Researchers from AstraZeneca, the University of Oxford, and its spinout company Vaccitech today published preliminary Phase I/II data showing their closely-watched COVID-19 vaccine candidate AZD1222 (formerly ChAdOx1 nCoV-19) to have an acceptable safety profile, and favorable immunogenicity against the virus.
“A single dose elicited both humoral and cellular responses against SARS-CoV-2, with a booster immunisation augmenting neutralising antibody titres. The preliminary results of this first-in-human clinical trial supported clinical development progression into ongoing phase 2 and 3 trials,” the researchers concluded in 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, published today in The Lancet.
“These results are extremely encouraging,” The Lancet’s editor-in-chief, Richard Horton, tweeted this morning.
The results came from the partners’ COV001 Phase I/II trial (NCT04324606). The single-blinded, randomized, multi-center study is designed to determine the efficacy, safety, and immunogenicity of AZD1222 in 1,077 healthy adult volunteers aged 18–55 years across five trial centers in southern England. The trial compared a single dose of AZD1222 against the meningococcal conjugate vaccine MenACWY as a control. Ten participants also received two doses of AZD1222 one month apart.
Among the 543 participants randomized to AZD1222, a single dose resulted in a four-fold increase in antibodies to the SARS-CoV-2 virus spike protein in 95% of participants at Day 28 after injection, the researchers reported. In all participants, a T-cell response was induced, peaking by day 14, and maintained two months after injection.
“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 program,” the researchers concluded in the study.
“Front runner candidate”
AZD1222 is based on an adenovirus vaccine vector and the COVID-19 spike protein. After vaccination, the surface spike protein of the coronavirus is produced, which primes the immune system to attack the coronavirus if it later infects the body.
Spike-specific T-cell responses among AZD1222 participants peaked on day 14, while anti-spike immunoglobulin G (IgG) responses rose by day 28 and were boosted following a second dose, the researchers reported.
Neutralizing antibody responses against SARS-CoV-2 were detected in 32 of 35 participants after a single dose when measured via microneutralization assay (MNA80) and in all 35 participants when measured via the 50% plaque reduction neutralization assay (PRNT50).
After a booster dose, all participants had neutralizing activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg virus neutralization [VN] on day 56). Neutralizing antibody responses correlated strongly with antibody levels measured by ELISA
Two-dose strategy suggested
“We saw the strongest immune response in participants who received two doses of the vaccine, indicating that this might be a good strategy for vaccination,” Professor Andrew Pollard, chief investigator of the Oxford Vaccine Trial at Oxford University and co-author of the trial, said in a statement released by AstraZeneca. “The interim Phase I/II data for our coronavirus vaccine shows that the vaccine did not lead to any unexpected reactions and had a similar safety profile to previous vaccines of this type. The immune responses observed following vaccination are in line with what we expect will be associated with protection against the SARS-CoV-2 virus, although we must continue with our rigorous clinical trial program to confirm this.”
In addition to suggesting a two-dose strategy, the trial also built a case for a single high dosage unlike the approach of several other leading COVID-19 vaccine candidate developers, observed Philipp Rosenbaum, PhD, Senior Infectious Diseases Analyst, and Michael Breen, PhD, Director of Infectious Diseases at GlobalData.
“Unlike CanSino, Moderna and Pfizer, AstraZeneca and Oxford University only tested one high-dosage formulation of the vaccine, providing less data on the optimal relation of antibody response induction to acceptable side effects,” Rosenbaum and Breen stated.
In the study, the researchers asserted that the trial’s protocol came about when the pandemic was accelerating in the U.K., and a single higher dose was chosen to provide the highest chance of rapid induction of neutralizing antibody.
“In the context of a pandemic wave where a single higher, but more reactogenic, dose might be more likely to rapidly induce protective immunity, the use of prophylactic paracetamol appears to increase tolerability and would reduce confusion with COVID-19 symptoms that might be caused by short-lived vaccine-related symptoms without compromising immunogenicity,” the researchers explained.
AZD1222 has been developed by the University’s Jenner Institute, whose researchers partnered with colleagues from the University’s Oxford Vaccine Group to begin recruiting patients for the COV001 trial on April 23, after U.K. Health Secretary Matt Hancock pledged £20 million ($25 million) in government funding to support development of the vaccine.
