Just last Monday, AstraZeneca (U.K.) and Oxford University (Oxford Vaccine Group) published their preliminary report on the safety and efficacy of their ChAdOx1 nCoV-19 COVID19 (AZD1222) vaccine in producing an immune response in people. This highly-anticipated article is published in the medical journal The Lancet. With over $1 billion worth of funding from the U.S. government, AZD1222 has gathered high expectations from the public as it potentially holds the key to freeing the world of the COVID19 pandemic.
A quick background about the AZD1222 vaccine
The AZD1222 vaccine is quite different from Moderna’s mRNA-1273. It uses a chimpanzee adenovirus vector (common cold virus that causes infections in chimpanzees) that has lost its ability to replicate. Inside of this adenovirus vector contains the full-length mRNA of the SARS-CoV-2 spike protein (s protein) engineered to also contain a tissue plasminogen activator leader sequence (to enhance immunogenicity) (Figure a).
A chimpanzee adenovirus is chosen because it is able to induce a strong immune response in humans. This is largely based on a previous study done by the group showing that a single dose of ChAdOx1 MERS was able to confer protection against MERS-CoV (van Doremalen et al., 2020). Figure a shows a quick comparison between AZD1222 and mRNA-1273 vaccines.
To reiterate again, a good indication of an effective vaccine is if it is able to induce an antibody and T cell response in the person receiving the vaccination. In this particular paper, they measured binding antibody responses, virus neutralization responses and T cell responses.
A little bit more about the virus neutralization tests
The virus neutralization test also known as plaque reduction assay or PRNT50 assay is used to determine the extent the serum (of blood) can be diluted and still reduce SARS-CoV-2 plaque formation by 50%. When antibodies against the virus particles are found in the serum, they will bind and neutralize the virus, preventing the virus from killing cells that have been growing in a layer on a petri dish (preventing plaque formation) (figure b). The more antibodies present in the serum of individuals, the more the serum can be diluted and yet be able to still reduce plaque formation (figure c).
Trial design
1077 healthy participants aged 18-55 years were recruited for the study, with about half receiving the AZD1222 vaccine (test group) and another half receiving a MenACWY vaccine against meningococcal bacteria (control group). A small group of 10 participants received a booster administered 28 days after the first dose (2 doses in total).
Results
1. An alarming 67% of the participants in the test group reported pain (mild to moderate intensity) after vaccination as compared to 38% of the control group. With the intake of paracetamol, pain was reported in fewer participants. Other systemic reactions reported in a large percentage of participants (without paracetamol) were fatigue, headaches and discomfort.
2. Not many other serious adverse effects were noted. Of note, neutropenia (low neutrophil count) were observed in 46% of the participants in the test group.
3. In the test group, antibodies against the SARS-CoV-2 s protein peaked by day 28 and remains high until day 56. The antibody response increased 3-4 times in participants who received the booster dose; somewhat comparable to the levels observed in plasma samples of individuals whom had COVID19.
4. 91% of participants who received the single dose were able to achieve 80% virus neutralization levels 28 days after vaccination (figure b). 100% of those who received the booster were able to achieve 80% virus neutralization levels.
5. T cell responses (measure by interferon-γ levels; interferon-γ is an important immune signal) were observed to peak as early as 14 days post-vaccination in the test group
Confounding variables you need to know
1. As with the trial for mRNA-1273, the majority (90%) of participants are white
- The lack of participants of other race and ethnic groups means that we are unsure if the outcomes observed are representative.
2. Participants are all healthy adults
- Will the vaccine elicit a similar outcome in babies and children? Will it be safe for them?
- What about individuals with pre-existing health conditions?
3. A small number of participants had high levels of neutralizing antibodies against SARS-CoV-2 before the vaccination
- While those whom have been tested positive for SARS-CoV-2 and those whom are at a higher-risk of SARS-CoV-2 infection i.e. front-line workers are excluded from the study, the authors note that some enrolled participants had high-level anti-s protein antibodies at baseline.
- This seems to indicate that these participants might have been asymptomatic individuals infected by SARS-CoV-2 before the study. It is important to note that their data are also included in the analyses.
My thoughts
Overall, this report provides confidence about the safety and effectiveness of the vaccine against COVID19. The single dose chosen was tolerable and induced good levels of T cell response as early as 7 days, peaking at 14 days and peak antibody responses were noted at 28 days. This might prove to be advantageous over two injections of mRNA-1273 (figure d).
Another strong point of this study is that unlike Moderna’s publication, this group used good positive controls – plasma samples from adults who were infected with SARS-CoV-2. These samples serve as a ‘gold standard’ to compare with the body’s natural responses when exposure to the virus.
Also while the use of paracetamol helps ameliorate the pain associated with the vaccination, I am still slightly concerned about the suitability of the vaccination for young children, the elderly and/or individuals whom are unable to consume painkillers due to medical reasons. In addition, the adverse side effect observed was lower neutrophil count which hopefully can be fully addressed by the group.
What’s next
Late-stage Phase II/III trials are currently underway in the UK, Brazil and South Africa and are due to start in the US (AstraZeneca press release, 2020).
Figure legend
a. A comparison between Moderna’s mRNA-1273 vaccine and AstraZeneca’s AZD1222 vaccine.
b. The underlying concept of the virus neutralization test/plaque reduction assay /PRNT50 assay
c. The goal of the PRNT50 assay is to determine how much serum can be diluted and still reduce SARS-CoV-2 plaque formation by 50%.
d. Comparing the trial design of the preliminary reports of Moderna’s mRNA-1273 vaccine and AstraZeneca’s AZD1222 vaccine. Red dots indicate when the samples of participants were obtained and analyzed.
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