Vaccines 1

Global Impact and Statistics of Vaccination

• Mortality Prevention: Vaccination prevents an estimated $2.5\text{ million}$ deaths annually.

• Current Mortality Gap: Despite vaccine availability, approximately $2.1\text{ million}$ people die every year from diseases that are preventable by widely used vaccines.

• Global Investment Goal: An investment of $3\text{ billion USD}$ a year could provide complete immunization coverage for every child in the developing world.

• Pediatric Mortality: Routine vaccination is the primary tool to prevent the cause of $1.5\text{ million}$ global deaths among children (Source: Black RE et al., The Lancet 2010).

• Primary References:   - World Health Organization: Immunization Against Diseases of Public Health Importance.   - UNICEF: Immunize Every Child: GAVI Strategy for Immunization Services.   - Black RE et al. (2010) The Lancet $375:1969-1987$.

Learning Outcomes and Lecture Aims

• Core Objectives:   1. Describe the distinction between passive and active immunity.   2. Explain the mechanisms of vaccine action and the development of immunological memory.   3. Discuss various vaccine types and their clinical applications.

• Lecture Scope:   - Background and history of vaccines.   - Vaccine development processes.   - Mechanics of immunological memory development.   - Vaccination programs and management of pandemics.   - Categorization of vaccine types.   - Specific uses and clinical implementations.

Historical Perspectives of Vaccination

• Thucydides (Athens, 430 B.C.):   - Proposed that an affected individual could pass a disease to an unaffected one.   - Recognized the concept of specific resistance: recognized that survivors of the Plague were immune to subsequent attacks of the Plague specifically, but not to other diseases.

• Smallpox Inoculation (China and India, 1500s):   - Methods included grinding up smallpox scabs and blowing them into the nostril.   - Scarification: Scratching matter from a smallpox sore directly into the skin.

• Edward Jenner (1790s):   - Observed that milkmaids who contracted cowpox were immune to smallpox.   - Experiment: Inoculated an $8\text{-year-old}$ boy with fluid from a cowpox pustule. Six weeks later, he intentionally infected the boy with smallpox; the boy demonstrated immunity as predicted.

• Louis Pasteur (1880s):   - Developed the vaccine for cholera in chickens, which was the first attenuated vaccine.   - Coined the term "vaccine" from the Latin word vacca, meaning "cow."   - 1885: Administered the first human vaccine to a young boy bitten by a rabid dog (Rabies vaccine).

Defining Vaccines and Mechanisms

• Composition: Generally contain either components of microbes or whole microbes that have been killed or weakened to prevent disease induction.

• Learning Mechanism: Vaccines utilize the body’s ability to learn how to eliminate pathogens and develop a memory for future exposures.

Timeline of Vaccine Licensing and Public Health Events

• 1945: Pertussis vaccine becomes part of the first $DTP$ childhood vaccine licensed.

• 1947: Diphtheria toxoid is licensed as part of $DT$, the first combination childhood vaccine.

• 1949: Last U.S. case of Smallpox recorded.

• 1955:   - Jonas Salk’s injectable polio vaccine licensed (uses killed virus).   - Cutter Incident: $202$ individuals were paralyzed or killed by a vaccine containing live polio virus.   - Tetanus toxoid licensed as part of $DT$ childhood vaccine.

• 1960: Albert Sabin’s oral polio vaccine licensed (uses live, weakened virus).

• 1962-1963: New laws allow the U.S. to channel funds for state and local vaccination.

• 1963: First measles vaccines licensed.

• 1964-1965: Historic rubella epidemic leads to the birth of $20,000$ disabled infants in the U.S.

• 1967: Mumps vaccine licensed (reported cases tracked since 1968).

• 1969: First rubella vaccines licensed and recommended for all children.

• 1971: First combined $MMR$ (measles, mumps, and rubella) vaccine licensed.

• 1981-2003: Chickenpox data reporting was inconsistent across states.

• 1981: Hepatitis B vaccine licensed (initial use for high-risk groups).

• 1985: Haemophilus influenzae type b ($Hib$) vaccine licensed.

• 1986: Congress creates the National Vaccine Injury Compensation Program following lawsuits against manufacturers.

• 1990: Hepatitis B recommendation expanded to all infants.

• 1993: U.S. Vaccines for Children program launched to provide free vaccines for low-income families.

• 1995:   - Chickenpox vaccine licensed and added to the routine schedule.   - Hepatitis A vaccine licensed for children in high-risk communities.

• 1998: Andrew Wakefield et al. publish a paper in The Lancet suggesting the $MMR$ vaccine causes autism.

• 1999-2001: Thimerosal (mercury-containing preservative) is removed from U.S. childhood vaccines.

