Coronavirus Notebook: Heterologous Vaccine Study Shows Positive Results, UK Offers Earlier Second Dose To Vulnerable People
A Regime Of Two Different Vaccines Could Lead To More Flexible Vaccination Campaigns
Executive Summary
The European Medicines Agency has extended the time that Comirnaty can spend in a fridge after defrosting and could this week issue advice to member states on sotrovimab for use in COVID-19 patients. Norway’s BerGenBio has published top-line data from a Phase II trial of of bemcentinib, and IcanoMAB has outlined the potential of its anti-IL-1R7 antibody.
It has been shown for the first time that a combination of two different COVID-19 vaccines can produce high immunogenicity in patients, with no unexpected side-effects.
On 18 May, Spain’s Carlos III Institute of Health presented the results of the CombivacS study, a Phase II randomized, multicenter adaptive trial which involved giving participants aged under 60 years a first dose of theAstraZeneca PLC/Oxford University vaccine (Vaxzevria) followed by a booster dose of the Pfizer Inc./BioNTech SE vaccine (Comirnaty) at least eight weeks later.
“The CombivacS study is the first worldwide to provide data on immunogenicity derived from the combined use of two different vaccines,” according to the institute.
“Early results indicate that this heterologous vaccination schedule is highly immunogenic and has no post-vaccination reactogenicity problems other than those already reported in the counterpart (solo) use of these same vaccines,” it reported.
The immune response was “greatly enhanced” after administration of Comirnaty as the second dose, while the observed side effects were within what was expected: they were mild or moderate in nature and were mostly restricted to the first two to three days after receiving the vaccine.
The first participant received the booster Comirnaty dose on 17 April and over the following six days a total of 673 people joined the study. After randomization, the group receiving the second dose of the vaccine was made up of 441 participants, while the control group (which has not yet received a second dose moment) consisted of 232 people.
The average age in both groups was 44 years and the proportion of women was 56% of the total sample. The stratification scheme allowed the avoidance of selection biases in sex, age and participation center.
“The antibodies produced [following the combined use of two different vaccines] were effective in protecting against SARS-CoV-2” – Carlos III Institute
In all cases it was shown that the use of a heterologous pattern potentiated the immune response: the antibody titers multiplied 150 times within 14 days of administering the heterologous booster dose, “an effect that was already very evident at seven days, with an increase multiplied by 123 initial titers,” according to the institute.
“In addition, the efficacy of antibodies generated by heterologous vaccination was tested by functional tests, demonstrating that the antibodies produced were effective in protecting against SARS-CoV-2.” Cell immunity studies will be available in the coming days, the Spanish center added.
Side effects in the first seven days post-vaccination were analyzed based on the severity perceived by the participants. “In short, no side effects caused extra medical attention or hospitalization under any circumstances. All adverse events that were perceived as serious by participants were explored in real time by the doctors of the participating center, and in no case was that perceived severity confirmed.”
Mild local side effects were common and were related to discomfort in the injection area. The most common systemic side effects were headache (44% of all cases), general discomfort (41%), chills (25%), mild nausea (11%), mild cough (7%) and fever (2.5%). In all cases the side effects were similar to those detected with standard vaccination schemes.
More Flexible Vaccination Campaigns
The Spanish institute said that following these early preliminary results, the study would track and measure antibodies of participants over the course of a year. "Moreover, as an adaptive trial, the design of CombivacS allows the possibility of including new intervention arms if deemed suitable to respond to scientific objectives."
It also noted that other European countries, including Germany, France, Sweden, Norway and Denmark, are already recommending combined vaccination in people under the age of 60 who have received a first dose of Vaxzevria. The UK is also running a study called ComCov, which involves different combinations of the AZ and Pfizer/BioNTech vaccines. (Also see "Coronavirus Notebook: UK ‘Com-Cov’ Trial To Test Alternating Vaccines, EMA Pilots Assessment Sharing Scheme" - Pink Sheet, 4 Feb, 2021.)
Knowing whether it is possible to implement heterologous vaccination regimes “would allow the design of more flexible vaccination campaigns” which in turn would make it possible to deal with issues such as interruptions in the vaccine supply chain, the Carlos III Institute suggested.
