A Universal Influenza Vaccine: The Strategic Plan for the National Institute of Allergy and Infectious Diseases
Associated Data
Abstract
A priority for the National Institute of Allergy and Infectious Diseases is development of a universal influenza vaccine providing durable protection against multiple influenza strains. NIAID will use this strategic plan as a foundation for future investments in influenza research.
The National Institute of Allergy and Infectious Diseases (NIAID) has a long-standing commitment to advancing basic and translational research on influenza to inform the development of new and improved diagnostics, therapeutics, and vaccines. The NIAID has made one of its highest priorities the development of a universal influenza vaccine that would provide long-lasting protection against multiple strains of the virus, including strains with the potential to cause a pandemic.
There are 2 epidemiological forms of influenza, seasonal (also known as “interpandemic”) and pandemic [1]. Seasonal influenza epidemics, caused by influenza A and B viruses, result in 3–5 million severe cases and 300000–500000 deaths globally each year [2, 3]. Influenza pandemics caused by influenza A virus emerge at unpredictable intervals. They cause significantly increased morbidity and mortality, compared with seasonal influenza. Four such pandemics have occurred in the past century, during 1918, 1957, 1968, and 2009 [4]. Furthermore, in the past few decades, animal influenza viruses, such as avian influenza A virus subtypes H5N1 and H7N9, have caused sporadic human infections and deaths [5]. These viruses, termed “prepandemic influenza viruses,” are acquired through close contact with infected animals but do not demonstrate sustained person-to-person spread. However, there is global concern that viral mutations may allow efficient transmission among humans and lead to the next influenza pandemic.
The effectiveness of seasonal influenza vaccine ranges between 10% and 60% [6]. The lowest effectiveness occurs when vaccine strains are not well matched to circulating strains. Reliance on egg passaging for vaccine production may allow for additional mutations during manufacturing and further compromise vaccine effectiveness in a given season [7]. Seasonal influenza vaccines provide virtually no protection against novel pandemic strains. The cornerstone of both seasonal and pandemic influenza prevention and control is strain-specific vaccination. Seasonal influenza viruses are subject to ongoing antigenic changes referred to as “drifts.” For influenza A virus, these drifts can be pronounced each season; they are much more gradual for influenza B virus. Strains used in annual vaccines are selected twice annually following the influenza seasons in the northern and southern hemispheres [1]. Similarly, the emergence of a novel influenza virus with pandemic potential requires the development of a strain-specific vaccine to protect humans for an epidemic that might never occur. The current strategy for seasonal influenza vaccination keeps us at least 1 year behind this ever-evolving virus. The strategy for pandemic influenza leads to making, testing, and stockpiling vaccines that may never be used.
To limit the public health consequences of both seasonal and pandemic influenza, vaccines that are more broadly and durably protective are needed. Figure 1 illustrates the steps that can guide ongoing research in this area. Advances in influenza virology, immunology, and vaccinology make the development of a “universal” influenza vaccine more feasible than a decade ago. For example, broad availability of deep-gene-sequencing techniques allows better and more-efficient characterization of viruses and enables tracking of genetic changes in influenza viruses over time [8]. In addition, advances in structural biology allow researchers to relate how seemingly minor changes in the structure and conformation of the hemagglutinin (HA) protein affect function, antigenicity, and immunogenicity [9, 10].
To focus research efforts, the National Institute of Allergy and Infectious Diseases (NIAID) convened a workshop in June, 2017, entitled “Pathway to a Universal Influenza Vaccine,” assembling scientists from academia, industry, and government to identify and develop criteria that would define a universal influenza vaccine Figure 2, to discuss knowledge gaps in the quest for this vaccine, and to identify research strategies to address these gaps [11].
