Introduction
Numerous diseases are transmitted by arthropod vectors, and for many of those diseases,
effective vaccines are still not available. The contribution of the vector to the
process of pathogen transmission is often overlooked, despite providing new avenues
for combating vector-borne diseases, some of which could complement and significantly
enhance ongoing efforts. To explore novel approaches to fighting vector-borne diseases,
the National Institute of Allergy and Infectious Disease (NIAID) convened a workshop
with experts in parasite immunology, vector biology, and entomology (listed in Table
1), who discussed possibilities of translating these basic research ideas into potential
commercial products. The feasibility of product development was analyzed for four
types of approaches: the use of vector-derived factors, such as arthropod saliva,
as vaccine candidates to prevent transmission; the evaluation of bioactive vector
saliva proteins as novel drugs; the use of vector saliva molecules as biomarkers of
vector exposure; and the modification of the vector microbiome to alter vector competence.
Some of these approaches are highly promising, some are already quite advanced, and
all have the potential to significantly reduce the transmission of vector-borne diseases.
However, the discussions also revealed significant regulatory and market challenges
in the path toward a commercial product, even for the most promising approaches.
10.1371/journal.pntd.0004107.t001
Table 1
Names and affiliations of speakers at the NIAID meeting “Arthropod Vectors and Disease
Transmission: Translational Aspects” held May 2014.
Speakers
Affiliation
Title of Presentation
Shaden Kamhawi
NIAID, NIH
Development of a Leishmania vaccine
Maha Abdelahim
NIAID, NIH
Sand fly saliva as adjuvant
Iliano V. Coutinho-Abreu
University of California, Riverside
Translation of sand fly saliva to a vaccine
Jose Ribeiro
NIAID, NIH
From bugs to drugs—a translation story
Anne Poinsignon
Institut de recherche pour le développement (IRD), Montpellier, France
Salivary factors to activate P. vivax hypnozoites
Joao Pedra
University of Maryland
Tick saliva and NLR signaling: A potential for therapeutics
Frank Remoue
Centre de Recherche Entomologique de Cotonou (CREC), Benin
Salivary factors as biomarkers
Andre Sagna
Espoir pour la Sante, Sénégal
Salivary factors as biomarkers for infectious bites
Zeljko Radulovic
Texas A&M, USA
Vector factors and immunomodulation: Potential source for immunotherapeutics
George Dimopoulos
Johns Hopkins University, Baltimore
Symbionts: The road to pathogen control
Nathan Dennison
Johns Hopkins University, Baltimore
From mosquito bugs to malaria drugs
Job Lopez
Mississippi State University
Tick saliva: Potential relapsing fever vaccine
Pamela Pennington
Universidad del Valle, Guatemala
Applying paratransgenesis for disease control
Novel Vaccines That Target the Vector, Not the Pathogen
Traditionally, vaccines against vector-borne infectious diseases target antigens expressed
by the infectious agent in an attempt to neutralize the pathogen or, at least, reduce
the disease burden and, thus, reduce morbidity and mortality associated with the disease.
However, a few vaccines instead target pathogen-associated antigens expressed during
life stages of the parasite that are associated with uptake by a vector (e.g., gametocyte)
or development inside the vector. Such transmission-blocking vaccines represent a
distinct second category of vaccines against vector-borne diseases and provide benefit
to the community in an endemic area, not in terms of affecting disease pathogenesis,
but by limiting the spread of the pathogen. A separate category of transmission-blocking
vaccines (vector-targeting, transmission-blocking vaccines) targets molecules inside
the vector, such as the Galectin PpGalec (Table 2) in the midgut of the sand fly [1].
