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Each year in the United States, there are approximately 76 million cases of food-borne illness, including 325,000 hospitalizations and 5,000 deaths. In an estimated 2 to 3% of these cases, chronic sequelae develop. These sequelae include renal disease, cardiovascular diseases, gastrointestinal disorders, neural disorders, and autoimmune disease. The estimated cost of food-borne illness in the United States is $23 billion annually. Mishandling of food is believed to be responsible for 85% of all outbreaks of food-borne disease in developed nations, primarily due to a lack of education. Food-borne pathogens [see Additional File 3] are also important because they represent one of the largest sources of emerging antibiotic-resistant pathogens. This is due in part to the administration of sub-therapeutic doses of antibiotics to food-producing animals to enhance growth. For example, certain strains of Salmonella show resistance to eight or more antibiotics. Studies have shown that antibiotic resistance in Salmonella cannot be traced to antibiotic use in humans, suggesting that antibiotic use in animals is the primary cause of resistance.
While much is known about the major microbes responsible for diseases, there are still many undiagnosed cases of infectious disease. It has been estimated that as many as three-fifths of the deaths from acute gastroenteritis per year in the United States are caused by an infectious organism of unknown etiology. Four of the major causes of food-borne infections (Campylobacter jejuni, Escherichia coli O157:H7, Listeria monocytogenes, and Cyclospora cayetanensis, Figure 2) were only recently recognized as causes of food-borne illness.
In the developing world, nearly 90% of infectious disease deaths are due to six diseases or disease processes: acute respiratory infections, diarrhea, tuberculosis, HIV, measles, and malaria [see Additional File 1]. In both developing and developed nations, the leading cause of death by a wide margin is acute respiratory disease. In the developing world, acute respiratory infections are attributed primarily to six bacteria: Bordetella pertussis, Streptococcus pneumonia, Haemophilus influenzae, Staphylococcus aureus, Mycoplasma pneumonia, Chlamydophila pneumonia, and Chlamydia trachomatis. These bacteria belong to four different taxonomic classes and illustrate how similar parasitic lifestyles can evolve in parallel within unrelated bacterial species (Figure 2). Major viral causes of respiratory infections include respiratory syncytial virus (Figure 5), human parainfluenza viruses 1 and 3 (Figure 5), influenza viruses A and B (Figure 5), as well as some adenoviruses (Figure 4).
The major causes of diarrhoeal disease in the developing and developed world have significant differences due to the great disparity of availability of pure food and water and the general nutritional and health status of the populations. Important causes of diarrhoeal disease in the developing world are those that tend to be epidemic, especially Vibrio cholera, Shigella dysenteriae, and Salmonella typhi. These organisms are gammaproteobacteria (Figure 2) that use many different metabolic pathways to ensure their survival in a wide range of environments. In the United States there is a much lower incidence of diarrhoeal disease overall, and a relatively greater impact of direct human-to-human infectious transmission. The most important causes of diarrhoeal disease in the United States are bacteria such as Escherichia coli, Campylobacter species, Clostridium difficile, Listeria monocytogenes, Salmonella enteritidis, and Shigella species (Figure 2); viruses, such as Norwalk virus (Figure 6) and rotaviruses (Figure 7); and parasites such as Cryptosporidium parvum, Cyclospora cayetanensis, Entamoeba histolytica, Giardia lamblia, while microsporidia are responsible for a smaller number of cases (Figure 3).
Infectious disease agents important to the public health in the U.S. are monitored by the CDC and listed in Additional File 2 [see Additional File 2]. There are no set criteria for inclusion on the notifiable disease list; rather, the list is created by the CDC in cooperation with state health departments. As diseases occur less frequently and new diseases emerge, the notifiable disease list changes. The list provides links to case definitions of each disease, including the etiological agent(s) responsible. In cases where the etiological agent was not listed or was unspecific (i.e. Brucella spp.), further research was done to determine an etiological agent and this information is in Additional File 2 [see Additional File 2].
Emerging infectious diseases under this category were subcategorized into 1a, 1b and 1c. Subcategory 1a covers known pathogens that occur in new ecological niches/geographical areas. A few past examples belonging to this subcategory are the introduction and spread of West Nile virus in North America; chikungunya virus of the Central/East Africa genotype in Reunion Island, the Indian subcontinent and South East Asia; and dengue virus of different serotypes in the Pacific Islands and Central and South America.18,19,20,21,22,23 Factors that contributed to the occurrence of emerging infectious diseases in this subcategory include population growth; urbanization; environmental and anthropogenic driven ecological changes; increased volume and speed of international travel and commerce with rapid, massive movement of people, animals and commodities; and deterioration of public health infrastructure. Subcategory 1b includes known and unknown infectious agents that occur in new host ‘niches'. Infectious microbes/agents placed under this subcategory are better known as ‘opportunistic' pathogens that normally do not cause disease in immunocompetent human hosts but that can lead to serious diseases in immunocompromised individuals. The increased susceptibility of human hosts to infectious agents is largely due to the HIV/acquired immune deficiency syndrome pandemic, and to a lesser extent, due to immunosuppression resulting from cancer chemotherapy, anti-rejection treatments in transplant recipients, and drugs and monoclonal antibodies that are used to treat autoimmune and immune-mediated disorders. A notable example is the increased incidence of progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system that is caused by the polyomavirus ‘JC' following the increased use of immunomodulatory therapies for anti-rejection regimens and for the treatment of autoimmune diseases.24,25,26 Subcategory 1c includes known and unknown infectious agents causing infections associated with iatrogenic modalities. Some examples of emerging infections under this subcategory include therapeutic epidural injection of steroids that are contaminated with Exserhilum rostratum and infectious agents transmitted from donor to recipients through organ transplantation, such as rabies virus, West Nile virus, Dandenong virus or Acanthamoeba.27,28,29,30,31
LPAIV H7N9 was identified as a newly emerging zoonotic pathogen in early 2013. It has caused since then a total of 680 cases of zoonotic infection, with a case-fatality rate of about 20%, principally in adult and elderly individuals. With an incubation time of 2–8 days, H7N9 virus infection can progress from initial symptoms of high fever and other influenza-like signs to more severe lower respiratory tract infection, respiratory distress and associated complications. Exposure to infected poultry is considered the primary risk factor for human infection. A total of 556 outbreaks have been reported in domestic poultry, including chickens, ducks, geese, pigeons and pheasants, largely concurrently to zoonotic cases of infection (Table 1). A few cases were reported in wild bird species. Because of their low pathogenic nature, H7N9 viruses typically cause asymptomatic or mild infections in birds.
