Lecture 11 - Principles of vaccines

define immunization

the act of making someone immune to a particular disease

define vaccination

the deliberate induction of an adaptive immune response by injecting a vaccine (dead, attenuated, non pathogenic) form of a pathogen

types of immunity

passive immunity

• passive transfer: protection by transfer of specific, high titre, Ab from immune donor to a non immune recipient

  • eg: isolating horse Abs for Hep B

• adoptive transfer: immune cells from an immunised individual

• immediate protection

• only offers transient immunity

Naturally aquired passive immunity

• required for neonatal protection

• IgG transferred from mother to foetus

  • IgG trough 3-6moths due to decline in maternal IgG

• Maternal IgA transferred through colostral transfer

artificial passive immunity

• pooled specific immunoglobin

• animal sera (anti-toxins, anti venoms)

• usually isolated from immunized large animals

  • eg horses used to neutralise toxins and venoms

  • stop them binding to target receptors on cell surfaces

Passive immunisation: Ebola

• Ebola virus infection causes a deadly heamorrhagic disease

  • (50% - 90% death rate)

• two licensed vaccines: monoclonal antibody therapies that target EBOV GP

• EBOV encoded glycoprotein (GP): affects ability of virus to bind to and infect cells.

• EBOV mainly infects endothelial cells, mononuclear phagocytes and hepatocytes

  • via C-type lectins, DC-SIGN and integrins

• secreted glycoprotein (sGP): essential role in the pathogenesis of Ebola Virus Disease (EVD).

exapmles of Ebola virus passive therapies

• PALM Trial: 681 patients November 2018 – August 2019

• Patients treated with

  • REGN–EB3 (Inmazeb) – cocktail of 3 McAb which bind to EBOV GP (31% DR)

  • Ebanga (Ansuvimab – previously m114) – isolated from immortalised B cells from a survivor of 1995 outbreak in Congo, Binds to EBOV GP (35% DR)

  • Zmapp – cocktail 3 McAb used in previous outbreaks (50% DR)

  • Remdesivar - antiviral drug (53% DR)

• Trial stopped and licence granted to REGN-EB3 and Ebanga (Oct and Dec 2020)

coronavirus and mAb Therapies

• Spike 1: receptor binding domain

• Many potential Monoclonal Antibody Therapies for SARS-COV but

  none licensed to date: immuno-evasion by new variants

Why vaccinate?

• gain immunity after recovery: memory B cells

• less susceptible to same pathogen

• less severe sypmtoms

• passive Ab therapy is best transient

• Chinese variolation: scabs from small pox survivors

• UK Edward Jenner: milkmaid and cowpox

Immunological memory

• immune system can respond more rapidly and effectively to pathogens that have been encountered previously

• Reflects the pre-existence of a clonally expanded population of antigen- specific T and/or B lymphocytes.

  • memory B cells generate high affinity IgG

• The goal of vaccines: artificially induce a long lived immunological memory in a host to protect against subsequent re- infection.

• Can last the life-span of the host – smallpox, yellow fever, polio, measles etc

B Cells

• The secondary response:

  • larger frequency of Ag specific cells (memory cells)

  • long lived: present after the primary response

  • proliferate more rapidly

  • produce bore Ab

  • Produce Ab with specialised effector function: IgG + IgA

  • Ab have higher affinity

  • better than naïve B cells

• During initial expansion of Ag specific B cell clones, some progeny cells do not develop into plasma cells

  • they revert to small lymphocytes that maintain same Ag-specific BCR on their surface (memory B cells).

Somatic hypermutation in B Cells

• a secondary immune response produces Ab with higher affinity

• SHM caused alterations in variable regions of light + heavy chain of memory cell Ab

• random process

T Cells

• Memory T cells are long lived, have increased frequency and proliferate more rapidly than naïve T cells.

• Naïve T cells express the tyrosine phosphatase CD45RA which does not associate with the TCR

• Memory T cells express CD45RO which associates with both the TCR and co-receptor (CD4).

• This complex tranduces signals more effectively than the receptor on naïve T cells.