Building on discussions conducted during the workshop, the NIAID herein proposes a strategic plan to reinvigorate pursuit of a universal influenza vaccine. This plan outlines activities in 3 main areas of influenza research: transmission, natural history, and pathogenesis studies using prospective cohorts; influenza immunity and correlates of immune protection; and strategies in rational vaccine design to elicit broad, protective immune responses. The 3 research areas are not prioritized, and advances in each are expected to be interdependent. The strategic plan also includes a description of research resources essential to advancing these 3 research areas that the NIAID will develop, support, and provide for the scientific community. Broad collaboration and coordination in the field is vital. The NIAID intends for this strategic plan to serve as a foundation for its own research investments and envisions a transformative effort toward successful development of a universal influenza vaccine.
RESEARCH AREA 1: IMPROVE UNDERSTANDING OF TRANSMISSION, NATURAL HISTORY, AND PATHOGENESIS OF INFLUENZA VIRUS INFECTION
Improvements in influenza vaccines have been hindered by an incomplete understanding of influenza transmission, natural history, and pathogenesis. Several cross-sectional studies have linked the results of viral surveillance with representative manifestations and characterization of host immune responses; however, there are no cohort studies that collect data from the same individuals over multiple influenza seasons with distinct vaccination and infection histories and apply modern approaches to analyzing the immune repertoire. Collection of clinical, immunologic, and virologic data from clinical cohorts, along with performance of comprehensive standardized assays, will be vital in understanding the evolving immune response to influenza and how repeated exposure to influenza viruses and vaccines shapes it. Similarly, influenza transmission has historically been difficult to study, and the impact of vaccination on transmission is not understood. Host and virologic factors that contribute to mild and severe disease, as well as the role of secondary infections, represent additional underdeveloped areas of influenza research. Investment in basic research, including natural history and pathogenesis studies, will inform more-effective strategies for universal vaccine design.
Objective 1.1. Expand Understanding of Influenza Transmission and Identify Targets for Improved Disease Control Measures
Our understanding of transmission of both seasonal and pandemic influenza is inadequate. Key unanswered questions include the relative contribution of aerosols, droplets, and fomites as modes of transmission and the impact of environmental factors (eg, temperature and humidity) on each; the role of specific human subpopulations in epidemic or pandemic spread; and the level of herd immunity required to interrupt seasonal or pandemic influenza transmission. A better understanding of how influenza transmission occurs, what factors drive transmission, and what will prevent transmission are important for the development of improved vaccines. Studies under this objective will
Identify physical and environmental factors (eg, droplet size, temperature, and humidity) that facilitate influenza transmission.
Determine dynamics of viral spread across geographic regions.
Identify host factors that impact transmission.
Identify clinical features of disease that facilitate transmission.
Develop analytic and modeling tools to define the level of immunity in the community required to prevent transmission.
Determine the contribution of anti-HA stem antibodies in prevention of transmission.
Determine the role of antineuraminidase (NA) antibodies in preventing virus budding, release, and transmission.
Objective 1.2. Identify Factors Associated With the Severity of Influenza
Most people with seasonal influenza have mild illness and recover in less than two weeks; however, some will have complications resulting in hospitalization and even death [13]. Those at high risk of complications from seasonal influenza include infants, elderly individuals, and people with medical comorbidities; these groups may respond differently to vaccination than healthy adults. An understanding of how to reduce severe influenza with seasonal or pandemic strains may guide novel strategies for the development of improved vaccines. Research addressing this objective will aim to
Identify viral factors impacting disease during human influenza virus infections.
Identify host genetic and nongenetic factors (eg, age and comorbidity) that affect susceptibility to severe influenza outcomes.
Identify immune markers associated with reduced disease severity.
Determine the mechanisms of immune dysregulation that may contribute to severe disease.
Determine the role of bacterial or viral coinfections in the severity of influenza.
Objective 1.3. Precise Characterization of Circulating Influenza Viruses
Knowing the antigenic diversity of influenza viruses that circulate in animals and humans is vital to guiding the development of universal influenza vaccines. Improving viral surveillance in animal reservoirs proximate to humans and characterizing the risk posed to humans may identify novel antigenic targets. Accurately predicting how circulating influenza viruses will evolve is critical to improving vaccine efficacy. Research addressing this objective will aim to
Develop the capability to rapidly characterize circulating influenza viruses from humans and animal reservoirs to assess the breadth of protection required from vaccines.
