by Gertrud U. Rey
On July 20, 2020, Oxford University’s Jenner Institute and the pharmaceutical company AstraZeneca reported preliminary results from phase I/II clinical trials assessing the safety and efficacy of a vaccine candidate against SARS-CoV-2.
The vaccine candidate, named AZD1222 (referred to in the publication as ChAdOx1 nCoV-19), consists of an adenovirus vector with an inserted gene that encodes the full-length SARS-CoV-2 spike protein. The notion of using a virus as a vector to deliver vaccines to humans is based on the ability of viruses to enter cells by attaching to host cell receptors and releasing their genome into the cell. Upon injection into a vaccine recipient, the vaccine vector should enter cells and serve as a code for host proteins to synthesize the SARS-CoV-2 spike protein from the inserted gene. Ideally, the spike protein will then act as an antigen to prime the immune system to recognize SARS-CoV-2 if it infects the body at a later time. As described in last week’s summary of the Moderna vaccine trial, the spike protein has been the primary antigenic choice for several SARS-CoV-2 vaccine candidates, because it mediates both binding of the virus to the ACE2 host cell receptor and fusion of the viral particle with the host cell membrane.
Adenoviruses are particularly suitable as vectors for delivering foreign genes into cells because they have a double-stranded DNA genome that can accommodate large segments of foreign DNA, and because they infect most cell types without integrating into the host genome. However, due to the prevalence of adenovirus infections in humans, most people have adenovirus-specific antibodies that could bind and neutralize these vectors, thus rendering them less effective at stimulating antibodies to the foreign gene product. To circumvent this problem, the Oxford/AstraZeneca investigators used an adenovirus of chimpanzee origin that does not normally infect humans. Thus recipients would not likely have pre-existing antibodies to the adenovirus vector itself. They also further optimized the virus by deleting two genes. Deletion of the first gene – which regulates viral replication – ensures that the virus cannot cause an infection in human cells. Deletion of the second gene creates more space inside the vector to allow for insertion of the gene coding for the SARS-CoV-2 spike protein.
The Oxford/AstraZeneca combined phase I/II clinical trial enrolled 1,077 healthy adult volunteers aged 18-55 who were randomly assigned to receive AZD1222 or a control vaccine. The control vaccine was a licensed vaccine against meningitis and is not viral-vector based. The trial was single-blinded, meaning that only investigators knew whether any particular subject received AZD1222 or the control vaccine, while the subject did not know. This is in contrast to double-blinded studies, where neither the investigators nor the subjects know who is receiving a particular treatment. The investigators chose the meningitis vaccine as a control to ensure that subjects remained blinded to which treatment they were receiving, because, like some vaccines, the meningitis vaccine causes a slight reaction. Use of a saline control would not have induced a reaction, causing subjects to possibly suspect that they received a placebo, which could create a subjective bias and affect experimental outcomes. The AZD1222 vaccine was administered as an intramuscular injection at a single concentration of 50 billion viral particles.
Volunteers were assigned to one of the following groups:
Group 1 – 88 subjects who received a single dose of AZD1222 or control vaccine were assessed for both side effects and vaccine immunogenicity;
Group 2 – 412 subjects who received a single dose of AZD1222 or control vaccine were assessed for both antibody and T cell immunity;
Group 3 – 10 subjects who received two doses of AZD1222 at a 28-day interval were assessed for both side effects and vaccine immunogenicity; and
Group 4 – 567 subjects who received a single dose of AZD1222 or control vaccine were only assessed for antibody immunity.
The basic findings were:
- Side effects were mild to moderate, mostly consisting of pain and tenderness at the site of injection. Participants had the option of taking acetaminophen (paracetamol) prior to vaccination, which prevented injection site pain and tenderness in at least half of those who took it, and had no effect on vaccine immunogenicity.
- All recipients of a single dose of AZD1222 (groups 1, 2, and 4) produced high levels of spike protein-specific total binding antibodies that were sustained to day 56 post-vaccination, and most subjects in these groups also produced neutralizing antibodies.
- The second dose of AZD1222 boosted the levels of existing total binding antibodies and induced neutralizing antibodies in all subjects in group 3.
- A single dose of AZD1222 induced high levels of spike protein-specific T cell responses in all subjects through day 56 post-vaccination. The second dose given to group 3 subjects did not boost these responses.
In general, the results of the trial are reassuring; AZD1222 seems to activate both arms of the adaptive immune response by inducing both neutralizing antibody and T cell responses specific to the SARS-CoV-2 spike protein. The study also involved a good number of subjects, a factor that is crucial for determining whether results are statistically significant for a phase I/II trial. Due to ethical implications, the efficacy of the vaccine cannot be tested by intentionally infecting (challenging) immunized subjects with SARS-CoV-2. However, results from such a challenge experiment previously done in rhesus macaques suggest that AZD1222 protected the animals against SARS-CoV-2 infection. Immunized macaques infected with SARS-CoV-2 had no signs of virus replication in the lungs, significantly lower levels of respiratory disease, and no lung damage compared to control animals. Even though macaques are not people, their immune responses often parallel those of humans and can provide important insights into human immunity.
Nevertheless, the trial also had several limitations. The vaccine was not tested in subjects over the age of 55, a group who often mount a weaker immune response and are at higher risk for severe COVID-19. The authors acknowledge the importance of a SARS-CoV-2 vaccine for this age group and note that the adenovirus vector used to make AZD1222 was previously shown to be immunogenic in individuals aged 50-78 when used to deliver an influenza virus vaccine. The majority of the volunteers were white, and it is well known that ethnic groups are disproportionately affected by COVID-19. The follow-up period was short, so we don’t know how long the observed immune responses will last and if there are any long-term side effects. It is also unclear why the study was only blinded to vaccine recipients, since double-blinded studies lead to more authentic conclusions because they reduce researcher bias.
The results obtained so far regarding the safety and efficacy of AZD1222 are only preliminary. Phase III trials aimed at assessing the vaccine’s efficacy in ethnically diverse populations as well as in older age groups with comorbidities are currently ongoing in Brazil, South Africa, and the UK, and will hopefully yield more conclusive results.
[The Oxford/AstraZeneca phase I/II clinical trial was also discussed on TWiV 644.]