The US Food and Drug Administration (FDA) has revised its guidance for developers of vaccines against COVID-19 as regulators and health authorities assess the need to adjust vaccines so they remain effective as new SARS-CoV-2 variants emerge.
For the time being, developers can expect to conduct immunogenicity studies for vaccines to address these variants that will enroll “on the order of few hundred individuals in terms of size,” said Peter Marks, MD, PhD, director of FDA’s Center for Biologics Evaluation and Research (CBER).
Marks spoke in a Monday press conference announcing this and three other new or newly revised guidance documents Monday that collectively address how vaccines, therapeutics, and tests may need to be adjusted. The guidance comes as the virus that causes COVID-19 changes and strains emerge that may affect effectiveness of vaccines and therapeutics, and accuracy of tests.
In terms of how long the studies might take, “We’d expect that that might take a few months, whether it be two or three – we can’t say exactly how long – but again on that type of a scale,” said Marks.
Marks’ remarks put some more concrete numbers to the guidance’s advice regarding immunogenicity studies. According to the appendix, sponsors should plan for both immunogenicity and booster studies, comparing the modified vaccine’s performance against the variant(s) of interest to the prototype vaccine’s performance against the virus upon which it was based. In the updated vaccine guidance, the agency left open the question whether modified vaccines against COVID-19 could one day be authorized without the need for clinical studies.
At present, though, FDA recommends that studies be powered to demonstrate neutralizing antibody seroresponse rates and geometric mean titers (GMTs) of the modified vaccine against the variant of interest using a noninferiority margin of -10% for seroresponse and 1.5-fold for GMTs, compared with the prototype vaccine’s immunogenicity profile against the virus it was intended to defeat.
“Like most RNA viruses, SARS-CoV-2 is constantly evolving, and new variants may emerge that improve virus fitness for transmission,” noted FDA in the new appendix to the vaccine emergency use authorization (EUA) guidance. Mutations of most concern to date involve changes in the virus’ spike (S) protein, the means by which the virus enters human cells and a key therapeutic and vaccine target.
The new recommendations, notes FDA in the guidance’s new appendix, “are specifically tailored to pandemic COVID19 vaccines that express the S protein and are made under the assumptions that neutralizing antibody to SARS-CoV-2 S is a major component of the vaccine protective response (or for a given vaccine construct, is likely to vary in proportion to the protective response), that an immune marker predictive of protection has not been established, and that it is not feasible to conduct clinical disease endpoint efficacy studies rapidly enough to respond to the emergence of SARS-CoV-2 variants that may escape immunity conferred by prototype vaccines.”
In terms of safety assessments, monitoring for solicited local and systemic adverse events for a 7-day period after each study vaccination may be sufficient to support an EUA amendment. However, should safety signals emerge, the modified vaccine may have to be evaluated in “a larger safety database than initially planned.”
The appendix addresses nonclinical studies that sponsors should conduct, bearing in mind that adjusted vaccines would generally be made by the same manufacturer and with the same process as the original vaccines, so it may not be necessary to repeat dose toxicity and developmental and reproductive toxicity studies. The guidance encourages developers to conduct animal studies with a relevant model, “in particular in situations where the results of clinical immunogenicity studies may be ambiguous.”
Developers should plan to identify which assays they will use for immunogenicity endpoints and submit standard operation procedures and validation reports with the EUA amendment. “Even though an immune marker predictive of protection against COVID-19 has not been established to date, depending on the vaccine construct, neutralizing antibody may be considered a relevant measure of immunogenicity,” wrote FDA in the updates to the guidance.
Chemistry, manufacturing and controls (CMC) considerations will mostly be the same for an adjusted vaccine as its prototype, noted FDA. “However, updated CMC data will need to be generated for the modified SARS-CoV-2 vaccine, as a scientific matter.” Though the vaccine platform will, in part, dictate which CMC data should be submitted, developers should all include “critical aspects of product characterization,” along with a potency assay and stability data with the modified vaccine.
Unaddressed issues still under consideration by the agency include what data would indicate there is need for a modified vaccine; which entity will make that decision and the recommendations that would flow from it; and what role FDA’s vaccines advisory committee would play in deciding the necessity for vaccine updates. Labeling requirements for updated vaccines were also not listed in the updates to the vaccine EUA guidance.
To continue reading this article please go to RAPS .