Vaccine types | Covid-19

Vaccine development and distribution

mRNA and how it works

mRNA vaccines

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mRNA platform expands upon existing preventative options

There are five main types of vaccines. These vaccines produce different types of immune response.

Live attenuated vaccines

Live attenuated vaccines contain live viruses that have been weakened.¹ Once injected, the weakened viruses can induce an immune response, but the disease-causing potential and virulence is reduced.¹ These vaccines may not be appropriate for people who are immunocompromised.²

Live attenuated vaccines induce a strong neutralizing antibody response,³ and CD4+ and CD8+ T cell-mediated immunity.³

Inactivated vaccines

To produce inactivated vaccines, the virus is grown and then killed by heat or chemical treatment.¹ Inactivated vaccines are typically well tolerated by people who are immunocompromised.²

Inactivated vaccines induce a robust neutralizing antibody response,³ but only limited T cell-mediated immunity.³

Protein-based vaccines

Protein-based vaccines contain antigenic subunits of a disease-causing pathogen, but do not include any genetic material.⁴ These vaccines typically require adjuvants, substances that increase the immunity produced by the vaccine.^1,5

Protein-based vaccines induce a strong neutralizing antibody response⁶ to the target pathogen but only limited
T cell-mediated immunity.³

mRNA vaccines

These vaccines use in vitro transcribed mRNA packaged inside carrier molecules, such as lipid nanoparticles.⁷ When this material is processed by a cell, the mRNA produces antigenic proteins like those of the disease-causing virus that triggers an immune response.⁸

mRNA vaccines induce strong neutralizing antibody responses⁹and CD4+ and CD8+ T cell-mediated immunity.^10,11

Viral-vector vaccines

These vaccines use a non-infectious virus, which can produce some of the same antigenic subunits as the disease-causing virus.^12,13 However, some viral vectors are not appropriate for people who are immunocompromised.^1,2

Viral-vector vaccines induce robust neutralizing antibody response and CD4+ and CD8+ T cell-mediated immunity.^3,13 Existing immunity to some viral vectors can reduce efficacy and immunogenicity.^1,13

Vaccine development occurs in phases, some of which can be run in parallel

To distribute a new vaccine, several developmental steps are required including preclinical and clinical trials, manufacturing, and approval processes. ^8,14

RESEARCH & DEVELOPMENT

TRADITIONAL CLINICAL RESEARCH TIMELINE¹⁵

ACCELERATED CLINICAL RESEARCH TIMELINE¹⁶

APPROVAL AND DISTRIBUTION

Delivery and accessibility remains a challenge for some vaccine types, but technology is adapting.

Live attenuated vaccines

It may be difficult to scale manufacturing because a multi-step manufacturing process with stringent quality controls, is required.^1,17
Freeze-dried before distribution, making them stable and easy to handle.¹⁸

Inactivated vaccines

It may be challenging to scale manufacturing because a multi-step process with high-level containment* is required.¹⁹
Storage costs can be low because inactivated vaccines are typically stable between 2°C and 8°C.^1,20

Protein-based vaccines

It may be relatively difficult to scale manufacturing because a multi-step process is required.⁴
Distribution can be low-cost because no live virus transport is required.^4,19

mRNA vaccines

This process is cell-free and rapidly scalable.¹⁹ The design process of mRNA vaccines can be easily adapted for new viral variants.²¹
Distribution may be costly because mRNA vaccines typically require ultra-low temperatures for shipping.^18,19

Viral-vector vaccines

Requires virus expansion but may be relatively easy to scale because it does not require high-level containment.^*19
Delivery infrastructure costs are low because most viral-vector vaccines do not require high-level containment* and can use established infrastructure.¹⁹

* Containment refers to the classification of dangerous pathogens.^19,22

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References:

Ghattas M et al. Vaccines (Basel) 2021;9:1490.

UK National Immunisation Office. Chapter 3: Immunization guidelines: information for healthcare practitioners. Available at: https://www.hse.ie/eng/health/immunisation/hcpinfo/guidelines/ (accessed February 2023).

