英语A of B结构的中心词怎样确定?比如:A vaccine will rid the world of malaria.想知道更多人的讲解.没人回答了吗?_百度作业帮
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英语A of B结构的中心词怎样确定?比如:A vaccine will rid the world of malaria.想知道更多人的讲解.没人回答了吗?
想知道更多人的讲解.没人回答了吗?
world为中心词,of malaria类似于中文中的定语成分.例如 the responsibility of your job .responsibility为中心词
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This article is part of the supplement:
Is vaccine the magic bullet for malaria elimination? A reality check
Roma Chilengi* and Jesse Gitaka
Corresponding author:
KEMRI-Wellcome Trust Research Programme, P.O. BOX 230, Kilifi, Kenya
University of Oxford, Nuffield Department of Health, Centre for Clinical Vaccinology and Tropical Medicine, UK
For all author emails, please .
Malaria Journal 2010, 9(Suppl 3):S1&
doi:10.75-9-S3-S1
The electronic version of this article is the complete one and can be found online at:
Published:13 December 2010
& 2010 Chilengi and G licensee BioMed Central Ltd.
This is an open access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Malaria remains a major health burden especially for the developing countries. Despite
concerted efforts at using the current control tools, such as bed nets, anti malarial
drugs and vector control measures, the disease is accountable for close to a million
deaths annually. Vaccines have been proposed as a necessary addition to the armamentarium
that could work towards elimination and eventual eradication of malaria in view of
their historical significance in combating infectious diseases. However, because malaria
vaccines would work differently depending on the targeted parasite stage, this review
addresses the potential impact various malaria vaccine types could have on transmission.
Further, because of the wide variation in the epidemiology of malaria across the endemic
regions, this paper proposes that the ideal approach to malaria control ought to be
tailor-made depending on the specific context. Finally, it suggests that although
it is highly desirable to anticipate and aim for malaria elimination and eventual
eradication, many affected regions should prioritize reduction of mortality and morbidity
before aspiring for elimination.
Background
Malaria transmission is falling in some parts of Africa as anti-malarials, bed nets
and other vector control measures become more widely available [-]. However, malaria disease continues to be a major public health disaster with persistent
transmission in vast areas and it is clear that additional control measures are required.
Indeed epidemiological data indicates that malaria is still a global health priority
and the statistics of estimated 5 billion people exposed and close to 1 million deaths
year remain valid [-]. This is especially important in the vast parts of sub-Saharan Africa where the social
and ecological environments render current control tools blunt. Recent successes in
malaria control using other approaches highlight the need and the potential impact
that could be gained from an efficacious vaccine [-]. Historically, vaccination has proved to be one of the most effective approaches
to controlling infectious diseases and many authorities believe that it will not be
possible to move from control to elimination without the addition of a malaria vaccine
to the armamentarium []. However, despite concerted international efforts, an efficacious vaccine against
malaria remains elusive.
The leading malaria vaccine candidate in development RTS,S, which is currently undergoing
phase III field evaluation in African children, has progressed based on demonstrated
efficacy against clinical malaria recently reported to be around 50% in the field
[]. This good news of a possible vaccine against malaria in the foreseeable future has
revived the possibility of enhanced malaria control and perhaps incited the call for
malaria elimination and eventual eradication. However, it is important to examine
current aspirations for malaria elimination in the light of key historical experiences
and scientific facts.
Following the Eighth World Health Assembly resolution on transition from malaria control
to its eradication, interruption of malaria transmission was achieved in many countries
of the temperate belt, and mortality from the disease decreased dramatically. By 1970,
about 1 billion people were freed from the risk of malaria, but it had already become
clear during the 1960’s that the available methods of control would not interrupt
malaria transmission in tropical Africa [-]. The point of note here is that expectations from control measures ought to be based
on the realistic possibility of what available tools can achieve. Figure
describes the relevant key terminology applicable to malaria elimination.
Definitions of key terminology.
How would a vaccine against malaria affect transmission?
Transmission can be expressed in terms of simplified mathematical models based on
easy to visualize parameters, the most useful of which is the Macdonald model []. This model describes the concept of basic case reproduction rate (R0), which, in short, is the number of secondary cases arising from a single case in
a fully susceptible human population. It is a tool for understanding and a way of
thinking, but it cannot be accurately applied in field situations []. Based on the possible transmission dynamic factors in the Macdonald formula, this
review looks at the potential impact of vaccines targeting the various malaria parasite
stages would have on the basic case reproduction rates.
shows the Macdonald mathematical formula and the summarized meaning of the basic
reproduction rate R0.
The Macdonald mathematical formula.