At the time, AstraZeneca agreed to provide the U.K. with access to the vaccine as soon as possible should it succeed in clinical trials. AstraZeneca also agreed to work with global partners on the international distribution of the vaccine, with emphasis on making it available and accessible for low- and medium-income countries.
“We are encouraged by the Phase I/II interim data showing AZD1222 was capable of generating a rapid antibody and T-cell response against SARS-CoV-2,” added Mene Pangalos, AstraZeneca executive vice president, BioPharmaceuticals R&D.
“While there is more work to be done, today’s data increases our confidence that the vaccine will work and allows us to continue our plans to manufacture the vaccine at scale for broad and equitable access around the world,” Pangalos added.
According to AstraZeneca, late-stage trials of AZD1222 include a Phase III trial in Brazil (2,000 participants, ISRCTN89951424), a Phase IIb/III trial in the U.K. (10,500 participants, 2020-001228-32), and a Phase II/III study in South Africa. In the U.S., the company plans to launch a 30,000-participant trial later this summer.
Pfizer, BioNTech report positive data
Another front runner candidate listed in GEN’s COVID-19 TRACKER released positive early clinical results today.
Pfizer and BioNTech have published initial data from an ongoing German Phase I/II, open-label, non-randomized, non-placebo-controlled, dose-escalation trial of their most advanced of four constructs of their mRNA vaccine candidate for COVID-19 (EU Clinical Trials Registry EudraCT number 2020-001038-36).
The preliminary data—from a preprint study published today—showed BNT162b1 to have elicited high, dose level-dependent SARS-CoV-2-neutralizing titers and receptor binding domain (RBD)-binding immunoglobulin G (IgG) concentrations after the second dose.
“The robust RBD-specific antibody, T-cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest multiple beneficial mechanisms with potential to protect against COVID-19,” researchers concluded in “Concurrent human antibody and TH1 type T-cell responses elicited by a COVID-19 RNA vaccine,” published today by medRxiv.
At Day 43, SARS-CoV-2 neutralizing geometric mean titers were in the range of 0.7-fold (1 µg) to 3.2-fold (50 µg) compared to that of a panel of SARS-CoV-2 infection convalescent human sera. Furthermore, sera of vaccinated subjects displayed broadly neutralizing activity in pseudovirus neutralization assays across a panel of 16 SARS-CoV-2 RBD variants represented in publicly available SARS-CoV-2 sequences and against the newly dominant D614G strain.
The initial German trial results also showed for the first time a concurrent induction of high level CD4+ and CD8+ T cell responses against the SARS-CoV-2 RBD for BNT162b1—thus indicating a strong potential for cell mediated anti-viral activity, according to BioNTech and Pfizer.
“The preliminary data indicate that our mRNA-based vaccine was able to stimulate antibody as well as T-cell responses at remarkably low dose levels. We believe both may play an important role in achieving effective clearance of a pathogen such as SARS-CoV-2,” Özlem Türeci, MD, CMO and co-founder of BioNTech, said in a statement.
BNT162b1 is a lipid nanoparticle-formulated, nucleoside-modified mRNA (modRNA) vaccine candidate that encodes trimerized SARS-CoV-2 spike glycoprotein receptor binding domain (RBD) antigen. BioNTech and Pfizer are evaluating four vaccine constructs of BNT162 in an mRNA-based clinical program the companies have dubbed “Project Lightspeed.”
BioNTech and Pfizer also announced early today that they signed an agreement committing them to supply the U.K. with 30 million doses of their BNT162, to be delivered this year and next. Financial terms of the agreement were not disclosed.
Pfizer and BioNTech said they remained on track to begin a Phase IIb/III safety and efficacy trial later this month in potentially up to 30,000 healthy participants. The companies plan to seek regulatory review as early as October 2020, manufacture globally up to 100 million doses by the end of 2020, and more than 1.3 billion doses by the end of 2021.
The German trial data came three weeks after the companies reported encouraging immunogenicity and a favorable safety profile in preliminary Phase I/II data from a U.S. trial (NCT04368728) also published in a medRxiv preprint.
“It is encouraging that the data on BNT162b1 from the German study cohort are very much in line with what we have seen in the U.S. study cohort,” Türeci added.