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 × 10
11 viral particles per mL or 5 × 10
10 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.gov,
NCT04341389.
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.
Emerging Vaccines for SARS-CoV-2
What do a replication-deficient chimpanzee adenovirus, a replication-defective human type-5 adenovirus, and a lipid nanoparticle have in common? When talking about prototype COVID-19 vaccines, they all contain the RNA that codes for the spike glycoprotein necessary for SARS-CoV-2 binding with, and entry into human cells. In addition, all three of these vaccines have now passed important waypoints along the pathway to licensure, recommendation, and widespread use. In many other ways, however, they are extremely different.
A chimpanzee adenovirus (ChAd) candidate vaccine emerged in response to the Middle East respiratory syndrome (MERS) coronavirus. Using a similar approach, a new vaccine (ChAdOx1) employs the replication-deficient ChAd as a vector containing the RNA sequence for the spike protein. In a phase I/II randomized controlled trial (RCT) involving 1077 participants, Folegatti and colleagues demonstrated peak T-cell response 14 days after immunization, rising anti-spike antibody at day 28, and neutralizing antibody responses in 91% to 100% of subjects for whom these assays were performed.1 Although local and systemic reactions were common and included pain, feverishness, chills, myalgia, headache, and malaise, no serious adverse events occurred.
Researchers in China have created a vaccine using a replication-defective type-5 human adenovirus as a vector of the full length spike protein gene. This vaccine—in two dosing strengths—or a placebo were administered to 508 participants in a phase II RCT in Wuhan, China.2 Seroconversion rates for receptor-binding domain antibodies were 96% to 97% depending on dose at day 28. In addition, both dosages produced neutralizing antibody to live SARS-CoV-2. Again, local and systemic reactions (pain, fever, headache, and fatigue) were common, and severe adverse events were noted in 9% of the higher-dose recipients. No serious side effects were reported.
We currently do not have any mRNA vaccines in our armamentarium against infectious diseases. A COVID-19 candidate, codeveloped by the National Institute of Allergy and Infectious Diseases and Moderna, is a “lipid nanoparticle-encapsulated, nucleoside-modified mRNA-based vaccine.”3 This vaccine was recently assessed in a phase 1 trial involving 45 participants who received two doses, 28 days apart. Three different doses (25 µg, 100 µg, or 250 µg) were used. The higher doses produced higher anti-spike antibody on day 29, and all levels were increased following the booster dose. Serum-neutralizing activity, measured after the second dose was comparable to that of convalescent serum. Vaccine side effects were common and included fatigue, chills, headache, myalgia, and injection site pain.
Taken together, these studies demonstrate that early endpoints for new vaccine development are being met: the novel candidates are producing measurable antibody in most vaccine recipients, which is able to neutralize SARS-CoV-2. They are achieving this seroconversion without notable serious adverse effects, although local and systemic effects are common. The challenge now comes in terms of these candidates’ ability to prevent SARS-CoV-2 infection/transmission and reduce the illnesses, hospitalizations, intensive care requirements, and deaths attributable to COVID-19, and in the durability of the imparted immune response. That is the role of phase III trials now underway and longitudinal monitoring. Such trials require large numbers of participants and sufficient time for exposure to and acquisition of SARS-CoV-2 infection allowing for estimates of effectiveness and better ascertainment of safety.
References
Emerging Vaccines for SARS-CoV-2
What do a replication-deficient chimpanzee adenovirus, a replication-defective human type-5 adenovirus, and a lipid nanoparticle have in common? When talking about prototype COVID-19 vaccines, they all contain the RNA that codes for the spike glycoprotein necessary for SARS-CoV-2 binding with, and entry into, human cells. In addition, all three of these vaccines have now passed important waypoints along the pathway to licensure, recommendation, and widespread use. In many other ways, however, they are extremely different.
A chimpanzee adenovirus (ChAd) candidate vaccine emerged in response to the Middle East respiratory syndrome (MERS) coronavirus. Using a similar approach, a new vaccine (ChAdOx1) employs the replication-deficient ChAd as a vector containing the RNA sequence for the spike protein. In a phase I/II randomized controlled trial (RCT) involving 1077 participants, Folegatti and colleagues demonstrated peak T-cell response 14 days after immunization, rising anti-spike antibody at day 28, and neutralizing antibody responses in 91% to 100% of subjects for whom these assays were performed.1 Although local and systemic reactions were common and included pain, feverishness, chills, myalgia, headache, and malaise, no serious adverse events occurred.
Researchers in China have created a vaccine using a replication-defective type-5 human adenovirus as a vector of the full-length spike protein gene. This vaccine—in two dosing strengths—or a placebo were administered to 508 participants in a phase II RCT in Wuhan, China.2 Seroconversion rates for receptor binding domain antibodies were 96% to 97% depending on dose at day 28. In addition, both dosages produced neutralizing antibody to live SARS-CoV-2. Again, local and systemic reactions (pain, fever, headache, and fatigue) were common, and severe adverse events were noted in 9% of the higher-dose recipients. No serious side effects were reported.
We currently do not have any mRNA vaccines in our armamentarium against infectious diseases. A COVID-19 candidate, co-developed by the National Institute of Allergy and Infectious Diseases and Moderna, is a “lipid nanopartical-encapsulated, nucleoside-modified mRNA-based vaccine.”3 This vaccine was recently assessed in a phase I trial involving 45 participants who received two doses, 28 days apart. Three different doses (25 µg, 100 µg, 250 µg) were used. The higher doses produced higher anti-spike antibody on day 29, and all levels were increased following the booster dose. Serum-neutralizing activity, measured after the second dose was comparable to that of convalescent serum. Vaccine side effects were common and included fatigue, chills, headache, myalgia, and injection site pain.
Taken together, these studies demonstrate that early endpoints for new vaccine development are being met: the novel candidates are producing measurable antibody in most vaccine recipients which is able to neutralized SARS-CoV-2. They are achieving this seroconversion without notable serious adverse effects, although local and systemic effects are common. The challenge now comes in terms of these candidates’ ability to prevent SARS-CoV-2 infection/transmission and reduce the illnesses, hospitalizations, intensive care requirements, and deaths attributable to COVID-19, and in the durability of the imparted immune response. That is the role of phase III trials that are now underway and longitudinal monitoring. Such trials require large numbers of participants and sufficient time for exposure to, and acquisition of, SARS-CoV-2 infection, allowing for estimates of effectiveness and better ascertainment of safety.
References