When antibodies in the blood meal of the sand fly’s host bind to these molecules in
the vector’s gut, they interfere with the attachment and, thus, development of Leishmania
parasites. The discovery that vector saliva includes immunosuppressive or immunomodulatory
molecules, which facilitate the establishment of an infection (reviewed in [2]), has
given rise to a third category of vaccines against vector-borne pathogens. The objective
of these vaccines is simple and elegant: Targeting vector saliva molecules that assist
pathogens during infection may either “unmask” the infectious inoculum and allow the
host’s immune system to eliminate it (e.g., tick-borne diseases as reviewed in [3]),
or induce an immune response that interferes with the establishment of an infection
by the vector-borne pathogen (as shown for Leishmania [4,5]). Such vaccines could,
in principle, be effective against multiple infectious diseases transmitted by the
same type of vector and would not be rendered ineffective by mutations in immunodominant
epitopes on pathogen-derived antigens, which conventional vaccines against infectious
diseases target. Despite the identification of numerous potent, immunomodulatory saliva
molecules from a broad spectrum of blood-feeding arthropods, the vast majority of
studies investigating them as vaccine candidates have, unfortunately, not moved beyond
early preclinical studies. Such saliva-based vaccines may have potential as stand-alone
products or, more likely, as an adjunctive component of traditional vaccines against
vector-borne diseases. In the latter case, they may be able to reduce the infectious
inoculum during a blood meal and facilitate recognition of the infectious agent by
the vaccine-primed host immune system. Combining saliva-based with pathogen-based
vaccines [6], though scientifically highly appealing, is, however, significantly more
complicated from a regulatory and intellectual property standpoint, as well as a manufacturing
and formulations standpoint, since it would involve multiple active components.
10.1371/journal.pntd.0004107.t002
Table 2
Accession/ID numbers of proteins mentioned in the article.
Protein
Species of origin
Accession number
PpGalec
Phlebotomus papatasi
GenBank AAT11557.1
gSG6
Anopheles stephensi
GenBank AAO74842
LJM11
Lutzomyia longipalpis
GenBank AAS05318.1
SP32
Phlebotomus papatasi
GenBank AFY13225.1
Ixolaris
Ixodes scapularis
GenBank AAM93647.1
Of all vector saliva-based vaccines, those designed to prevent leishmaniasis are the
most advanced. Leishmania infection represents an excellent choice for a first-in-class
vaccine targeting the vector for the following reasons: an effective human vaccine
against leishmaniasis is still not available; it is a widespread, albeit neglected,
tropical disease; and the vaccine does not necessarily have to be administered to
humans, since it could be used to target other mammalian hosts such as dogs in an
effort to reduce transmission from animal hosts to humans. An approved and effective
veterinary vaccine would also represent a significant stepping stone for the subsequent
development and approval of a human vaccine. The lower regulatory bar for veterinary
vaccines, and particularly for animal species not used for meat production, makes
the targeting of animal reservoirs—rather than human hosts—an attractive approach.
Research on sand fly saliva as a vaccine against Leishmania parasites has yielded
valuable insights into the mechanism of protection mediated by vector antigen-based
strategies: unexpectedly, protection by such vaccines is mediated not by neutralizing
antibodies against the targeted saliva antigens, but by a Th1-biased delayed-type
hypersensitivity (DTH) response capable of preventing vector-transmitted leishmaniasis
in mice, hamsters, dogs, and primates. In these animal models, the protective immune
response induced by the vector saliva-based vaccine broadened after parasite challenge
to also include immunity against Leishmania antigens, thus representing a unique and
highly desirable form of epitope spreading.
While saliva antigen-specific antibody responses were found not to be relevant in
the case of Leishmania infection, would it still be useful to develop vaccines that
primarily induce a humoral response? Anti-saliva vaccines may be used to target saliva
proteins essential for blood feeding to reduce the size of the blood meal. In theory,
this would interfere with the ability of the vector to obtain a full blood meal, resulting
in reduced egg production and, thus, decreasing the vector population. Whether such
a strategy would result in vectors seeking more, but smaller, blood meals would need
to be addressed carefully, since it may result in an inadvertent increase in disease
transmission. This strategy may also be more appropriate for ticks rather than winged
and more mobile vectors.