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Maruggi G et al. Mol Ther 2019;27:757–772.

Health and Safety Executive Northern Ireland. The approved list of biological agents. Available at: https://www.hseni.gov.uk/publications/misc-208-fourth-edition-approved-list-biological-agents (accessed February 2023).

mRNA has capabilities to use cellular machinery

Introduction

Messenger RNA (mRNA) was first discovered in 1961,^1,2 but the first-in-human COVID-19 mRNA-based vaccination under authorization for temporary use occurred at the end of 2020;^3,4 resulting in a culmination of nearly 60 years of research.

To better understand these novel mRNA-based vaccines, some fundamental concepts of molecular biology need to be understood.

One of these concepts is the process by which cells use DNA to create RNA, and RNA to create proteins.⁵ It is important to understand the difference between RNA and mRNA. RNA is a type of nucleic acid while mRNA is a type of RNA that is encoded to produce proteins.⁶

The central dogma of molecular biology⁵

Transcription

Transcription is the process whereby genetic information from DNA is used to form a mature mRNA molecule inside the nucleus.⁶

What are RNA molecules?

RNA molecules can be divided into protein-coding and non-protein-coding functions.⁶Protein coding RNAs are called mRNA. mRNA-based vaccines use modified protein-coding mRNA to produce target antigens⁷

More about transcription

Transcription occurs in the cell’s nucleus and begins with DNA, which is genetic material containing the information needed for synthesizing protein molecules.^8,9

A small section of double-stranded DNA opens, allowing an enzyme called RNA polymerase to bind to and scan the DNA.¹⁰ The DNA serves as a template for RNA polymerase to create a complementary strand of RNA through base-pairing of the DNA and RNA nucleotides;¹¹ this copy is called pre-mRNA.¹²

Pre-mRNA requires alterations before it can be used in protein synthesis.¹² A protective cap and poly(A) tail are added to stabilize the mRNA, facilitate its export out of the nucleus into the cytoplasm, and promote translation.¹³

Translation

Translation is the process whereby mRNA is used as a genetic template to create proteins outside the nucleus.^6,14

More about translation

Translation begins with assembly of the ribosome around the mRNA.¹⁴ The ribosome scans the mRNA until it reaches a “start codon”,¹⁴which initiates the delivery of a transfer RNA carrying the first amino acid that marks the beginning of the synthesis of the protein polypeptide chain.¹⁵

The polypeptide chain grows as more codons are scanned and subsequent amino acids are delivered to the ribosome.¹⁶

When a stop codon is reached, the ribosome halts its scanning of the mRNA and disassembles, releasing the mRNA strand and the newly synthesized protein.¹⁴

mRNA cannot freely return to the nucleus as specific proteins are required for nuclear import.¹⁷

What are codons?

Codons are composed of three nucleotides that correspond to amino acids¹⁸

mRNA degradation

mRNA either spontaneously degrades or is degraded by enzymes inside the cell.^19,20

Once mRNA has been degraded, it can no longer function in the translation process, so it cannot be used to make additional proteins¹⁹

More about mRNA degradation

mRNA is characteristically unstable and can spontaneously degrade.²⁰ It can also be targeted by enzymes that degrade it.²¹ After mRNA degradation, the resulting short nucleotide pieces are salvaged by the cell and recycled for synthesis of new RNA and DNA molecules.²²

Molecular hijacking: How do viruses take over?

Viruses use host cell mRNA translation pathways to replicate.²³

More about molecular hijacking

Viruses typically hijack cellular translational processes to replicate.²³ The virus begins its replication cycle by first binding to cell-surface receptors and is internalized into the cytoplasm through a vesicle.²³

Viral RNA is then released into the cytoplasm where it is translated into proteins, using the same translation machinery as human mRNA.²³

Newly translated viral proteins and viral RNA join to form virus particles, which are released from the cell to infect other cells or are expelled from the body to infect other people.²³

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References:

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Public Health England. Vaccine update: issue 322, June 2021, COVID-19 phase 2 special edition. Available at: https://www.gov.uk/government/publications/vaccine-update-issue-322-june-2021-covid-19-phase-2-special-edition/vaccine-update-issue-322-june-2021-covid-19-phase-2-special-edition (accessed February 2023).

