How do different types of vaccines work?

What is a vaccine?

A vaccine is a pharmacological product that gives the recieving patient's immune system a chance to learn how to fight infection with decreased risk of illness. Vaccination involves administering antigenic material (the vaccine), resulting in immunity to the disease.

Vaccine dosing and the need for boosters

Certain vaccines require boosters at appropriate intervals to maintain effective immunity. Boosters simulate pathogen re-infection, providing antibody-producing cells with another chance to build up immunity. For example, the 6 in 1 (diphtheria, tetanus, pertussis, polio, Hib, Hep B) vaccine needs to be given at 2 months, 4 months, and 6 months. This is because maternal antibodies block the epitopes on the vaccines making them less effective.

Vaccine Efficacy & Herd Immunity

Unfortunately, some individuals produce inadequate immune responses. However, this is not a problem if most of the population (table detailing herd immunity threshold below) is immune, as they can shield the unvaccinated population. This method of preotection is known as herd immunity. Herd immunity is achieved when a high percentage of the population is immune to a disease, either through vaccination or prior illness, making the spread of the disease from person to person unlikely. Herd immunity is thought to have stopped the spread of the Zika virus in Brazil. Two years after the outbreak began, 63% of the population have been exposed to the virus. A community reaches herd immunity when the reproduction number of the virus reaches 0. The reproduction number is the average number of people infected by a single person who is not already immune.

Types of Vaccination strategy

Passive immunity

Passive immunity is generated through injecting per-formed antibodies (immunoglobin from donors). This is commonly given to leukaemia and immunodeficient patients. Another group that often receives per-formed antibodies is infants at high risk of RSV (Respiratory syncytial virus) infection. Palivizumab is a humanised monoclonal antibody directed against the F protein of RSV that is administered to these high-risk infants. Studies have indicated that Palivizumab is anywhere between 45-82% effective against RSV related hospitalisation in high-risk infants.

The advantage of passive immunisation is that the protection is immediate. However, the disadvantage is that there is no long-term protection, and if an animal source is used for the antibodies, patients can experience serum sickness.

Active immunisation

Active immunisation aims to establish long-term protection and immunological memory resulting from the activation and proliferation of T cells and B cells and the generation of memory cells.

Types of vaccination for active immunisation

• Whole organism vaccines:
  • • • • • • • • • • • Live attenuated vaccines
                      • Inactive killed vaccines

• Purified macromolecules:
  • • • • • • • • • • • Recombinant proteins
                      • Toxoids

• Recombinant vector vaccines

• Nucleic acid vaccines

Whole organism vaccines

Attenuated vaccines

Attenuated vaccines contain viruses that have lost their pathogenicity (ability to cause disease) but can still grow transiently in the host (person or animal being vaccinated). Attenuated vaccines are developed by culturing the disease-causing organism on a growth media with a different environment than what they encounter in the host. One example of this is the Rubella vaccine is grown in duck embryos and human cell lines. Another example is the Sabin polio vaccine cultured in monkey kidney epithelial cells.

Advantages of attenuated vaccines are that the pathogen has the capacity for limited growth, allowing for prolonged exposure of multiple epitopes to the host immune system. Attenuated vaccines will trigger mucosal immunity (inner lining of organs and body cavities, e.g., nose, mouth, lungs, and stomach). Patients only require one vaccination for long-term protection.

Disadvantages of attenuated vaccines include the possibility that the virus will revert to its virulent (disease-causing) form, and attenuated vaccines cannot be given to immunodeficient patients.
Inactivated vaccines

Viruses can be inactivated through heat or chemical treatment. However, heat inactivation is not favoured because the epitope structure is essential for activating the immune system. Chemical inactivated by formaldehyde and alkylating agents are commonly used. Disadvantages to inactive vaccines include the requirement of repeated boosters to provoke a humoral response (transforming B cells into plasma cells that produce antibodies).

The advantages of inactivated vaccines are that they give sufficient humoral immunity if the boosters are given. Another advantage is that there is no risk of mutation or reversion, and they can be given to immunodeficient patients. A disadvantage of inactivated vaccines is that there is little mucosal immunity.

Comparison of inactivated and live vaccines: the Polio vaccine.

Poliovirus spreads through the faecal-oral route. In about 0.5% of cases, patients will have irreversible paralysis. This paralysis can result in breathing problems requiring a patient to require a respirator or iron lung for the rest of their lives.

