A research and development (R&D) roadmap for broadly protective coronavirus vaccines: A pandemic preparedness strategy.

Broadly protective coronavirus vaccines are an important tool for protecting against future SARS-CoV-2 variants and could play a critical role in mitigating the impact of future outbreaks or pandemics caused by novel coronaviruses. The Coronavirus Vaccines Research and Development (R&D) Roadmap (CVR) is aimed at promoting the development of such vaccines. The CVR, funded by the Bill & Melinda Gates Foundation and The Rockefeller Foundation, was generated through a collaborative and iterative process, which was led by the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota and involved 50 international subject matter experts and recognized leaders in the field. This report summarizes the major issues and areas of research outlined in the CVR and identifies high-priority milestones. The CVR covers a 6-year timeframe and is organized into five topic areas: virology, immunology, vaccinology, animal and human infection models, and policy and finance. Included in each topic area are key barriers, gaps, strategic goals, milestones, and additional R&D priorities. The roadmap includes 20 goals and 86 R&D milestones, 26 of which are ranked as high priority. By identifying key issues, and milestones for addressing them, the CVR provides a framework to guide funding and research campaigns that promote the development of broadly protective coronavirus vaccines.

Vaccine Preparedness for the Next Influenza Pandemic: A Regulatory Perspective.

The response to SARS-CoV-2 demonstrated the tremendous potential of investments in vaccine research and development to impact a global pandemic, resulting in the rapid development and deployment of lifesaving vaccines. However, this unprecedented speed was insufficient to either effectively combat initial waves of the pandemic or adapt in real time to new variants. This review focuses on opportunities from a public health oriented regulatory perspective for enhancing research, development, evaluation, production, and monitoring of safety and effectiveness to facilitate more rapid availability of pandemic influenza vaccines. We briefly review regulatory pathways and processes relevant to pandemic influenza, including how they can be strengthened and globally coordinated. We then focus on what we believe are critical opportunities to provide better approaches, tools, and methods to accelerate and improve vaccine development and evaluation and thus greatly enhance pandemic preparedness. In particular, for the improved vaccines needed to respond to a future influenza pandemic better and more rapidly, moving as much of the development and evaluation process as possible into the pre-pandemic period is critical, including through approval and use of analogous seasonal influenza vaccines with defined immune correlates of protection.

The Regulatory Evaluation of Vaccines for Human Use.

A vaccine is an immunogen, the administration of which is intended to stimulate the immune system to prevent, ameliorate, or treat a disease or infection. A vaccine may be a live attenuated preparation of microorganisms, inactivated (killed) whole organisms, living irradiated cells, crude fractions, or purified immunogens, including those derived from recombinant DNA in a host cell, conjugates formed by covalent linkage of components, synthetic antigens, polynucleotides (such as the plasmid DNA vaccines), mRNA, living vectored cells expressing specific heterologous immunogens, or cells pulsed with immunogen. Vaccines are highly complex products that differ from small molecule drugs because of the biological nature of the source materials such as those derived from microorganisms as well as the various cell substrates from which some are derived. Regardless of the technology used, because of their complexities, vaccines must undergo extensive testing and characterization. Special expertise and procedures are required for the manufacture, control, and regulation of vaccines. Throughout their life cycle from preclinical evaluation to post-licensure lot release testing, vaccines are subject to rigorous testing and oversight by manufacturers and national regulatory authorities. In this chapter, an overview of the regulatory evaluation and testing requirements for vaccines is presented.

Human Challenge Studies for Vaccine Development : Regulatory Aspects of Human Challenge Studies.

The traditional regulatory pathway for the evaluation of new vaccine candidates generally proceeds from preclinical through three successive phases of human trials, and the demonstration of efficacy is usually done through randomized-controlled clinical trials. However, human challenge trials or controlled human infection models have been used in vaccine clinical development to generate supportive data for establishment of correlates of protection, supportive data for licensure, as well as licensure in the case of Vaxchora® by the US FDA. Despite this, there are no codified regulations from national regulatory authorities (NRAs) that specifically address HCTs, nor guidance related to standardization of approaches to HCTs among regulators. NRAs may agree that HCTs are innovative, promising tools to accelerate vaccine development; however, a strong benefit/risk assessment is needed to ensure the safety of study participants. Lastly, it is important to consider the regulatory framework in which the human challenge trial may be conducted.

The Regulatory Evaluation of Vaccines for Human Use.