Pre-erythrocytic vaccines
Ideally, pre-erythrocytic vaccines would induce some form of sterile protection that
prevents infection by the sporozoite beyond the liver stage [,-]. However, a review of the global malaria vaccine pipeline [] shows that all the current candidate vaccines have a profile aiming at “partial protection”
against malaria episodes meaning that at best, they would not completely interrupt
the malaria parasite cycle in all vaccinees. The irradiated sporozoite vaccine approach
is thus far the only one that has shown to be highly efficacious at protection of
humans as well as animals, but this protection is yet to be demonstrated in malaria
endemic populations [,]. The most advanced candidate vaccine RTS,S recently showed an adjusted efficacy against
clinical episodes of malaria at 53% (95% CI 28-69; P&0.001) in Kenyan and Tanzanian
children [].
Such pre-erythrocytic stage vaccines would impact transmission by reducing both “b” and “h” and thus overall, reduce R0 by a proportion that could possibly correlate to its protective efficacy. It is difficult
at this stage to assume that such an impact will roll on to either affect the length
of the sporogonic cycle or survival rate in mosquitoes. What is apparent however,
is that other control measures, such as ITNs [,-], use of repellants [,], indoor residual sprays [,] and indeed prophylactic anti-malarial drug usage [-], would be synergistic to pre-erythrocytic vaccine effects. In the Macdonald model,
these control methods would contribute to reductions in R0 by additionally pulling both “a” and “m” lower and ultimately shrinking “h” which respectively, are the frequency of mosquito bites, female mosquitoes per person
and proportion of humans actually infectious.
Blood stage vaccines
According to the WHO’s malaria vaccine Rainbow tables, there are currently at least
15 different sub-unit candidate vaccines targeting the parasite asexual (blood) stages
in clinical development []. There are several hypothesized mechanisms through which asexual stage vaccines may
function: that antibodies bind parasite antigens to sufficiently agglutinate and prevent
release of merozoites, or block invasion of erythrocytes leading to protection against
clinical disease and/or its severity [-]; that vaccines such as MSP3 and GLURP would induce cytophilic classes of antibodies
killing parasites with help from monocytes [-]; and that others (such as PfEMP1, Rifins, Pf332) would enhance splenic clearance
or complement mediated lysis, or diminish parasite nutrition and growth or reverse
endothelial adherence and glycoprotein binding to result in prevention of toxic effects
In essence, these vaccines are expected to prevent manifestation, or limit the severity
of clinical malaria disease in immunized individuals, when they get infected. This
was well illustrated in the results of the trial of malaria vaccine Combination B
in Papua New Guinea, which demonstrated a 62% (95% CI 13-84) reduction in parasite
density in children but no effect on infection and in fact, a higher incidence of
morbid episodes associated with the variant parasites (with FC27-type) not covered
in the vaccine []. One major foreseeable challenge for vaccine candidates targeting the blood is strain-specificity
of the vaccines antigens and the extent to which they would cover parasite polymorphisms
encountered in field coupled with the variability displayed in the cell invasion pathways
P. falciparum[-].
On the transmission front however, we can expect infections to continue within a vaccinated
population for several transmission cycles. The variables m, a, b, and P in the Macdonald’s formula would be unaffected (at least during the first encounter
following deployment of the vaccine). The proportion of humans actually infectious
“h” would be reduced while the recovery rate “r” would greatly increase. All factors remaining the same, it is plausible that “b”, the sporozoite bites resulting in human infection, would be reduced by the next
generation of parasites and eventually reduction in “b” would substantially contribute lowering R0 within the vaccinated population. The standard control measures of early diagnosis
and effective chemotherapy would greatly enhance this impact [-,,]. Current recommendations to use two or more blood schizonticidal drugs with independent
modes of action and different biochemical targets aims at both improving the efficacy
and retarding the development of resistance to the individual components of the combination.
This concept has been realized in multiple-drug therapy for leprosy, tuberculosis
and cancer and, more recently in antiretroviral treatments. In malaria, this has also
been the approach with the development of such drugs as sulphadoxine-pyrimethamine,
atovaquone-proguanil, mefloquine-sulphadoxine-pyrimethamine and lately artemisinin-based
combinations. In the context of reducing malaria transmission, drugs that are implicated
in gametocytogenesis, such as sulphadoxine/pyrimethamine [] may actually enhance transmission by causing an increase in “h”; the proportion of humans actually infectious.
Sexual stage vaccines
Vaccines targeting the sexual stages of the parasite are termed transmission-interrupting
vaccines because they would stimulate antibodies that inhibit exflagellation and fertilization
of gametocytes, that render them non-infectious for the mosquitoes when taken up during
a blood meal []. Antibodies could also block the process by which ookinetes develop into oocysts
and prevent transmission of infectious sporozoites to humans [-]. Examples of potential vaccine antigens like this include Pfs25, Pfs48/45 and Pfs230.
