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dcyphr | Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial

Abstract

This study sought to test the immunogenicity (the ability of something to create an immune response) and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine. This vaccine is the first COVID-19 vaccine candidate in a clinical trial, and is a genetically modified virus that is unable to replicate and expresses SARS-CoV-2 spike protein, generating an antibody response against this protein. The researchers also wanted to determine a safe and effective dose of this vaccine.


The researchers conducted a randomized, blinded, placebo-controlled phase 2 trial of the vaccine at a single hospital in Wuhan, China. Healthy adults aged 18 years or older and had previous SARS-CoV-2 infection were assigned to one of two different doses of the vaccine or a placebo. Randomization was conducted by an independent statistician, and all staff involved in analyses were blinded to what participants were assigned to what groups. The endpoint for immunogenicity were measures of antibody responses to SARS-CoV-2 at day 28. The endpoint for safety evaluation was whether there were any harmful side effects within 14 days. 


603 participants volunteered and all were enrolled in the study. 253 received 1x1011 viral particles in the vaccine, 129 received 5x1010 particles, and 126 received the placebo. Both doses of the vaccine generated a significant neutralizing antibody response to SARS-CoV-2, with the lower dose generating less antibodies and neutralizing response. Harmful effects were seen in 183 of 253 and 96 of 129 participants in the 1x1011 and 5x1010 viral particles dose groups, respectively. Severe harmful effects were reported by 24 participants in the 1x1011 group and one participant in the 5x1010 viral particles dose group. No serious harmful effects were reported. In conclusion, the Ad5-vectored COVID-19 vaccine at 5x1010 viral particles is safe and generates significant immune responses in a majority of those who are vaccinated.

Aims

The researchers wanted to determine whether the Ad5-vectored COVID-19 vaccine was safe and effective, as well as it’s optimal dose.

Introduction

The current pandemic highlights the need for effective prevention to reduce new infections by SARS-CoV-2. Although vaccine development normally takes decades, for COVID-19 it has become expedited in many countries and about 250 vaccines against SARS-CoV-2 are now in development. At least 17 of these vaccine candidates are undergoing clinical trials.


In a previous study, the researchers conducted a first, in-human phase 1 clinical trial with the adenovirus type-5 (Ad5)-vectored COVID-19 vaccine using various doses. The various doses were generally safe and immunogenic, except the high-dose vaccine which was associated with severe harmful side effects. So, the researcher decided to conduct this phase 2 trial using the two lower doses, 5x1010 and 10x1011 viral particles.

Results

603 participants were recruited with 95 being excluded, with 508 participants being enrolled in the study. 253 were assigned to the 1x1011 viral particles vaccine, 129 to the 5x1010 viral particles vaccine, and 126 to the placebo group. The mean age of participants was 39.7 years, and more participants were younger (18-44). Baseline characteristics were similar across treatment groups. Around half had high pre-existing immunity to the Ad5 vector, while the other half did not. All participants completed all scheduled safety visits and gave blood samples.


Antibody responses against the SARS-CoV-2 spike protein were detected from day 14 onwards, with higher antibody levels in the higher-dose vaccine group. Similar results were observed at day 28. The placebo group showed no increased antibodies from baseline. Both vaccines also generated significant neutralizing antibody responses against SARS-CoV-2. No significant differences were observed between the two vaccine groups. These results can be observed in Figure 2.


There were several factors that weakened the vaccine’s effect in some participants. Participants who had high pre-existing anti-Ad5 antibodies had lower antibody levels than those with low-preexisting immunity. Older age also negatively impacted vaccine efficacy, especially for participants 55 years or older. But, antibody levels were still higher in the vaccinated groups than the placebo group.

In terms of specific T-cell response, which measures the ability of the immune system to neutralize SARS-CoV-2, both dose groups had similar results. The placebo showed negative results.

72% of participants in the 1x1011 viral particles group and 74% of those in the 5x1010 group reported adverse reactions within 2 weeks, much higher than 37% of the placebo group. The most common reactions reported were fatigue, fever, and headache. Most reactions were reported as mild or moderate, but 9% of participants in the 1x1011 group had severe reactions, significantly higher than those receiving the lower dose vaccine or placebo. The most commonly reported severe reaction was fever, which was associated with high pre-existing Ad5 immunity, older age, and male sex. However, these reactions were resolved within 72-96 hours. No serious adverse events were reported within 28 days.

Discussion

This study is the first randomized controlled phase 2 trial for the immunogenicity and safety of the Ad5-vectored COVID-19 vaccine. Both vaccine doses administered generated significant neutralizing antibody responses against SARS-CoV-2. Pre-existing immunity to Ad5 and increasing age could inhibit the vaccine’s efficacy.


Most side effects reported after vaccination were mild or moderate. Although more side effects were reported in the vaccine groups than placebo, they were generally not severe and resolved within 2 days. Almost all severe adverse reactions were reported in the 1x1011 viral particles group. These results suggest that the vaccine is safe in healthy adults.


In their previous study, the researchers hypothesized that the two vaccine doses would have similar safety profiles, with the higher dose being more effective. However, the researchers found that the lower-dose vaccine had a better safety profile and comparable immunogenicity to the higher-dose vaccine.


Age and pre-existing Ad5 immunity may have affected the vaccine’s safety and efficacy. Providing an additional dose between 3-6 months after the first injection may enhance vaccine efficacy in these groups. Further study is necessary to understand these and other factors that could influence vaccine safety and efficacy.


Both neutralizing antibody and T-cell responses are important in eliminating disease from patients with COVID-19. Although antibodies are very effective against SARS-CoV-2, indicated by the success of convalescent plasma transfusions, it is unknown whether antibodies alone can prevent infection. More studies are necessary to understand how T-cell responses, in addition to antibodies, are important for a successful vaccine.

Methods

Study Design and Participants

This study was a randomized, double-blinded, placebo-controlled phase 2 trial. Eligible participants were healthy adults who were 18 years or older, HIV-negative, and had not been previously infected by SARS-CoV-2. 


Randomization and Masking

The vaccine contained Ad5 virus that were genetically engineered to be unable to replicate but expressed the SARS-CoV-2 spike protein. The placebo contained all non-viral contents of the vaccine. Vaccines had identical packaging to blind the researchers. Eligible participants were given a randomization number by an independent statistician, and injected with the vaccine or placebo that matched that number. The participants, researchers, and staff involved in analyses were blinded to group allocation.


Procedures

A single injection of vaccine or placebo was given to participants in the arm, and participants were monitored for 30 minutes for any harmful side effects. Participants were followed up at 14 days and 28 days, and any harmful side effects were documented.

Multiple assays were used to determine immunogenicity, including ELISA kits, ELISpot, and serum neutralization assays.


Outcomes

The primary objectives were to determine the immunogenicity and safety of the Ad5-vectored COVID-19 vaccine and a safe dose to administer it. The primary endpoint for safety was adverse reactions within 14 days of vaccination. The primary endpoints for immunogenicity were measurements of antibody responses against SARS-CoV-2 28 days after vaccination. Secondary endpoints were adverse events within 28 days and serious adverse reactions within 6 months.


Statistical Analysis

A sample size of 500 participants was determined based on expert opinion and minimal sample size requirements for clinical trials in China, which provided enough statistical power for the study. All analyses were done in SAS.

Conclusion

In conclusion, the results of this study have confirmed that Ad5-vectored COVID-19 vaccines are safe and effective, and support the testing of the vaccine in phase 3 trials in healthy adults.