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Adv Exp Med Biol - Advances in Microbiology, Infectious Diseases and Public Health (2017) 6: 7–16

DOI 10.1007/5584_2016_199
# Springer International Publishing Switzerland 2017
Published online: 18 February 2017

How to Tackle Natural Focal Infections:


From Risk Assessment to Vaccination
Strategies

Luca Busani, Alexander E. Platonov, Onder Ergonul,


and Giovanni Rezza

Abstract
Natural focal diseases are caused by biological agents associated with
specific landscapes. The natural focus of such diseases is defined as any
natural ecosystem containing the pathogen’s population as an essential
component. In such context, the agent circulates independently on human
presence, and humans may become accidentally infected through contact
with vectors or reservoirs. Some viruses (i.e., tick-borne encephalitis and
Congo-Crimean hemorrhagic fever virus) are paradigmatic examples of
natural focal diseases. When environmental changes, increase of reser-
voir/vector populations, demographic pressure, and/or changes in human
behavior occur, increased risk of exposure to the pathogen may lead to
clusters of cases or even to larger outbreaks. Intervention is often not
highly cost-effective, thus only a few examples of large-scale or even
targeted vaccination campaigns are reported in the international literature.
To develop intervention models, risk assessment through disease mapping
is an essential component of the response against these neglected threats
and key to the design of prevention strategies, especially when effective
vaccines against the disease are available.

Keywords
Natural Focal Diseases • Viruses • TBE • CCHF • Vaccination

O. Ergonul
L. Busani Department of Infectious Diseases, Koç University,
Department of Veterinary and Food Safety, Istituto Istanbul, Turkey
Superiore di Sanità, Roma, Italy
G. Rezza (*)
A.E. Platonov Department of Infectious Diseases, Istituto Superiore di
Central Research Institute of Epidemiology, Moscow, Sanità, Viale Regina Elena, 299 Roma, Italy
Russia e-mail: giovanni.rezza@iss.it

7
8 L. Busani et al.

A “natural focus of an infectious disease” is a and the environment, which provides for the
concept deriving from the theory of focality of existence of the pathogen” (Korenberg 2010).
diseases, proposed by the Russian scientist Such process is a series of consecutive cycles of
Eugene Pavlovsky in 1939. According to this pathogen reservation (restriction) and spread
theory, some pathogens are associated with spe- (circulation), providing the process to be limited
cific landscapes, and the natural “focus” or in time and space by the presence of specific
“nidus” of an infectious disease is defined as conditions needed by the pathogen. Moreover,
“any natural ecosystem that contains the popula- the circulation of the pathogen in the natural
tion of a pathogen as an essential component” foci is independent on human presence, and
(Korenberg 2010). The determinant feature of human infection, with rare exceptions, is a
natural-focal diseases is that the pathogen “biological dead end” for the pathogen. The
circulates in nature independently from human interaction between pathogens and humans is an
presence. As a rule, humans beings become accidental event and does not have any coevolu-
infected when they get into the focus and have tionary consequence (WHO 2016). An outbreak
contact with the infectious vector or, in some directly connected with natural foci is actually
cases, with the reservoir host (Korenberg 2010). the sum of individual disease cases occurring in
To develop the concept of natural focality, different places independently on each other,
Pavlovsky, in his original theory, analysed tick- with infection often being acquired from one or
borne pathogens in Russia, and for such several sources not connected with other dis-
pathogens he stated that the focus of infection eased persons (Korenberg 2010). This concept
should have three critical elements: is important to distinguish zoonoses with natural
focality and human infections acquired from
1. The aetiological agent of the disease; domestic animals. Another difference between
2. vertebrate hosts playing different roles (infec- natural focal diseases and other zoonoses is the
tious and susceptible recipient hosts, relevance of the socio-ecosystem level in the
reservoirs); structure of the epidemic process, which may be
3. environmental factors enabling the circulation high for several zoonotic infections but usually
and persistence of the agent. does not play any role in case of zoonoses with
natural focality.
Starting from this original formulation related However, it should be taken into account that
to vector-borne diseases, the definition of natural biological and social factors, and increasingly
focality was applied also to non-vector-borne intensive human activities, can cause drastic
zoonoses, such as hemorrhagic fever with renal changes in the structure and functioning of para-
syndrome, Ebola (when restricted to its natural sitic systems, the frequency and forms of human
nїche), leptospirosis, and other infectious contact with natural foci, and even the pathway
diseases. Finally, natural focality for a large of pathogen transmission to humans.
group of sapronotic infections, whose agents This “basal” interpretation of the epidemic
live in soil or aquatic ecosystems, was also process in infections with natural focality
described and discussed. For some vector-borne remains unchanged. It should only be taken into
zoonoses, the concept of a focus (nidus) may be account that people themselves create conditions
implemented as well. Thus, the phenomenon of for their exposure, favouring the entrance of
natural focality is widespread, and includes many pathogens from natural ecosystems into their
natural-focal diseases with different types of immediate environment, and for their active
transmission. reproduction and amplification in this new envi-
The natural transmission of a pathogen, in the ronment. For example, epidemic outbreaks of
context of natural focality, should be considered hemorrhagic fever with renal syndrome, a typical
a “continuous interaction of the pathogen popu- zoonosis with natural focality, are usually
lation with the populations of its natural hosts associated with virus shedding by animal
How to Tackle Natural Focal Infections: From Risk Assessment to Vaccination Strategies 9