A number of useful insights have been gained in the area of research on vector factor-based
vaccines: (1) Despite considerable progress in characterizing vector saliva components,
finding the most appropriate vaccine candidate(s) in a complex mixture of saliva proteins
is a highly empirical process, especially when the (immunological) function of individual
proteins is not known. This slows the development of new vaccines, and represents
a challenge for academic researchers to develop appropriate assays to screen candidates
for functional responses. (2) The identification of the ideal vaccine platform, as
well as a suitable adjuvant, to deliver a vector-derived antigen will require extensive
basic research, because it is unknown what type of immune response against the vector
antigen is protective. (3) One reason for vaccine failure in field trials against
infectious diseases (e.g., malaria) has been the heterogeneity of the target antigen
expressed by different strains of the pathogen. It will be important to avoid a similar
shortcoming of vector-antigen vaccines by determining the variability of the antigen
between vector subspecies found in the area where the vaccine will be deployed. (4)
Molecular mimicry is a relatively common phenomenon and represents an immune escape
strategy used by various pathogens. The expression of pathogen-derived antigens that
resemble host proteins has been linked to autoimmune diseases after exposure to certain
pathogens, such as systemic lupus erythematosus (SLE) following malaria infection
or Chagas disease following infection with Trypanosomes [7,8]. Proteins in vector
saliva, however, have been under little to no evolutionary pressure to avoid the immune
system of host species by using molecular mimicry, thus eliminating concerns about
their potential to break immunological tolerance to structurally similar host proteins—and
induce autoimmunity—when used as vaccine candidates.
Immune Responses to Saliva Proteins As Biomarkers of Exposure
The vertebrate host mounts an antibody response to at least certain arthropod saliva
proteins, providing a “signature” or “record” of prior—and mostly recent—vector exposure,
despite the minute amounts of saliva injected into the bite site, and despite the
host’s suppressed immune response to the inoculum. It remains unclear if these antibodies
significantly affect the ability of the vector species to obtain an efficient blood
meal or interfere with a vector-borne infection since certain saliva proteins clearly
aid during the initial stages of infection. It is possible that the subtype or specificity
of those naturally induced anti-saliva antibodies is significantly different from
those induced by a saliva protein-based vaccine. Nevertheless, the bite-induced humoral
response represents a useful indicator of bite frequency. Humoral responses against
saliva proteins correlate well with the extent of exposure at a population level and
can, therefore, be used as an objective method to assess the usefulness of vector-control
measures. While the majority of susceptible animals in an endemic area tend to be
uninfected, the relative rate of infected vectors can easily be determined and, together
with the serological data from those living in the area, be used to estimate the risk
of infection.
What are the practical considerations for using vector-specific antibody responses
as biomarkers of vector exposure? While the heterogeneity of saliva proteins between
vector species limits the broad-based effectiveness of saliva-based vaccines, the
uniqueness of a vector species’ sialiome makes it possible to determine what type
of vector has been feeding on a host. Therefore, vector-specific test kits are feasible
and could be used to estimate the risk of infection from diseases transmitted by a
particular vector species. However, research has clearly shown that measuring overall
IgG responses against whole saliva of a particular vector species, such as Anopheles
mosquitoes, may not be a useful approach. In this case, test kits will need to be
based on individual and carefully selected saliva proteins and/or specific salivary
peptides. An example of such a candidate is gSG6-P1 (Table 2), a peptide from the
saliva of Anopheles. It is found in all Anopheles species, is antigenic (recognized
by specific antibodies) in exposed individuals from major endemic areas (Africa, South
Asia, South America), is unique to the genus, and does not show cross-reactivity with
saliva proteins from other vector species. Exposure markers for sand flies have also
recently been identified, namely LJM11 (Table 2) and LJM17 (Table 2) for Leishmania
lutzomyia [9] and the SP32 (Table 2) protein for Phlebotomus papatasi [10,11]. In
contrast to these vector species, non-fractionated saliva from Glossina morsitans
submorsitans may be a useful reagent for assays designed to determine exposure to
the vector [12]. Thus, the requirements for such test kits will be highly dependent
on the vector species.
The first generation of such vector-exposure kits is already within reach, but they
will not address the question of whether or not vector bites had been infectious.
Determining the frequency of infected vectors in a particular area requires tedious,
manual analysis of captured animals. However, the ratio of infected versus uninfected
vectors counted in the field does not necessarily reflect the frequency with which
the two vectors bite their hosts. To determine the exposure to infectious bites more
reliably and conveniently, it may be possible to take advantage of the fact that infection
can change the saliva composition of the vector (e.g., the changes in tsetse fly saliva
due to trypanosome infection [13]). Therefore, if immunogenic proteins, which are
uniquely associated with the saliva of infected vectors, can be identified, they may
be included in second-generation test kits. With such kits, the ratio of antibodies
against “constitutive” and infection-induced salivary proteins could be used to quickly
and easily determine the relative rate of infectious bites compared to the total number
of bites an individual in an endemic area receives. Such measures of vector exposure
could be supplemented by the measurement of antibody responses to pathogen-derived
antigens, providing a basis for the comprehensive analysis of pathogen transmission.