Most animal outbreaks and zoonotic cases of low pathogenic avian influenza H7N9 virus infection occurred in mainland China, while imported zoonotic cases were identified in Canada and Malaysia (Fig. 1). The first epidemic of H7N9 virus infection in poultry peaked in April 2013 soon after the first identification of the virus as a cause of a zoonotic case of infection. Epidemics subsequently re-occurred in winter 2014 and 2015, with the highest reported numbers of animal outbreaks and zoonotic cases of infection during the months of January–February of each year.
LPAIV H7N9, in contrast to most other avian influenza viruses, can bind to the cellular receptors used by seasonal influenza viruses,. This ability is associated with one or two specific amino-acids in the hemagglutinin glycoprotein. Because seasonal influenza viruses and LPAIV H7N9 peak coincidentally during the winter months, they may co-infect an individual and subsequently reassort. This may give rise to a transmissible variant, against which the human population has little pre-existing immunity, and may be at the origin of a new influenza pandemic. Strict monitoring and isolation measures are therefore essential to limit the risk of seasonal influenza and reassortment in individuals with zoonotic H7N9 virus infection.
Historical information as well as microbial sequencing and phylogenetic constructions make it clear that infectious diseases have been emerging and reemerging over millennia, and that such emergences are driven by numerous factors (Table 1). Notably, 60 to 80 percent of new human infections likely originated in animals, disproportionately rodents and bats, as shown by the examples of hantavirus pulmonary syndrome, Lassa fever, and Nipah virus encephalitis–. Most other emerging/reemerging diseases result from human-adapted infectious agents that genetically acquire heightened transmission and/or pathogenic characteristics. Examples of such diseases include multidrug-resistant and extensively drug-resistant (MDR and XDR) tuberculosis, toxin-producing Staphylococcus aureus causing toxic shock syndrome, and pandemic influenza–.
Although precise figures are lacking, emerging infectious diseases comprise a substantial fraction of all consequential human infections. They have caused the deadliest pandemics in recorded human history, including the Black Death pandemic (bubonic/pneumonic plague; 25–40 million deaths) in the fourteenth century, the 1918 influenza pandemic (50 million deaths), and the HIV/AIDS pandemic (35 million deaths so far),.
Examples of past emerging infectious diseases under this category are antimicrobial resistant microorganisms (e.g., Mycobacterium tuberculosis, Plasmodium falciparum, Staphylococcus aureus) and pandemic influenza due to a new subtype or strain of influenza A virus (e.g., influenza virus A/California/04/2009(H1N1)).9,32,33,34,35 Factors that contribute to the emergence of these novel phenotype pathogens are the abuse of antimicrobial drugs, ecological and host-driven microbial mixing, microbial mutations, genetic drift or re-assortment and environmental selection. Accidental or potentially intentional release of laboratory manipulated strains resulting in epidemics is included in this category.
Human microbiologic infections, known as zoonoses, are acquired directly from animals or via arthropods bites and are an increasing public health problem. More than two thirds of emerging human pathogens are of zoonotic origin, and of these, more than 70% originate from wildlife. In novel environments, viruses, particularly RNA viruses, can easily cross the species barrier by mutations, recombinations or reassortments of their genetic material, resulting in the capacity to infect novel hosts. Because of their adaptive abilities, RNA viruses represent more than 70% of the viruses that infect humans. When socio-economic and ecologic changes affect their environment, humans may encounter increased contact with emerging viruses that originate in wild or domestic animals.
Wolfe et al. in 2007 and Karesh et al. in 2012 described different stages in the switch from an animal-specific infectious agent into a human-specific pathogen. The key stage is the transition of a strictly animal-specific infectious agent (originating from wildlife or domestic animals) to exposed human populations, resulting in sporadic human infections (Figure 1). If the pathogen is able to adapt to its human host and acquire the means to accomplish an inter-human transmission, horizontal human-to-human transmission occurs and maintains the viral cycle. Sometimes, an intermediate host, such as a domestic animal, is the link between sylvatic viral circulation and human viral circulation. For example, some human infections originating from bats, such as Nipah, Hendra, SARS and Ebola viral infections, may involve intermediate amplification in hosts such as pigs, horses, civets and primates, respectively (Figure 1). Genetic, biologic, social, political or economic factors may explain a switch in viral host targets. For example, climate changes may influence the geographical repartition of vector arthropods, leading to new areas of the distribution of infectious diseases, like Aedes albopictus and Chikungunya infections in the Mediterranean. Morens et al. listed different key factors that may contribute to the emergence or re-emergence of infectious diseases, such as microbial adaptation to a new environment, biodiversity loss, ecosystem changes that lead to more frequent contact between wildlife and domestic animals or human populations, human demographics and behavior, economic development and land use, international travel and commerce, etc.. These patterns of transmission allow identifying different animals to follow in order to monitor the appearance of new or re-emerging infectious agents before its first detection in the human populations. Therefore, hematophagous arthropods, wildlife and domestic animals may serve as targets for zoonotic and arboviral disease surveillance, particularly because sampling procedures and long-term follow-up studies are more easily performed in these hosts than in humans.
Historically, classic viral detection techniques were based on the intracerebral inoculation of suckling mice or viral isolation in culture and the subsequent observation of cytopathic effects on cell lines. Later, immunologic methods, e.g., seroneutralization or hemaglutination, were used to detect viral antigens in various complex samples. These techniques were based on the isolation of viral agents. With the progresses of molecular biology, polymerase chain reaction (PCR)-based methods became the main techniques for virus discovery and allowed the detection of uncultivable viruses, but these techniques required prior knowledge of closely related viral genomes. Next-Generation Sequencing (NGS) techniques make it possible to sequence all viral genomes in a given sample without previous knowledge about their nature. These techniques, known as viral metagenomics, have allowed the discovery of completely new viral species. Because of their low cost, the use of NGS techniques is exponentially increasing.
The transmission of infections between humans occurs after a pathogen from a wild or domestic animal contacts with exposed human populations. The human exposures may or may not be mediated by the bite of bloodsucking arthropods. Surveillance programs may target wildlife, domestic animals or arthropods for emerging viruses before their adaptation to human hosts.
Emerging and re-emerging viral infections have been a major threat to public health worldwide, since their recognition in the late 20th century. These infectious diseases include those caused by newly identified viruses, previously known viruses that acquired additional virulence traits, and those showing spread to unaffected regions. In the last ten years, re-emergence has been noted for Zika, Ebola, MERS, Dengue, Chikungunya and avian influenza, while SFTS (severe fever with thrombocytopenia syndrome) was recognized to be caused by a novel virus. These diseases are free to move across national borders according to rapid human mobility via global airline network. With this background, any novel infectious disease anywhere in the world may have the potential for global spread.