reservoirs (murine rodents) migrating to can be plotted, trying to identify the geographical
populated areas, where favourable conditions distribution of the natural foci of infection in a
for virus amplification are created when the given area. Therefore, medical geography has an
abundance of these animals reaches high values important task: evaluating the risk of epidemic
(Korenberg 2010). hazards of natural ecosystems and providing
In the past two decades, views on the diver- public health authorities with recommendations
sity, spread, and epidemic significance of necessary to prevent disease outbreaks and con-
infections with natural focality have changed duct epidemiological surveillance.
substantially all over the world. Some new
pathogens have been discovered, and periodic
epidemic manifestations of natural foci have
1 Eco-Epidemiology: How
become a matter of great concern. Moreover,
to Predict and Control
increasing human activity (e.g., intensive subur-
the Occurrence of Natural
ban construction around big cities, expansion and
Focal Infectious Diseases
growth of recreational pressure) have led to a
significant increase in contact between human
Current understanding about the global distribu-
populations and natural foci, creating favourable
tion of most infectious diseases is surprisingly
epidemiological conditions for the spread of
limited. In particular, the spatial distribution of
natural-focal diseases (Malkhazova et al. 2014).
the vast majority of natural focal diseases
The large outbreak of Ebola occurred in West
remains largely unknown and many questions
Africa from December 2013 to March 2016,
are still unsolved, mainly because of the poor
affecting three countries (Guinea, Liberia, and
knowledge of their local variations and of the
Sierra Leone), is an example of the epidemic
characteristics of the ecological niches that
potential of natural focal diseases if virus
allow the permanence of such diseases in their
properties (capacity of inter-human transmis-
natural environment. Due to their intrinsic
sion), environmental factors, and social
features, the transmission of focal diseases to
conditions concur to increase the force of infec-
humans is highly heterogeneous in space and
tion, leading to large-scale virus circulation
time. At the micro-epidemiological scale, numer-
throughout human communities. At the end of
ous factors influence the transmission dynamics
the outbreak, more than 28,000 cases and 11,000
of the diseases in endemic foci, and variations in
deaths were reported (WHO http://www.who.int/
the distribution of these factors, even in a small
csr/disease/ebola/en/).
area, can result in spatially heterogeneous trans-
Natural-focal disease prevention is one of the
mission and appearance of disease hotspots,
most challenging public health problems. Agents
where transmission intensity is higher than in
and vectors of these diseases are part of natural
the surrounding areas.
landscapes and the spread of these diseases,
There are several reasons for mapping the
which may represent a serious hazard for people,
geographical distribution of infectious diseases.
is determined by natural factors. Such factors can
Maps of disease distribution and intensity allow
be identified and described in the affected area, in
an immediate visualization of the extent and
order to identify the “hot spots” of the disease,
magnitude of the public health problem. These
which are the most suitable places for the agents
maps can also document the background level of
and vectors. As proxy of the landscape features,
the disease in order to monitor its trend and to
also historical data on biocenosis, health records
evaluate interventions. Another reason is that
of humans and other vertebrate hosts (domestic
maps may also provide information on the
and wild animals) can be used. With such infor-
factors that favour the emergence of infectious
mation, predictions on the probability that a
diseases.
given biological agent is present in a specific
area are possible. Moreover, this information
10 L. Busani et al.