This would provide a powerful and rapid diagnostic tool to evaluate vector control
measures, vector infectivity, and seasonal changes in both parameters, as well as
allow the geographic identification of infection hotspots for a more targeted deployment
of vector control measures. It would also provide a valuable tool to monitor areas
declared free of a disease, e.g., malaria, after an elimination campaign to be able
to rapidly and effectively respond to any re-emergence of the disease.
Bugs to Drugs
The saliva of blood-feeding arthropods contains bioactive molecules, which have evolved
over the course of more than 100 million years to exert specific pharmacological effects
even when only minute amounts are present at the bite site. They modify the bite site
to facilitate the blood meal, but are also exploited by vector-borne pathogens, which
take advantage of the immunosuppressive environment established by certain saliva
proteins. The vector sialome is an enormous, largely unexplored, and virtually untapped
source of pharmacological agents. Its size is largely due to the fact that blood feeding
was independently invented by multiple vector species, thus giving rise to multiple
sets of evolutionarily unrelated saliva proteins with overlapping functions (e.g.,
anticoagulants, which are used by virtually every vector species).
Vector saliva proteins that can be produced by recombinant expression methods have
a variety of potential applications: Saliva components that function to skew immune
responses (either to a Th1 or Th2 phenotype) may be useful as immunomodulators, for
example, in the treatment of autoimmunity, or as vaccine adjuvants. Several saliva
proteins exhibit immunosuppressive activity, such as Sialostatin L2, which suppresses
inflammatory responses and could be used for the treatment of inflammatory diseases
[14–16]. Salivary glands of sand flies are the source of several anti-inflammatory
molecules, such as LJM111 from saliva of members of the genus Lutzomyia [17], or nucleosides
from the saliva of Phlebotomus, which impair dendritic cell functions [18]. Such molecules
may find applications in the treatment of arthritis and other inflammatory diseases.
Similarly, clinical applications can be envisioned for the many vasodilators, anticoagulants,
cytokine modulators, histamine-binding proteins, complement inhibitors, or Ig-binding
proteins found in the saliva of blood-feeding arthropods. A specific example cited
at the workshop was the treatment of pulmonary arterial hypertension with inhibitors
of tissue factor such as Ixolaris (Table 2) from ticks [19,20]. This particular molecule
has also shown potential as a tumor therapeutic agent and for treating macular degeneration
and arthritis. The potential for using vector saliva factors to combat autoimmune
disease or as immunosuppressive agents after organ transplantation should also be
considered and explored.
What are the potential disadvantages of using saliva protein-based therapeutic agents?
Unlike most small molecules, such foreign proteins will eventually trigger the induction
of neutralizing antibodies, which will limit the duration of their use in an individual
patient. This may be circumvented by taking advantage of the broad variety of evolutionarily
and structurally unrelated saliva proteins from different vectors, which have the
same or similar biological functions. This approach would mimic the strategy of blood-feeding
ticks, which are capable of using multiple gene-loci-encoding saliva proteins with
overlapping functions, but which are immunologically not cross-reactive. Therefore,
despite the extended exposure of the host to tick saliva proteins, no neutralizing
antibodies are induced. Field studies suggest that antibody responses against saliva
proteins triggered by mosquito bites are short-lived [21], but it is not known yet
whether this phenomenon is related to the nature of these proteins or to the small
amounts delivered during a blood meal.
The Vector Microbiome, or “Bio-prospecting Vectors for Microbes of Interest”
Traditionally, efforts to combat vector-borne diseases have focused on either vector
control or the elimination of the pathogen inside the host following transmission
through an arthropod vector. However, both approaches have significant limitations.
