How to handle COVID variants? Global regulators turn to flu vaccines

A global consortium of regulators is turning to seasonal influenza vaccine authorization as a model for how to address variant-adjusted version of authorized COVID-19 vaccines.
 
New guidance available from the ACCESS consortium, including the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA), directs vaccine developers to focus on demonstrating robust immune response against new variants when trialing modified COVID-19 vaccines. In addition to MHRA, the ACCESS consortium includes regulators from Australia, Canada, Singapore and Switzerland.
 
In the new guidance’s regulatory vision for COVID-19 vaccines, sponsors need not engage in large, lengthy clinical trials because these studies “do not add to the regulatory understanding of a vaccine’s safety, quality or effectiveness,” wrote MHRA in a statement announcing the release of the guidance.
 
In addition to addressing effectiveness through immunological studies, manufacturers should expect to provide data ensuring safety and quality; the prior large and thorough clinical trials conducted for currently authorized vaccines can bolster applications.
 
“This is not an unprecedented situation; it may be feasible to apply concepts from the regulation of influenza vaccines,” according to the guidance. “There are regulatory principles which have been developed for influenza viruses which may well be applicable to other viruses like SARS-CoV-2.”
 
The guidance reviews specific regulatory concepts that can be drawn from regulation of influenza virus vaccines. These include the concept of antigen drift, a gradual change that is responsible for the usual season-to-season change in influenza viruses. Influenza vaccines that are adjusted for year-over-year antigen drift usually do not need non-clinical or clinical data beyond updated pharmaceutical quality data, though some clinical data addressing immunogenicity is desirable. As with other authorized vaccines, post-authorization measures are retained.
 
Antigen shift, by contrast, is a “phenomenon specific to influenza viruses which carry a segmented genome” allowing a reassortment of genes that is likely to mean that a “decisively different” vaccine would be needed after antigen shift. Virus variants that come from antigen shift have “pandemic potential,” according to the guidance.
 
Vaccines known as “pandemic preparedness vaccines” are increasingly being prepared to address the potential for antigen shift of viral strains that may blossom into pandemics. Much of the regulatory groundwork addressing quality, safety, immunogenicity and, sometimes, efficacy can be laid with the preparedness vaccine, building a “core dossier.” Such a speedy approach was used in the 2009 H1N1 influenza pandemic, according to the guidance.

One question left up in the air by the guidance document is exactly how to handle regulatory control of the sequence of the updated antigen. A point in favor of centralized regulatory control, according to the guidance, is the opportunity for harmonization and an assurance of the accuracy of the characterization of the antigen.
 
However, this more regulated approach might slow down discovery and production of effective vaccines. In the context of a virus as transmissible as SARS-CoV-2, countries may find themselves overrun with dangerous new variants as they await a centralized regulatory decision and consensus.
 
The guidance, therefore, recommends a middle way: “It is considered that, in a rapidly evolving pandemic and public health need, international harmonization of both the definition on key virus variants and regulatory requirements are desirable but not a prerequisite for moving ahead in effective and enabling regulation of vaccine updates.”
 
Specific quality considerations are laid out in the guidance, which calls for manufacturers to include such elements as which specific segments and sequence differ between the new vaccine moiety and the previously licensed one; confirmation of the new antigenic sequence and verification of its match with the wild-type variant sequence; vaccine construction and synthesis details; risk assessment characterization; and other manufacturing and process validation considerations.
 
Non-clinical considerations include the probable need for humoral and cellular immunogenicity data from an animal model, as well as comparison between prototype and variant vaccines. Where a suitable challenge model can provide non-clinical protection data, such a study is desirable, according to the guidance: “Cross-protection data in animals could test whether the new version of the vaccine is able to provide protection against the existing virus to inform on whether vaccination against both versions of virus should be considered.”
 
Clinical considerations will depend, among other factors, on whether the new formulation is an adjustment in the sequence of the prototype vaccine, or the addition of a new sequence to the current vaccine. The guidance walks vaccine developers through appropriate steps and regulatory checkpoints for each approach.
 
Within the UK, the guidance document acknowledges that the usual approach of completing a dossier update by way of a Type II variation, as for influenza, would be the usual approach. However, since the unpredictability of the course of the current pandemic makes it possible that two or more versions of a given vaccine “have to co-exist and be used,” regulators will work to “find an appropriate route for the required scenario.”

“Our priority is to get effective vaccines to the public in as short a time as possible, without compromising on safety. Should any modifications to authorized COVID-19 vaccines be necessary, this regulatory approach should help to do just that,” said Christian Schneider, MBBS, MHRA’s chief scientific officer, in the press release.
 
MHRA guidance