Hereby we present some innovative unsampled areas, predict invasive potential in


approaches to disease mapping which provide other regions/continents, predict likely distribu-
useful information and predictions. tional change with changing land use, predict
likely distributional change with changing
climates, and build scenarios for understanding
1.1 Ecological Niche Modelling and characterizing unknown disease behaviour.
Hence, ecological niche modelling offers a pow-
A wide range of approaches has been developed erful tool for characterizing ecologic and geo-
for empirical modelling of species and disease graphic distributions of species across real-
distributions, making use of data on point world landscapes (Peterson 2008a, b).
observations of disease occurrence, with the
objective of identifying the fundamental niche
of the target organism (Hay et al. 2013). Some 1.2 The Boosted Regression Trees
of these approaches allow to account for environ- Method
mental covariates, data on presence of pathogens
and natural hosts, landscapes, and climate To map the occurrence of a given disease, the
information. boosted regression trees method (Elith et al.
The concept of ecologic niche was proposed 2008; De’ath 2007) is one of the most performing
by Joseph Grinnell (1917) who was the first to methods; it is flexible in being able to accommo-
explore connections between ecological niches date different types of predictor variables
and geographic distributions of species. (e.g. continuous or categorical data) and easy to
According to his proposal, the ecologic niche of understand, implement and uses reliable. The
a species is the set of conditions under which maps generated with such approach are simple
species populations may be maintained without to interpret and include a ranked list of environ-
immigration of individuals from other areas. The mental predictors.
idea behind niche modelling is that known Another approach that has recently been more
occurrences of species across landscapes can be widely applied in infectious disease mapping is
related to raster geographic information system the model-based geostatistics (Diggle and
coverages summarizing environmental Ribeiro 2010) that has important advantages
variations across those landscapes, to estimate when compared to the boosted regression trees
the ecological niche of the species (Peterson method: (i) it deals explicitly with the spatial
et al. 2002). Such a modelling approach can be (and with extension temporal) autocorrelation
used to identify potential distributional areas for of disease data. This is still widely ignored in
species on any landscape, which may include occurrence mapping; (ii) it offers a much more
unsampled or unstudied portions of the native robust parameterization of factors that can affect
landscape (López-Cárdenas et al. 2005), areas disease endemicity (such as age of the
of actual or potential invasion by species with individuals sampled, the diagnostic technique
expanding ranges (Townsend Peterson and Kluza used, the influence of covariates etc.); (iii)
2003), or changing potential distributional areas outputs can also show the full uncertainty of the
as a consequence of change (e.g., land use prediction in all parts of the predicted maps by
change or climate change) (Escobar et al. 2015). fitting the models using Bayesian inference.
Ecological niche modelling, may be used to
characterize distributional areas of species in
complex, linked geographic and ecologic spaces. 1.3 Macroecology
It permits researchers to characterize ecological
needs of species, interpolate between sampling The “macroecology” appears to provide a new
points to predict full distributions of species, perspective in identifying drivers of infectious
predict species distribution into broadly disease patterns and impacts at the broadest
How to Tackle Natural Focal Infections: From Risk Assessment to Vaccination Strategies 11