Insecticides can be quite effective in eliminating a vector species temporarily and
locally, but this approach is expensive. For example, a nationwide spraying campaign
was conducted in Guatemala starting in 2002 to combat triatomine-transmitted Chagas
disease [22] at a cost of US$10/house, but the impact of the campaign was short-lived.
Long-term application of pesticides harms other species (e.g., honey bees) and results
in the selection of insecticide-resistant vectors. Bed nets protect against blood-feeding
by vectors during peak times of transmission only when properly used and maintained.
Environmental modifications such as the draining of swamps are not feasible everywhere
and are extremely costly, in addition to having potentially devastating effects on
the environment. Finally, repellants only work as long as they are used properly (i.e.,
continuously), thus limiting their usefulness.
Similarly, pathogen-directed therapeutic and preventative measures have numerous limitations.
Drugs targeting the pathogen eventually and inevitably result in the selection of
drug-resistant pathogen strains. They are expensive (particularly for developing countries),
and frequently have undesirable side effects. Vaccines are the most attractive of
all strategies, based on a cost-benefit calculation and the potential to protect against
infection for extended periods of time. However, vaccines against vector-borne diseases
have been largely unsuccessful so far due to insufficient immunogenicity and efficacy.
Furthermore, immune responses against many pathogen-derived antigens are unexpectedly
short-lived. Other reasons for failure in field trials include an insufficient understanding
of the targeted antigen. For example, AMA-1 was thought to be an essential protein
for the invasion of host cells by apicomplexan parasites such as Plasmodium or Toxoplasma
[23], and became the focus of intense vaccine research. However, subsequent studies
demonstrated that the antigen is dispensable for host cell invasion. The sheer complexity
of host-pathogen interactions, including manipulation of the host immune response,
represents a formidable, though not insurmountable, challenge to design effective
vaccination strategies. A valuable lesson learned from trials with the RTS.S malaria
vaccine has been that the efficacy of a vaccine against a vector-borne disease could
be dramatically improved by simply changing the vaccination regimen [24].
Workshop participants discussed an alternative approach to control vector-borne pathogens,
one focusing on a stage of the transmission cycle which has received little attention
until recently—the time a pathogen spends inside the vector. The infection of a vector
and the infectivity of this vector are, to a significant extent, controlled by the
vector’s immune system. This makes the vector’s own immune defense mechanism an attractive
target for intervention, since it may be possible to enhance it to a point where the
vector can either no longer be successfully infected or can eliminate the pathogen.
A major obstacle in developing such strategies is the highly limited understanding
of the arthropod immune system. A recommended solution was to enhance integration
of research on the immune system of vectors and Drosophila, with the latter being
significantly more advanced.
What approaches could be used to make vectors pathogen-resistant? Two strategies were
discussed: First, it is possible to engineer vectors that constitutively over-express
immune defense genes. Unfortunately, the constitutive expression of such genes results
in a variety of issues that affect the health and survival of such animals in the
field. However, by placing the vector’s immune defense genes under the control of
promoters from genes that are activated by blood feeding, the vector’s immune status
could be temporarily enhanced following a blood meal that contains the pathogen. As
with any genetically-modified species, it is essential that a modification will not
affect the animals’ life span, fecundity, or overall fitness. Any negative impact
on those parameters, even if very minor, will prevent the modified vectors from replacing
the wild type population and potentially doom the success of an expensive release
of these organisms. Inevitably, this requirement will raise safety concerns, since
the modified population could no longer be controlled after release, which raises
the bar for safety studies and increases regulatory scrutiny.
