Phase II trials from AstraZeneca, CanSino, and Pfizer poised to move on to phase III

As the Covid-19 pandemic rages on, the race for a vaccine is heating up. On Monday, July 20, promising early results of three vaccine trials were announced, two published in The Lancet — one from the University of Oxford and AstraZeneca, and the other from CanSino Biologics — and the third, from Pfizer and BioNTech, published by medRxiv, the results of which have not yet been peer reviewed.

The first vaccine, dubbed ChAdOx1 nCoV-19, from the Oxford Vaccine Trial Group, is a chimpanzee, adenovirus-vectored vaccine. Participants in the trial — healthy adults age 18-55 years — were randomized to receive either the adenovirus-vectored vaccine or a meningococcal conjugate vaccine (MedACWY).

“Our preliminary findings show that the candidate ChAdOx1 nCoV-19 vaccine given as a single dose was safe and tolerated, despite a higher reactogenicity profile than the control vaccine, MenACWY,” Andrew Pollard, from the University of Oxford, and the Oxford Vaccine Trial Group wrote. “No serious adverse reactions to ChAdOx1 nCoV-19 occurred. The majority of adverse events reported were mild or moderate in severity, and all were self-limiting.” They also noted that the reported adverse events were similar to those of other related simian adenoviruses.

The single-dose vaccine elicited “an increase in spike-specific antibodies by day 28 and neutralizing antibody in all participants after a booster dose,” the researcher wrote.

Meanwhile, the news from China is also encouraging, as researchers there conducted a randomized controlled trial testing the immunogenicity of a non-replicating adenovirus type 5 (Ad5)-vectored Covid-19 vaccine. Tested against placebo in healthy adults age 18 or older, the vaccine yielded a significant immune response and was found to be safe.

“The vaccine induced seroconversion of the neutralizing antibodies in 59% and 47% of participants, and seroconversion of binding antibody in 96% and 97% of participants, in the 1×10¹¹ and 5×10¹⁰ viral particles dose groups, respectively,” Feng-Cai Zhu, from the NHC Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevent, Nanjing, China, and colleagues wrote.

“These trial reports are hugely anticipated,” Naor Bar-Zeev and William J. Moss, from the International Vaccine Access center, Johns Hopkins Bloomberg School of Public Health, Baltimore, wrote in a commentary accompanying the studies in The Lancet. “The results of both studies bode well for phase 3 trials, where the vaccines must be tested on much larger populations of participants to assess their efficacy and safety. Overall, the results of both trials are broadly similar and promising…”

The Oxford Vaccine Trial Group set out to compare the ChAdOx1 nCoV-19 vaccine at a dose of 5×1010 viral particles to a single intramuscular injection of the meningococcal vaccine at five trial sites in the U.K. The participants did not have a history of laboratory confirmed SARS-CoV-2. Prophylactic paracetamol (acetaminophen) was given before vaccination at two sites.

The phase I/II trial also assigned 10 participants to a group that was non-randomized and unblinded to receive a booster of ChAdOx1 nCoV-19 given 28 days after the initial vaccination.

“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,” Pollard and colleagues wrote.

There were 1,077 particpants enrolled and randomized to ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534) from April 23 to May 21, 2020, as well as the 10 in the booster group.

In the vaccine group, more adverse events were reported, although none were serious, and they were somewhat mitigated by paracetamol.

“In those who did not receive prophylactic paracetamol, 328 (67%) of 487 participants in the ChAdOx1 nCoV-19 group and 180 (38%) of 477 participants in the MenACWY group reported pain after vaccination, which was mostly mild to moderate in intensity,” Pollard and colleagues wrote. “With prophylactic paracetamol, pain was reported by fewer participants: 28 (50%) in the ChAdOx1 nCoV-19 group and 18 (32%) in the MenACWY group. Tenderness of mostly mild intensity was reported in the ChAdOx1 nCoV-19 group by 403 (83%) participants without paracetamol and 43 (77%) with paracetamol, and in the MenACWY group by 276 (58%) participants without paracetamol and 26 (46%) with paracetamol. ”

In the vaccine group, 340 participants (70%) who were not given paracetamol and 40 (71%) who were given the analegesic reorted fatigue compared with 227 (48%) in the MenACWY group not given the analgesic and 26 (46%) given paracetamol. The results were similar for headache between the two groups — 331 (68%) participants without paracetamol and 34 (61%) with paracetamol in the MenACWY group versus 195 (41%) participants without paracetamol and 21 (37%) participants with paracetamol in the vaccine group.