Currently, there is no candidate vaccine targeting this stage that has made it to
clinical field evaluation, but there are two candidates in pre-clinical evaluation,
both of which are based on Pfs 25 [].
The hallmark of this category of vaccines is that they would have no immediate clinical
benefit to recipients in terms of protection against malaria infection and disease,
but will benefit the wider community [,]. In terms of transmission model dynamics, if transmission-blocking vaccines are effectively
and completely deployed in a population viewed as a homogeneous compartment, they
would disrupt transmission by shrinking “P”, the survival rate in mosquitoes. By the next generation of parasites, the proportion
of humans actually having the infection “h” as well as the survival rate in mosquitoes “P” would be remarkably lowered. The key challenge to vaccine development here is that
entire populations would have to be immunized and the vaccine effects should last
through several transmission cycles. However, other vector control measures including
ITN use, in-door residual spraying, use of repellents as well as adverse climatic
conditions against the mosquito vector (such as drought) would greatly enhance these
effects as earlier discussed.
Gauging the expectations
From an epidemiological view point, progress towards malaria elimination can be viewed
in terms of reduction in disease specific at reductions in the
ov the extent to which a d proportion to
elimin and then eradication and ultimately extinction as shown
in Figure .
Expression of stages of malaria control towards eradication.
Aspirations for malaria elimination and eventual eradication should indeed be the
vision or ultimate goal of any malaria control programme. However, while grappling
with high case fatality rates, overwhelming disease burden and failure to implement
or sustain available control measures, it may be too optimistic, if not unrealistic
to consider elimination issues in many contexts in Africa. Figure
illustrates in a simplified way, the stages at which malaria endemic regions may
be placed depending on the level of control, or the lack of it that the region experiences.
The progress of endemic countries or regions on this scale is affected by many factors
including, its level of endemicity by entomological inoculation
rates, efficiency at implementation of available tools, social economic situation
of the region, health systems efficiency, climatic conditions as well as political
stability including that of neighbouring regions. Therefore, the immediate or short
to medium term goals of a particular region should depend on what stage they are in
these series.
So is elimination all wishful thinking?
Interventions using current tools can result in major reductions in malaria transmission
and the assoc however, in high transmission settings they are
insufficient to drive prevalence below the pre-elimination threshold []. A malaria vaccine offers, therefore, great potential for improved malaria control,
particularly in Africa, where effective mosquito control over long periods has proved
difficult or impossible to maintain []. Indeed recent successes in malaria control using other approaches highlight the
need and the potential gains that could come from an efficacious vaccine [,]. However, to adequately measure vaccine impact will require enhanced surveillance
and standardized reporting mechanisms. Unfortunately, the large range of R0 estimates in literature confirms the fact that malaria control presents variable
challenges across its transmission spectrum and a ‘‘one-size-fits-all’’ malaria control
strategy would be inefficient in the broader context of malaria elimination []. Large reductions in transmission from targeted control are possible only if programmes
are able to identify those who are bitten most, and specific interventions packaged
and implemented efficiently. Vector control measures can impact reductions to the
1% parasite prevalence threshold in low- to moderate-transmission settings especially
when the main vectors are primarily endophilic (indoor-resting), provided a comprehensive
and sustained intervention programme is efficiently managed. In high-transmission
settings and areas, where vectors are mainly exophilic (outdoor-resting), additional
new tools that target exophagic (outdoor-biting), exophilic, and partly zoophagic
mosquitoes will be required [,,]. Depending on which stage (see Figure ) in control a particular region might be at, specific tailor-made interventions would
be required to move from one stage to the next. In areas where R0 is low such as those around stage 3, local elimination of malaria may be practical
and concerted efforts should focus on that goal []. The immediate realistic focus of control should be reducing the mortality and disease
burden in general, for areas where R0 may be high such as those around stage 1 and 2.
On the other hand, the impact of the malaria interventions should not be limited to
the estimated level of efficacy and coverage alone. The potential impact of vaccines
could generally be wider than expected due to synergies and doubling of effects, which
is hard to theoretically predict. For example, RTS,S was observed to have an impressive
reduction in severe disease incidence in Mozambican children despite being a pre-erythrocytic
stage vaccine []. This trial was designed to primarily assess vaccine efficacy against clinical malaria
disease, which at six months was found be 29·9% (95% CI 11·0–44·8; p 0·004) while
efficacy against severe malaria was 57·7% (95% CI 16·2–80·6; p 0·019). Could synergies
between a partially protective malaria vaccine and currently available control tools
further enhance the impact of vaccine?