A vaccine is an immunogen, the administration of which is intended to stimulate the immune system to result in the prevention, amelioration, or therapy of any disease or infection (US Food and Drug Administration. Guidance for Industry: content and format of chemistry, manufacturing, and controls information and establishment description information for a vaccine or related product). A vaccine may be a live attenuated preparation of microorganisms, inactivated (killed) whole organisms, living irradiated cells, crude fractions, or purified immunogens, including those derived from recombinant DNA in a host cell, conjugates formed by covalent linkage of components, synthetic antigens, polynucleotides (such as the plasmid DNA vaccines), living vectored cells expressing specific heterologous immunogens, or cells pulsed with immunogen. Vaccines are highly complex products that differ from small molecule drugs because of the biological nature of the source materials such as those derived from microorganisms as well as the various cell substrates from which some are derived. Regardless of the technology used, because of their complexities, vaccines must undergo extensive characterization and testing. Special expertise and procedures are needed for their manufacture, control, and regulation. The Food and Drug Administration (FDA) is the National Regulatory Authority (NRA) in the United States responsible for assuring quality, safety, and effectiveness of all human medical products, including vaccines for human use.The Center for Biologics Evaluation and Research (CBER) within the US FDA is responsible for overseeing the regulation of therapeutic and preventative vaccines against infectious diseases. Authority for the regulation of vaccines resides in Section 351 of the Public Health Service Act and specific sections of the Federal Food, Drug, and Cosmetic Act (FD&C). Vaccines are regulated as biologics and licensed based on the demonstration of safety and effectiveness. The vaccine development process can be divided into two major categories: those events that are not under the regulatory authority of the FDA and are exploratory in nature and those events that are subject to regulatory authority by the FDA. Exploratory events or research and development cover basic research drug discovery processes that occur before the sponsor submits an investigational new drug application (IND) to the FDA. There are four main stages of vaccine development under the purview of regulatory authorities: preclinical, clinical (IND), licensing, and post-licensure. Throughout their life cycle from preclinical evaluation to post-licensure lot release testing, vaccines are subject to rigorous testing and oversight by manufacturers and NRAs. In this chapter an overview of the regulatory evaluation and testing requirements for vaccines is presented.

Food and Drug Administration regulation and evaluation of vaccines.

The vaccine-approval process in the United States is regulated by the Center for Biologics Evaluation and Research of the US Food and Drug Administration. Throughout the life cycle of development, from preclinical studies to after licensure, vaccines are subject to rigorous testing and oversight. Manufacturers must adhere to good manufacturing practices and control procedures to ensure the quality of vaccines. As mandated by Title 21 of the Code of Regulations, licensed vaccines must meet stringent criteria for safety, efficacy, and potency.

Considerations for licensure of influenza vaccines with pandemic and prepandemic indications.

With over 409 human cases of avian influenza and over 256 deaths worldwide resulting from infection with avian influenza (H5N1), an influenza pandemic is still a real threat, especially with H5N1 continuing to evolve into antigenically distinct clades. The Food and Drug Administration (FDA) along with other national regulatory authorities (NRAs) recognize the important role that safe and effective vaccines will play in protecting the public health from the threat of an influenza pandemic. The challenges to the FDA and other NRAs are significant as regulatory agencies pursue the development of new scientific and regulatory criteria to evaluate vaccines against pandemic influenza strains for licensure. To this end, the FDA is actively utilizing current regulatory processes such as accelerated approval and priority review as well as developing the regulatory pathways needed to speed the availability of vaccines against pandemic influenza. In May of 2007, the FDA issued two final guidance documents, one describing the clinical data recommended to support the licensure of annual influenza vaccines, and the other describing the clinical data recommended to support the licensure of pandemic influenza vaccines. These guidances contain specific approaches outlined by the FDA to assist manufacturers in developing new vaccines to increase the supply of safe and effective influenza vaccines for both annual and pandemic use. In this article we define the nomenclature "pandemic" and "prepandemic," describe the regulatory pathway for licensing new influenza vaccines for pandemic and prepandemic use, and outline considerations for evaluating pandemic/prepandemic vaccines that have been formulated using new approaches such as cell culture and non-aluminum salt adjuvants.

Aluminum salts in vaccines--US perspective.

Aluminum in the form of aluminum hydroxide, aluminum phosphate or alum has been commonly used as an adjuvant in many vaccines licensed by the US Food and Drug Administration. Chapter 21 of the US Code of Federal Regulations [610.15(a)] limits the amount of aluminum in biological products, including vaccines, to 0.85 mg/dose. The amount of aluminum in vaccines currently licensed in the US ranges from 0.85-0.125 mg/dose. Clinical studies have demonstrated that aluminum enhances the antigenicity of some vaccines such as diphtheria and tetanus toxoids. Moreover, aluminum-adsorbed diphtheria and tetanus toxoids are distinctly more effective than plain fluid toxoids for primary immunization of children. There is little difference between plain and adsorbed toxoids for booster immunization. Aluminum adjuvants have a demonstrated safety profile of over six decades; however, these adjuvants have been associated with severe local reactions such as erythema, subcutaneous nodules and contact hypersensitivity.