Develop and test models predicting the influence of preexisting immunity on virus evolution to anticipate the next emerging dominant seasonal influenza virus strain.
Improve genotypic and phenotypic characterization of circulating viruses associated with adverse clinical outcomes, host immunity, and vaccine failures.
Improve understanding of antigenic drift and immunodominance of various influenza virus antigens.
RESEARCH AREA 2: PRECISELY CHARACTERIZE INFLUENZA IMMUNITY AND CORRELATES OF IMMUNE PROTECTION
In contrast to strategies for the development of seasonal influenza vaccines, the goal of most universal influenza vaccine strategies is to induce broadly protective immunity. The ability of influenza viruses to undergo antigenic drift and evade antibody-mediated immunity complicates the design of broadly protective vaccines. The role of T-cell–mediated immunity in influenza virus infection and disease has historically received little research attention; however, it may offer another pathway to achieve broad protection. While current seasonal influenza vaccine approaches do not induce strong CD8+ T-cell responses, universal influenza vaccine strategies may need to incorporate this component of the immune response to be fully successful.
The immune correlate of protection used historically as a surrogate of influenza vaccine efficacy, the hemagglutination inhibition (HAI) assay finding, reflects antibody-mediated inhibition of viral attachment, and as such, limits comprehensive assessment of vaccine-elicited immunity. “Functional” antibodies are measured by microneutralization (MN) assays, which measure the effect of antibodies on viral attachment and infection of mammalian cells. It will be essential to identify immune correlates beyond HAI and neutralizing activity in both humans and animal models, as well as by means of standardized assays to measure potential correlates of protection, to accelerate design, development, and testing of a universal influenza vaccine.
Comprehensive profiling of human immune responses, coupled with high-throughput viral sequencing and bioinformatics, can determine the critical immune components required for induction of long-term, broadly protective immunity against influenza. By applying these techniques across populations, biomarkers and correlates of effective responses can be elucidated [14]. The knowledge gained from research area 2 will help to elucidate protective immune mechanisms triggered by both natural influenza virus infection and vaccination.
Objective 2.1. Improve Understanding of How and When Exposure to Influenza Antigens Shapes the Host Response to Influenza Virus Infection and Vaccination
Humans encounter numerous influenza virus strains and vaccinations throughout their lifetime, with immune responses determined by the genetics of the virus, as well as by intrinsic host factors, such as genetics, age, health, and immune status. Recent data provide strong evidence that infection with influenza virus strains circulating during one’s childhood elicits a lifelong immunologic imprint that influences subsequent responses to vaccinations and to novel strains and helps protect against unfamiliar HA subtypes from the same phylogenetic group, as the original infecting virus [15]. This phenomenon is termed “immunologic imprinting.” While induction of protective immunological memory can be a positive outcome of such prior exposures, some evidence suggests that preexisting immunity from infection or vaccination may limit the generation of protective responses to novel influenza virus strains or vaccines [16–18]. The emergence of transformative new technologies such as high-throughput sequencing and single-cell sorting provides the opportunity to understand in a fundamental manner viral evolution and human immune repertoires. Further research addressing the following aims will enable our understanding of the mechanisms that underlie the role of immunologic imprinting and the effect of serial influenza exposure and vaccination on vaccine efficacy:
Explore how immunity develops and evolves over time in different age cohorts.
Characterize differences between immunity resulting from vaccination and from influenza virus infection.
Define the influenza virus–specific B-cell repertoire by birth year during times of changing viral subtype dominance across several decades.
Characterize immune responses in those with a limited HAI response to infection or to vaccination.
Define the balance of antibody responses to HA and NA and the level of protection afforded.
