Three different vaccines have been authorised for emergency use in the United Kingdom to control the pandemic: two of them are mRNA vaccines, and one is based on a viral vector. The latter, called AZD1222, has been developed by Oxford University in collaboration with the biopharma company Astra Zeneca.
AZD1222 is based in a chimpanzee Adenovirus, modified in such a way that it can not replicate inside the infected cells, and it carries the DNA sequence necessary for the production of the Spike protein of SARS-CoV-2.
This is the first vaccine of this type to be approved, but this technology has been available and studied to be used for other vaccines since the early 2000s.
Initially, viral vectors based on Adenoviruses were developed to be used in gene therapy, as shuttles to transfer the correct version of a mutated gene in the cells of patients with genetic diseases. it was soon evident, however, that this kind of treatment in many cases induced an immune response against the vector: what was a disadvantage for a gene therapy vector was a useful characteristic to be exploited as a vaccine platform. Other advantages of the Adenoviruses are that they cause very mild symptoms (for example the common cold is caused by an Adenovirus), they can infect different cell types, and they are relatively stable.
The Adenoviruses that infect humans, cause both acute symptomatic infections and persistent asymptomatic infections. Some of them are very common and infect during childhood. The abundance of human Adenoviruses and the frequency of the infections imply that many of us (45-80% of the population depending on the geographic area) have an armoury of antibodies able to recognize and neutralize them. For these reasons, less common human Adenoviruses (that infect 5-15% of the population) or Adenoviruses that infect other species (eg, chimpanzees), are used for the development of vaccines.
Adenoviruses used as viral vectors are genetically modified in order to
- Eliminate disease-causing genes
- Make the virus unable to replicate inside the cells
- Make the virus unable to kill the cells
- Eliminate viral genes that inhibit the antiviral defenses of the cells
- Produce a protein of another pathogen against which we want to produce antibodies
It is very important to understand that the vaccine is not a virus of the chimpanzees, but it is a genetically modified vector (recombinant virus) that maintains only the beneficial characteristics of the natural virus, while those potentially dangerous or disadvantageous have been permanently removed.
Moreover, the DNA of these vectors can not integrate into the human DNA, and can not interfere in any way with the activity of human genes.
Upon vaccination, the recombinant virus enters the cells in the injection site and releases its DNA into their nucleus. There, the DNA is transcribed into RNA, the RNA leaves the nucleus and it is transcribed to produce the Spike protein of SARS-CoV-2. As in any other protein produced during a viral infection, Spike will be digested into small fragments, some of them being exposed on the surface of the cell. The cells of the immune system that patrol the tissue, will see the Spike fragments and will recognize them as “non-human”. At the same time, some viral particles used as a vaccine will be caught by other immune cells and brought to the lymph nodes. All these events will start an immune response, that will culminate, among other things, with the production of specific antibodies against Spike, that will be able to attack the real SARS-CoV-2 in case of infection.
The vaccination strategy with AZD1222 consists of two doses, administered with an interval between 4 and 12 weeks. Clinical trials have shown that:
- The second dose causes less and milder secondary effects than the first one (less pain and swelling in the injection site, fewer patients reporting fever, headache, malaise, or muscle ache)
- The intensity of the possible secondary effects does not have any correlation with the efficacy of the vaccination
- After the first dose, the body produces a certain amount of antibodies against the viral vector, but they do not impair the efficacy of the second dose and do not increase after the boost
- Vaccination induces a higher quantity of anti-Spike antibodies than that observed in patients who recovered from COVID-19, measured between 28 and 91 days after a positive PCR test
- The production of antibodies increases after the second dose
- The antibodies produced upon vaccination have different functions in the immune response (phagocyte activation, complement activation, Natural Killer cell activation)
- The vaccination as well induces a T cell-mediated immune response, important for the resolution of the natural infection (a good cellular response has been observed in patients with mild symptoms and fast recovery)
- The efficacy of the vaccination is 70.4%: of 131 cases of symptomatic infections that have occurred among 11.636 participants who received the second dose, 30 have been registered among those who had received the actual vaccine (5.807) and 101 among those in the control group (5.829)
- The efficacy does not change when the second dose is administered 4, 6, 8, or 12 weeks after the first dose.
Based on this latest result, the UK government has decided to use all the doses currently available to guarantee the first administration to the highest possible number of people, and to delay the administration of the boost dose up to 12 weeks (when just as many doses will be available). This strategy aims to allow as many people as possible to start mounting an immune response in the shortest time, given the current emergency situation. The second dose will be in any case guaranteed to everybody within 12 weeks.
Some scientists have also suggested the possibility to use different vaccines for the first dose and the boost dose, since every type of vaccine induces a slightly different activation of the immune system, arguing that a combination may induce a more complete immune response. To date, however, this solution has been not yet adopted.
Picture: Adenovirus, TEM, by David Gregory & Debbie Marshall, Creative Commons Attribution (CC BY 4.0) https://wellcomecollection.org/works/d34rspdt
Bibliography:
https://www.gov.uk/government/news/oxford-universityastrazeneca-covid-19-vaccine-approved
Replication-defective vector based on a chimpanzee adenovirus, Farina SF et al., Journal of Virology 2001 http://doi.org/10.1128/JVI.75.23.11603-11613.2001
Adenoviruses as Vaccine Vectors, Tatis N et al., Molecular Therapy 2004 http://doi.org/10.1016/j.ymthe.2004.07.013
Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses, Barrett JR et al., Nature Medicine 2020 https://doi.org/10.1038/s41591-020-01179-4
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK, Voysey M et al., The Lancet 2020, http://doi.org/10.1016/S0140-6736(20)32661-1
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