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Safety and Immunogenicity of the ChAdOx1 nCoV-19 Vaccine Against SARS-CoV-2
TAKE-HOME MESSAGE
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In this phase I/II study assessing the immunogenicity and safety of a potential COVID-19 vaccine, neutralizing antibody responses were detected in 91% of 35 patients receiving a single dose of this novel chimpanzee adenovirus–vectored vaccine against SARS-CoV-2; 100% of recipients expressed neutralizing antibody responses after a second dose.
- This novel vaccine was found to be safe with promising immunogenicity, and efficacy will be further evaluated in an ongoing phase III trial.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2.
METHODS
We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606.
FINDINGS
Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493-1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96-317; n=127), and were boosted following a second dose (639 EU, 360-792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001).
INTERPRETATION
ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme.
FUNDING
UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
Additional Info
Disclosure statements are available on the authors' profiles:
Safety and Immunogenicity of the ChAdOx1 nCoV-19 Vaccine Against SARS-CoV-2: A Preliminary Report of a Phase 1/2, Single-Blind, Randomised Controlled Trial
Lancet 2020 Jul 20;[EPub Ahead of Print], PM Folegatti, KJ Ewer, PK Aley, B Angus, S Becker, S Belij-Rammerstorfer, D Bellamy, S Bibi, M Bittaye, EA Clutterbuck, C Dold, SN Faust, A Finn, AL Flaxman, B Hallis, P Heath, D Jenkin, R Lazarus, R Makinson, AM Minassian, KM Pollock, M Ramasamy, H Robinson, M Snape, R Tarrant, M Voysey, C Green, AD Douglas, AVS Hill, T Lambe, SC Gilbert, AJ PollardFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
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