scales of organisation. Macroecology animals and wildlife, and the few ecological
investigates patterns and processes at broad spa- studies on diseases with natural focality
tial, temporal and taxonomic scales, expanding (Malkhazova et al. 2014).
scientific understanding of global infectious dis- The knowledge of human distribution in many
ease ecology. In particular, it could help areas of the World remains also surprisingly
providing new insights about scaling properties poor. For many low income countries of the
across all living taxa, and new strategies for World, spatially detailed, contemporary census
mapping pathogen biodiversity and infection data do not exist. This is especially true for much
risk. Macroecology seems a useful framework of Africa, where currently available census data
to more accurately predict global patterns of are over a decade old, and at administrative
infectious disease distribution and emergence boundary levels just below national-level (Hay
(Stephens et al. 2016). Research in the relatively et al. 2005; Tatem et al. 2008). This information
new discipline of macroecology covers impor- is of significant importance for deriving
tant findings and advances in computational and populations at risk and infection movement
statistical methods explaining how estimates.
macroecological approaches can inform human Another key factor that may affect the distri-
health and conservation initiatives. The bution and the prediction of natural focal
advanced computational techniques are applied diseases, together with a large number of other
to enormous data sets to look for patterns; in the human and animal diseases, is climate change.
case of disease ecology, this kind of analysis can Species’ response to climate change are variable
help scientists understand relationships among and diverse, yet our understanding of how differ-
parasites, hosts and their environments. ent responses (e.g. physiological, behavioural,
Indeed, the development of the principles and demographic) relate and how they affect relevant
methods of synthesizing information from differ- population parameters (e.g. population persis-
ent sources, including geography, to obtain new tence) is lacking. Much of the research on
knowledge about the spatial distribution patterns responses to climate change does not consider
of natural-focal diseases using new approaches is how population size, population growth rate, or
a research interest. The scientific and methodo- extinction risk varies as a function of climate;
logical basis of disease mapping, using informa- consequently, the mechanisms causing climate-
tion on landscape and environment, induced population changes are still poorly
mathematical methods, and multivariable analy- understood (van de Pol et al. 2010). Such lack
sis, is well developed and under continuous of knowledge impacts on the capability to make
improvement; however, practical experience are consistent predictions of the population dynam-
extremely limited in mapping diseases at a ics of both hosts and related pathogens.
broader level (nation, area, continent).
The ability to map a disease stems largely
from the type and quality of data that are avail- 2 Natural Focal Diseases
able for mapping. The accuracy of maps is then Mapping and Control: Two
largely determined by the abundance, spatial rep- Paradigmatic Examples
resentativeness and heterogeneity of those data
(Hay et al. 2013). Detection of the hotspots of natural focal
Differences in quality and incompleteness of diseases through the different mapping
initial information make it difficult to obtain a approaches is a key action to better target control
complete picture of the distribution of natural- efforts and to reduce/stop infection transmission
focal diseases within a territory. In particular, in those areas where transmission intensity is
details on disease/pathogen presence or absence higher for several reasons. The identification of
in a given area is limited, due to the limitation of areas and human populations at risk is essential
the surveillance activity in humans, domestic for better address vaccination campaigns and
12 L. Busani et al.

other interventions. However, only few natural In mammal hosts, the prevalence of infection
focal diseases have been studied in detail is poorly investigated, especially in wildlife.
mapping their foci, and vaccines are available Domestic ruminants play a crucial role in the
for few of them. Hereby we report available life cycle of the vector ticks and the transmission
information for two important natural focal and amplification of the virus. In most livestock
viral diseases. species viremia can lasts up to 14 days, thus
immune response starts, and the antibody preva-
lence in those animals is a good indicator for the
2.1 Crimean-Congo Hemorrhagic presence of CCHFV in a region. Recent studies
Fever: A Mapping Exercise conducted in different regions of Bulgaria and
Turkey showed an overall prevalence in domes-
Crimean-Congo hemorrhagic fever (CCHF) is a tic ruminants between 26 and 57%, but in some
tick borne disease characterized by fever and areas the prevalence was up to 90% (Mertens
hemorrhagic manifestations, with fatality rates et al. 2016). The potential usefulness of small
up to 30%. The disease was initially described ruminants as indicator animals to determine the
by Russian scientists in the ‘40s, while the virus presence or absence of CCHFV in a given region
was isolated the first time in the Democratic is also highlighted by Schuster et al. (2016), who
Republic of Congo some years later. CCHF pointed out also the limited knowledge about the
virus (CCHFV) circulation has been reported mechanisms governing the dynamics of CCHFV
throughout broad regions of Africa, Europe, the circulation in a suitable habitat and the role of the
Middle East, and Asia, with a geographic distri- various animals. Such circulation is linked
bution overlapping that of the Hyalomma tick, variables like age of the animals, with
the main vectors of CCHFV. CCHFV is one of dimostration of increasing antibody prevalence
the most geographically widespread tick-borne by increasing age of the tested animal population
pathogens of medical importance and may spread (Wilson et al. 1990; Barthel et al. 2014) hus-
to new areas if globalization and climate changes bandry conditions, usage of repellents, host-
create new opportunities for virus introduction preferences of the ticks and susceptibility of ani-
and amplification in suitable ecological niches mal species and breeds for CCHFV.
(Hewson 2007) (Papa et al. 2015). Large ungulates and livestock are usually
CCHF is considered a disease with natural asymptomatic and only active testing can show
focality, since the CCHFV is maintained in infection in these species. Because the lack of
active foci through a complex cycle that involves symptoms in animals and the short life-cycle of
ixodid ticks, mainly of the genus Hyalomma Hyalomma ticks, without active virological and
(the role in nature of other tick species in the serological surveillance in animals and ticks it is
natural transmission or maintenance of CCHFV unlikely to detect infection in animals earlier
is not clearly demonstrated) and reservoir hosts than in humans. Thus, the detection of human
(e.g. wild and domestic ungulates, domestic live- cases is often the first sign of CCHFV circulation
stock), on which adult ticks feed. Also other in an area.
mammals (rodents, pets) and birds can play a Mapping of the human cases is a way to rep-
role in the spread and maintenance of the virus resent the CCHF distribution. The World Health
transmission cycle. Organization (WHO) produced maps of the dis-
Little is known about the infection rates in ease at global scale, (http://www.who.int/csr/dis
both vectors and hosts in nature. In Hyalomma ease/crimean_congoHF/Global_CCHFRisk_
ticks, prevalence of infection is estimated to be 20080918.png?ua¼1), but this map represents
about 5%, but large geographical variability merely the reported occurrence of human disease
exists, due to local environmental conditions, rather than the distribution of the virus. This is
and to presence and abundance of the different due to the characteristic of the surveillance
types of hosts. (capacity to detect human cases in different
How to Tackle Natural Focal Infections: From Risk Assessment to Vaccination Strategies 13