• 2004: Institute of Medicine report finds no link between Thimerosal or $MMR$ vaccine and autism.

• 2005: CDC extends Hepatitis A recommendation to all children.

• 2006: $HPV$ vaccine licensed for girls (expanded to boys in 2011).

• 2010: The Lancet retracts the 1998 Wakefield paper.

• 2014-2015: Measles outbreak at Disneyland focuses public attention on vaccine resistance.

Statistical Impact of Vaccines in the United States (Pre- vs. Post-Vaccine Era)

Note: Table data sourced from CDC Statistics of Notifiable Diseases (January 2017).

Modern Vaccine Development and Challenges

• HIV: Human trials showed promising results in July 2018; potentially protects globally.

• Tuberculosis (TB): Failure of a major booster vaccine trial noted in February 2013 by Prof Helen McShane (University of Oxford).

• Ebola: Ongoing work to contain outbreaks; WHO continues vaccinations in the DRC.

• Malaria:   - Ghana led pilot programs for the world's first malaria vaccine in 2018.   - Oxford scientists developed a "world-changing" vaccine reported in September 2022.

• Zika: Research began on a $\pounds 4.7\text{ million}$ project to protect women following the 2015 outbreak in Brazil.

• Reference for Ideal Vaccine: British Medical Bulletin, Volume 62, Issue 1, 2002.

Types of Acquired Immunity

Passive Immunity

• Acquisition:   - Natural: Maternal $IgG$ crossing the placenta; maternal $IgA$ in breast milk.   - Artificial: Injection with preformed antibodies (antiserum).

• Characteristics:   - Does not activate the host's natural immune response.   - No immunological memory is formed.

• Applications:   - Treatment for congenital immune deficiencies.   - Immediate treatment after exposure to botulism, tetanus, diphtheria, hepatitis, measles, and rabies.   - Antidote/antivenom for poisonous bites.   - Situations where the pathogen causes death faster than an immune response can develop.

• Risks:   - Anti-isotype response: If the antibody is from another species, the host may experience systemic anaphylaxis.   - Type III hypersensitivity: Activation of complement immune complexes through $IgM$ or $IgG$.

• Examples:   - Zmapp: A drug for Ebola composed of three humanized monoclonal antibodies harvested from mice.   - Passive Antibody Therapy in COVID-19: Research into monoclonal antibodies ($mAbs$) targeting the $SARS-CoV-2$ spike protein epitopes to block $ACE2$ receptor binding and internalization into endosomes.

Active Immunity

• Acquisition:   - Natural: Natural infection.   - Artificial: Vaccination.

• Characteristics:   - Immune system plays an active role.   - Activation of antigen-specific $T$ and $B$ cells.   - Formation of protective memory cells.   - Primary goal: Elicit a secondary immune response that eliminates the pathogen upon re-exposure.

Mechanism of Vaccine Action

1. Uptake: The vaccine (entire pathogen or antigenic components) is taken up by phagocytes.

2. Activation/Migration: Professional Antigen-Presenting Cells ($APCs$) are activated and migrate from the tissue to peripheral lymphoid organs.

3. Antigen Presentation: $APCs$ present antigens to $T$ cells and $B$ cells.

4. Activation: Proliferation and differentiation of $T$ and $B$ cells.

5. Memory Development: Generation of long-lasting protection via memory cells.

The Principles of Immunological Memory

T-cell Activation and Memory

• T-cell Recap: Requires $TCR$ signaling ($TCR$/$MHC$), costimulatory interaction ($CD28$ and $CD80/86$), and cytokine signaling (autocrine $IL-2$, paracrine $IL-12$).

• Four Types of Memory T-cells:   1. Stem cell memory T cells: Located in secondary lymphoid organs ($SLO$); give rise to central memory cells.   2. Central memory T cells: Reside within secondary lymphoid organs.   3. Effector memory T cells: Circulate through the tissues.   4. Resident memory T-cells: Settle in peripheral tissues long-term; provide the first response to re-infection.

B-cell Activation and Memory

• B-cell Recap: Involves $MHCII-antigen$ interaction with $CD4+$ Helper $T$ cells ($T_{FH}$ cells) and cytokine release.

• Memory B-cell Development:   - Naïve follicular $B$ cells are activated in secondary lymphoid organs.   - Clonal expansion produces plasma cells (antibody production) and dormant memory cells.   - Affinity Maturation: Occurs in germinal centers through somatic hypermutation and selection by $T_{FH}$ cells to produce high-affinity memory cells.

• Longevity: Memory cells provide immediate protection and generate secondary responses that are more rapid and of a higher magnitude than the primary response.