UK Offers Vulnerable People Earlier Second Jab
As the UK relaxes its lockdown amid growing concern over the rapid spread of the B.1.617.2 variant of the SARS-CoV-2 virus, the UK government is offering the most vulnerable people an earlier second dose of COVID-19 vaccine.
Health secretary Matt Hancock said on 17 May that 2,323 cases of the variant, which was first detected in India, had been confirmed in the UK. This is up from 1,313 cases on 13 May, with 86 local authorities having five or more cases.
“Appointments for a second dose of a vaccine will be brought forward from 12 to eight weeks for the remaining people in the top nine priority groups” – UK health secretary Matt Hancock
“Appointments for a second dose of a vaccine will be brought forward from 12 to eight weeks for the remaining people in the top nine priority groups who have yet to receive their second dose,” the government said. “This is to ensure people across the UK have the strongest possible protection from the virus at an earlier opportunity.”
The move follows updated advice from the independent Joint Committee on Vaccination and Immunisation (JCVI), which has considered the latest available evidence on the variant.
“While there is no evidence to show this variant has a greater impact on severity of disease or evades the vaccine, the speed of growth is of note and the government is working quickly to ensure the appropriate action is being taken,” it said.
UK To Host ‘Global Vaccine Confidence Summit’
In an effort to boost vaccine uptake amid vaccine hesitancy and misinformation, the UK is organizing what it calls the “world’s first Global Vaccine Confidence Summit” on 2 June, as part of its presidency of the G7. Speakers so far include Hancock and Heidi Larson, director of the Vaccine Confidence Project at the London School of Hygiene and Tropical Medicine, with more names to be announced.
The virtual event will discuss ways that governments, civil society and the private sector, including social media companies, can “tackle vaccine misinformation and amplify public health messages to improve vaccine confidence,” the government said.
Larson said that ensuring high levels of vaccine uptake required “true cross-sectoral input to build trust across the various relationships – from scientists and health authorities to business partners and communities.”
As of 17 May, the total number of vaccine doses administered in the UK had reached 56,992,075. First doses totaled 36,704,672 and second doses 20,287,403.
EU Eases Storage Conditions For Comirnaty
At EU level, the European Medicines Agency’s human medicines committee, the CHMP, has recommended an extension to the approved refrigerator storage period for the Comirnaty vaccine that will facilitate the planning and logistics of the vaccine’s rollout across the EU.
The CHMP said that the unopened vaccine vial could be stored for 31 days at standard refrigerator temperatures of 2-8°C after removal from deep-freeze conditions (between -70°C and -80°C), rather than just five days as at present.
“The extended storage period is effective immediately and accounts for all currently available and future batches” – BioNTech
If the move is replicated in the US and elsewhere, as is expected, it will make it easier to distribute the vaccine in countries where the current storage conditions make it impracticable.
“The extended storage period is effective immediately and accounts for all currently available and future batches,” said BioNTech, the EU marketing authorization holder for Comirnaty. BioNTech and Pfizer have submitted a similar request to the US Food and Drug Administration and plan to request additional amendments with other regulatory authorities worldwide.
The change in storage conditions is based on new data from stability studies that confirmed the product’s quality for 31 days – the formulation of the vaccine is unchanged, BioNTech said.
Within the 31-day period, transport of the thawed, undiluted vials is still possible for a maximum of 12 hours in total, BioNTech noted. “The shelf life of the diluted vaccine does not change and is stable for 6 hours at 2-30°C from the time of dilution and must be administered within this time.”
The new information will be added to the product information and labeling.
CHMP Nears Opinion On Sotrovimab
On the therapeutics front, the CHMP is this week expected to adopt a scientific opinion on Vir Pharmaceuticals/GlaxoSmithKline plc’s monoclonal antibody, sotrovimab, for treating patients with COVID-19 who do not require oxygen supplementation and who are at high risk of progressing to severe disease.
The opinion will be given under an Article 5(3) procedure, which offers harmonized advice to EU member states wishing to authorize the emergency use of a medicine before it has been formally approved.