Although various factors are considered to be associated with an increase of emerging/ re-emerging infectious diseases, they can be summarized as three major changes on the global level, i.e., (1) change in human/society/behavior, (2) change in environment/ecosystem, and (3) change in microorganisms. These changes are considered to synergistically increase the risks for the emergence of pathogens, transmission of pathogens, and opportunity of infection (susceptible hosts).
Factors related to humans and society are the most responsible for emergence and spread of infectious diseases. At present, global population is estimated to be 7.4 billion and growing rapidly, described as “a population explosion”. This increase is remarkable in sub-Saharan Africa and South Asia. Increase of population is a common issue in developing regions and facilitates poverty, and leads to urbanization associated with the growth of megacities (37 cities as of 2017) with a population of more than 10 million. High population and its density increase the risk for transmission of infectious pathogens via human-to-human contact, and low hygienic condition arising from undeveloped infrastructures (e.g., sewerage system). Naturally, population explosion and urbanization facilitate the expansion of residence area of humans, which promote forest development associated with environmental destruction. During the process, humans may encounter unknown viruses which have been lurking in any animal but harmful to humans. Although it has not yet been fully demonstrated, Ebola virus is suggested to reside in some species of fruit bats as potential natural host, from which this virus might have transmitted to humans, causing Ebola Virus Disease (EVD).
International tourists who traveled abroad reached over 1.1 billion in 2014, and have been constantly increasing. The development of airline networks enables infectious pathogen to spread globally in a few days. Such typical situation was evident for the outbreak of SARS (severe acute respiratory syndrome) in 2003, when the unknown pathogen, which was later revealed to be a novel coronavirus, was disseminated from China to at least 17 countries within a week via air travel of infected patients. The recent outbreak of MERS coronavirus in Korea (2015) was also caused by a returnee from the Middle East. Spread of emerging viruses is indirectly related to socioeconomic problems including civil wars, an increase of refugees, and natural disasters. These human factors always compromise human health and increase the risk for emerging/re-emerging infectious diseases.
More than 200 virus species have been known to be able to infect humans. Historically, the number of newly identified virus species/family has been constantly increasing since the 20th century, which was associated with the development of technology, from tissue culture and serological detection, to genetic identification represented by PCR and high throughput sequencing. Among more than 1000 pathogens of humans, over 50% of them were considered to have originated in animal species (vertebrates). Emerging viruses are considered more likely to be zoonotic. The number of infectious diseases outbreaks increased globally about 4 times from the 1980s to 2010, associated with an evident increase of zoonosis as well as vector-borne disease, compared with human-specific infections. Increase of zoonosis and vector-borne diseases is related to global changes in environment and ecosystem which may be caused by climate change associated with global warming. Floods, fierce heat, and drought which arise as an influence of climate variation, may cause an increase of vectors, facilitating their move from an endemic area, and a decrease of natural enemies to vectors. Phylogenetic analysis combined with chronological tracing indicated that recent global spread of Chikungunya was caused synergistically by factors of humans, environment, vectors, and viruses. In the 1980s and 1990s, illegally dumped waste tires increased due to globalized trading and industrialization. These tires provided water pool for the proliferation of mosquitos, enhancing local endemicity. Thereafter, viruses with vectors have disseminated via international airline network, associated with the occurrence of genetic diversity in viral genome. A mutation in the envelope protein conferred increased viral growth in mosquito, which facilitated spread of this vector-born disease. Thus, spread of emerging viral diseases is considered to be caused by multifactorial mechanisms.
Currently, globally important viral infectious diseases may be classified into following categories with features such as (1) high frequency worldwide (diarrhea, respiratory infections, etc.), (2) pandemic concern (EVD, etc.), (3) directed to eradication/elimination (e.g., poliomyelitis), and (4) neglected tropical diseases (e.g., rabies). These viral diseases are prone to be prevalent in developing countries, because of 1) higher population (density), 2) higher prevalence of vector/reservoir of virus pathogens, 3) shortage of medical/preventive resources against viral diseases and 4) low socioeconomic/hygienic status. Furthermore, it is difficult to predict the emergence or spread of novel viral infections, and particularly zoonosis is impossible to eradicate because wild animals/vectors carry viral pathogens. Despite such situations, scientists have a significant role to reduce the risks of emerging viral diseases. The first priority is to ensure adequate surveillance of viral diseases, i.e., to maintain epidemiological study on humans, animals, virus strains from various sources including environment, which is relevant to “One Health” approach advocated recently. Molecular epidemiology and population dynamics of viruses provide suggestions for the genetic, phenotypic, and epidemiologic trend of the viral diseases. Outcomes from those efforts are definitely essential for developing diagnostic methods, therapeutic approaches, and vaccines.
Frugivorous, insectivorous or hematophagous bats worldwide have been studied for their role as reservoirs of infectious agents. Many viruses isolated from bats are able to cross the species barrier and infect humans, regularly causing severe diseases in humans (e.g., SARS, Ebola hemorrhagic fever, Nipah, rabies) (Table 2a). Most metagenomic studies targeting wildlife have been conducted on bats (Table 2b), as Calisher and collaborators reviewed in 2006, Wong and collaborators in 2007, Smith and Wang in 2013 or Luis et al. in 2013. Because “bat science” is a large and well-studied area in infectious diseases, this review will not focus more on this topic.
Two major categories of emerging infections—newly emerging and reemerging infectious diseases—can be defined, respectively, as diseases that are recognized in the human host for the first time; and diseases that historically have infected humans, but continue to appear in new locations or in drug-resistant forms, or that reappear after apparent control or elimination. Emerging/reemerging infections may exhibit successive stages of emergence. These stages include adaptation to a new host, an epidemic/pathogenic stage, an endemic stage, and a fully adapted stage in which the organism may become nonpathogenic and potentially even beneficial to the new host (e.g., the human gut microbiome) or stably integrated into the host genome (e.g., as endogenous retroviruses). Although these successive stages characterize the evolution of certain microbial agents more than others, they nevertheless can provide a useful framework for understanding many of the dynamic relationships between microorganisms, human hosts, and the environment.
