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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

https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31605-6/fulltext

Summary

Background

This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an appropriate dose of the candidate vaccine for an efficacy study.

Methods

This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1?×?1011 viral particles per mL or 5?×?1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.govNCT04341389.

Findings

603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1?×?1011 viral particles n=253; 5?×?1010 viral particles n=129) or placebo (n=126). In the 1?×?1011 and 5?×?1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1?×?1011 and 5?×?1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1?×?1011 and 5?×?1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1?×?1011 and 5?×?1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1?×?1011 viral particles dose group and one (1%) participant in the 5?×?1010 viral particles dose group. No serious adverse reactions were documented.

Interpretation

The Ad5-vectored COVID-19 vaccine at 5?×?1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation.

Funding

National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 12·1 million cases of COVID-19 worldwide, resulting in 551?000 deaths and severe economic disruption.  

 After the initial outbreak, with more than 80?000 cases and 3000 deaths in China, COVID-19 has now spread to 216 countries and territories. Large numbers of cases and deaths are reported daily from Europe, the USA, Brazil, Russia, India, and many other countries.

 The current pandemic has highlighted the need for effective preventive solutions to reduce burden and spread of the disease. As long as there is a COVID-19 epidemic in one area in the world, there is a risk of a pandemic.

Research in context

Evidence before this study
We searched PubMed on July 16, 2020, for clinical trial reports with the terms “COVID-19” or “SARS-CoV-2”, “vaccine”, and “clinical trial”. Using the same terms, we also searched ClinicalTrials.gov for unpublished trials of COVID-19 vaccines. Except for the results of our earlier phase 1 study with the adenovirus type-5 (Ad5)-vectored vaccine and a phase 1 clinical trial with an mRNA vaccine (mRNA-1273) done in a small number of participants, no other COVID-19 vaccine data from clinical trials have been reported. We found registered trials with 11 candidate COVID-19 vaccines at ClinicalTrials.gov, including three recombinant protein-based vaccines, two viral vector-based vaccines, one DNA vaccine, two mRNA vaccines, two inactivated virus vaccines, and one autologous dendritic cell-based vaccine loaded with antigens from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The majority of the trials registered were in early phases; only ChAdOx1 nCoV-19 developed by the University of Oxford (Oxford, UK) is going to be evaluated in a phase 3 trial.
In the previously reported open-label, non-randomised, phase 1 trial, we found that the Ad5-vectored COVID-19 vaccine was tolerable and immunogenic in healthy adults. One dose of the vaccine induced rapid specific T-cell and humoral responses by 14 days.
Added value of this study
This study provides more evidence for the immunogenicity and safety of the Ad5-vectored COVID-19 vaccine in a larger population. To assess the vaccine in a more diverse population, we removed the age cap for the recruitment of participants for this phase 2 trial. Older individuals (ie, aged ≥55 years), many of whom often have chronic illness, have a high risk of serious illness and death associated with SARS-CoV-2 infection; thus, they are an important target population for a COVID-19 vaccine. Our results suggest a single-dose immunisation schedule of Ad5-vectored COVID-19 vaccine at 5?×?1010 viral particles is an appropriate regimen for healthy adults. Compared with the younger population, we found older people to have a significantly lower immune response, but higher tolerability, to the Ad5-vectored COVID-19 vaccine. Therefore, an additional dose might be needed to induce a better immune response in the older population, and this will be evaluated in a phase 2b trial.
Implications of all the available evidence
Evidence from this phase 2 study indicates the candidate Ad5-vectored COVID-19 vaccine has a good safety profile, with only mild, transient adverse events related to vaccination and no serious adverse events. Single-dose immunisation with the vaccine induced rapid onset of immune responses within 14 days and significant humoral and cellular immune responses within 28 days in the majority of the recipients. We are planning an international multicentre, randomised, double-blind, controlled phase 3 effectiveness trial to further evaluate the efficacy of the vaccine. We are in the midst of a global COVID-19 pandemic; thus, timely sharing of the results of clinical trials with candidate vaccines is critical. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31605-6/fulltext
By Roman Ribnikov especially for Medical Express
15.08.2020 1659

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