarslyMay 18, 2009

A brief history of vaccination

• Immunity: comes from the Latin “immunis” meaning “exempt”

• Concept dates to 430 B.C. when Thucydides, the historian of the Peloponnesian War, wrote that those who had recovered from Plague could care for those with disease

• Variolation - used in ancient Asia; brought to Europe in 1721 by Lady Mary Wortley and subsequently used in the Revolutionary War

• 1796: Jenner used cow pox to protect from smallpox. The term “vaccination” (“vacca” is Latin for “cow”) derives from this.

History, cont.

• 1870’s: Koch proved that infectious diseases are caused by microorganisms- anthrax

• 1860’s-1880’s: Louis Pasteur developed vaccines against cholera quite by accident - attenuation.Coined “vaccine” in honor of Jenner. Also made first anthrax and rabies vaccines.

Vaccines do not prevent infection

But…They can prevent disease

THE GOAL OF IMMUNIZATION: MEMORY

Polio: another success story• 1952: 58,000

Americans contract polio

• Salk: inactivated polio vaccine - 50th anniversary last year

• Sabin: live vaccine• 1994: Western world

“free” of polio• Success leads to

modification of recommendation

Passive Cellular Immunity

• Transfer of NK cells or activated NK cells - LAK therapy

• Transfer of immune T cells - Tumor infiltrating lymphcytes

Lyme Disease

1998

Cholera toxin1992

Hepatitis B1986

Pertussis1981

Hepatitis B1981

Tetanus1927

Diphtheria1923

Pneumococcus2000

Haemophilus influenzae b

1987

Typhoid fever1998

Haemophilus influenzae b

1985

Meningococcus1982

Pneumococcus1977

Tick-borne encephalitis

1990

Hepatitis A1995

Japanese encephalitis

1992

Rabies1980

Polio1956

Influenza1936

Pertussis1914

Plague1897

Cholera1896

Typhoid Fever1896

Adenovirus1980

Rubella1969

Mumps1967

Measles1963

Polio1963

Smallpox1800

Yellow Fever1938

Tuberculosis1927

Rabies1880

LIVE VACCINESLIVE VACCINES

INACTIVATED VACCINESINACTIVATED VACCINES

POLYSACCHARIDE VACCINESPOLYSACCHARIDE VACCINES

PROTEIN VACCINESPROTEIN VACCINES

Varicella1996

Typhoid fever1985

Rotavirus1998

Cholera1995

Traditional Vaccine Approaches

Live, Attenuated

• Mimic natural infection without disease• Can be delivered at appropriate site• Classically done by passaging virus in foreign

host cells or by temperature• Often work with one administration - develop

good immunological memory and long-term protection. Major advantage in developing world

• Now can be done by deletion of virulence factors from the organism

Inactivated Vaccines

• Typically chemicaly inactivated -formaldehyde treated

• Advantages: Stable; safer than live vaccines; refrigeration not reqd.

• Disadvantages: Weaker immune response; boosters reqd.

• Salk vs. Sabin polio vaccines– Why the switch?

• Reversion 1:2.4 million; may spread through water system

Toxoid Vaccines

• Disease is caused by a toxin released by the organism

• Give chemically modified toxin - “toxoid”• E.g. tetanus, diptheria

Conjugate Vaccines - H. Flu

• Haemophilus influenzae– Infection problematic in young children– Antibody to capsular polysaccharides is protective– Young children respond poorly to polysaccharide

vaccines (T independent response weak; poor memory)

– Creation of polysaccharide-toxin conjugate enables child to respond

• H flu polysaccharides conjugated with tetanus toxoid, known to induce strong immune responses in children

Figure 6-37

Multi-valent subunit vaccine

LIPOSOME or ISCOMS: DELIVER ANTIGEN TO THE CYTOPLASM

VACCINIA VIRUS VECTORS

Dangers of Vaccination

Current recommendation: Salk

Flu also

Acellular

How do we know if someone is immune?

• Check for antibody - just knowing the individual is immunized isn’t enough– IgG vs. IgM - titer

• Measure T cell proliferation to antigen• Measure CTL responses• Skin test - e.g. PPD• Boosters: stimulate memory cells, raise

affinity, raise Ab titer

Does Immune Response = Immunity?

• Not Necessarily!– E.g. HIV-1 initially induces a good antibody

response, but it is not protective– HIV-1 vaccines that induce antibody

haven’t been protective

Why do I need a flu vaccine every year?

• Antigenic shift and antigenic drift: virus escapes immune response

• Short incubation time (2 days)– No time to activate memory cells– No time to boost antibody levels– Existing antibody might not be protective

anyway

What about the “Novel flu”?• “Novel flu” (AKA H1N1, swine flu)• Nearing pandemic levels - what does this mean?• Has genes from two swine flu viruses, common

human flu and bird flu• Arising by….. (fill in the blank)• Last seen at pandemic levels in 1957 - seems less

deadly than expected in older individuals, suggesting memory is helpful

• Young individuals more affected?– Unclear if this is holding up– “Cytokine storm” resulting in too robusts an immune

response?– Some immunity in older individuals

• Sensitive to antivirals (e.g. Tamiflu)• Vaccine?