It is also worth noting that the dynamic and complicated nature of many emerging infections often leaves distinctions between emerging and reemerging infections open to question, leading various experts to classify them differently. For example, we describe as “reemerging” new or more severe diseases associated with acquisition of new genes by an existing microbe, e.g., antibiotic resistance genes, even when mutations cause entirely new diseases with unique clinical epidemiologic features, e.g., Brazilian purpuric fever. Similarly, we refer to SARS as an emerging disease a decade after it disappeared, and apply the same term to the related MERS (Middle East Respiratory Syndrome) β coronavirus which appeared in Saudi Arabia in late 2012.
Globally, environmental and anthropogenic changes are impacting ecosystems, and perturbing plant and animal demographics and behaviors. These changes contribute to the increasing pace of infectious disease emergence worldwide, largely driven by increasing contacts between and among species,. Drivers of disease emergence include mobility and trade, encroachment of natural habitats and climate change, as well as intrinsic characteristics of pathogens, such as wide host range for animal pathogens and the ability of plant pathogens to hybridize.
The vast majority of emerging infectious diseases in humans are zoonotic in nature,. Often, they escape their natural wildlife reservoirs and infect captive or domestic animals and humans upon cross-species transmission. While the majority of zoonotic pathogens spread limitedly among humans, occasionally some do evolve the ability to efficiently transmit. These may cause devastating epidemics, if not pandemics, and may establish as novel human pathogens. Emerging infectious diseases of animals likewise have typically the ability to cross species barriers and invade new host species. In contrast, introduction of pathogens into new geographical areas and climate change play an essential role in the emergence of plant diseases, and the hybridization of plant pathogens that are not naturally sympatric is repeatedly reported to be involved in plant disease emergence events. The consequences of emerging pathogens in newly infected species, be it wild or domestic, or in new geographical areas, can have dire repercussions on human welfare, for example, through the disruption of ecosystem services or from large agricultural economic losses,. As such, emerging infectious diseases are One Health threats to the global community.
Despite progress in our understanding of the mechanisms and drivers of pathogen emergence and adaptation, infectious disease emergence and associated health and economic burdens remain essentially unpredictable. They continue to impose heavy burdens on the global community, as most recently painfully demonstrated by the emergence of MERS coronavirus in the Middle East and Ebola virus in West Africa. Because the nature, time and location of the next One Health threat cannot be forecasted, preparedness and responsiveness are essential to curb future emerging infectious disease burdens.
Surveillance is key to preparedness by identifying and monitoring new threats to plant, animal and human health, and raising early-warning flags upon changing epidemiology. Major global initiatives have profoundly revolutionized the scope of infectious disease surveillance in plants, animals and humans. These include the World Animal Health Information Database (WAHID) Interface of the OIE, the Global Animal Disease Information system EMPRES-i of the FAO, the situation assessments and reports of the WHO, and the internet-based Program for Monitoring Emerging Diseases (ProMED) of the International Society for Infectious Diseases.
Using the data collected from these different sources, we present the current status of major One Health threats. In this update, the current status of low pathogenic avian influenza virus (LPAIV) H7N9, highly pathogenic avian influenza viruses (HPAIVs) of the H5 subtype, MERS coronavirus and Ebola virus are summarized. The present report will be updated every three months, with newly acquired data on the diseases listed above, as well as with data on any new One Health threat that would have emerged during that period.
Immunization is arguably the most appropriate way of preventing infectious disease. The control of many important viral pathogens by vaccination is perhaps one of the outstanding achievements of medical intervention.
Vaccine‐induced immunity that is established in advance of virus infection relies primarily on adaptive immune responses for protective efficacy. Critically, vaccination depends on the properties of antigen recognition, activation, expansion, memory, trafficking and the multitude of specialist functions of lymphocytes. The extent to which vaccine‐induced immunity is successful also determines the spread and maintenance of a viral pathogen within a population. Viral vaccines have had profound and enduring consequences for human and animal health; the worldwide eradication of smallpox and rinderpest are testament to their outstanding contribution to modern society.
Nevertheless, infectious diseases still pose one of the greatest threats to public health, and the past three decades have brought a constant barrage of new human pathogens. More than 70% of these infections are zoonotic 1, 2, entering either directly from wildlife reservoirs or indirectly via an intermediate domestic animal host 1, 3. HIV, avian influenza, Hendra (HeV) and Nipah (NiV) viruses, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome coronavirus (MERS‐CoV), Ebola and Marburg filoviruses, Lassa virus (LASV), Rift Valley fever virus (RVFV) and Crimean–Congo haemorrhagic fever (CCHF) viruses are all examples of zoonoses currently emerging from wildlife. All these emerging zoonoses present a serious and increasing threat to health, biosecurity and economies worldwide. The mechanisms underlying disease transmission from animals to humans are becoming better understood 4 with the emergence of pathogens from wildlife (which represents the greatest threat to global health) occurring in a non‐uniform pattern, being localized to distinct geographic ‘hotspots’ in Africa, Asia and South America, and with each high‐threat pathogen being weighted towards a key wildlife species (e.g. bats, rodents or non‐human primates (NHPs). It is clear that such diseases will continue to place a substantial burden on global health, especially in dense human populations where the pressures on environmental and economic resources are greatest. More than one billion cases of human zoonotic disease are estimated to occur annually, and emerging zoonoses result in enormous economic losses 5. Increased urbanization, international travel, commerce and climate change increase the likelihood that emerging zoonosis will continue, if not worsen, in the future.
When a zoonotic virus spills over into a susceptible new species, it often has the advantage that the new host has little or no pre‐existing immunity, enabling attachment, entry and replication of the virus in receptive cells. The amplified virus may then evade clearance by host defences for long enough to be transmitted to another susceptible host, and the lack of herd immunity will result in a rapid dissemination of the virus, leading to disease in more virulent cases of infection. Each step in the process represents an opportunity for vaccine‐induced immunity and, through such intervention, transmitters and susceptible hosts are removed from a population by the pre‐emptive development of protective immunity, so that the spread of infection becomes less likely. Vaccination is therefore a powerful strategy for preventing and controlling emerging zoonotic infectious disease. The development of vaccines for such emerging infections, however, needs to contend with several key challenges associated with such viruses. An emerging infection may be a recently discovered virus and the result of a rare outbreak for which basic biological information such as correlates of protection, antigenic variability or immunodominance are unknown. There may be a lack of time to develop an appropriate animal model of disease in which to study viral immunology and evaluate vaccine candidates for preclinical assessment of protective efficacy and safety. Additionally, many emerging viruses have high case fatality rates, spread easily and cannot be treated. These characteristics mandate that all experimental investigations with such infectious material be carried out at high levels of bio‐safety, such as BioSafety levels 3 or 4. For such pathogens the availability of resource‐heavy laboratory infrastructure is a bottleneck to basic research. Moreover, the often standard vaccine approach of using attenuated strains or inactivated viral vaccines is not always a feasible option, because of the possibility of reversion to virulence or the requirement for large‐scale culture and production in high containment facilities. In addition to these significant hurdles, the economic cost of novel human vaccine development for rare pathogens, which are unlikely to provide an effective payback on investment, has been a major impediment to progress. Thus, basic research into many emerging pathogens has been neglected for years.