But how did the vaccine work?

“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),” Pollard and colleagues wrote. “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). Neutralizing 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 neutralizing activity… neutralizing antibody responses correlated strongly with antibody levels measured by ELISA (R²=0.67 by Marburg VN; P<0.001).”

Limitations of the ongoing study are the short follow-up period reported so far, as well as the small number of participants and the single-blinded design. The study authors also noted that the findings may not be generalizable, given the participants were fairly young, healthy, and white.

Nonetheless, the positive preliminary results are enough to fuel the ongoing phase II and III trials, where “[o]lder age groups with comorbidities, health-care workers, and those with higher risk for SARS-CoV-2 exposure are being recruited and assessed for efficacy, safety, and immunogenicity of ChAdOx1 nCoV-19 given as a single-dose or two-dose administration regimen…” Pollard and colleagues wrote. They will also assess the vaccine in children.

Zhu, et al’s randomized, double-blind, placebo-controlled trial tested their Ad5-vectored Covid-19 vaccine in a single center in Wuhan, China. They recruited 603 participants age 18 or older who did not have HIV or SARS-CoV-2 from April 11 to 16, 2020. The 508 eligible participants were randomized 2:1:1 to receive the vaccine at a dose of 1×10¹¹ viral particles per mL or 5×10¹⁰ viral particles per mL, or placebo. Half of the participants were male, and the mean age of those in the trial was 39.7 years — 253 received the 1×10¹¹ viral particles vaccine, 129 received the 5×10¹⁰ viral particles vaccine, and 126 received the placebo.

“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,” Zhu and colleagues wrote. “Both doses of the vaccine induced significant neutralizing 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.”

Adverse reactions were higher in the vaccine groups than the placebo group.

“The most common systemic solicited reactions in the 5×10¹⁰ and 1×10¹¹ viral particles dose groups were fatigue, reported by 42% and 34%; fever, reported by 32% and 16%; and headache, reported by 29% and 28%, respectively,” Zhu and colleagues noted. More than half of the vaccine recipients in both dose groups reported injection site pain.

Twenty-four participants in the 1×10¹¹ viral particles dose group and one (1%) participant in the 5×10¹⁰ viral particles dose group reported severe adverse reactions, but as in the U.K. trial, there were no serious adverse events.

Limitations of their trial include starting the phase II trials before the data from phase I was analyzed and that all of the participants were from Wuhan, China, which might limit generalizability.

Just as with the U.K., these preliminary results support going on to a phase III efficacy trial.

Finally, the trial from Pfizer and BioNTech reported “robust” antibody and T-cell responses for their BNT162b1 vaccine, which is an mRNA-based vaccine.

  1. ChAdOx1 nCoV-19 vaccine, for the Oxford Vaccine Trial Group, given as a single dose, was found to be safe and well-tolerated, despite a higher reactogenicity profile than the control vaccine, MenACWY, that it was compared to.
  2. The non-replicating adenovirus type 5 (Ad5)-vectored Covid-19 vaccine, tested against placebo, induced seroconversion of the neutralizing antibodies in 59% and 47% of participants, and seroconversion of binding antibody in 96% and 97% of participants.

Candace Hoffmann, Managing Editor, BreakingMED™

Folegatti et al’s study is funded by 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.

The University of Oxford has entered into a partnership with AstraZeneca on vaccine development.

Zhu et al’s study was funded by the National Key R&D Programmer of China and CanSino Biologics.

Zhu disclosed no relevant relationships.

Bar-Zeev and Moss disclosed no relevant relationships.

 

Cat ID: 190

Topic ID: 79,190,254,930,791,932,570,730,933,190,31,926,561,927,151,928,925,934