Objective 2.2 Delineate the Innate and Adaptive Immune Responses to Both Natural Infection and Influenza Vaccination
Development of a universal influenza vaccine requires a deeper understanding of innate and adaptive immune responses that are necessary for protection, both systemically and at local tissue sites. Innate immune mechanisms may contribute to the protection afforded by HA antibodies. Growing evidence suggests that tissue-resident innate and adaptive immune cells play a dominant role in protection and that development of tissue-specific immunity is influenced by the route or location of initial antigen exposure, vaccine formulation, and vaccine modality [19, 20]. Once influenza virus infection is established, protection from clinical symptoms requires both B-cell/antibody and T-cell responses [21]. Research efforts under this objective aim to
Determine the contribution of innate immune cells in guiding adaptive immune responses to influenza virus infection and vaccination.
Define the mechanisms of broadly protective humoral immunity against influenza, including processes that affect immunodominance, based on antigen specificity, avidity, accessibility, or precursor frequency.
Evaluate the roles of CD4+ and CD8+ T cells in protective immunity to influenza and immune-mediated pathogenesis and immune dysregulation, including the use of vaccine prototypes in the human challenge model.
Define mechanisms regulating the induction, development, regulation, trafficking, and maintenance of tissue-resident B- and T-cell immunity, and the impact on protection from influenza virus infection.
Objective 2.3. Identify Alternative Mechanisms of Protection Beyond HAI-Mediating Antibodies
The commonest way to measure immunity against influenza is to determine HA antibody levels that prevent viral attachment. However, recent evidence indicates that some broadly cross-reactive antibodies protect by mechanisms other than virus neutralization, such as by antibody-dependent cellular cytotoxicity (ADCC). Standard neutralization assays do not assess these alternative mechanisms of protection. Therefore, novel assays are needed to test these mechanisms as additional correlates of human immunity relevant to vaccine efficacy. Research efforts under this have the following objectives:
Identify additional immune correlates of protection in the context of influenza vaccination.
Develop methods to measure cytokines, antibody/B-cell, and T-cell responses in relevant tissue sites.
Improve the epitope specificity of immunological measurements.
Define how the mechanisms of protective immunity differ for induction of sterilizing immunity versus protection from symptomatic disease.
Objective 2.4. Standardize/Harmonize Non–HAI-Based Assays
To facilitate the characterization of the immune responses, new assays and reagents must be developed, standardized, and harmonized, particularly as new vaccine platforms and antigenic targets evolve. The following research efforts will address this objective:
Measure specific HA stem antibody responses, including standardized protocols and reagents for assay development and validation.
Develop standard in vitro high-throughput surrogate assays to measure influenza virus–specific ADCC, antibody-dependent cellular phagocytosis, or complement dependent cytotoxicity [22–24].
Improve high-throughput assays for measuring neutralization against multiple influenza virus strains.
Determine NA content in vaccine and correlate levels of NA antibody commensurate with protection.
Assess T-cell–mediated immune responses, including tissue-resident responses.
RESEARCH AREA 3: SUPPORT RATIONAL DESIGN OF UNIVERSAL INFLUENZA VACCINES
Annual influenza vaccines do not provide robust protection against antigenically drifted variants, different influenza viral subtypes, or durable protection extending beyond the next influenza season. The next-generation influenza vaccine must capitalize on knowledge gained by assessment of the protective immune correlates elicited by natural infection and seasonal vaccination and by experimental vaccine formulations (including adjuvants) and prime-boost regimens to rationally advance vaccine designs that maximize antibody- and cell-mediated immune responses. One path forward would use a coordinated, iterative approach in which correlates of protection identified in trials conducted through the NIAID’s clinical trial network informed the design of next-generation vaccines. Targeted, incremental advances in vaccine design (eg, inclusion of additional antigens or adjuvants) may help improve seasonal influenza vaccine effectiveness; inform efforts to achieve a universal influenza vaccine that confers broad, durable protection against multiple influenza viruses; and reduce the need for annual vaccinations. An alternative path forward would use the combination of new insights and knowledge of the humoral and T-cell responses defined by this strategy to design wholly new vaccine candidates for comparison to seasonal influenza vaccines in terms of superior efficacy, breadth, and durability.
