COVID-19 Vaccine Safety Technical (VaST) Work Group: Enhancing vaccine safety monitoring during the pandemic.

During the COVID-19 pandemic, candidate COVID-19 vaccines were being developed for potential use in the United States on an unprecedented, accelerated schedule. It was anticipated that once available, under U.S. Food and Drug Administration (FDA) Emergency Use Authorization (EUA) or FDA approval, COVID-19 vaccines would be broadly used and potentially administered to millions of individuals in a short period of time. Intensive monitoring in the post-EUA/licensure period would be necessary for timely detection and assessment of potential safety concerns. To address this, the Centers for Disease Control and Prevention (CDC) convened an Advisory Committee on Immunization Practices (ACIP) work group focused solely on COVID-19 vaccine safety, consisting of independent vaccine safety experts and representatives from federal agencies - the ACIP COVID-19 Vaccine Safety Technical Work Group (VaST). This report provides an overview of the organization and activities of VaST, summarizes data reviewed as part of the comprehensive effort to monitor vaccine safety during the COVID-19 pandemic, and highlights selected actions taken by CDC, ACIP, and FDA in response to accumulating post-authorization safety data. VaST convened regular meetings over the course of 29 months, from November 2020 through April 2023; through March 2023 FDA issued EUAs for six COVID-19 vaccines from four different manufacturers and subsequently licensed two of these COVID-19 vaccines. The independent vaccine safety experts collaborated with federal agencies to ensure timely assessment of vaccine safety data during this time. VaST worked closely with the ACIP COVID-19 Vaccines Work Group; that work group used safety data and VaST's assessments for benefit-risk assessments and guidance for COVID-19 vaccination policy. Safety topics reviewed by VaST included those identified in safety monitoring systems and other topics of scientific or public interest. VaST provided guidance to CDC's COVID-19 vaccine safety monitoring efforts, provided a forum for review of data from several U.S. government vaccine safety systems, and assured that a diverse group of scientists and clinicians, external to the federal government, promptly reviewed vaccine safety data. In the event of a future pandemic or other biological public health emergency, the VaST model could be used to strengthen vaccine safety monitoring, enhance public confidence, and increase transparency through incorporation of independent, non-government safety experts into the monitoring process, and through strong collaboration among federal and other partners.

Clinical Development Strategies and Considerations for Zika Vaccine Licensure.

The Zika outbreak that began in 2015 has spread from Brazil to countries across the Western Hemisphere including the United States, presenting global public health challenges that call for the expedited development and availability of preventive vaccines to protect against Zika virus disease. While the general principles guiding the nonclinical and clinical development for Zika vaccines are the same as those of other preventive vaccines, unique considerations apply, in particular if development occurs during a public health emergency. Furthermore, incomplete information about the pathogenesis of Zika virus disease and the mechanism by which candidate preventive vaccines potentially may confer protection presents additional challenges to their clinical development. Nevertheless, definition of clinical development strategies to enable sound regulatory assessment, with a goal toward licensure is critical for these products. This article will provide an overview of the regulatory considerations for the clinical development and licensure of Zika vaccine candidates including a discussion of clinical study designs, approaches to demonstrate vaccine effectiveness, and regulatory pathways to licensure.

Clinical evaluation of pertussis vaccines: US Food and Drug Administration regulatory considerations.

The resurgence of pertussis in the United States has stimulated considerable public health interest in developing new vaccination strategies to improve control of pertussis. The purpose of this article is to review the US Food and Drug Administration's regulatory framework for the prelicensure clinical evaluation of preventive vaccines and the clinical approaches that have been used to demonstrate effectiveness of US-licensed vaccines containing an acellular pertussis component.

Analysis of relative levels of production of pertussis toxin subunits and Ptl proteins in Bordetella pertussis.

Pertussis toxin is transported across the outer membrane of Bordetella pertussis by the type IV secretion system known as the Ptl transporter, which is composed of nine different proteins. In order to determine the relative levels of production of pertussis toxin subunits and Ptl proteins in B. pertussis, we constructed translational fusions of the gene for alkaline phosphatase, phoA, with various ptx and ptl genes. Comparison of the alkaline phosphatase activity of strains containing ptx'- or ptl'-phoA fusions indicated that pertussis toxin subunits are produced at higher levels than Ptl proteins, which are encoded by genes located toward the 3' end of the ptx-ptl operon. We also engineered strains of B. pertussis by introducing multiple copies of the ptl genes or subsets of these genes and then examined the ability of each of these strains to secrete pertussis toxin. From these studies, we determined that certain Ptl proteins appear to be limiting in the secretion of pertussis toxin from the bacteria. These results represent an important first step in assessing the stoichiometric relationship of pertussis toxin and its transporter within the bacterial cell.

Membrane localization of the S1 subunit of pertussis toxin in Bordetella pertussis and implications for pertussis toxin secretion.

Pertussis toxin is secreted from Bordetella pertussis with the assistance of the Ptl transport system, a member of the type IV family of macromolecular transporters. The S1 subunit and the B oligomer combine to form the holotoxin prior to export from the bacterial cell, although the site of assembly is not known. To better understand the pathway of pertussis toxin assembly and secretion, we examined the subcellular location of the S1 subunit, expressed with or without the B oligomer and the Ptl proteins. In wild-type B. pertussis, the majority of the S1 subunit that remained cell associated localized to the bacterial membranes. In mutants of B. pertussis that do not express pertussis toxin and/or the Ptl proteins, full-length S1, expressed from a plasmid, partitioned almost entirely to the bacterial membranes. Several lines of evidence strongly suggest that the S1 subunit localizes to the outer membrane of B. pertussis. First, we found that membrane-bound full-length S1 was almost completely insoluble in Triton X-100. Second, recombinant S1 previously has been shown to localize to the outer membrane of Escherichia coli (J. T. Barbieri, M. Pizza, G. Cortina, and R. Rappuoli, Infect. Immun. 58:999-1003, 1990). Third, the S1 subunit possesses a distinctive amino acid motif at its carboxy terminus, including a terminal phenylalanine, which is highly conserved among bacterial outer membrane proteins. By using site-directed mutagenesis, we determined that the terminal phenylalanine is critical for stable expression of the S1 subunit. Our findings provide evidence that prior to assembly with the B oligomer and independent of the Ptl proteins, the S1 subunit localizes to the outer membrane of B. pertussis. Thus, outer membrane-bound S1 may serve as a nucleation site for assembly with the B oligomer and for interactions with the Ptl transport system.