In 2014 the unpredicted size, speed and reach of the Ebola virus outbreak in West Africa 6 acted as a wake‐up call for researchers, pharmaceutical communities and governments, emphasizing the importance of investment into the study of emerging pathogens. Spurred on by this development and at the request of its 194 Member States in May 2015, the World Health Organization (WHO) convened a broad coalition of experts to develop a research and development (R&D) Blueprint for Action to Prevent Epidemics. Focusing on severe emerging diseases with the potential to generate public health emergencies, and for which no, or insufficient, preventive and curative solutions exist, the R&D Blueprint specifies R&D needs, including vaccine research. Through international governance, the programme aims to define R&D roadmaps for prioritized pathogens and to catalyse funding strategies 7.
Emerging infectious diseases (EIDs) have led to cooperation between countries, the first international epidemic response conference in 1851 and the establishment of WHO in 1948.
EIDs are diseases that have appeared recently or that have recently increased in frequency, geographical distribution or both (1). Since the end of the 20th century, there has been a constant stream of newly identified pathogens and an increasing occurrence of pandemic threats to global health (2).
These infections are due to new agents (HIV-1, Severe Acute Respiratory Syndrome CoronaVirus-SARS-CoV- (2003), avian influenza virus H5N1 (2005), H1N1 (2009)), geographical area in extension (West Nile, Dengue, Chikungunya, and Zika viruses), increased incidence of infectious disease (HIV, tuberculosis, plague), modification of virulence (Neisseria meningitidis) or acquisition of resistance (Extended-spectrum betalactamases -ESBL- or carbapenemase producing enterobacteriaceae and multidrug-resistant -MDR- tuberculosis).
We can also compare the re-emerging infections (polio virus (2014), Ebola virus (2014), etc.) (3, 4).
EIDs threaten public health and are sustained by increasing global commerce, travel and disruption of ecological systems and in particular urbanization. Urbanization is characterized by rapid intensification of agriculture, socioeconomic change, and ecological fragmentation, which can have profound impacts on the epidemiology of infectious disease (5). However, their interactions with travel and migrations are less well known.
Travelers could play a role in importing EIDs and could be a sentinel of major epidemics.
In France, there are more than 20 million travelers every year, 4.5 million of which are destined for areas at high risk for health. There are several modes of travel: tourist, business or visiting friends and relatives. Trips can be very short or extended in time.
Infectious diseases are rare health events, with the exception of common infectious diseases such as traveler’s diarrhea and are a single cause of death, far behind accidents and cardiovascular disease (6).
The risk of emerging infections such as dengue in a risk zone was estimated at 1% for one month of travel (7).
We have seen (re-)emergence of diseases imported by travellers in Europe, such as chikungunya and dengue in France and Itay, and malaria in Greece (8-10). Apart from these examples, these are rare situations. However, with global travel growth, the risk could become more tangible (11).
A particular concern is that of Multidrug Resistant Enterobacteriaceae (MRE) carriage. MRE acquisition is very frequent among travellers to tropical regions (12). The acquisition was higher in Asia (72%) than in sub-Saharan Africa (48%) or Latin America (31%). However, the same study showed that MRE carriage was limited in time and disappeared after a few months.
Migration is a global phenomenon that influences the health of individuals and populations over the course of their lives (13). Migrants are special travellers who, in most case, do not migrate by choice. Migrants are considered at higher risk for a range of health problems including infectious diseases as HIV, hepatitis B, tuberculosis, schistosomiasis and malaria (14, 15). This higher risk is partly due to poor socioeconomic conditions and, in some countries, is due to the lack of rights to health coverage for undocumented migrants (16-19).
Existing evidence from different European countries highlights the difficulties to access health services that migrants are facing (20-23). These infectious diseases unequally expose the majority population, from none at all (e.g., malaria) to a little (e.g., tuberculosis).
One can take the examples of epidemics of Middle East Respiratory Syndrome Coronavirus -MersCov- and Ebola, for which no secondary case has been reported in France.
Among the published studies on migrants and infectious diseases, the majority were non-emergent diseases with the exception of MDR tuberculosis and multidrug-resistant bacteria (24, 25).
In connection with the increased use of antibiotics in low-resource countries, there is a worrying increase in the prevalence of multidrug-resistant bacteria (26, 27). This increase could lead to an increased risk for migrants and their relatives, but there are few data on this point (28). The risk seems particularly increased when they return home to visit friends and relatives (29). While antimicrobial resistance is of concern, the prospects for pandemic spread of a bacterial or fungal emerging pathogen by migrants seem less likely (30).
Endemic disease, as tuberculosis, impose a far higher public health burden than epidemic disease (31). Denmark experienced an increase in the incidence of tuberculosis in the 1990s in relation to the increase in the number of cases among migrants (32). The rate of tuberculosis in France is 10 times higher among immigrants than in the majority population. Refugees and asylum seekers may have a heightened risk of MDR-TB infection and worse outcomes but the data remains poor (33).
Thus, there is little evidence to support the theories by which migrants would expose the host population to significant infectious risk. However, human diseases acquire a social status based on their perceived risk that determines their acceptability (31).
In a study that we conducted with a number of 347 doctors in France (infectious diseases and general practitioners), they were asked if first-time migrant people represent a vector of infectious diseases different from the majority population: 8% answered no, 13% yes but weakly, 44% yes but moderately, 27% yes significantly and 9% did not know.
Thereby, apart from infections such as tuberculosis and multidrug-resistant bacteria, the introduction of EIDs into human populations seems to be more often a consequence of economic development that brings zoonotic reservoirs in closer proximity to people.
Indeed, most pandemic threats are caused by viruses from either zoonotic sources or vector-borne sources (30). There is a need for rapid diagnosis of EIDs. Systems biology approaches can lead to a greater understanding of EIDs pathogenesis and facilitate the evaluation of newly developed vaccine-induced immunity in a timely manner (30, 34).
Close collaboration is therefore needed between specialists in tropical medicine, in public health, immunologists and biologists to anticipate the risk of EIDs in order to achieve the Sustainable Development Goals established by the United Nations in 2015(35).