The new era of vaccinology is driven by advances in structural biology and genomics, multiparameter single-cell sorting technology to facilitate B-cell and T-cell repertoire interrogation, rapid isolation of broadly neutralizing antibodies, and novel computational methods for protein design. In addition, new/improved T-cell epitope predictive algorithms are providing insights into the effector/regulatory functionality of HLA-restricted, epitope-specific T-cell subsets. These advances support a multidisciplinary and rationally informed approach toward the design of vaccines for viruses whose major antigenic determinants are too variable to use conventional vaccine approaches. These emerging strategies and approaches, coupled with a multitude of new vaccine expression and delivery platforms, make the next generation of improved influenza vaccines within reach. Research area 3 aims to demonstrate the usefulness of new antigen design strategies, platforms, and adjuvants in eliciting protective immune responses against influenza. Resulting vaccine strategies will be evaluated using an iterative approach to deliver clinical evidence supporting advancement of influenza vaccine(s) that provide broader protection against multiple influenza virus types and subtypes. The NIAID has a history of pioneering structure-based and rational vaccine design through its intramural Vaccine Research Center, as well as through its extramural grantees. Coordination of these resources will be promoted in the NIAID strategic plan toward development of a universal influenza vaccine.
Objective 3.1. Design New Immunogens That Elicit a Wider Breadth of Protection
Current seasonal influenza vaccines are focused on eliciting immunity to the globular head domain of the major viral glycoprotein, HA. However, this domain exhibits high plasticity and evolves continuously. Hence it does not represent an ideal target for broad protection. In contrast, conserved parts of the virus, such as the membrane-proximal stem domain of HA, the viral NA, the ectodomain of the ion channel M2 (M2e), and internal viral proteins, may be better targets. In addition to neutralizing activity, the contributions of other antibody effector functions and T cells must be considered when designing immunogens to achieve robust broad and durable protection against influenza. Research efforts under this objective have the following aims:
Advance new vaccine approaches into clinical trials that exploit emerging antigen design strategies, novel technologies, and/or platforms.
Refine and optimize vaccine products on the basis of correlates of protection data obtained from cohorts, preclinical studies, and clinical trials, including data specific to age and risk subgroups.
Identify vaccine candidate(s) that provide broad protection, superior to that of the seasonal influenza vaccine, and advance candidates to the next phase of testing.
Define mechanisms of vaccine-induced protection.
Explore trial designs testing the efficacy of vaccines that do not have traditional immunological end points of HAI or neutralization.
Objective 3.2. Test Adjuvants and Alternative Delivery Methods to Enhance Breadth and Durability of Immunity
Adjuvants not only enhance the immune response against an immunogen and provide dose-sparing benefits, they can also be used to enhance specific components of the immune response that can impact durability and breadth of protection. To date, a limited number of influenza vaccines licensed in the United States include an adjuvant. Durable protection from influenza may require new vaccine designs that apply advances in the discovery and development of adjuvants to optimize vaccine responses. In addition, vaccine trial designs involving heterologous prime-boost strategies and/or alternative vaccination routes may offer broader and more-effective tissue-resident protection, compared with classical intramuscular administration. Research efforts under this objective have the following goals:
Identify new antigen/adjuvant combinations that induce broad and long-term protection.
Evaluate alternate routes of vaccine delivery (eg, intranasal, oral, and topical routes) in preclinical and clinical studies.
Perform studies to examine heterologous prime-boost approaches to maximize protective immune responses.
Evaluate currently available vaccines delivered by alternative methods or in different sequences and combinations.
Objective 3.3. Test Promising Vaccine Platforms/Candidates in Iterative Phase I/II Clinical Trials
Early preclinical assessment will aid in downselection of novel vaccine platforms, adjuvants, and delivery systems. Clinical trials currently underway testing next-generation vaccine candidates will reveal whether specific immune strategies are feasible, are safe, and elicit broad, durable cross-reactive responses. Together, data on immunological assessments of correlates of protection generated from longitudinal cohort studies and ongoing and future phase I/II novel vaccine trials will inform clinical refinement of influenza vaccine platforms through this iterative process. Research efforts under this objective have the following aims:
Conduct phase I clinical evaluation in healthy volunteers (including children) of new influenza vaccine candidates that have demonstrated broad protection in preclinical models.