The second strategy is based on replacing the vector’s microbiome with microorganisms
that impact the vector’s pathogen load [25]. This approach has already been explored
in field trials. Replacement microbiota may represent unmodified microbial species
that normally do not colonize a particular vector species, or genetically engineered
symbiotic bacteria [26]. Various distinct mechanisms can mediate the inability of
the vector to transmit pathogens: (1) The newly introduced microorganism may directly
affect the pathogen’s ability to colonize the vector and survive in it (e.g., anti-Plasmodium
effector proteins produced by Pantoea agglomerans [26]). (2) The vector’s immune system
may constitutively respond to the presence of the animal’s microbiome, thus ramping
up the immune status of the vector (e.g., by Enterobacter cloacae [27]). (3) The microorganism
may shorten the vector’s lifespan and thus interfere with the transmission of pathogens
that require a relatively long period of development in their arthropod host (e.g.,
Wolbachia pipientis wMelPop, which blocks Dengue transmission through this mechanism
[28]). The first two phenomena are not restricted to arthropods, but have also been
observed in vertebrates, including humans. The potential for blocking disease transmission
by altering the vector microbiome has received considerable attention in recent years,
following the high-profile releases of vectors carrying modified microbiota; specifically,
Aedes aegypti mosquitos infected with a mosquito-adapted Wolbachia strain obtained
from Drosophila have been successfully released in Australia and other countries to
control dengue transmission. This strategy successfully interferes with the transmission
of Plasmodium [29] as well as other vector-borne pathogens. Data from large-scale
releases indicate that the approach appears to be safe and does not appear to have
unintended negative side effects. Since Wolbachia is a ubiquitous microorganism, no
new organism is being introduced into the environment by this strategy.
A vector’s microbiome can be altered either through the stable “conversion” of vector
populations in the wild or by introducing the desirable microbiota through bait stations,
which allows for a continuous modification of vector populations. The latter approach
is particularly useful for microbiota, which are not (or only poorly) transmitted
horizontally, or vertically. The bait has to be cheap and designed for a particular
vector species (e.g., CRUZIGARD is specific for Rhodnius by simulating feces; Anopheles
bait offers sugar water or nectar). Alternatively, lab-generated (paratransgenic)
colonies of vectors are released with the objective of eventually pushing out the
naturally-occurring populations. The latter approach, while technically more attractive,
faces significant hurdles in part because the necessary regulatory framework does
not yet exist, and because of public resistance when the released vector species is
perceived to be a genetically modified organism.
Wolbachia is particularly suitable as a “replacement microbiome” since it is efficiently
transmitted between mosquitoes and, thus, easily maintained in the vector population
after release. However, there are likely many more useful microbial species that simply
have not yet been explored. They may be used by themselves or as part of a microbiome
cocktail (together with Wolbachia) to further improve the effectiveness of this strategy,
and as the “replacement microbiome” for additional vector species. The analysis of
novel microbiota that prevent the pathogen colonization of vector species may also
accelerate the identification of novel therapeutic agents, such as an antifungal cyclic
dehydropeptide lactone isolated from Aeromonas [30]. This approach to identify novel
therapeutics against infectious diseases may be more attractive than the currently
used screening of (existing) libraries of chemical compounds for several reasons.
First, compounds produced by bacteria with antimicrobial activity have been evolutionarily
selected and optimized and, second, a highly relevant and relatively inexpensive in
vivo screening system is already available in the form of the vector animal [31,32].
Product Development: Lessons for the Field of Vector-Based Intervention
The process of “translating” exciting scientific ideas into tangible products begins
with a simple acknowledgment—that the motivations and goals of basic scientists differ
from those involved in the business of developing products. Numerous non-scientific
aspects need to be considered and addressed before advancing a promising scientific
discovery, such as those discussed above, into the pathway for product development.
Most of these translational considerations are pragmatic ones and require a fundamentally
different mindset than that found in basic research, which often seeks to explore
and pursue new ideas. By contrast, business development is driven by cycles of planning
and risk assessment designed to anticipate known problems that are often encountered
by product developers. There are a few basic guidelines that may be helpful to those
seeking to go beyond the bench and into the world of translational development.
First, it is important to clearly articulate the properties and anticipated uses of
the product—the so-called “target product profile.” This helps focus early discussions
on the attributes (intended use, target population, potency, specificity, stability,
tolerability, ease of manufacture, etc.) that the product must have to be successful.
For example, for a vector saliva-based product, the considerations may include the
following: Is the target population humans or an animal host which serves as a reservoir
for the pathogen (e.g., dogs in the case of Leishmania)? Is the salivary antigen highly
variable between vector species from different geography areas? Is it enough to include
one protein in the vaccine or should multiple antigens be targeted to increase efficacy
and overcome potential variability? What vaccine adjuvant is required to obtain an
effective immune response, and has that adjuvant previously been used in humans? Although
potentially essential for obtaining adequate immunogenicity, a human vaccine that
includes both a novel antigen (i.e., vector saliva proteins) and novel adjuvant (i.e.,
adjuvants not part of a licensed vaccine) will face more regulatory scrutiny. Can
the formulated vaccine be stored at 4°C, does it have to be stored frozen, or is bedside
mixing of components required? The latter two significantly complicate deployment
and delivery.