The WHO established a Department of Pandemic and Epidemic Diseases in 2011 to better prepare for and respond to EIDs.
In conclusion, in connection with the extension of poverty, urbanization, extensive livestock rearing and globalization, we could be exposed to a third epidemiological transition characterized by zoonotic diseases and infections with multidrug-resistant bacteria (36).
The risk appears low for EIDs, or very low for high-risk EIDs, but higher for MRE carriage with possibly limited consequences. The role played by migrants is weaker than imagined (except for tuberculosis). Immigrants don’t play the role of sentinel epidemic so far. They could play a role in importing MRE, but it is poorly evaluated.
Genomics techniques, like PCR and high-throughput deep and whole-genome sequencing, that now greatly facilitate the discovery of EIDs (e.g., the etiologic agents of hantavirus pulmonary syndrome and Kaposi sarcoma) also reveal previously unimagined genomic diversity among microbes. This diversity includes complex and evolving viral quasispecies and microbes that have undergone considerable interbacterial horizontal gene transfer, creating new phenotypic properties of virulence and drug resistance.
Given these and other advances in science and technology, it is now possible to perceive, as Dawkins argued decades ago (15), that the evolution and natural selection of human diseases are not simply a struggle between microbes and hosts. Rather, it is fought out at a more basic level of gene-to-gene competition, pitting the genomes of microbes against those of their hosts (many of whose genomes contain genetic evidence of past microbial encounters). Dawkins contended that the visible evidence of genomic survival is an organism’s expressed phenotype, its “survival machine,” which is akin to a simple virus being protected by its external protein coat; however, Dawkins proposed that we should think of natural selection as operating at the level of the gene, not the organism it encodes.
This picture becomes more complex when we consider the human microbiome. Specifically, our gut flora represents a complex “external” organ system comprising at least three different “enterotypes” that have coevolved with us over millennia and appear to affect our health, including by preventing and modifying infection (16, 17). Indeed, fecal transplantation is now a novel treatment for Clostridium difficile colitis (a potentially fatal EID) (18). Infants who start life with or develop “reduced” flora (e.g., via pre- or postnatal antibiotics) may be at increased risk of IDs and EIDs. Variations in the microbiome may also affect the occurrence of certain chronic diseases, allergies, and malnutrition (19). In this newer view, humans are not just static victims of virulent microbes but hubs of gene flow in which pathogens not only “seek” to survive environmental barriers and natural and acquired immunity but also compete with other microbes on the playing field that we think of as “us.”
Additional conceptual advances in EIDs include the realization that many chronic diseases have a direct or indirect infectious basis, e.g., cervical, hepatic, and gastric cancers; gastroduodenal ulcers; hemolytic-uremic syndrome; and possibly some types of tics and obsessive-compulsive disorders (6, 12). We also have become aware of the critical role of microbial coinfections in the pathogenesis of certain infectious diseases (e.g., HIV and numerous opportunistic infections; influenza and measles in association with secondary bacterial pneumonias) and of nutrition, e.g., the link between vitamin A and measles (20, 21).
The “one-health” concept, which emphasizes understanding and studying the unity of human and animal infectious diseases (22), reflects growing awareness that the majority of human EIDs, probably more than 60 per cent (11), are of animal origin (zoonotic), a realization that has implications not only for disease surveillance but also for understanding pathogenesis and controlling disease. For example, HIV/AIDS, influenza, Lyme disease, tuberculosis, measles, plague, smallpox, and possibly even leprosy are directly or primarily of animal origin. Viral host switching, in some cases associated with rapid and complicated microbial comutations (23), has become an important research topic (23, 24) for both newer EIDs, such as SARS, and reemerging ones, such as influenza. The processes by which animal-adapted microorganisms leave their hosts and adapt to new species, such as humans, are largely unknown and represent an important challenge in the study of EIDs.
Moreover, host-switching is not just a one-way street from other animals to humans. For example, Ebola virus, a devastating disease for humans, has decimated African gorilla populations; in the United States, suburban expansion associated with deforestation has driven raccoons into the suburbs, increasing rabies transmission to and from them; and a human strain of Staphylococcus aureus has adapted to chickens, spread globally, and developed new mutations enhancing avian virulence (25, 26). These examples remind us that ecosystem dynamism in which humans play a critical role is a key variable in EID occurrence and prevention (6, 12).
Throughout recorded history, infectious diseases have plagued human existence. One effective approach to limiting these diseases has been vaccination. For example, in a recent report by Roush and colleagues at the U.S. Centers for Disease Control and Prevention (CDC), ever since the introduction of vaccines the incidence of infectious diseases like diphtheria, mumps, pertussis, tetanus, hepatitis A and B, Haemophilus influenza and varicella zoster has declined by more than 80% in the U.S. Furthermore, after the introduction of vaccines, large scale transmission of measles, rubella, and polio has been eliminated in the U.S., while smallpox has been eradicated worldwide. However, new emerging infectious pathogens such as HIV (human immunodeficiency virus), SARS coronavirus (severe acute respiratory syndrome virus), and highly pathogenic avian influenza (H5N1) viruses have adapted strategies to rapidly change their genetic compositions. As the influenza pandemic of 1918 (H1N1) killed approximately 20 to 50 million people worldwide, massive disease and death is similarly feared from newly emerging pathogens. In addition, the current novel swine derived H1N1 pandemic further exemplifies the need for a rapid and effective vaccine against emerging pathogens. Thus a vaccination strategy to control emerging diseases will require a more effective and rapid response than available from conventional approaches such as live-attenuated vaccines, inactivated vaccines, or protein subunit vaccines. Plasmid DNA vaccines, as reviewed in this article, may be an option to effectively combat current emerging infectious diseases.
It is now becoming accepted that disease eradication has a legitimate place in the armamentarium of responses to EIDs (6). Smallpox, a devastating reemerging disease for millennia, was eradicated in 1980, and the epizootic morbillivirus (measles-related) disease rinderpest was eradicated in 2011 (32, 33). With dracunculiasis and polio disease close to eradication, with measles on the path to eradication, and with significant strides in controlling such diseases as hepatitis B and even malaria and HIV infection being made, it is now possible to realistically consider eradication as an ultimate means of controlling certain EIDs.
Even though antibiotic resistance has accelerated alarmingly, new generations of antibiotics have kept pace (albeit, barely), and vaccines against some of the most important diseases have been developed or improved, such as those against Haemophilus influenzae type B, pneumococci, and cancer-causing human papillomavirus strains. The development of antivirals and antiviral combination therapies has led to a historic breakthrough in helping to control HIV/AIDS (12) and major strides in curing chronic hepatitis C virus infection. Future directions in research and drug development likely will include better antibacterial and antiviral combination therapies as well as the development and use of more narrow-spectrum drugs against infective agents, which are less likely to cause polymicrobial resistance.
