Vaccines for Emerging Viral Diseases

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Introduction

Infectious diseases continue to plague mankind and evolve to keep pace with the efforts to control them. Sir William Osler captured the ongoing fear of infectious pathogens when he said, “Humanity has but three great enemies: fever, famine, and war; of these by far the greatest, by far the most terrible, is fever.” Despite the significant impact of antimicrobials and vaccines on public health, there has only been one major human pathogen eradicated—variola virus, the agent of smallpox. In its place have been a series of new and reemerging microbes responsible for isolated infections, regional outbreaks, and global pandemics. Bacterial, fungal, and parasitic pathogens have the capacity to cause widespread epidemics such as the “Black Death” caused by Yersinia pestis in 14th century Europe. However, bacteria, fungi, and parasites are less likely to cause widespread human pandemics at this point in history and are less amenable to vaccine strategies than viral diseases. Focusing on viruses, a catalogue of newly discovered human pathogens from the beginning of the 20th century shows a predictable and nearly linear rate of new agents discovered over time. However, of the more than 100 virus families, only 22 have been associated with human infections, a number that seems to have plateaued. In this chapter we will concentrate on vaccines for emerging viral diseases.

Experiences over the last 3 decades with HIV, SARS, and Ebola have taught us the potential consequences of viral infectious threats on global health, and economic and political stability. Emerging viral infections with pandemic potential can be chronic, persistent, or acute in nature. They can be disseminated by respiratory droplet or other bodily fluids. They can emerge from animal reservoirs and spread via insect vectors, and can be precipitated by changes in climate, animal habitats, human population dynamics, and other ecological events. And they can emerge as a consequence of human activity in the context of deliberate viral modification as a form of biowarfare. We are faced with important questions including what can be done to anticipate these events and how can we best prepare to intervene when new or changing viral threats arrive?

Most current licensed antiviral vaccines utilize live-attenuated or whole-inactivated viruses, although there are now a few examples of effective virus-like particle (VLP) vaccines. In the setting of a new pandemic viral threat and without the advantage of a preexisting understanding of its pathogenesis, growth or attenuating features, it would be difficult to quickly develop traditional live-attenuated or whole-inactivated vaccine approaches due to uncertainty about the safety of attenuating mutations or the production of replication-competent virus in bulk. Therefore, it is more likely that developing vaccines for emerging infections will involve new technologies, some of which have not yet been licensed for human use. Using technologies that can provide a candidate vaccine based on information derived entirely from target gene sequences is safer and more expeditious than procedures requiring virus isolation and growth that require a high level of containment. Therefore, even for virus families for which there are currently licensed vaccines, additional approaches beyond live-attenuated and whole-inactivated products should also be pursued.

Historically, decades have elapsed between when a new virus is discovered and when a relevant vaccine becomes available for human use ( Fig. 28.1 ). In the setting of an epidemic, such protracted vaccine development timelines are incompatible with rapid deployment of a vaccine intervention and therefore not a practical consideration for immediate control of the outbreak. In part because of the 2014 West African Ebola outbreak, emergence of new viral threats to public health are becoming more of a global concern and have more media and political visibility. Fortunately, this is a time of remarkable technical advances in human monoclonal antibody discovery, structure-guided antigen design, and nucleic acid sequencing—making rapid development of biologics more feasible. Therefore, defining new approaches and pathways to efficiently deploy vaccine interventions for emerging infections is a priority for public health agencies, commercial entities, government officials, and nonprofit organizations. However, the key to a rapid vaccine response is advanced preparation.

Several steps are needed to improve preparedness for emerging viral infectious diseases. These can be divided into 4 broad categories: (1) surveillance and discovery, (2) reagent, assay, and animal model development, (3) vaccine design and product development, and (4) manufacturing, clinical evaluation, and an appropriate regulatory framework.

Depending on features of the virus structure, transmission dynamics, entry requirements, tropism, and replication strategy, a vaccine approach should be proposed, designed, and evaluated in small animals for immunogenicity and protection against challenge. Manufacturing a candidate vaccine for which there is no immediate market poses a significant dilemma because most stages of advanced vaccine development are carried out by large pharmaceutical companies that need to make profit to stay in business. While emerging infectious diseases pose a public health threat, they rarely present a compelling commercial opportunity. Vaccines require a large investment and historically have a relatively low probability of being successful without an extensive iterative process of evaluation and redesign. Therefore, in addition to new biological tools, there needs to be political will to prioritize public funding of advanced vaccine development and new business models for managing this process.

In this review, we describe the vaccine development efforts for three distinct viruses that collectively capture many of the challenges faced when developing vaccines for emerging viral threats. Ebola, a member of the Filoviridae family, is spread by body fluids and secretions with a relatively low attack rate but causes a systemic disease with high mortality. Chikungunya, an alphavirus in the Togaviridae family, is transmitted by mosquito vectors with a high attack rate and causes a systemic disease with low mortality but high frequency of chronic disabling arthritis. Middle East Respiratory Syndrome (MERS CoV), a beta-coronavirus and member of the Coronaviridae family, is spread by respiratory droplets and causes a relatively high mortality in persons with underlying disease. It has a reproductive rate ( R ₀ ) of <1 for person-to-person spread, but occasional “super-spreaders” can infect multiple people. The MERS reservoir, dromedary camels, will continue to be a source of new human infections.

Ebola, Chikungunya, and MERS CoV are representative infectious pathogens with pandemic potential. Use of new technologies to arrive at a more comprehensive understanding of viral structure and pathogenesis has paved the way for rational vaccine design for each of these viruses. Herein we elaborate on the iterative path taken to develop and evaluate candidate vaccines for Ebola, Chikungunya and MERS CoV and the factors that propel or delay progress. We focus our discussions primarily on the candidate vaccines developed at the NIAID Vaccine Research Center, not because they are necessarily the most promising or advanced, but because we are more familiar with the events associated with their development, and the factors impacting advancement and implementation.

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