Lecture 5: Vaccines -> Harnessing the Adaptive Immune Response

Natural Infection

pathogen -> primary IR -> disease -> death or survival -> immunity (virulency)+ memory

Vaccination

vaccine A -> primary IR -> immune to pathogen -> pathogen A -> memory -> no disease; provides protective immunity of secondary response prior to natural infection

Primary Infection

clonal selection/expansion/memory; first infection X/vaccination X

Secondary Infection

second infection/first natural infection; faster, higher magnitude, same antigen specificity, long-lived immunity to pathogens

Vaccine Principles

1. prevent disease by exposure of IS to non-pathogenic form of pathogen, 2) elevate preparedness of IS - first natural pathogen -> strong memory response > weak primary response, 3) maximizes immunogenicity, minimizes pathogenicity, 4) provide health benefits > risks

Vaccine Adjuvants

effective vaccine activates innate/adaptive immunity; antigen/adjuvant components

Antigenic Component

non-replicating/weak replicating; inadequate PAMP/DAMP; antigen is pathogen-derived and is a target of adaptive immunity

Adjuvant Component

contain PAMP/DAMPs recognized by PRRs on innate cells; oil-in-water emulsion with bacterial components added -> provoke innate immune response, support strong antigen-specific response

Micelle

lipid molecule aggregation in aqueous solution; bacterial components that act like PAMPs added

Vaccine Antigen/Adjuvant Formation

antigen (adaptive) + adjuvant (innate) -> vaccine -> shots, nose, oral

Shots-Intranasal/Oral Vaccine

priming in lymph nodes —--priming in MALTs, mucosal immunity

Herd Immunity

indirect protection from disease to non-immunized people when vaccination levels are high

Not Immunized

not safe (newborns, immunodeficiency disease), vaccination/not-protected, hesitancy

Vaccine Safety

bc medicine given to someone healthy + not ill; do no harm; ST/LT affects + rate of occurrence

Vaccine Efficacy

how effective is it? percentage of protection from disease in immunized people?

Testing Vaccines

research/development -> pre-clinical studies -> phase 1-3 -> phase 4; requires months/years, long + expensive; (in vitro -> animal -> 100 -> 100s -> 1000s -> ongoing); relevant antigens + candidates -> safety/efficacy? -> safety/efficacy/immunogenicity/dose-schedule -> safety/benefit-risk

Adverse Event Reporting

examples show decreases in adverse effects + what adverse events were occurring; reaction near site, allergy, rash, neurologic event, systemic event; all decreasing in occurrence -> ongoing

Whole Organism

killed (inactivated), attenuated (live); pathogen grown -> heat kill, structure intact

Attenuated

weakened; small degree replication, mostly immunogenic, revert - pathogenicity, cold storage

Inactivated

non-replicating, no reversion to pathogenicity, no cold storage, less immunogenic

Subunit

proteins, carbs (lipids), isolated components; like inactivated, less chance of impurities -> side effects; greater need for effective adjuvants

Protein Subunit Vaccine

target -> surface protein of pathogen, vaccine induces ABs that prevent pathogen from infecting the hose; purification of protein + recombinant DNA tech

Purification

pathogen + protein -> disrupt pathogen -> vaccine antigen (protein) -> shot

Recombinant DNA Tech

vaccine antigen -> gene encoding antigen -> plasmid -> induce bacteria to form plasmid -> purify vaccine antigen -> recombinant vaccine (cheaper, safer, easier)

DNA/RNA Vaccines

in situ, vaccine antigen -> gene encoding -> plasmid w/ antigen gene -> DNA vaccine with DNA plasmid; gene encoding antigen -> into viral vector -> DNA vaccine (viral vector) -> local cells

Toxoid Vaccines

anti-toxin antibodies that bind/clear toxin, preventing disease; toxin proteins can be chemically modified so they are inactive; ex. tetanus/diphtheria

Toxins

bacteria secretions that cause disease due to their effects on host cells

Bacterial Conjugate Vaccines Structure

bacterial surface polysaccharides (carbs with repetitive subunits); bacteria + capsular polysaccharide -> isolated polysaccharide -> protein carrier (unrelated) w/ strong T response

Bacterial Conjugate Problem

no T cell epitopes -> suboptimal antibody response (low affinity IgM

Bacterial Conjugate Solution

link polysaccharide (B epitopes) to unrelated antigenic protein (T cell epitopes) to form conjugates (ex. toxoids)

Bacterial Conjugate Process

conjugate vaccine -> binds to BCR -> internalization -> protein fragmentation of protein -> binds to TCR -> plasma cell differentiation -> polysaccharide specific antibody; IgG, higher affinity, long-lasting memory

Poliovirus

highly infectious, fecal-oral route transmission, replicates in gut surface -> CNS tissue via circulation -> destroy motor nerve -> permanent paralysis -> death by lung paralysis (iron lung assist)

