Vaccine Treatment and Evaluation Units: Why Support a “Ready Base” of Clinical Trial Sites?

Abstract

The National Institute of Allergy and Infectious Diseases has funded a clinical trial infrastructure to advance products and strategies to improve treatment and prevention of infectious diseases. This infrastructure includes dedicated research clinics, such as the Vaccine and Treatment Evaluation Units (VTEUs). For more than 6 decades, the VTEUs have maintained quality systems to advance investigational products to licensure by conducting trials that de-risk private sector investment in clinical development. They have developed novel clinical trial approaches, such as controlled human challenge models, responded rapidly to pandemic threats, engaged impacted communities across a variety of diseases, and provided mentorship and training to the next generation of clinical investigators.

For decades, the National Institute of Allergy and Infectious Diseases (NIAID) has supported a clinical trial infrastructure—clinical research sites and, in some focused scientific areas, leadership groups—that develops and prioritizes concepts to test in clinical trials. NIAID’s Vaccine and Treatment Evaluation Units (VTEUs) were initiated in 1962. Since then, they have served as a flagship program for conducting clinical trials of vaccines and treatments for infectious diseases. To date, they have conducted hundreds of clinical trials, many of which have contributed to vaccine and drug licensure.

Pharmaceutical companies and clinical research organizations in the private sector also support clinical trials that address similar objectives. These trials may also advance regulatory approval of their products. One might reasonably ask: Why should NIAID allocate taxpayer dollars to support the same? Can’t pharmaceutical companies conduct clinical trials and advance products just as well without the support of government? Is this even the right question to ask?

Public tax dollars for science can make a difference by addressing gaps that cannot be supported by the private sector alone, such as supporting basic foundational research. Public funding for translational research can also reduce the risk at key points along the development pathway (ie, support product development through the “valley of death,” a term that refers to the challenging trajectory from discovery to human trials) [1]. That support might include conducting phase 1/2 clinical trials, especially for products that address a critical public health need. In the best scenario, a commercial developer will see a favorable path forward for that product if early phase trials show promise of benefit. For decades, NIAID has supported clinical research to address public health needs that the private sector cannot or will not support alone.

Here, we summarize the reasons why a “ready base” of clinical trial infrastructure, such as the VTEUs, has been supported by NIAID for more than 60 years and how it continues to serve as an essential resource in the journey from discovery to implementation. We provide specific examples of success that would not have been achieved by the private sector research enterprise alone. In this supplement, the features and unique efforts that contribute to the success of this network are described in greater detail. In the article by Belshe et al, the history of this investigator network over the 6 decades of its existence is documented. Additional articles provide details on the strategic value of the NIAID-funded VTEU network to the broader clinical research effort in infectious diseases. These articles include a description of efforts focused on special populations (Bruxvoort et al), the development of capability to respond rapidly to infectious diseases outbreaks and pandemics (Atmar et al), successful approaches to mentoring junior investigators (Danziger-Isakov et al), as well as network contributions to innovation in clinical trial design (Jano et al).

DE-RISK INVESTMENT STEPS IN CLINICAL DEVELOPMENT

Infectious diseases typically take the heaviest toll on health in low- and middle-income countries, where the calculated return on investment for a candidate product may not be perceived as acceptable for the mainstream pharmaceutical industry. Moreover, regional health officials are often more confident and receptive to implementing a vaccine in their own setting if clinical trial data represent participants in their local community. Through partnerships with Malian investigators, NIAID-funded VTEUs recently provided data that led to a World Health Organization recommendation to vaccinate all infants aged 9–18 months with the pentavalent NmCV-5/MenFive product throughout the African meningitis belt [2]. Mitigating the global impact of infectious diseases (which do not respect country boundaries) is a public good. Products and strategies that reduce morbidity and mortality from infectious diseases in low- and middle-income settings will continue to be supported by NIAID. High-income countries are not spared from these challenges. Rare and devastating diseases, such as acute respiratory diseases or acute flaccid myelitis in toddlers due to enterovirus D-68 (EVD-68), occur. Developing treatment or prevention tools for these types of diseases is also not viewed as commercially favorable for private sector investment due to relatively low incidence and unpredictable epidemiology. The NIAID-funded VTEUs recently launched a phase 1 trial to evaluate the safety and pharmacokinetics of a monoclonal antibody that targets EVD-68, which may mitigate the devastating disease due to EVD-68 if outbreaks in the United States reoccur [3, 4].

MAINTAIN CONTINUOUS QUALITY MANAGEMENT SYSTEMS

Turning discovery into health often involves a complicated sequence of steps. Clinical trials that generate safety and efficacy data for regulatory approval are a late step in that sequence. The trial protocol document, the consent process, product stability data, validation of electronic data submissions, and safety monitoring are all subject to regulation and may be audited prior to regulatory approval. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has developed standards endorsed by the US Food and Drug Administration, European Medicines Agency, and other regulatory authorities [5]. Core competencies for members of the team that conduct clinical trials have been described and often require a completely different set of skills and aptitude than those needed for generating innovative scientific concepts for clinical studies [6]. Meeting and maintaining high standards for pivotal trials require specialized training, with ongoing support and retention of experienced multidisciplinary staff. These members of the research team must understand and assiduously adhere to ICH standards in clinical trial implementation and work to promulgate a culture of quality improvement at their site. We have found that commitment of stable support for these capabilities at a clinical trial site, rather than boluses of support on a protocol-by-protocol basis, is the better investment for a successful clinical trial infrastructure that yields the high-quality data needed to withstand regulatory and scientific scrutiny.