Synopsis (from http://www.cdc.gov/h1n1flu/update.htm):During week 18 (May 3 - 9, 2009), influenza activity remained at approximately the same level as last week in the United States, indicating that there are higher levels of influenza-like illness than is normal for this time of year.

One thousand four hundred fifty-four (11.9%) specimens tested by U.S. World Health Organization (WHO) and National Respiratory and Enteric Virus Surveillance System (NREVSS) collaborating laboratories and reported to CDC/Influenza Division were positive for influenza.The proportion of deaths attributed to pneumonia and influenza (P&I) was below the epidemic threshold.Three influenza-associated pediatric deaths were reported.The proportion of outpatient visits for influenza-like illness (ILI) was above the national baseline. Three of the ten surveillance regions reported ILI above their region-specific baselines.Eight states reported geographically widespread influenza activity, 14 states reported regional activity, the District of Columbia and 15 states reported local influenza activity; and 13 states reported sporadic influenza activity.

Overall: 4,714 confirmed cases in US, 4 deaths. 14 in New Jersey

During a normal flu season, up to 20% of Americans are infected and up to 36,000 die.

What’s New…..• Flumist - live influenza vaccine, cold

attenuated• Papilloma virus vaccine - cervical cancer• Viral vectors - e.g. canarypox• DNA vaccines - stable at room temp.• DC vaccines - let the DC choose the

epitopes– tumors (melanoma, others), infectious disease

What’s Needed?

• Effective vaccines for HIV, HSV, EBV, malaria etc.

• Better compliance - e.g. measles - Can it be eradicated?

• Better adjuvants for human use– Adjuvants increase magnitude and duration of

response - stimulate expression of co-stimulatory molecules

– Most current vaccines induce Th2 responses• Asthma connection

– Need adjuvants that will favor Th1, costimulation• Inclusion of cytokine, plasmid DNA (CpG)

What’s needed (cont.)

• Safer vaccines• More effective vaccines• Cheaper vaccines - fewer whole

organisms?• Stable vaccines - no refrigeration

– DNA vaccines

Can we eradicate more diseases by vaccination?

• Smallpox vs. measles– Smallpox eradicated; goal to eradicate measles by

2010, but it’s still a major killer in 3rd world– Relatively low infectivity vs. higher infectivity.

• Herd immunity: the number of people needed to give immunity to population depends on the infectivity of the virus and the rate of vaccine “takes”; for measles, this required rate is much higher than for smallpox

– Man is only host for both (no animal reservoir); no latency

– Immunity lifelong to both but measles requires two doses

– Compliance: Timing and dosing; Should vaccination be a choice?

Other Vaccine Strategies

• Therapeutic vaccination- enhance host immune response against existing cells– Tumor vaccines: enhance immunity to

existing tumors.– Therapeutic vaccination in infectious

disease - turn on or switch to more protective immunity

• HIV?

Challenges to Developing an HIV Vaccine

Surface Glycosylation

Confirmational epitopes

Latency/Integration

Reservoir sites

Why we need a vaccine against HIV

Source: World Health Organization and Joint United Nations Programme on HIV/AIDS (UNAIDS) 2006 Report

Percentage of population in need receiving antiretroviral therapy

Worldwide variation of HIV

gp120 Subunit Vaccination Ineffective

February 24, 2003

LARGE TRIAL FINDS AIDS VACCINE

FAILS TO STOP INFECTIONBy ANDREW POLLACK WITH LAWRENCE K. ALTMAN

The first AIDS vaccine ever to be tested in a large number of people has failed, over all, to protect them from infection with the virus that causes the disease, the company that makes it, VaxGen, said today.

Viral Vectors

Poxviridae:– Canarypox– Fowlpox– Modified Vaccinia Ankara

Adenovirus In development –Semliki Forest Virus, VEE, alphavirus, AAV

Pre-exisiting anti-vector immunity is a limitationPriming with DNA vaccines improves immunogenicity

Merck STEP Trial Overview3000 HIV negative participants at high risk for HIV infection

Vaccinated with Ad5gag/ Ad5pol/ Ad5nef at months 0, 2, 6

Primary STEP Data Analysis

n (HIV neg) n (HIV pos) Incidence

Vaccine 741 24 2.92

Placebo 762 21 2.51

n (HIV pos) VL mean log

Vaccine 24 40,903 4.61

Placebo 21 25,862 4.41

Immunosuppressive/immunoregulatory Therapies

• Steroids• NSAIDS - ibuprofen, aspirin etc. - anti-

inflammatory• Cyclosporin, FK506 - inhibit signaling• Anti-histamines

Other immunotherapies• IFN-alpha/beta: MS, cancer, HCV

– Direct antiviral effects– Augment immune responses to viral, tumor Ags– Shift response in MS?

• Anti-TNF or TNF-R antibodies - rheumatoid arthritis, Crohn’s– Risk: severe infection

• Anti-IgE therapy for severe asthma, peanut allergy• “Allergy shots”: shift from Th2 to Treg - “desensitize”• Ascaris egg therapy: Crohn’s - shift from a Th1 to a

Th2 response• Gene therapy: e.g. ADA SCID