Source : 'The Pink Sheet'
Companies seeking marketing approval of vaccines against variants of the SARS-CoV-2 virus will need to provide solid justification for the choice of variants they intend to include in their vaccines, based on a good understanding of the strains circulating at the time the variant is selected.
Regulators are discussing how new versions of existing COVID-19 vaccines can be rapidly approved, and the European Commission is close to completing a proposed legal and regulatory framework for doing so.
And while good progress has been made towards a common regulatory approach, it would be a good idea to set up a global forum to make recommendations on which strains should be incorporated into any future vaccines.
These were some of the observations made during a virtual hearing organized on 15 March by the European Parliament's public health committee (ENVI) and featuring presentations by representatives of the European Centre for Disease Prevention and Control (ECDC), the European Medicines Agency and the World Health Organization.
High on the agenda was concern over the emergence of more transmissible variants of the SARS-CoV-2 virus and the level of protection that might be offered against them by current COVID-19 vaccines.
Bruno Cianco, head of surveillance at the ECDC, outlined the current threat posed by the three main “variants of concern” (VOCs): B.1.1.7 (first identified in the UK), B.1.351 (South Africa) and B.18.104.22.168 (Brazil, also known as P1).
In Europe, about 24,000 cases of B.1.1.7 have been detected in 28 EU/European Economic Area countries. The South African variant, which is thought to be about 60% more transmissible than the ancestral virus, has been found in 18 EU/EEA countries (some 900 cases).
“In the EU we are strengthening our ability to monitor and identify variants, but we are not yet there” – Bruno Cianco, ECDC
Cianco said that the Brazilian variant, P1, was “more transmissible and can cause reinfection of previously infected people,” although it remained “sporadic in the EU,” with about 200 cases in nine EU/EEA nations. He noted that while most cases were linked to travel, it was “concerning that community transmission is suspected in some countries” in Europe.
He was also worried that not enough was being done by EU countries to keep an eye on emerging variants, particularly in view of the lower-than-expected vaccination rates across the bloc.
“In the EU we are strengthening our ability to monitor and identify variants, but we are not yet there,” Cianco declared. “By the end of February only nine countries were sequencing at a level sufficient to detect and monitor emergence of these variants. So there are quite a number of EU countries that are not able to rapidly identify and monitor and therefore control VOCs.”
The efficacy of current COVID-19 vaccines against the new variants, and the regulatory situation regarding the development of new versions of existing vaccines or those still in development, were discussed during the hearing by Marco Cavaleri, head of biological health threats and vaccines strategy, and chair of the COVID-19 Emergency Task Force, at the EMA.
Cavaleri noted that a small South African study of the AstraZeneca PLC vaccine in around 2,000 people “didn’t show any efficacy of the vaccine in terms of mild disease in a situation where the supposed South African variant was the main virus circulating at the time, so this data would raise a bit of concern with respect to the ability of the vaccine to prevent COVID 19.”
However, he said it was “important to stress that we talking about mild disease in a small study and we don’t know whether protection from severe disease could still be retained by this vaccine, and we would need more data to ascertain the capacity of this vaccine to still be protective, which we cannot exclude at this point in time.”
"This is really good evidence and reassuring on the fact that these vaccines could still protect from COVID-19 due to the new variants” – Marco Cavaleri, EMA
As for the Janssen Pharmaceutica Inc. vaccine, the latest to be approved in the EU, Cavaleri noted that it had been studied in large trials around the world including Brazil and South Africa. “What they are seeing is in South Africa at a time when the [South African] variant was the main one circulating, still there was protection demonstrated, both in terms of moderate disease but also importantly for serious disease.”
In terms of protection from severe disease, the level was “pretty similar to what we have seen in other parts of world where the original ancestral strain was circulating, like the US, so this is really good evidence and reassuring on the fact that these vaccines could still protect from COVID-19 due to the new variants.”