countries/areas, underreporting, underdiagnosis); carried out due to the costs and the difficulties
the disease (a variable but relevant proportion of to establish reliable surveillance activity in
cases are subclinical, and this proportion may animals, especially in wildlife. Serological
vary in different geographical areas); specific surveys in livestock have been conducted in dif-
local conditions, like in Spain, where virus circu- ferent countries, providing snapshots of the cir-
lation was detected in ticks since 2010, but no culation of the virus in domestic animals (Adam
human cases were observed until the summer of et al. 2013; Lotfollahzadeh et al. 2011).
2016 (Estrada-Peña et al. 2012; Garcı́a Rada Surveys in ticks have also been carried out to
2016). identify areas with potential virus circulation.
A new perspective on the use of occurrence Recent experience of systematic tick surveillance
data, which was firstly developed for dengue by demonstrated the recent colonization of the con-
Bhatt et al. (2013), has been then applied to tinental France by H. marginatum; this region
CCHF by Messina et al. (2015). This approach was considered free from the tick (Vial et al.
is based on the creation of a large database by 2016).
assembling contemporary data on CCHF occur- In Europe, ticks are the most important
rence together with geographical location and a vectors of human and animal infectious diseases,
suite of environmental covariates. Such data and transmit more pathogens than any other
have been collected from many different sources arthropod (Jongejan and Uilenberg 2004;
of information, including the reporting of official Colwell et al. 2011). Monitoring of ticks requires
surveillance systems, the scientific and technical integrated approach, with expertise in environ-
literature and informal online resources. New mental science and entomology as a complement
modelling approaches are then applied to the to the human and animal health competencies.
large dataset to maximise the predictive power
of occurrence data. As a result, high resolution
spatial map of the probability of occurrence of 2.2 A Vaccine for CCHF: Give
human CCHF infection can be derived at global Prevention a Chance
level (Messina et al. 2015).
An example of successful modelling approach Initial attempts to develop CCHF vaccines goes
is the prediction of CCHF expansion in Western back to the 1960s, when Soviet scientists
Palearctic made by Estrada-Peña et al. They advocated the immunization of local populations
developed a dynamic model for CCHFV trans- in endemic areas. In 1974, the Soviet vaccine
mission in western Palearctic that considered the was licensed in Bulgaria. This inactivated virus
tick vector, Hyalomma marginatum and the vaccine is the currently only available CCHFV
effects of variations in temperature and water vaccine, however its clinical efficacy was not
vapour on hte tick survival (Estrada-Peña et al. clearly demonstrated (Mousavi-Jazi et al. 2012).
2013). The main outcome was that increase of More modern approaches, such as DNA
the temperature is compatible with the spread of vaccines, recombinant viral protein-based
CCHFV in the western Palearctic, because vaccines, and virus-like particle vaccines, are
expansion of the habitat suitable for tick vectors. under development. The lack of suitable animal
According to this scenario, increased virus circu- models in the past has hampered the develop-
lation would happen in sites where high tick ment of new, preventive, and therapeutic
populations may already exist. This scenario measures. In a recent study, IFNAR-/- mice was
was confirmed by the occurrence of a human found to be highly susceptible to the Turkey-
case in Spain in 2016 (Garcı́a Rada 2016). Kelkit06 strain of CCHFV. Immunization with
Combination of surveillance in humans, host the cell culture based vaccine elicited a signifi-
animals, and vectors is much more informative cant level of protection against high dose chal-
of the distribution of the virus and the areas at lenge (1000 PPFU) with a homologous CCHFV
risk of human exposure; however, it is rarely in IFNAR-/- mice (Canakoglu et al. 2015). The
14 L. Busani et al.