What a malaria vaccine will not do
As the discussion on the possibility of malaria elimination in some African contexts
goes on, it is imperative that expectations from the potential role of an efficacious
vaccine are moderated. To do so, it is important to consider what not to expect from
the current generation of vaccines in clinical development:
1. Be 100% protective efficacy: None of the vaccines currently in clinical development will be close to 100% protective
efficacy. The malaria vaccine Technology Roadmap rightly predicts that by 2015, the
licensed vaccine could achieve a 50% reduction in malaria deaths and severe illness
among young children in sub-Saharan Africa and by 2020, license a vaccine that can
achieve an 80% reduction [].
2. Be deployed by the vaccine developer: Once an efficacious vaccine is licensed, it will be available to governments and
their Ministries of Health to include in their control programmes, procure and deploy.
African countries who have had to change their national anti-malarial drug policy
will recognize the complexities of harmonizing various national treatment guidelines,
developing effective in-service training, ensuring adequate drug supply and educating
the patient population [,].
3. Eliminate malaria from countries in stages 1 & 2: Existing tools may be sufficient to reduce the burden of disease and bring it under
control in many low transmission areas. However, the situation in much of sub-Saharan
Africa is such that partially protective vaccines currently in clinical development,
may not in themselves bridge the control gap [,].
4. Count the numbers to document control and elimination: The capacity to accurately account for the impact of malaria vaccines towards elimination
will be critical. Improved surveillance and reporting systems will be necessary to
demonstrate any vaccine impact .
5. Reduce the cost of malaria control: Even if the vaccine will ultimately be paid for by donors, sub-Saharan African governments
should expect successful deployment of a vaccine to come at a cost to their already
strained health budgets. Thus, availability of an efficacious (and affordable) malaria
vaccine should be viewed initially as a cost before the rewards of control will be
It is notable that currently, there is a significant effort to categorize diseases
by their global morbidity and mortality impact and this has developed substantially
during the last decade, epitomized by the reporting the Global Burden of Diseases
and the Disease Control Priorities project [,]. Unfortunately, despite these efforts, the evidence base for allocating resources
for malaria control on a global scale is still poor [-] and no meaningful improvement will come without affected regions themselves taking
on serious initiatives and responsibility.
Need to visit the drawing board
Although there is renewed motivation towards malaria elimination, most of the vaccines
currently in the global portfolio were not conceived in the context of malaria elimination
[]. The focus on vaccines that are deployable through the expanded programme on immunization
is certainly useful in targeting the most vulnerable and most affected by the disease,
but may not at all deal with the reservoir hosts available in older children and semi
immune adults. It does also appear evident that sub-unit vaccines with a single parasite
antigen target may not be sufficient to interrupt malaria transmission especially
in areas with higher than moderate transmission. To attain to malaria elimination,
research and development must continue even when partially protective vaccines become
available. More efforts on combined and multi-stage vaccines with potent adjuvants
will be necessary ingredients for the malaria elimination agenda [].
This call for malaria elimination should be extended to all stakeholders from funders
of malaria vaccine work through endemic country governments, research institutions,
control programmes and down to the individual family faced with the daily challenge
of malaria sickness. There is need for an entire paradigm shift if malaria elimination
is to eventually be realized and it is not enough to simply pump more funds into research
and development [,]. The mere possibility of having a vaccine against malaria highlights the fact that
there is now a need, more than ever before, to rethink how to integrate all available
tools and resources towards malaria elimination.
Conclusion
Is vaccine the magic bullet for malaria elimination? Probably not today. The global
community working towards malaria control and eventual elimination is faced with many
difficult challenges which cannot be fixed by a magic bullet. The fact that malaria
transmission and clinical manifestation is so varied demands a variety of approaches
be made in the fight against the scourge. Strategic planning for malaria control should
consider R0, the spatial scale of transmission and human population density in tailor-making
interventions so that multiple, integrated and sustained control methods are focused
in populations where R0 is highest [].
The current efforts for vaccine development have rightly targeted falciparum malaria, which is the major cause of morbidity and fatality. However, because Plasmodium
inter-species characteristics are said to be products of evolutionary dynamics, it
is important to be circumspect and not forget the possibility of a “new malaria problem”
(more so with Plasmodium vivax ), once Plasmodium falciparum is eliminated [].
The protracted fight against malaria should have taught us that the parasite is a
resilient enemy able to mount various escape strategies and therefore, it must be
approached with multi pronged approaches. Malaria vaccines currently in clinical development
represent pre-clinical knowledge and thinking of 10-20 years ago. The present landscape
however, demonstrates the need to design vaccines with the goal of eliminating and
eventually eradicating malaria.
Competing interests
The authors declare that they have no competing interests.
Acknowledgements
This article has been published as part of Malaria Journal Volume 9 Supplement 3, 2010: Building Knowledge for Action: Proceedings of the 5th
Multilateral Initiative on Malaria Pan-African Malaria Conference. The full contents
of the supplement are available online at .
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