The as yet unapproved Novavax, Inc. vaccine was tested in the UK and South Africa. In the UK, with B.1.1.7 now the main variant in circulation, the studies “showed really high efficacy, 90% overall, really remarkable results," Cavaleri said. "But even in South Africa, with the South African variant… the level of protection was around 60%, again a very good signal that these vaccines can protect against such a variant.”
As for developing new variant vaccines, Cavaleri said regulators were proactively discussing how to rapidly approve new versions of approved vaccines that incorporate variant strains.
“To do that we started discussing with international regulators and the WHO and in a workshop with international regulators under the auspices of ICMRA [International Coalition of Medicines Regulatory Authorities] we came up with a common agreed position on the way forward for the development of such vaccines.”
The EMA subsequently released a reflection paper on the manufacturing and clinical data that would be needed to such variant vaccines, and “after that we had a conversation with marketing authorization holders of vaccines already approved in Europe in order to agree on the way forward and come up very swiftly with a potential approval of variant vaccines with sufficient evidence on efficacy and safety.”
Cavaleri also noted that the commission’s health directorate, DG SANTE, is drafting legislation that will allow a shorter authorization time for variant vaccines in the EU. “Very importantly we had the chance to support the legal and regulatory framework that has been put up by DG SANTE,” he said.
“The legal proposal is expected to be launched soon and we are very much supportive of this as we think it will create right conditions to be flexible and swift in coming up with regulatory decisions on the approval of variant vaccines.”
Pascal Canfin, who chairs the ENVI, observed that the committee had been due to discuss and vote on the legislative proposal the following day (16 March), but "we still don't have the text of the act. We are ready and waiting for it."
As for the choice by sponsors of which strain to include in future vaccines, Cavaleri said this would have to be based on “a good understanding of disease surveillance and the characterization of strains circulating at the time of selection of such variants.”
But he said it was also important to set up a global forum, for example under the WHO, to make global recommendations on which strains should be incorporated in any future variant vaccines.
On the clinical aspects of variant vaccines, he said the EMA would expect the demonstration of efficacy and safety to come from “small clinical trials that will look at bridging immunogenicity from the original vaccine that has been shown effective in the field and would be sufficient for us to derive enough information to say the vaccine will be protective.”
He identified two settings where the efficacy of a monovalent or multivalent variant vaccine could be inferred from the provision of immunogenicity data:
After primary vaccination with the variant vaccine – this should be compared with primary vaccination with the ancestral strain vaccine.
Then in a booster setting where a single shot of variant vaccine would be given to subjects who received a primary vaccination with the parent vaccine.
Another aspect of evaluating potential variant vaccines is the feasibility of studies looking at non-inferiority for clinical efficacy compared with authorized vaccines, Cavaleri noted.
This “may not be straightforward as the amount of data will be big and not easy to collect to give enough information to say non-inferiority is shown.” Cavaleri said: “I believe we need to look into the possibility of conducting non-inferiority studies using immune response as primary outcome” – something he said was being discussed with international regulators and developers.
At global level, a great deal of guidance on evaluating changes to vaccines has already been produced, and this week the WHO is publishing guidance on prequalification and Emergency Use Listing of variant vaccines, Katherine O’Brien of the WHO’s Department of Immunization, Vaccines and Biologicals told the webinar audience.
She said regulatory approaches to evaluating modified vaccines needed to be closely aligned on two key assumptions: “that the modified vaccine would be developed by same manufacturer and the same manufacturing process as the existing vaccine, and that neutralizing antibodies are important to protection, notwithstanding that we don’t yet have a clear correlate of protection.”
Clinical efficacy “would not be a requirement of a regulatory approach, and a large safety database would also not be a requirement, given the safety database of the original product,” O’Brien declared.
A globally coordinated response would be “essential for identifying variants of concern, any modifications to vaccine composition, and especially on vaccines access and allocation, which remains highly inequitable although [this has changed] quite a bit in recent weeks,” she noted.
“Enhanced surveillance, strain characterization and regulatory alignment to assess modifications to vaccine composition have largely been achieved but further regulatory guidance is needed for vaccine candidates that are in Phase III or earlier stages of development.”
By Ian Schofield