There were two polio vaccines developed. The first, made in 1955, the Salk (name of inventor), was an inactive vaccine administered via injection. The Salk vaccine went through a vast clinical trial of 2.8 million children, although studies showed it failed to produce mucosal immunity. The second was the Sabin vaccine, an attenuated oral vaccine, which was a massive success as it mimics the virus route of infection, triggering mucosal immunity.

Recombinant Antigen Vaccines

Recombinant technology means that any pathogen-related protein can be cloned and expressed as a recombinant protein. This method was first used to develop a vaccine against hepatitis B surface antigen. Another example would be the Human Papillomavirus (HPV) virus vaccine.

The HPV vaccine

Genital HPV is the most common STI in the United States, with an estimated 6.5 million new cases a year. Most injections are brief, but persistent infection with high-risk types of HPV can lead to cervical, anogenital, and oropharyngeal cancers. The most high-risk types of HPV-16 and HPV-18. Only 60% of women infected produce anti-HPV antibodies. This poor natural immune response is due to the virus not infecting antigen-presenting cells, causing minor tissue damage, does not cause viremia.

The HPV vaccine is an example of a recombinant viral antigen vaccine. Using recombinant technology, the sequence of the L1 capsid protein of the HPV is incorporated into the genome of yeast or insect cells. These cells produce L1 protein which naturally assembles into virus-like particles/empty virus capsids that are morphologically indistinguishable from the exterior of the natural virus. The HPV vaccine contains these empty virus capsids with no viral DNA inside. HPV vaccines are administered as intramuscular injections, which results in entry into blood and lymph, generating an adequate immune response. Patients produce 50-10,000 times as many antibodies as natural infections. Antibodies from vaccination persist for 7-9 years.

Recombinant vector vaccines

These vaccines consist of living, replicating viruses, the vector, engineered to contain different genes that code for the antigens/proteins of interest. Typical vectors include poxviruses and adenoviruses alphaviruses. The AstraZeneca and Johnson & Johnson covid-19 vaccine is an example of a recombinant vector vaccine.

How does the AstraZeneca vaccine work?

1. The AstraZeneca covid-19 vaccine uses modified chimpanzee DNA adenovirus. This virus does not generate an immune response; only the viral protein encoded by the extra DNA triggers an immune response. The AstraZeneca vaccine uses the adenovirus vaccine vector known as ChAdOx1.
2. The DNA vector is used as a template to generate new chimpanzee adenovirus replicas and produce the viral protein that elicits the immune response.
3. This is then injected into humans and latches onto host cells; the DNA is then released into the cytoplasm, migrating into the cell nucleus; but it is NOT incorporated into cellular DNA.
4. The template DNA will be converted into mRNA through the human cells' cellular machinery, migrates back to the cytoplasm, and interacts with ribosomes. Ribosomes translate mRNA into proteins which are then expressed in the cell membrane.
   Ribosomes are cellular machinery found within cells and form and perform biological protein synthesis. As the mRNA specifies, ribosomes link amino acids together, forming polypeptide chains. Ribosomes are composed of 2 components: a small ribosomal subunit and the large ribosomal subunit.
   
5. These proteins then trigger an immune response; activate T cells and antibodies

Nucleic acid Vaccines

Nucleic acid vaccines involve the insertion of genetic material encoding the expression of the protein of interest directly into the patient. For uptake, nucleic acids can be coupled to a delivery system, e.g., gold particles and lipid nanoparticles. The nucleic acid is either plasmid DNA or mRNA.

1. Plasmid DNA vaccines are injected into the patient, are transcribed, and translated to produce antigen of interest.
   
2. mRNA vaccine is injected into the patient and is translated to produce the antigen of interest.
   

How does the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine work?

The sequence encoding for the SARS-CoV-2 spike protein is isolated and transcribed into mRNA outside the patient. The mRNA is then packaged into a lipid nanoparticle and injected into the patient. Lipid nanoparticles include ionisable lipids, which are positively charged to bind to negatively charged mRNA, pegylated lipids, which help stabilise the particles, and phospholipids and cholesterol molecules, which contribute to the structure of the particles. mRNA is released into cells, where the rRNA is taken up by the ribosomes and translated into proteins expressed on the cell membrane. These proteins then trigger the immune system, resulting in antibody production. The Moderna SARS-CoV-2 vaccine works comparably.