Viral Prototypes for Pandemic Preparedness: The Road Ahead

Abstract

The coronavirus disease 2019 (COVID-19) pandemic demonstrated how rapidly vaccines and monoclonal antibodies (mAbs) could be deployed when the field is prepared to respond to a novel virus, serving as proof of concept that the prototype pathogen approach is feasible. This success was built upon decades of foundational research, including the characterization of protective antigens and coronavirus immunity leading to the development and validation of a generalizable vaccine approach for multiple coronaviruses. For other virus families of pandemic concern, the field is less prepared. The articles in this special issue have highlighted research gaps that need to be addressed to accelerate the development of effective vaccines and mAbs, to identify generalizable vaccine and mAb strategies, and to increase preparedness against other pandemic threats. Successful implementation of the prototype pathogen approach will require a systematic, multidisciplinary, coordinated approach with expertise and crosstalk among researchers of different virus families.

The National Institute of Allergy and Infectious Diseases (NIAID) organized and hosted the virtual “Workshop on Pandemic Preparedness: The Prototype Pathogen Approach to Accelerate Medical Countermeasures—Vaccines and Monoclonal Antibodies” in November 2021. The preceding papers in this supplement reviewed the viral families of pandemic concern and prototype pathogens discussed at the workshop (Table 1) [1–8]. Here, we discuss future directions that would address the gaps in research for those prototype pathogens that would need to be completed to be better prepared in the event of an outbreak.

A recurring feature of the past 3 decades has been the emergence of viruses that spread rapidly among immunologically naive populations to cause significant disease. While the 2020 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic had the greatest impact on global health, others included SARS-CoV-1, Middle East respiratory syndrome coronavirus (MERS-CoV), West Nile and Zika viruses, Ebola virus, chikungunya virus, and multiple reassortments of influenza A virus [9]. Despite remarkable scientific progress in recent years, the development of vaccines and monoclonal antibodies (mAbs) in response to many of these outbreaks was too slow to impact the course of the epidemic or to provide sufficient time to establish the efficacy of the medical countermeasures (MCM) in clinical field trials before the number of infections waned [10–12]. Notable exceptions to this limitation included SARS-COV-2 and Ebola virus, where sustained transmission or repeated outbreaks provided sufficient opportunity to evaluate MCM success.

Advanced scientific preparedness is a critical element of an impactful response to an unanticipated emerging threat. Multiple groups, such as the World Health Organization (WHO) and the Coalition for Epidemic Preparedness Innovations (CEPI), have identified individual priority pathogens that could threaten global health and have invested in research and MCM development. However, it is not certain that one of these priority pathogens will be the causative agent of the next pandemic. The Prototype Pathogen Approach is complementary to investments in individual priority pathogens, and focuses on identifying and validating countermeasure strategies for a viral “prototype” that applies broadly to multiple viruses within a taxonomic group, including those that may not yet be known [13–15]. The remarkable pace of the development of mRNA vaccines for SARS-CoV-2 is proof of concept for this approach. Rapid development was made possible by extensive foundational research on coronaviruses that included solving the atomic structure of multiple coronavirus spike (S) proteins [16, 17], the development of approaches to stabilize the S protein [18], and the demonstration that this concept could be applied to multiple coronaviruses [19]. The stabilization of the S protein was also informed by previous efforts to stabilize the viral entry proteins of other viruses [20–24]. Earlier investments in the modified messenger RNA (mRNA) platform enabled the accelerated deployment of the S immunogen candidate by leveraging existing safety data from the platform [25]. Similarly, numerous mAbs had been identified and characterized for their neutralization potency and binding epitope to other coronaviruses such as MERS-CoV [26, 27], informing the rapid selection and development of protective mAbs for SARS-CoV-2 (reviewed in [28]). The NIAID Pandemic Preparedness Plan details a complementary approach of prototype pathogen research combined with research on enabling technologies and priority pathogens to mitigate the risks of previously unknown pathogens while building a robust research portfolio advancing basic and translational science.

THE PATH FORWARD FOR THE PROTOTYPE PATHOGEN APPROACH

A prototype approach to MCM development requires a multidisciplinary effort of considerable breadth. The goal of this approach is not a single vaccine or mAb to protect against the prototype species of a prioritized viral family, or to develop a universal vaccine or mAb that protects against all members of the family, despite the benefit to public health these advances would offer. Instead, a prototype-directed initiative involves targeted research to discover features of the virus and its interaction with humans that can be exploited in designing MCMs against other viral species in the same family. Because not all promising vaccine or mAbs concepts may work when applied to related viruses, intensive study of secondary viruses within the family will be required to validate generalizable MCM development approaches. Validation would include evaluating whether the vaccine design expresses the conformationally correct antigen for related viruses, as well as establishing that immunization elicits the immune response shown to be protective for the prototype virus and is protective for other family members. For mAbs, validation would include determination of whether mAbs with similar epitopes or functional properties are also potently protective for other virus family members. The applicability of the foundational knowledge, vaccine designs, and mAb characteristics will need to be established for both closely related and more distally related family members. Studying instances where approaches are found to not apply broadly across a family may provide additional virological or immunological insights and enhance the ability to predict whether an established approach is likely to work for a newly emerging virus. As described in the preceding supplement papers, multiple knowledge gaps exist across the viral families, including establishing reliable animal models of disease, relevant viral strains, and mechanisms of immune protection and validating reagents and assays. Closing these gaps within families will be an important part of the prototype pathogen approach and preparing for the next public health emergency.