Inactivated Polio Vaccine

Jonas Salk, intramuscular injection induces systemic IgG response -> prevents disease, not infection + still virus transmission; still replications in gut, no antiviral AB in gut but in blood

Oral Attenuated Polio Vaccine

Albert Sabin, oral administration of mucosal IgA response -> prevents infection -> prevents disease and transmission; neutralizes virus in the intestine -> song about sugar

Eradicate Polio

Nigeria polio-free, still in Afghanistan/Pakistan; situation affects risk-benefit analysis

Low Vaccination Rates

OPV in endemic (circulation) regions; breaks transmission among unimmunized, cheaper, easier but low chance of live -> pathogenicity

High Vaccination Rates

IPV, maintain eradication; no pathogenicity reversion BUT community transmission possible but susceptible hosts low = risks low

1796 Jenner

Jenner vaccination for smallpox protection; don’t know microbes -> disease or any IS mechanism

Late 1800s/GTD

accepted, microbes cause disease; Pasteur, non-pathogenic pathogen -> immunization agent; cholera, rabies, anthrax vaccines

1900s

increasing number of pathogens -> disease identified + vaccines; by 2000, over 25 vaccines

Vaccination Trends

significant reduction in disease incident from 1900s - 2001; 2-3 mil deaths per year

Routine Immunization

protect against pathogens that commonly circulate population in vaccine absence; 15 vaccines given on schedule, in childhood to establish immunity, may require booster -> efficiency of IR

HBV Vaccine

unsafe sex, needles, mother-infant route; asymptomatic, latent (inactive) -> illness due to liver cancer/cirrhosis; vaccine prevents infection + reduces deaths from liver cancer/cirrhosis, WW -> Africa/Asia

HPV Vaccine

sexual activity, diff subtypes -> cervical, anal, vaginal cancer; vaccine protects against subtypes that cause cancer; a lot of the diagnoses of these cancers are due to HPV

Vaccine-Preventable Deaths/Disease

deaths/illnesses that occur as result of disease when there is safe vaccine

Conflict

wars/civil unrest interfere with public infrastructure

Human Migration

no stable home location, difficult for management/scheduled immunization

Economics

regions that need vaccine cannot afford the cost

Vaccine Hesitancy

reluctance to vaccinate based on perception that risk > benefits deposit safety testing

Invisible Benefit

childhood diseases are rare now, forget the big benefit of vaccines

Risk Misunderstanding

lack of information + misinformation that persists but is false about vaccines

Jenner/Smallpox

milkmaids rarely ill; took cowpox from milkmaid -> injected into infected boy -> healthy

Smallpox/Cowpox

closely related structurally, antibodies/T cells recognize both antigens (cross-reactivity); cowpox acts as attenuated form of smallpox -> generates IR (immunogenic) but no disease (not pathogenic)

Heterologous Vaccine

vaccine agent is based on a related but not identical pathogen

Smallpox Symptoms

remained endemic, many cases and deaths, diagnoses left blind/disfigured

Smallpox Eradication Campaign

Cold Chain Infrastructure/Ring Vaccine -> eradication, 300 mil

Cold Chain

transportation/storage system developed to keep vaccine cold

Ring Vaccination

fast, cost-effective interruption of transmission; infected person -> close contacts, etc..

Endemic

present in a community at all times

Tuberculosis

major infectious killer -> vaccine; most deadly, caused by mycobacterium tuberculosis -> inside lungs but also systemic (brain, SC, kidney)

Tuberculosis History

not new, evolved while ago, evidence in civilizations, leading cause of death in 1897

Tuberculosis IR

adaptive can’t -> immune cell circle infection site + bacteria inside wall (granuloma)

Latent TB

if immunity strong -> infection is asymptomatic for life

Active TB

weak IS -> bacteria escape granuloma -> symptomatic; weight loss, cough, tissue damage

TB Vaccine

people vulnerable to active TB, immunocompromised (malnutrition, co-infection, treatment); antibiotic resistance on the rise

BCG Vaccine

Bacillus Calmette-Guerin; attenuated form mycobacterium bovis; 50% effective, no pulmonary protection (community transmission still occurs), used on children in endemic regions

Emergent Pathogen

pathogen whose incidence is new/suddenly increasing in population; may be new evolved, known in animals -> humans, ongoing microbial evolution

Emergent Pathogens Ex

Ebola -> haemorrhagic fever; 2009 Influence, Zika virus (fetal abnormalities), novel coronavirus (respiratory diseases) -> SARS, MERS, SARS-2

Control Emergent Pathogen

isolate pathogen -> understand disease/transmission -> 1) reduce transmission 2) vaccine development 3) define treatment

Reduce Transmission

define + implement public health -> social distance/hand hygiene, masks

Vaccine Development

widespread, long-lasting protective immunity;

Define Treatment

identify/develop drugs that reduce disease impact; hydroxychloroquine/remdesivir/BCG