Second, it is crucial to identify a suitable customer or a collection of stakeholders
for the novel product, since the end-users (inhabitants of endemic areas in developing
countries, for most of the innovations discussed here) may not be able to afford even
reasonably priced products. Therefore, it is necessary to determine at the outset
the level of interest by potential benefactors and/or investors (government agencies,
non-governmental organizations [NGOs], or companies), a challenging process that requires
a significant outreach effort.
Third, a major consideration influencing product feasibility is the regulatory path
that will be required. In some cases adequate precedent exists, based on similar products
and their intended uses. In the case of saliva-based vaccines, challenges include
the fact that there are no licensed (human) vaccines yet that are based on vector
saliva, although a veterinary vaccine against tick-borne pathogens (TickGARD) has
been on the market for many years. Furthermore, a vector saliva-based vaccine may
require an adjuvant that had not previously been used in a vaccine licensed for use
in humans. Using technologies already in place can accelerate the process of commercializing
a novel approach. For example, for the continuous introduction of novel microbiota,
it is advisable to explore the usefulness of already available bait stations. For
novel diagnostic kits, it is advisable to determine whether commercially available
testing kits could be modified. The benefit of a smoother commercialization pathway
is, however, partially offset by the need to enter into licensing agreements with
the intellectual-property owners of the platform technology in question. In those
cases where a truly novel solution is proposed, substantial early discussion and negotiation
with regulators may be required; a case in point might be the introduction of vectors
with modified microbiomes for which no regulatory framework exists in most countries.
Finally, most research scientists have limited or no business experience. When taking
a new invention to market, it is essential to find a business partner to share the
responsibilities of product development. An experienced businessperson will likely
bring other issues forward, including competitive advantage over existing products,
macroeconomics, marketing strategy, and long-term sustainability of the market. Concepts
like these are often viewed as unfamiliar and uninteresting by research scientists,
but they may determine if a good scientific idea actually makes good “business sense.”
The juxtaposition of these world views requires that scientific investigators relinquish
some control over the innovation and not attempt to micromanage the product development
process.
Even if one is able to find sponsors for a novel product and overcome the major scientific,
technical, and regulatory hurdles, a new product to combat vector-borne diseases may
face yet another set of challenges: the cultural and ethical standards of the environment
where it will be used and deployed. Even products that are approved by regulatory
agencies may not be aligned with the cultural norms required for acceptance of these
new approaches, as the experience with genetically modified organisms has shown. It
should be expected that novel technologies and approaches will elicit concerns and
apprehension in the target population. Outreach, advocacy by local leaders, and education
of the intended population very early in the process of deploying the new technology
can make the difference between successful engagement and rejection. The issues surrounding
product commercialization and sustainment represent a daunting challenge, but not
an insurmountable one. What is needed is an appreciation of the careful planning needed
to anticipate and overcome key risks and the many factors that contribute to achieving
success.
Key Learning Points
Numerous infectious diseases are transmitted by arthropod vectors, and effective vaccines
against these diseases are still lacking.
Vector-derived molecules such as saliva proteins are actively involved in the transmission
process and are attractive targets for the development of novel vaccines against vector-borne
diseases, since protection cannot be bypassed through mutations in pathogen-associated
proteins and since they may prevent infection rather than inducing an immune response
against an establishing or established infection.
Antibody responses to vector saliva proteins are reliable indicators of the exposure
to vector bites and can, for example, be used to monitor the effectiveness of vector-control
strategies.
Because of their potent biological activities, vector saliva proteins are being explored
as novel pharmaceuticals, for example, as anticoagulants or immunomodulators.
The microbiome of the vector significantly influences the ability of pathogens to
be transmitted by vectors. Replacing, or adding to, a vector population’s microbiome
with appropriate microbiota (such as Wolbachia) can significantly reduce transmission
rates of vector-borne diseases.