Conduct phase I/II trials of vaccine candidates proven to be safe and to have promising immunogenicity profiles in targeted age groups or at-risk populations.
Evaluate the results of phase II trials to identify next-generation vaccine candidate(s) that elicit profiles predictive of broad protection against multiple influenza virus types and subtypes that is durable for >1 year.
RESEARCH RESOURCES AND CROSSCUTTING TOOLS TO IMPROVE INFLUENZA VACCINES
A coordinated effort of guided discovery, facilitated product development, and managed progress through iterative testing in clinical trials will be critical to achieving the goal of a universal influenza vaccine. The NIAID will support gaps as outlined in Table 1 and will also coordinate the efforts of a consortium of scientists to ensure movement toward the short-, medium-, and long-term goals outlined in Supplementary Data. In addition, the NIAID will expand its support of the following research resources to enable progress in research areas 1–3 outlined in this strategic plan.
Table 1.
Filling the Research Gaps Leading to a Universal Influenza Vaccine
| Variable | Research Gaps | Actions |
|---|---|---|
| Research area | ||
| 1. Improve understanding of transmission, natural history, and pathogenesis of influenza virus infection | Understanding influenza transmission Identify factors that influence disease severity Expand characterization of circulating influenza viruses | Expand existing programs Increase support for investigator-initiated applications Launch targeted funding opportunities |
| 2. Precisely characterize influenza immunity and correlates of immune protection | Improve understanding of host response to infection/vaccination Delineate innate and adaptive immune response to natural infection and vaccination Identify mechanisms of protection beyond HAI Standardize/harmonize non–HAI-based assays | Expand existing programs Increase support for investigator-initiated applications Launch targeted funding opportunities Initiate study of infant immunity imprinting in response to vaccination and infection |
| 3. Support rational design of universal influenza vaccines | Design new immunogens to widen breadth of protection Test adjuvants and delivery methods Test candidates in iterative phase I/II trials | Expand existing programs Increase support for investigator-initiated applications Launch targeted funding opportunities Use NIAID clinical trial sites |
| Research resources and crosscutting tools | Develop/improve animal models and reagents to advance vaccine
development Establish longitudinal cohorts Expand human challenge study capability and capacity Develop systems biology approaches for influenza | Expand existing programs Increase support for investigator-initiated applications Launch targeted funding opportunities Initiate study of infant immunity imprinting in response to vaccination and infection Use NIAID clinical trial sites |
| NIAID to launch a multidisciplinary consortium and coordinate activities to advance all research areas | ||
Abbreviations: HAI, hemagglutination inhibition; NIAID, National Institute of Allergy and Infectious Diseases.
Animal Models to Advance Vaccine Development
No single animal model completely recapitulates human disease. Currently, mice and ferrets are extensively used in basic research and translational studies, with recent advances enabling researchers to interrogate many aspects of influenza virus pathogenicity, transmission, and host immunity. However, there are still gaps and limitations in these models, including a lack of immunological tools for species other than mice, differences in host immune responses across species, inability to recapitulate in animals the effects of the complexities of preexisting immunity in humans, and a lack of standardized assays across different laboratories. The following activities will address the gaps in existing animal models:
Determine the optimal use of current animal models for studying efficacy, natural history/pathogenesis, transmission, and mechanisms of immunity.
Develop appropriate tools and reagents to maximize the usefulness of current and future animal models.
Develop new models to mimic the human immune response and to replicate the human experience of influenza immunity building over time.
Establish Longitudinal Cohorts for Influenza Research
Humans encounter numerous influenza virus strains and vaccinations throughout their lifetimes, and responses are determined by viral genetics, host factors, and prior exposure experiences. Expanded studies of influenza in humans will help answer questions related to transmission, pathogenesis, and immunity. Recent data provide strong implications regarding “immunologic imprinting” and the impact of serial vaccination that requires further investigation using long-term human cohorts, including cohorts of infants naive to influenza virus infection or vaccination [15, 16]. Data from natural history studies in prospective cohorts are essential to understanding the immune response to influenza virus infection and vaccination. The following activities will address current knowledge gaps:
Determine how various factors (eg, genetics, age, and immune status) influence influenza immunity and pathogenesis.