Types of T cells

• Effector memory T cells

  • upon Ag re-stimulation, rapidly mature into effector cells

  • move into tissues

  • lose CCR7 expression

  • Release lots of effector associated cytokines

    • e.g. IFN-g and IL-4

• Central memory T cells

  • mature into effector cells slower

  • maintenance of CCR7: stay in lymph node for longer

  • Take longer to secrete effector associated cytokines

• Central Memory T cells CD45RO+ve and CCR7 +ve ,

• Effector Memory T cells CD45RO +ve and CCR7 -ve

If the aim of a vaccine is to induce memory cells – what must it do?

1. Be captured and processed by APC for MHC presentation to activate T cells via TCR (generates Signal 1)

   • class- switched antibody responses require T cell help

2. Activate innate cells (including APC) via Pattern Recognition Receptors PRR.

   • Activated APC will express co-stimulatory molecules and so deliver Signal 2 (B7 on APC interacting with CD28 on T cell) and Signal 3 (cytokines) to activate T cells

3. Induce high levels of T and B cell primary activation, with a high efficiency of generating both T and B memory cells.

4. Contain several epitopes that are recognized by several TCRs and BCRs in order to activate multiple T/B clones (to counter any antigenic variation).

5. Provide a constant and long lasting source of Ag in lymphoid tissue.

6. To induce a protective response(s) to pathogen without causing disease.

Requirements of an effective vaccine

• Safe (minimal side effects)

• high level of protection

• long-lasting protection

• right type of response (local, systemic, B or T cells or both)

• Efficacy of vaccine depends on many people being vaccinated (Herd Immunity), so must be:

  • Low cost

  • Stable (in high temperatures)- cold chain requirements

  • Easy to administer

  • Minimal side-effects

Common Vaccination Approaches

1. Live attenuated vaccines

2. Killed vaccines

3. Sub-unit vaccines

4. Conjugate vaccines

5. Recombinant vaccines

Live Vaccines

• Measles, mumps, rubella, oral polio (Sabin), BCG, Yellow fever.

• Attenuated (e.g. oral polio (Sabin)) - cold attenuated, host range mutants, long term culture, adapts to culture environment, so dies in humans before xausimg disease

• The measles virus used as a vaccine today was isolated from a child with measles in 1954

• In 1988 wild polio virus (WPV) was found in 125 countries with some 350 000 children being paralysed.

• Fallen to 12 cases (2023) in 2 countries

Problems with live attenuated vaccines

• If a population is seriously under-immunised, there will be susceptible children

• If the vaccine-virus circulates for a prolonged period it can mutate and over the course of 12-18 months reacquire neurovirulence.

• These viruses are called circulating vaccine-derived polioviruses (cVDPV)

  • 800 cases in 10 years

• If a population is fully immunized against polio, it will be protected against the spread of both wild and vaccine strains of poliovirus.

pros of live vaccines

• Single dose effective

• May be given by natural route (oral)

• May induce local (gut) and systemic (blood) immunity

• May induce right type of response (IgA)

cons of live vaccines

• Reversion/alteration to virulence (Sapolio - cVDPV)

• Possibility of contamination

  • e.g. Hep B contamination of Yellow Fever Vaccines

• Susceptible to inactivation - heat

• Can cause disease in immunocompromised host

Killed vaccines

• Examples of killed vaccines: include (Salk polio vaccine), pertussis (whooping cough), typhoid, cholera.

• must survive killing

• May have side effects

• A common way to kill organisms is with chemicals such as formaldehyde

• Advantages of killed vaccines:

  • stable in storage

  • will not cause disease through residual virulence and cannot revert

(Purified) subunit vaccines

• made from biochemically purified components of pathogens

• components must elicit protective immune responses

• Examples: HiB (Haemophilus influenza B which causes meningitis, pneumonia etc)

  • The vaccine is made from purified capsular polysaccharides.

• Influenza vaccine = purified haemagglutinin (H) + neuraminidase (N) antigens of the particular strain that is prevalent

(Recombinant) subunit vaccines

• To avoid the problems involved in bulk culture of pathogens recombinant vaccines have been introduced

• by inserting DNA of antigen into bacteria to express

• Hepatitis B was the first recombinant vaccine licensed for human use

  • inserted antigen DNA in yeast

• Ab to Hepatitis B surface antigen (HBsAg.) are protective in natural infections

• Respiratory Syncytial Virus – subunit vaccine introduced by NHS September 2024 – Pregnant Women and adults 75-79

• Contains RSV Subgroups A and B stabilised recombinant F antigen.