DEVELOP NOVEL CLINICAL TRIAL APPROACHES

A controlled human infection model (CHIM) is a novel type of clinical study that allows for pathogen exposure and a precise assessment of the course of resulting illness, usually one that is mild and self-limited or readily treated, in human volunteers. Manufacturing a qualified challenge product and characterizing the optimal dose and timing of clinical specimen collection are the initial essential steps in CHIM development. Clinical trials that use a well-characterized CHIM can be used to test the utility of a vaccine or therapeutic in a controlled setting. All volunteers are exposed to the pathogen; in natural field settings, only a fraction of volunteers are exposed. In some cases, this provides an efficient path to product approval for combating infectious diseases that occur rarely and have unpredictable epidemiology. Clinical samples collected for a CHIM can lead to the identification of biomarkers of a host immune response, for example, one that is predictive of successful vaccine protection. CHIM development in the VTEUs has led to the regulatory approval of a cholera vaccine indicated for travelers (Vaxchora), the first time that CHIM data in an efficacy trial supported regulatory approval of a vaccine [7]. The VTEUs have been instrumental in developing or refining CHIMs for a variety of other pathogens. Trials conducted in the VTEUs focused on malaria, influenza, and shigella have used CHIMs to advance vaccines forward into larger clinical trials [8–10].

PROVIDE SURGE CAPACITY IN A PUBLIC HEALTH EMERGENCY

The coronavirus disease 2019 pandemic illustrated the added value that experienced clinical investigators, such as those who lead the VTEUs, can provide in rapidly evaluating vaccines and therapeutics to curb the public health impact of a novel virus. The VTEUs opened enrollment for the phase 1 Moderna mRNA-1273 vaccine within 65 days of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral sequence becoming publicly available [11]. Once the public health emergency was declared, the NIAID-supported VTEUs, together with human immunodeficiency virus/AIDS clinical trial networks supported by the NIAID Division of AIDS, were able to pivot rapidly to focus efforts on SARS-CoV-2 [12]. Through partnerships with other NIAID-supported networks and with vaccine companies, they were able to support the implementation of the large-scale efficacy trials for 4 SARS-CoV-2 vaccines. Other SARS-CoV-2 vaccine trials that followed tested these vaccines in a variety of circumstances and populations: pregnant women, children, heterologous prime-boosting combinations, and combination variant boosting regimens [13–16].

This NIAID-funded clinical trial infrastructure has also contributed significantly to our understanding of what vaccine designs and dosing regimens are required to protect against a pandemic influenza threat. Trials conducted in the VTEUs established safe and immunogenic dosing schedules for adjuvanted hemagglutinin-based influenza A vaccines that target avian strains. Early trials provided the basis for the approval of the Sanofi-Pasteur H5N1 vaccine that became part of the pre-pandemic stockpile in the United States. Later trials of adjuvanted vaccines that target H7N9 strains addressed considerations and provided novel insights for homologous and heterologous prime/boost intervals to expand the breadth of elicited immunity and enhance pandemic responsiveness [17].

ENGAGE IMPACTED COMMUNITIES

The clinical research that NIAID supports must test strategies and interventions that could make lives better. Engagement of the community impacted by a disease is essential to achieving this objective. Enrolling volunteers who represent the diversity of the population at risk may improve uptake of a product after regulatory approval. As a trial sponsor, NIAID alone cannot engage all the diverse communities impacted by infectious diseases. NIAID relies heavily on community representatives to tell them how to address problems in infectious diseases research, what the most meaningful outcomes might be from a patient perspective, what nature and intensity of procedures will be acceptable in a protocol, and how trial recruitment efforts can be successful. Ultimately, any hope for uptake of a successful intervention, such as a beneficial vaccine, may depend on the trusting relationships that investigators can build with successful community engagement throughout the life of the trial.

TRAIN THE NEXT GENERATION OF CLINICAL INVESTIGATORS

A successful career in science requires mentorship, especially at the early stages of training. Staff at NIAID must ensure that the scientific workforce of the future is capable of meeting the challenges that old and new infectious diseases will bring. Successful career development can be strongly supported by structured mentorship programs designed with deliberation and supported by NIAID resources [18]. Within its clinical trial networks, NIAID is committed to supporting multilayered development programs. Pairing senior clinical investigators with junior investigators as protocol cochairs supports a transition to independence. Pilot projects conducted within the network as substudies under the auspices of a mentoring committee can lead to publications, then subsequently to National Institutes of Health grant submissions for early career development under the oversight of members of that same committee. These activities are all within the scope of VTEUs and have proven successful in the recent past.

Our VTEUs have evolved with NIAID over 6 decades. It is expected that they will continue to evolve as new infectious diseases threats emerge and our knowledge and technology advance to provide new tools to fight them. NIAID will continue to support a clinical trial infrastructure that is nimble, flexible, robust, and broadly collaborative to continue to rise to the challenges that infectious diseases bring in the future.