Identify and use existing community-based, prospective, longitudinal cohort studies of influenza or other respiratory infections that may allow assessment of influenza immunity or vaccine effectiveness.
Improve understanding of the heterogeneity of virus shedding among individuals and within the same individuals over time.
Increase Capacity and Capability for Conducting Human Challenge Studies
There are many limitations of current animal models and clinical studies of natural infection in humans. Disease and susceptibility patterns in typical animal models such as ferrets and mice do not represent the spectrum of disease observed in humans. Natural history studies of humans are limited by the inability to pinpoint exposure and timing of illness, the lack of understanding of preexisting immunity, and the inability to predict what viruses are circulating yearly. Influenza challenge trials in healthy human volunteers may overcome certain of these limitations and offer a unique opportunity to ask focused questions regarding influenza virus pathogenesis and vaccine efficacy in a controlled manner. The following activities will address these gaps:
Increase the number of sites capable of performing human challenge studies.
Optimize and standardize available influenza virus challenge strains, disease models, and infection methods.
Use the human challenge model to address questions related to influenza virus pathogenesis, immunity, and correlates of protection.
Evaluate next-generation universal influenza vaccine candidates in healthy volunteers for downselection by comparing them to the best available conventional vaccines.
Compare data from human challenge studies to data from studies of natural infection.
Develop Systems Biology Approaches for Influenza
Systems biology is an interdisciplinary field that seeks to integrate diverse data sets and computational and mathematical analysis to build models of biological processes. The complex process by which individuals respond to an infection or vaccine and the diversity of responses that individuals generate to the same infection or vaccination are well suited to systems biology analysis [14, 25]. The application of these approaches to analyze samples from infected persons or vaccinees may prove critical in revealing molecular and cellular signatures and biological processes that reflect effective, broad and long-term protective immunity against influenza. To address the knowledge gaps outlined above, specific goals include the following activities:
Develop analytical tools to integrate and analyze diverse and multiscale influenza virus infection and vaccination data sets from clinical samples to uncover correlates of protection and signatures of effective responses.
Identify pathogen and host factors that correlate with and/or contribute to heterogeneous responses to influenza virus infection and vaccination, including protection from disease.
Identify novel molecular signatures associated with vaccine/adjuvant candidates.
Promote open sharing of data sets from clinical cohorts and animal models to enable computational identification of correlates of interest across multiple studies.
Develop computational models that can predict protective responses to infection or vaccination.
CONCLUSION
Developing an influenza vaccine that improves the breadth and durability of protection against seasonal influenza and provides protection from pandemic strains is a high scientific priority for the NIAID. The NIAID will accelerate its efforts for developing a universal influenza vaccine by supporting a consortium of scientists focused on addressing obstacles that have limited progress toward this goal. The NIAID will also support the expansion of research resources by establishing longitudinal cohorts, supporting improved animal models of influenza virus infection, and expanding capacity for conducting human challenge studies. In collaboration with scientists, industry, international partners, the World Health Organization, and regulatory agencies, the NIAID is committed to helping achieve this important public health goal.
Supplementary Data
Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Supplementary Data
Notes
Acknowledgments. We thank our colleagues (Marciela DeGrace, Andrew Ford, Charles Hackett, Teresa Hauguel, Sonnie Kim, Amy Krafft, Chelsea Lane, Wolfgang Leitner, Christina McCormick, Adrian McDermott, Daniel Rotrosen, and Jon Yewdell), who provided expertise that greatly assisted this publication.
Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
Presented in part: Pathway to a Universal Influenza Vaccine Workshop, National Institute of Allergy and Infectious Diseases, Rockville, Maryland, 28–29 June 2017.
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