The CHMP’s Article 5(3) review of sotrovimab (also called VIR-7831 and GSK4182136) began last month and included an assessment of data from an interim analysis of safety and efficacy data from the Phase III COMET-ICE trial. (Also see "EMA Reviews GSK/Vir’s COVID-19 Antibody To Support Early Use By Member States" - Pink Sheet, 16 Apr, 2021.) The product is also under a rolling review at the EMA, which could lead to an application for a formal EU marketing authorization.
IcanoMAB’s Anti-IL-1R7 Antibody
Updates have also been announced on a number of other potential COVID-19 therapies.
German biotech company IcanoMAB GmbH said it had received “positive regulatory advice” for the development program for its anti-IL-1R7 antibody for use in late-stage COVID-19 patients. It has also published the preclinical Proof-of-Concept for the product, which blocks the signal transduction of the IL-18 receptor.
IcanoMAB said that elevated levels of the pro-inflammatory cytokine IL-18 initiate the avalanche of effects in cytokine-release-syndrome, which is known to correlate with the severity of late-stage COVID-19.
The company added that the preclinical Proof-of-Concept for the anti-IL-1R7 MAb was published by scientific partners including the US Dinarello Lab at the Department of Medicine, University of Colorado, the Radboud University Medical Center in Nijmegen, the Netherlands, and the Department of Infectious Disease and Institute of Clinical Medicine at Aarhus University Hospital in Denmark.
IcanoMAB, which focuses on the preclinical and clinical development of novel precision canonical antibodies for cancer, immune system-related diseases and COVID-19, said it was “currently entering discussions with interested parties for a development partnership of its anti IL-1R7 antagonist antibody.”
Effective treatments “are urgently needed for severely affected late-stage COVID-19 patients,” it noted.
Mixed Results For BerGenBio’s Bemcentinib
Another European biotech company, Norway’s BerGenBio ASA, has published top-line data from a randomized Phase II clinical trial of bemcentinib in hospitalized COVID-19 patients.
BerGenBio develops novel, selective AXL kinase inhibitors for severe unmet needs. It said that the trial, BGBC020 began in October 2020 and was conducted across multiple sites in South Africa and India, with 115 patients having been enrolled by the end of March.
Patients were randomized to receive standard of care (SOC) only, or bemcentinib with SOC. 76% of patients received steroids and 51% also received remdesivir as part of their therapy.
The primary endpoint of the study was time to improvement by two World Health Organization grades from baseline, or time to discharge or fitness for discharge. The study “marginally favored bemcentinib treatment over SOC, but the difference was not statistically significant,” the company declared.
Noting that the endpoint was subject to a “broad range of subjective factors” such as variations in clinical practice, local case rates and resource availability, it said it “may not directly measure the individual patient’s health or the benefit from bemcentinib.”
A post-hoc analysis identified a subgroup of patients with higher baseline severity, representing more than 50% of patients in the study. This showed “encouraging evidence of stronger treatment effect by bemcentinib across all endpoints evaluated,” the company noted. Bemcentinib was well tolerated and no safety signals of concern were identified, it added.
Analysis of overall survival in the study was combined with that of the ACCORD2 study, which conducted in the UK with an analogous Phase II design, according to BerGenBio. “The ACCORD2 platform study recommenced enrolment in the UK winter wave of the local epidemic, enrolling patients between December 2020 and March 2021 (30 to the bemcentinib arm in both phases of the study, with 32 eligibility-matched control patients).”
Mortality rates in ACCORD2 standard of care-treated patients were higher than those in BGBC020 at day 29: five of 32 patients (16%) in ACCORD2, versus three of 57 (5%) in BGBC020.
“Overall in the combined studies, survival to day 29 was 96.5% (83 of 86 evaluable patients) in the bemcentinib arm versus 91.0% (81 of 89) treated with SOC alone,” BerGenBio said.
“The totality of data clearly informs a benefit from bemcentinib in treating a substantial subset of hospitalized COVID-19 patients," it stated. “This will support ongoing engagement with regulatory agencies, government partners and industry.”