Bulgarian vaccine was used in CCHFV-endemic human exposure to infected ticks. In addition,
areas of the country for military personnel and however, the establishment of new natural foci
medical and agricultural workers over 16 years of TBE virus circulation has been described in
of age. None of the vaccinated military personnel areas previously considered free of TBE. In
has contracted CCHF, and none of the vaccinated Europe, Austria had the highest recorded mor-
laboratory personnel working with CCHFV bidity for TBE, with several hundred
became infected even after occasional exposures hospitalized patients per year and several deaths
by needle (Keshtkar-Jahromi et al. 2011). How- (Kunz 2003). A vaccine against TBE became
ever, detailed information on vaccination commercially available in 1976 and was
strategies adopted to reduced the burden of dis- administered to those at higher risk (e.g., people
ease in endemic foci and their possible outcome handling the infectious virus in the laboratory
are not available. The availability of other effec- and professional people working in forests in
tive and safe vaccines would represent a great highly endemic regions). Following the evidence
opportunity and needs to be considered in pre- of a limited impact of vaccination of at risk
paredness plans and control strategies, along groups only, mass vaccination campaign
with public information and behavioral organized by the Austrian Health authorities
prevention. began in 1981. The vaccination coverage of the
Austrian population increased from 6% in 1980
to 82% in 2013 and has exceeded 90% in some of
2.3 Tick Borne Encephalitis: Vaccine the high-risk areas. The increasing vaccination
Use to Control a Natural Focal coverage led to a steady decline in the number of
Disease TBE cases, that are ten times less than the 1976,
in addition, between 2000 and 2011, an estimate
Tick-borne diseases (TBDs) are among the most of 4000 hospitalized TBE cases were prevented
rapidly expanding infections worldwide. Many by vaccination (Heinz and Kunz 2004; Heinz
new human tick-borne pathogens are discovered et al. 2013). These results have been achieved
and several novel TBDs are recognized. Increas- thanks to the high awareness among the Austrian
ing burden of TBDs shows that current available population and the large use of an effective and
public health interventions and approaches are well-tolerated vaccine (Kunz 2002). However, it
not effective enough. Vaccination could be a could be challenging to maintain a high vaccina-
highly cost-effective intervention for preventing tion coverage in the future. Moreover,
TBDs (Šmit and Postma 2016). Among TBDs for recommendations to people visiting affected
which vaccines are currently available, tick- areas should be delivered, since pathogens and
borne encephalitis (TBE) is one of the most vectors are still there.
widespread in Europe. TBE can affect the central
nervous system, which may result in long-term/
permanent neurological sequelae or even death 3 Conclusions
(Dumpis et al. 1999). At the European level, TBE
presents an increasing public health concern with The importance of natural focal diseases has
vaccination against TBE less widely used than been largely neglected for a long time. However,
possible to reduce the disease burden (Šmit and the expansion of foci characterized by intense
Postma 2016). TBE incidence shows strong viral activity, even in previously free areas, has
annual variations as well as long fluctuations raised the attention on this threat. Viral diseases
over time in affected countries, and an overall like CCHF and TBE, initially restricted into
upsurge has been reported in certain parts of small geographical niches, have now an impor-
Europe. These changes have been related to cli- tant impact on human health in several areas of
matic, ecological, environmental and socioeco- the world. In some cases, although it may appear
nomic factors that can lead to an increased risk of paradoxical, mass vaccination campaigns have
How to Tackle Natural Focal Infections: From Risk Assessment to Vaccination Strategies 15

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