Featured Journal Content
The Critical Role of Biomedical Research in Pandemic Preparedness
Hilary D. Marston, MD, MPH1; Catharine I. Paules, MD1; Anthony S. Fauci, MD1
JAMA. Published online October 4, 2017. doi:10.1001/jama.2017.15033
Unusual reports of Kaposi sarcoma and Pneumocystis carinii (now P jiroveci) pneumonia in previously healthy gay men in 1981 alerted the world to a new infectious disease threat, heralding the HIV/AIDS pandemic. The medical and public health communities faced a steep learning curve in coordinating public health and biomedical research efforts as the pandemic evolved.
Since then, international partners in academia, government, and industry have devoted substantial efforts to pandemic preparedness, building on lessons learned from HIV and other outbreaks ranging from the abrupt onset of the severe acute respiratory syndrome coronavirus (SARS-CoV) to the spread of Zika in the Americas to the devastating outbreak of Ebola in West Africa.
Comprehensive preparedness is a multifaceted endeavor including global surveillance networks, health care infrastructure ranging from primary care centers to referral hospitals, health care workforce capacity, and engagement with affected communities. Governments, the United Nations, and other nongovernmental organizations have made important strides in these areas. For example, the World Health Organization’s International Health Regulations, updated in 2005 after the SARS-CoV epidemic, helped improve global disease surveillance.1 Individual nations worked together to build on this foundation, creating the multilateral Global Health Security Agenda (GHSA) to “prevent, detect and respond” to new threats. Nearly 60 nations including the United States have joined the GHSA, collaborating in multisectoral preparedness including enhanced capacity for surveillance and laboratory diagnostics.2
A critical component of effective pandemic preparedness is biomedical research, including domestic and international research capacity. The research enterprise complements other elements of preparedness by improving understanding of the pathogenesis of infectious diseases and by developing interventions in the form of diagnostics, treatments, and vaccines. The foundation of this work is a portfolio of basic research applicable to multiple pathogens of public health significance. Through these investigations, the research community develops an understanding of the microbiology and pathogenesis of known infectious diseases.
Even for pathogens not yet identified as major human health threats, research on related organisms can bolster efforts in the event of an outbreak. When Zika virus emerged in the western hemisphere, investigators working on the closely related dengue flavivirus were quickly marshaled against Zika. The presence of active researchers with relevant expertise facilitated the rapid launch of the Zika research response. For example, applying knowledge gained from work with dengue and other flaviviruses, researchers rapidly developed mouse models that recapitulate critical aspects of Zika infection, including replication and disease in the fetus; these were subsequently used as surrogates to study congenital Zika syndrome. These tools have been used to evaluate treatments, including monoclonal antibodies capable of neutralizing Zika and protecting mouse pups.3 Evaluation in human trials is under consideration.
The basic research portfolio leads naturally into and is complemented by investments in countermeasure development. Although treatments and vaccines are essential
countermeasures, so too are rapid, deployable, and point-of-care diagnostics. The latter are key to an effective response in an evolving pandemic.4 In the case of arthropod-borne viruses, research into novel methods of vector control is also critical.
In shaping the research agenda for pandemic preparedness, prediction of microbes likely to cause outbreaks is often more art than science; as HIV, SARS, and Zika have demonstrated, no single algorithm will “get it right” all the time. For this reason, several research approaches are pursued in pandemic preparedness, including (1) pathogen-specific work; (2) platform-based technology; and (3) prototype-pathogen efforts. Each approach has strengths and weaknesses. Vaccine-related efforts serve as examples for each approach.
In pathogen-specific work, resources are invested between outbreaks to advance countermeasure development for microbes deemed most likely to emerge and cause significant morbidity and mortality. Given finite resources, only a handful of pathogens can be prioritized. The World Health Organization’s Research and Development Blueprint offers a robust method for pathogen selection, assessing lethality and severity of disease, transmissibility, animal hosts and vectors, and dearth of existing countermeasures.5 The list allows the global research community to target its countermeasure development programs.
