AZ and Oxford paper spotlights the swerves on the road to pooled vaccine efficacy readout
A dive into AZ and Oxford’s efficacy analysis for AZD1222
A dive into AZ and Oxford’s efficacy analysis for AZD1222 reveals how the partners navigated data pooling in the face of protocol changes, and the questions now facing regulators.
The first peer-reviewed paper on pivotal data from a COVID-19 vaccine details the unplanned protocol shifts complicating the pooled efficacy analysis of AstraZeneca and Oxford’s AZD1222.
The Lancet study, published Tuesday, contains the efficacy and safety data for the adenoviral vector vaccine, which AstraZeneca plc (LSE:AZN; NASDAQ:AZN) and University of Oxford have submitted to regulators around the world.
It also provides details on two major protocol modifications: the decision to administer two vaccine doses instead of one, and the correction of quantification methods that led some participants to unintentionally receive a lower, but ultimately more effective, first dose.
These changes created unexpected differences across the four trials in the study, two of which the company combined into a pooled efficacy analysis; the other two trials, which didn’t have enough events to evaluate efficacy, were included in a pooled safety analysis.
In particular, the shifts generated wide variability in the time between the first and second vaccine doses, which was four weeks for some participants and more than 12 weeks for others. That variability in timing drove a further wedge between the subgroups and trials that were pooled together in the final analysis.
All the protocol changes, and the pooling strategy, were approved by regulators at multiple agencies before they went into effect, said Oxford Professor of Vaccinology Sarah Gilbert at a press briefing Tuesday.
Gilbert, a co-author on the study, led the team that designed AZD1222 at the university’s Jenner Institute. She added that the study only represents data collected through Nov. 4, and there is “a lot more to come.”
One question is whether regulators set to evaluate the interim data package will focus on the dosing regimen with more evidence but lower efficacy, and drill down on participant subgroups with similar time lags between doses.
Another is whether the company will seek to generate more data on the higher-performing lower prime dose. AZ EVP of biopharmaceuticals R&D Sir Mene Pangalos said the company had not decided on what its next trial would be.
AZ and Oxford believe AZD1222’s efficacy, which was 70.4% overall across pivotal trials in the U.K. and Brazil, and 62.1% across all participants given two full doses, is sufficient for conditional approval, and will play an important role in the pandemic response despite higher performance by vaccines from Moderna Inc. (NASDAQ:MRNA) and partners Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX).
Among the subset of patients given a low first dose followed by a standard second dose, the efficacy of AZD1222 was 90%, closer to the competitors.
Pangalos highlighted the lack of severe COVID-19, hospitalization or COVID-19-related deaths among vaccinated participants at least 21 days after the first dose; all ten such incidents occurred in the control group. “The impact on healthcare systems, and the population at large, will be important.”
The partners have submitted data to MHRA, EMA, Health Canada, Brazil’s National Health Surveillance Agency, and other regulators around the world. Pangalos said that includes the U.S., but the assumption is that FDA will not consider authorizing AZD1222 until its U.S. trial reads out.
Dosing does it
Early data points from the partners’ first two trials prompted a series of protocol amendments over the summer.
The switch from one dose to two was based on immunogenicity data from the Phase I/II COV001 study in the U.K, published in July. The results showed neutralizing antibodies in 100% of patients surveyed (9/9) from the trial’s small prime-boost arm, compared with 91% (32/35) of those studied who received a single dose.
AstraZeneca and Oxford announced the pivot when the paper went live, and protocol amendments for COV001, the U.K. Phase II/III study COV002 and the Brazilian Phase III study COV003 followed later that month. COV004, a Phase I/II South African study launched June 28, enrolled all participants to receive a double dose from the get-go.
The dose strength issue was discovered earlier, but was not disclosed until the partners announced topline results in November.
The issue came down to the methods used to quantify the adenoviral particles in vaccine formulations from three manufacturers: University of Oxford’s Clinical Biomanufacturing Facility (CBF); Advent Srl, a CMO unit of IRBM S.p.A. in Italy; and the U.K.-based viral vector CDMO Cobra Biologics AB, partnered with fill/finish CMO Symbiosis Pharmaceutical Services.
COV001 used a dosage of 5x10^10 viral particles as measured by spectroscopy, which was later shown to be 2.2 x10^10 viral particles as determined by qPCR.
In consultation with MHRA, the COV002 sponsors planned to use the spectroscopy method to align with the first trial, but changed course after seeing the reactogenicity in trial subjects was lower than expected, and realizing that the formulation from Advent, which prioritized qPCR as a quantification method, had excess levels of the emulsifier polysorbate 80, which was throwing off spectroscopy readings.
With regulators’ approval, AZ and Oxford deemed that doses from Advent quantified via spectroscopy were a low, or “half” dose. Advent doses determined to contain 5 x 10^10 viral particles via qPCR, and all doses from Oxford’s CBF or Cobra/Symbiosis, were deemed a standard, or “full” dose.
The sponsors then developed a harmonized suite of assays to use for all standard doses going forward, with a target range of 3.5-6.5 x 10^10 viral particles per dose. That assay was used for all of the doses administered in the COV003 trial, and most of the doses administered in COV004; 44 participants received a low vaccine dose produced before adoption of the harmonized assays.
Study protocols in the paper’s appendix indicated that COV001 included both low doses and standard doses, but did not give a breakdown of how many participants received each type of dose, or whether there were changes in the study’s dose-quantification protocol.