non-randomised, first-in-human trial
Background
A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain.
Methods
We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays.
Findings
Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 [46%]), fatigue (47 [44%]), headache (42 [39%]), and muscle pain (18 [17%]. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination.
Interpretation
The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation
To our knowledge, this is the first report on a first-in-human clinical trial of a novel Ad5 vectored COVID-19 vaccine. The Ad5 vectored COVID-19 vaccine was tolerated in healthy adults in all three dose groups. The most common adverse reactions were fever, fatigue, headache, and muscle pain with no significant difference in the incidence of adverse reactions across the groups. Most adverse events reported were mild or moderate in severity. We noticed a higher reactogenicity profile of the high dose at 1·5 × 1011 viral particles, presenting as severe fever, fatigue, muscle pain, or joint pain, which might be associated with viraemia caused by Ad5 vector infection. However, the severe adverse reactions were transient and self-limiting. Additionally, no abnormal changes in laboratory measurements were clinically significant or considered to be related to the vaccine. The profile of adverse events reported in this trial is similar to that of another Ad5 vector-based Ebola vaccine expressing glycoprotein.
To accelerate the process of clinical evaluation of the candidate COVID-19 vaccine, we selected doses for the phase 2 study mainly on the basis of the safety profile of the candidate vaccines shown in the participants within 7 days and 14 days post-vaccination. We chose the low dose (5 × 1010 viral particles) and middle dose (1 × 1011 viral particles) to be further assessed in a phase 2 clinical trial.
The Ad5 vectored COVID-19 vaccine was immunogenic, inducing humoral and T-cell responses rapidly in most participants. Onset of detectable immune responses was rapid, with T-cell responses peaking at day 14 after vaccination and antibodies peaking at day 28. The antibody response to the vaccine in the high dose group was slightly greater than that in the middle dose and low dose groups. A single dose of Ad5 vectored COVID-19 vaccine was able to elicit a four-fold increase in binding antibodies to RBD in 94–100% of participants, and a four-fold increase to live virus in 50–75% of participants. Despite differences in magnitudes of the antibodies measured through different methods, there was a strong positive correlation between binding antibodies and neutralising antibody titres to the live virus. High proportions of participants with positive T-cell responses were noted across the all dose groups post-vaccination. The activation of both CD4+ T cells and CD8+ T cells was observed in vaccine recipients, particularly for antigen-specific CD4+ T cells and CD8+ T cells. However, both the specific antibody response and T-cell response induced by vaccination were partly diminished by the presence of high pre-existing anti-Ad5 immunity.
Currently, correlates of protection for a vaccine against COVID-19 are unknown, and the roles of the specific antibodies or T cells in building effective protection are not yet defined. Therefore, we are unable to predict the protection of the Ad5 vectored COVID-19 vaccine on the basis of the vaccine-elicited immune responses in this study. However, previous studies investigating SARS and Middle East respiratory syndrome (MERS) found that the increases in specific antibodies were temporary, and declined quickly in patients after recovery, whereas the specific CD4+ and CD8+ T-cell responses played an essential role in immunity.A similar rapid decline of the specific antibody amounts in patients with COVID-19 after recovery was also noted, suggesting that both specific cellular and humoral immunity are potentially important for a successful COVID-19 vaccine. Here, we only report the data within 28 days after the vaccination, but we are going to follow up the vaccine recipients for at least 6 months, so more data will be obtained.
This study was done in Wuhan, Hubei province, which was the centre of the COVID-19 epidemic in China.
People living in the city of Wuhan had a much higher risk of SARS-CoV-2 infection compared with those living in other cities outside of Hubei province, even though when we initiated this trial, the city had already begun lockdown and implemented mandatory home isolation for residents. Therefore, we did serological screening, nucleic acid testing, and chest CT to exclude participants who had been previously exposed to SARS-CoV-2 during recruitment. In addition, we arranged for all participants in our study to stay in a designated hotel for 14 days post-vaccination. This arrangement facilitated the observation of adverse events after the immunisation of the participants, and reduced the risk of SARS-CoV-2 exposure during the following 2 weeks. These measures allowed the study to be done successfully without interference by the circulation of SARS-CoV-2, which is especially important in the absence of a placebo control.