In the 20 years since the IOM report on EIDs, remarkable progress has been made in understanding and controlling them. In 1992, HIV infection was considered a death sentence for most patients. In 2012, after the tragedy of more than 35 million AIDS deaths, persons treated early with combination antiretroviral therapy, although not “cured” of their viral infection, can expect to live normal life spans with only a low risk of transmitting infection to others. In 1992, at least a million children died annually of measles. In 2012, fewer than 100,000 are expected to die, and measles eradication based upon an already-available effective vaccine is a realistic near-term goal. In 1992, it was possible to enter villages in many developing countries to monitor poliovirus circulation by conducting childhood “lameness surveys.” In 2012, most lame individuals are adults whose children are largely free of the threat of polio and probably will live to see it eradicated (poliovirus type 2 has already been extinguished).
Despite extraordinary progress during the past 2 decades, infectious diseases still kill 15 million people each year (6), and new and deadly diseases continue to emerge and reemerge. The perpetual nature of the emergence of infectious diseases poses a continuing challenge, which is volatile and ever-changing. This challenge includes a need for constant surveillance and prompt, efficient diagnosis; a need to develop and deploy new vaccines and drugs to combat new diseases; and a need for ongoing research not only in developing countermeasures but also in understanding the basic biology of new organisms and our susceptibilities to them. The future is ever uncertain, because unimagined new diseases surely lie in wait, ready to emerge unexpectedly; however, our ability to detect and identify them, our armamentarium of treatment and prevention options, our capacity to undertake and maintain basic and applied research, and our commitment to eradicating certain EIDs have never been greater. We have made far-reaching advances in the past 20 years since the original IOM report, and scientists are guardedly optimistic that further breakthroughs lie ahead.
Ethical approval for the clinical database and its subsequent use in this study was granted by the TTSH Hospital SARS Clinical Management Workgroup and the institutional representative for the hospital.
The One Health concept is important in the development of interventions and actions that optimize outcomes for human, animal, and environmental health. The growing challenges presented by globalization, climate change, environmental contamination, human population growth, agricultural and urban development, and degraded ecological integrity pose substantial risks to global health, food security, and ecological sustainability, especially through the spread of emerging and zoonotic diseases. With the multitude of influencing factors, not only will occurrences of emerging infectious diseases persist, but the rate at which emerging infectious diseases are observed will also increase. Improved regulatory frameworks and holistic management strategies are needed to mitigate these emerging threats. To guide this response, clear multi-sector outcomes need to be defined. Understanding the epidemiology of relevant diseases, the unique challenges presented by each disease, and the current strategies used in the management of applicable diseases is needed to undertake properly informed decision-making and to support a One Health, systems-based approach to the development of interventions that will reduce risks and balance needs of humans, animals, and the environment. The ultimate goal will be to focus on long-term action directed at reducing the factors driving emerging diseases and contaminants and to provide interdisciplinary scientific approaches to manage environmental contaminants and emerging, high-consequence disease risks in order to achieve optimal outcomes for human, animal, and environmental health.
The precise mechanism of the induction of immunity after pDNA vaccination is complex and multi-factorial (Figure 1).
It is thought that after immunization, transfected muscle cells may produce antigen or foreign proteins that then directly stimulate B cells of the immune system, which in turn produce antibodies. Transfected muscle cells could possibly transfer the antigen to so-called antigen presenting cells (as demonstrated by cross priming) which then transport the proteins via distinct pathways (the MHC I for CD8+T cells or MHC II for CD4+T cells) that result in the display of different processed fragments of expressed proteins (antigens). Finally, direct transfection of antigen presenting cells (such as dendritic cells) with subsequent processing and display of MHC-antigen complexes may also occur. Because the process of antigen production by host cells after DNA vaccination mimics the production of antigens during a natural infection, the resulting immune response is thought to be similar to the type induced by pathogens. Indeed, DNA vaccination generates antigens in their native form and with similar structure and function to antigens generated after natural infection.
To gauge the impact of preemptive bird market closures, we analyzed temporal trends in cumulative daily A/H7N9 incidence by fitting an exponential curve to data for the combined provinces of Shanghai and Zhejiang, in the pre-intervention period 1 March to 6 April (Figure 5). Our results indicate a statistically significant (non-zero) intrinsic growth rate at 0.101 case/day (95% CI: 0.070 to 0.143). The model can be used to predict disease incidence past 6 April had there been no intervention. We note a deceleration in growth rate of observed cases past 6 April, outside of confidence bounds predicted by the pre-intervention model (Figure 5). In particular, the model identifies a statistically significant departure from predicted incidence by 18 April and throughout the end of the study period. A similar pattern was obtained by using nationally aggregated incidence data instead of province-level data [see Additional file 1: Figure S5].
In conclusion, we have shown that the available epidemiological data on influenza A/H7N9 are consistent with subcritical transmission potential below R = 0.6 in the first three months of virus circulation in Shanghai and Zhejiang provinces, suggesting infrequent human-to-human transmission events. A decline in the growth rate of influenza A/H7N9 cases in April 2013 highlights the beneficial impact of live bird market closures. The estimated transmission potential of A/H7N9 appears lower than that of other zoonotic threats, although uncertainty remains important due to limited statistical information in the available data. Our proposed approach could be useful to quantify the progression of the outbreak and the impact of control measures in the coming months and help monitor the pandemic potential of this emerging pathogen in near real-time.
A large majority of participants reported that they were more eager to apply infection control measures since the onset of MERS-CoV in KSA. Unexpectedly, almost two thirds of respondents were unaware of guidelines or protocols for the care of patients with MERS-CoV infection. Only 22.8% reported having received training about dealing with infectious disease outbreaks, 37.1% reported training in infection control policies and procedures, 54.4% reported training in hand hygiene and 45.6% reported training in N95 mask wearing techniques (Table 3).
A high proportion of respondents agreed that emergency department overcrowding, poor hand hygiene and mask use contributed to the risk of HCW being infected with MERS-CoV. Similarly, a high proportion agreed that a lack of knowledge about the mode of transmission, a lack of policies and procedures, and insufficient training in infection control procedures also contributed to the risk (Table 3).