The US government used its own priority pathogen list based on the potential use of microbes as agents of bioterror (as designated by the Centers for Disease Control and Prevention) in the wake of the 2001 anthrax attacks. Ebola, one of the hemorrhagic fever viruses, was on the list of Category A Agents of Bioterrorism, and as a result, several Ebola vaccine candidates were developed. In response to the Ebola outbreak of 2014-2016 in West Africa, these vaccine candidates were advanced into phase 1 trials and field efficacy trials in early 2015.6
Some organizations, such as the Coalition for Epidemic Preparedness Innovations, are working to compress this timeline further, closing the gap between outbreak initiation and countermeasure availability by preparing selected vaccine candidates a priori for rapid evaluation in an outbreak. These efforts are promising; however, their utility depends on predictive capability of the prioritization algorithm. In the cases of HIV, SARS, and Zika, no list or algorithm predicted their public health impact.
In platform-based technology, developers are agnostic about specific pathogens. Research instead focuses on the platform used to present a relevant immunogen to the host. Vaccine platforms such as viral vectors can be used with genetic material coding for the relevant immunogen against which an immune response would be directed. In theory, such a platform could be used to present the genes from a range of pathogens. In this area, preparedness efforts typically involve the development of the platforms themselves, including manufacturing capacity.
Platform technology was used in the 2002-2003 SARS outbreak, during which the National Institute of Allergy and Infectious Diseases (NIAID) at the US National Institutes of Health (and others) developed vaccine candidates to meet the emerging threat. The platform in this case was a DNA plasmid into which was inserted the gene for the SARS glycoprotein serving as the immunogen. In 2003 and 2004, one program spanned just 17 months from sequencing the SARS-CoV genome and identifying the relevant gene to be inserted into the plasmid to initiation of the first clinical trial of a DNA vaccine for SARS, although the epidemic ended before trial results were obtained.7 In addition to DNA, vaccine platforms include nanoparticles, virus-like particles, and mRNA, among others.
Another approach using prototype pathogens can hasten the platform-based approach by prospectively filling research gaps necessary to advance successful candidates as efficiently as possible. In this approach, investigators would conduct countermeasure research for prototype pathogens, understanding that the prototype may not emerge as a threat but assuming that techniques would be applicable to closely related microorganisms (oral communication, Barney S. Graham, MD, PhD, and Nancy J. Sullivan, PhD, June 2017).
One example is the flavivirus prototype. Zika virus was not on priority pathogen lists before 2015, and essentially no Zika-specific research had been undertaken at NIAID. However, because of an extensive research portfolio on related flaviviruses such as dengue and West Nile viruses, researchers were able to leverage approaches such as animal models, immunogenicity assays, and vaccine design elements to develop Zika vaccine candidates. In this regard, DNA vaccine development for Zika took 13 weeks to move from sequence selection to first-in-human trial, largely because of the “road map” that West Nile research provided. The vaccine candidate is currently in a phase 2/2b trial; however, further development and distribution will require a commercial partner. Adapting this model for the future, countermeasure development approaches could be mapped out for multiple prototype pathogens, and if that pathogen (or a related one) emerges, the community would be poised for rapid countermeasure development, evaluation, and implementation.
While priority-pathogen lists might not reflect the next emerging threat, platform and prototype-pathogen approaches run the risk of taking too long. The most prudent path is to invest in research on all 3, bolstering the current ability to predict emerging infections, developing platforms that can be more rapidly adapted to new threats, and pursuing prototype-pathogen efforts to accelerate candidate development. However, broad availability of vaccines requires partnerships with industry, affected countries, and local communities. Moreover, even though considerable attention has been given to improved vaccine preparedness, solutions for treatments and diagnostics require further consideration, as both may play critical roles in any effective response.
Infectious disease outbreaks have been with humankind forever and will continue to occur. Whether dealing with HIV/AIDS, SARS, Ebola, Zika, or the inevitable unanticipated pathogen that will surely emerge, research has played and will play a critical role before, during, and after the outbreak. Looking ahead, the biomedical research community must maintain its critical role in comprehensive pandemic preparedness.
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