Interpretation of the results of this study is limited by the small size of the cohort, the short duration of follow-up, and the absence of a randomised control group. As it was a first-in-human study of the Ad5 vectored COVID-19 vaccine, it was not designed to measure the vaccine efficacy. However, in preclinical studies, seven out of eight ferrets were protected from having detectable virus copies when challenged by SARS-CoV-2 through nasal dripping 21 days after immunisation with the vaccine, whereas only one out of eight ferrets in the control group was negative for virus copies (Wei C, unpublished). We aimed to evaluate the safety and tolerability of the candidate vaccine in healthy adults, with no interference by underlying diseases or medicines. However, results of our study indicated that older age could have a negative effect on the vaccine-elicited responses to SARS-CoV-2. In this trial, no participants were older than 60 years and only 16% of the participants were older than 50 years, providing limited information on the capability of generating a potent cellular and humoral response in the older population. Since age has also been identified as an independent risk factor for severe disease associated with SARS-CoV-2 infection, and there is a possibility that an even lower immune response might be found in the older population, we are going to include participants who are older than 60 years in the phase 2 study considering this population as an important target population for a COVID-19 vaccine. Additionally, experience with vaccine candidates for SARS and MERS have raised concerns about the antibody-dependent enhancement in participants who are infected with a circulating SARS-CoV-2 post-vaccination.
However, this study was not statistically powered to measure any safety outcome, especially for the concerns around immunopathology and antibody-dependent enhancement events associated with the full-length spike glycoprotein vaccine antigen.Our study found that the pre-existing Ad5 immunity could slow down the rapid immune responses to SARS-CoV-2 and also lower the peak of the responses, particularly for humoral immunity. The high pre-existing Ad5 immunity might also have a negative effect on the persistence of the vaccine-elicited immune responses. In previous studies, heterologous prime-boost combinations or homologous prime-boost regimens with Ad5 vectored vaccines were shown to be able to induce more strong and durable immunogenic responses in populations with high pre-existing Ad5 immunity.Nevertheless, limited information is available for the effects of multiple doses of the candidate Ad5 vectored COVID-19 vaccine in humans, which warrants further investigation.
Over the past decade, the vaccine industry and clinical research centres have been asked to provide urgent responses to epidemics of emerging infectious diseases, such as H1N1 influenza, Ebola virus, Zika, MERS, and now SARS-CoV-2.The risk of COVID-19 caused by SARS-CoV-2 is ongoing, making the need for effective vaccines even more urgent.
We started the development of this candidate vaccine in January, 2020, when SARS-CoV-2 was first isolated and sequenced. The full-length spike glycoprotein was selected as the vaccine antigen, mainly on the basis of previous experience with SARS and MERS vaccines. Previous findings suggested that those vaccines expressing full-length spike glycoprotein can induce good immune responses and protective efficacy.Although the RBD comprises the critical neutralising domains for the coronaviruses, the neutralising epitopes located outside the RBD were also identified.The full-length spike was chosen in most of the viral vectored, mRNA, or DNA COVID-19 vaccines in development.
The Ad5 vector vaccine platform is highly efficient and well established as a vaccine antigen delivery system. In addition to our candidate Ad5 vectored COVID-19 vaccine, there are several other Ad5-based vaccines against COVID-19 listed in the WHO draft landscape of COVID-19 candidate vaccines, including Ad5 S (GREVAXTM platform) in the USA, and Oral Ad5 S (Stabilitech Biopharma) in the UK.
However, aside from pre-existing anti-Ad5 immunity, there is a concern about the increased risk of HIV-1 acquisition associated with Ad5 activated CD4+ T cells.Although the association between HIV-1 acquisition risk and Ad5 vectored vaccine is controversial and its mechanism is unclear, the potential risks should be taken into account in studies with this viral vector delivery platform. We plan to monitor the participants in our upcoming phase 2 and phase 3 studies to assess the indication for any such acquisition.
In conclusion, we found that the Ad5 vectored COVID-19 vaccine is tolerable and immunogenic in healthy adults. Specific humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination, and rapid, specific T-cell responses were noted from day 14 after one shot of the vaccine. There is potential for further investigation of the Ad5 vectored COVID-19 vaccine for the control of the COVID-19 outbreak. An ongoing phase 2 trial in China will provide more information on the safety and immunogenicity of the Ad5 vectored COVID-19 vaccine.
Reference & source information: https://www.thelancet.com/
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