Emerging infectious diseases, defined as novel or known infectious diseases increasing in incidence within a specific location or population, and environmental contaminants pose global and profound threats to human, animal, and environmental health. The rise of emerging infectious diseases demonstrates the dynamic relationship among pathogens, hosts, and their environment. Over sixty percent of emerging infectious diseases are zoonotic, and over seventy percent of those zoonoses have a wildlife origin, including highly pathogenic avian influenza (HPAI), sylvatic plague, Lyme disease, anthrax, and severe acute respiratory syndrome (SARS). These diseases increase burdens on public health systems, negatively impact the world economy, cause declines and extinctions of animal species, and increase loss of ecological integrity. The potential global impact of a wildlife-associated pathogen on human health is exemplified by the over 35 million people currently infected with human immunodeficiency virus (HIV), which is reported to have originated from a simian (primate) virus. Likewise, negative effects of emerging and resurging diseases on agriculture, food safety and security, wildlife health, and human health in Southeast Asia have resulted from outbreaks of HPAI. There are also several newly described pathogens and diseases that have resulted in wildlife population declines and global extinctions. Batrachochytrium dendrobatidis, a cutaneous fungal infection of amphibians, is linked to global declines of amphibian populations, and Pseudogymnoascus destructans, the etiologic agent of white-nose syndrome, has caused precipitous declines in the abundance of North American hibernating bat species. Such large-scale losses of animal species and biodiversity subsequently jeopardize the ecosystems on which all life depends. Of particular concern are novel emerging infectious diseases of wildlife origin as they are difficult to anticipate, devastating to wildlife populations, challenging to manage, and have the potential to have ecological ripple effects. Emerging diseases and pathogens of wildlife origin are increasing globally at alarming rates, in both incidence and by geographic location, which can be largely attributed to the driving forces of globalization, an increasing human population, and climate change.
Globalization, including the rising amounts of international human travel and trade in animal- and plant-based products and other goods, potentiates the spread of pathogens. Emerging infectious diseases are also driven by socio-economic, environmental, and ecological factors, including ecological disruption, microbial adaptation, and lack of preventative measures. For example, outbreaks of HPAI in Southeast Asia present ongoing challenges to biosecurity and food safety related to trade, transport, and marketing of poultry within and between countries. The growing human population and the ensuing urban development increase interactions among people, domestic animals, and wildlife, further escalating the risk for transmitting pathogens and initiating novel disease outbreaks. Climate change can also facilitate the movement of pathogens into new geographic regions. Additionally, climate change is altering insect population dynamics and increasing the potential for spread of vector-borne diseases, which constitute twenty to thirty percent of all emerging infectious diseases.
As a demonstration of an interconnected system, bats contribute up to 50 billion USD annually to the United States of America (US) agricultural economy through their part in insect control. However, the emergence of white-nose syndrome has resulted in the death of over 6 million bats in North America resulting in a marked decrease in insect control. Additionally, while bats are critical components of world ecosystems, they are also potential reservoirs of zoonotic viruses, including rabies, Marburg virus, and Nipah virus. In today's age of dynamic changes in the emergence of infectious diseases associated with increasing interactions among humans, domestic animals, and wildlife, the need to consider these interactions fully becomes crucial for effective management that balances the needs of humans, animals, and the environment.
Such issues are not limited to infectious diseases. For example, while it has long been known that human exposure to unsafe levels of methylmercury is predominantly through dietary consumption of contaminated fish and shellfish, recent technological advances in high-resolution mass spectroscopy now provide a means to “fingerprint” the contributing mercury and determine its source. For example, many locations are impacted by both point-source releases as well as nearly ubiquitous atmospheric fallout of mercury. This new fingerprinting capability has extended the capacity to determine which mercury sources contribute to fish, wildlife, and human exposures, thereby informing environmental decision makers of the most effective means to reduce such exposures.
Emerging pathogens represent one of the greatest risks to global health. There is already good evidence 1, 5 that zoonotic pathogens will most probably be transmitted from a few key animal species in resource‐poor areas of the world. Based on recent history, it is probable that such pathogens have never been seen before. The global impact of the West African outbreak of Ebola virus in 2014 underlines how stark differences in health‐care infrastructure can impact upon human‐to‐human transmission of emerging pathogens. Until basic health‐care infrastructure in all countries can be raised to a level that enables early identification and control of high‐risk pathogens at source, we will continue to respond to outbreaks of emerging disease long after epizootics have spilled over into human populations. Innovative strategies are therefore urgently required to control such pathogens, vaccination is a proven approach.
Many novel vaccination strategies that have been developed during recent years have the potential to specifically address the growing threat of new and emerging disease. The use of well‐defined vaccine vector platforms, with an extensive record of safety and efficacy against similar pathogens, can expedite the process of development, validation and production (Table 1). Accordingly, the design and licensure for particular platform vaccine technologies will help to accelerate the development of new vaccines, as only the simple substitution of a new antigen gene into the vector platform is required. This allows manufacturers to move to a new target disease with minimal changes in chemistry, manufacturing and controls. Thus, new vaccine development can focus on the safety and efficacy of the inserted gene. In addition, the ability of platforms to target multiple pathogens helps to justify the investment required to build and maintain manufacturing infrastructure that specializes in one platform, because a single manufacturing facility can be ready to produce multiple vaccines at any time.
In addition, further research into, and the development of, self‐disseminating vaccines to control potential pathogens in their wild‐life reservoirs should be encouraged. However, the progress of new vaccines through the necessary regulatory pathways to bring them to the clinic requires long‐term investment by governments and international organizations.
Another major problem arising from genetic changes is the development of resistance to drugs. A typical example is seen in HIV. Besides drug-drug interactions and toxic side effects, drug resistance arising from drug pressure coupled with high rate of genomic variation (during viral replication) is a major obstacle in HIV antiretroviral therapy, leading to treatment failure and necessitating regimen switches [107, 108]. Current antiretroviral therapy therefore employs a combination of anti-HIV compounds from at least two classes or drug groups with different mechanisms of action against HIV replication. Combination ART is necessary to suppress plasma HIV viremia, restore immunologic function, and reduce likelihood of drug resistance development for favourable treatment outcomes. The problem of emergence of drug resistant microbes and resistance to antimicrobial agents very well characterizes many bacterial infectious agents such as Escherichia coli, Pneumococcus, Neisseria gonorrhoeae, and Staphylococcus aureus. Many well known antibiotics no longer clear bacterial infections due to microbial resistance. Evolution of drug resistant pathogens thus necessitates continued development of new antiviral and antimicrobial products. As such for HIV alone there are currently at least 25 anti-HIV compounds licensed for the treatment of AIDS.