Conjugate vaccines

• Young children don’t make an immune response against carbohydrates

• B cell binds to an internalised bacterial polysaccharide, can’t present for the T-cell

• Haemophilus influenzae type b capsular polysaccharide (carbohydrate) conjugated to tetanus toxoid

• Converts TI-2 polysaccharide antigen to a TD form

• peptide are presented to T-cell

• activated Bcell produces Ab against polysaccharide Ag

• Young children can respond

• Conjugation of a T Independant (non-protein) component to a TDepentant (protein) component has to be performed biochemically rather than using recombinant DNA technology

Other considerations when chosing a vaccine

Different pathogens require differential immune responses: Adjuvants

Adjuvants

• Highly purified antigens alone often fail to induce strong immune responses.

• Early studies showed impure antigens or antigens mixed with whole bacteria triggered better immunity.

• This is because antigen-presenting cells (APCs) need activation by PAMPs (pathogen-associated molecular patterns) or DAMPs (damage-associated molecular patterns) binding to pattern recognition receptors (PRRs).

• Adjuvants enhance immune responses by mimicking these natural signals, but stronger adjuvants sometimes cause more tissue damage.

• For non-live vaccines, safe and effective adjuvants are crucial.

• Aluminum salts were among the first adjuvants used with diphtheria and tetanus vaccines, and remain in use today (e.g., HepA, HepB)

• Aluminum activates the Nalp3 inflammasome in APCs, aiding immune activation.

Herd Immunity

• Immunization needs to be sustained at a population level

• Disease declines in a population if the majority of the population are immune (herd immunity)

• Estimated thresholds of population immunity for vaccine preventable diseases:

  • Mumps 75% - 86%

  • Smallpox 83%-85%

  • Pertussis 92% - 94%

  • Covid-19 Unknown

• Requires continuous immunization to avoid a pool of susceptible hosts

Herd Immunity and Whooping Cough

• Immunization levels fell to 31% in 1978 due to some doctors suggesting that he vaccine could cause brain damage

• Between 1977 & 1982 >110,000 cases

• 26 children died; similar numbers suffered brain damage

Herd Immunity and MMR

• MMR vaccination introduced in 1988

• Bad publicity linking MMR vaccination to autism and bowel disease (1998) led to a decrease in uptake of MMR and mumps outbreaks

• Since 2004 the majority of confirmed cases = outbreaks in Universities.

Current Worldwide Vaccination Projects

1. Tuberculosis Vaccine

2. Malaria Vaccienes

Tuberculosis Vaccine

• The tuberculosis vaccine, BCG, was first used in 1921

• most widely administered vaccine globally.

• BCG contains = live attenuated strain of Mycobacterium bovis

• Children: prevents TB meningitis

• Adults: little efficacy against pulmonary disease

• Tuberculosis is caused by Mycobacterium tuberculosis.

• 2022 1.3 million people died

• Tuberculosis subunit vaccine showed 50% protection against development of pulmonary disease in phase II trial (2019)

• large phase III trial launched in March 2024 across South Africa and six other countries

Malaria Vaccienes

• Malaria causes 250 million acute clinical cases per year.

• 0.6 million deaths annually

• The malaria parasite has a complex life cycle in both humans and mosquitoes

  • plasmodium: bite> liver> blood

  • each life cycle stage has distinct Ag

• Many Phase I and II malaria vaccine trials have shown limited clinical success.

Recently licensed vaccines:

• Mosquirix 2021 = circumsporozoite antigen + Hepatitis B surface antigen (36% reduction clinical malaria)

• Matrix-M 2023 = subunit sporozoite + Hepatitis B surface antigen with Matrix-M adjuvant (77% reduction symtoms)

New sporozoite vaccine study (Olivia AC et al, 2024):

• Used genetically modified sporozoite that halts development in the liver 6 days post-infection.

• GA2 (late-arrested) group showed significantly higher protection than GA1 (early-arrested) group (12.5%).

• Potential issues with administration (delivery via mosquito bites)