UK Medicines & Healthcare products Regulatory Agency. Summary of the Public Assessment Report for COVID-19 Vaccine Pfizer/BioNTech. Available at: https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19/summary-public-assessment-report-for-pfizerbiontech-covid-19-vaccine (accessed February 2023).

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mRNA is another platform for vaccine development and production

Design and delivery

mRNA vaccines contain lipid nanoparticles encapsulating mRNA strands that encode protein antigens.^1,2

Myth: mRNA vaccines can cause infection with the targeted virus.

Fact: mRNA vaccines do not contain live virus.³

Myth: mRNA vaccines are formulated with toxic chemicals.

Fact: The manufacturing process for mRNA vaccines does not involve toxic chemicals.^2,4

More about design and delivery

Disease-causing pathogens typically display antigens, usually proteins, on their outer surface.⁵

Once the antigen of choice from the target pathogen is identified, the coding gene is sequenced and engineered to produce mRNA strands.¹
Highly purified mRNA molecules are then packaged into lipid nanoparticles and delivered into cells.^1,2,6

Inside the body: Protein translation and immune response

Upon vaccination, the encapsulated mRNA is taken up by cells, released into the cytoplasm, and then translated into protein antigens that trigger an immune response.^1,2

Myth: mRNA vaccines can alter a person’s DNA.

Fact: mRNA cannot enter the nucleus of a cell, so DNA is not affected.^2,3

Myth: mRNA can build up in the body over time.

Fact: mRNA does not remain inside the cell because it gets degraded by natural processes.²

More about protein translation and immune response

3. Once inside the cell, lipid nanoparticles release the mRNA into the cytoplasm.¹

4. In the cytoplasm, the mRNA is translated into protein antigens by host machinery.¹

5. Newly synthesized protein antigens are detected by the immune system, which triggers a robust immune response involving antibodies and T cells that specifically recognize and react against the antigen.⁷ The immune system “remembers” the antigen via antigen-specific lymphocytes. Any future encounters with the pathogen (or parts of it) will trigger a rapid and robust immune response.^7,8

A vaccine platform

The mRNA vaccine development platform allows for rapid development and large-scale deployment of new vaccines.^1,3

Myth: The development of mRNA vaccines against COVID-19 was shortened.

Fact: COVID-19 mRNA vaccines use existing technology, development was accelerated, without eliminating any required steps in research, development and approval.^2,9,10

More about vaccine platform

Infectious diseases caused by mutating pathogens may present a challenge for traditional vaccine development platforms.^1,11New, sudden outbreaks require a rapid and effective response.^1-3

The mRNA vaccine platform is fast and flexible, allowing for the development of new mRNA vaccines rapidly once gene sequence information is obtained.¹

Explore more

Learn more about diagnosing COVID-19

Find out more about COVID-19 diagnosis and patients who may be at high-risk of progression to severe disease.

Signs & symptoms

High risk patients

Testing

References:

Maruggi G, et al. Mol Ther 2019;27:757 -722.

Pardi N, et al. Nat Rev Drug Discov 2018;17:261 -279.

Ghattas M, et al. Vaccines (Basel) 2021;9:1490.

Centers for Disease Control and Prevention. Myths and Facts about COVID-19 Vaccines. Available at: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/facts.html (accessed February 2023).

MedlinePlus. Immune Response. Available at: https://medlineplus.gov/ency/article/000821.htm (accessed February 2023).

Tenchov R, et al. ACS Nano 2021;15:16982 -17015.

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Ball P. Nature 2021:589:16 -18.

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Servín-Blanco R et al. Hum Vaccin Immunother 2016;12:2640–2648.