Successful prototype MCM development will undoubtedly require a detailed understanding of a complex network of virological, structural, and immunological features of each virus family. It may require iterative translational advances to refine protective antigens, adjuvants, and effective vaccine platforms. Among these, establishing the characteristics of a protective immune response and correlates of protection are critical elements of the prototype concept. Defining the repertoire of antibodies elicited by infection or vaccination can lead to identifying features of viral antigens to include in vaccine candidates, establishing immunodominance hierarchies, and advancing the identification of mAb with prophylactic therapeutic potential. The most predictive immune correlates may reflect the activities of only a subset of virus-reactive antibodies and those that contribute mechanistically to protection via effector mechanisms independent of their capacity to neutralize virus infection. T cells are critical for supporting the development of a robust antibody response and make important direct contributions to immunity, as emphasized by their importance in protection against coronavirus disease 2019 (COVID-19) [29, 30] and poxviruses [31]. A catalog of B and T cell epitopes alone is insufficient for the rational design of vaccines. Rather, a dissection of protective immune mechanisms will greatly inform design immunogen design. The development of appropriate animal models of viral infection, pathogenesis, and disease is required to support immunological studies of these types for many of the prioritized viral families.

Structure-guided immunogen design is a powerful complement to studies of the immunological basis of protection [24, 32]. Advances in electron microscopy have catalyzed tremendous progress in an understanding of the structure of viral entry proteins [24], tropism, and the biogenesis, morphology, and function of virions [33–35]. Epitope mapping using structural techniques is a powerful approach to inform mechanisms of action studies that may reveal features of viruses shared among related viruses that may be exploited to design vaccines or select potent mAbs. Virions are now understood to be ensembles of structural states that may be complicated further by structural heterogeneity and variable host modifications [36–39]. How virion structural complexity shapes the immune response, varies in response to immune pressure, and can be captured in the design of potent immunogens is a significant challenge. Viral diversity that results in antigenic variation is an additional critical consideration for understanding immunity and MCM development informed by the lens of structural biology.

Prototype-guided MCM development will require highly collaborative networks of scientists to make the enabling discoveries in viral biology, pathogenesis, and immunity required to evaluate MCM concepts in multiple viral models and advance promising candidates toward clinical trials. This creates opportunities for investigators from multiple fields or with specialized technical expertise to collaborate in new ways. Progress in MCM development for one prototype will likely be advanced by the discoveries of other prototype campaigns, as multiple issues are cross-cutting. Pandemic preparedness will be advanced considerably not only by directed science in prioritized areas but by optimized approaches to organizing capabilities to accelerate enabling science and MCM candidate identification and development.

NIAID supports pandemic preparedness efforts ranging from preclinical basic science research, including animal model development and discovery of vaccines, antibodies, and therapeutics, through Invesitigative New Drug (IND)-enabling translational and early clinical development. To accelerate the discovery and development of vaccines and mAbs using the prototype pathogen approach for virus families of pandemic concern, the NIAID plans to establish a new cooperative network of basic and translational research centers to carry out in-depth research on prototype members of viral families of pandemic concern. The goal of the Research and Development of Vaccines and Monoclonal Antibodies for Pandemic Preparedness (ReVAMPP) network is to advance the scientific knowledge needed to develop vaccines and mAbs for prototype viruses, including the discovery and evaluation of generalizable countermeasure approaches for these selected virus families based on shared functional and structural properties. A coordinating and data sharing center will facilitate information exchange, and collaboration among the research centers to address cross-cutting issues and advance discoveries for all virus families. NIAID has released Notices of Funding Opportunities (RFA-AI-23-019, RFA-AI-23-020, and RFA-AI-23-021) for the ReVAMPP network and awards are planned to be made in early 2024. The ReVAMPP network will enhance the field's ability to respond to emerging viral threats.

CONCLUSIONS

A multipronged approach is required to be prepared for successfully responding to the next pandemic, including pathogen discovery and surveillance, and MCM and diagnostic development. Discovery science to identify generalizable vaccine and mAb strategies are a key component for pandemic preparedness that must be validated in early phase clinical trials before a threat emerges. Advances in delivery platforms and manufacturing technology will be required to rapidly deploy these strategies when needed. Significant investments in each of these areas will be essential for preparedness for the next pandemic.

Notes

Acknowledgments. We thank Jean Patterson, Mark Challberg, Kim Taylor, Michael Schaefer, and Candice Beaubien for their contributions to the development of the ReVAMPP Network concept and helpful discussions about pandemic preparedness.

Financial support. This article was written by the National Institutes of Health employees in the course of their usual duties without additional funding support. T. C. P. is supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH.

Supplement sponsorship. This article appears as part of the supplement “Pandemic Preparedness at NIAID: Prototype Pathogen Approach to Accelerate Medical Countermeasures—Vaccines and Monoclonal Antibodies,” sponsored by the National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD.

References

Author notes