Module 1 Flashcards
Define core group
sub populations with higher rates of partner change that sustain transmission and persistence in the wider population
Are sex workers a core group?
Idea was that there would be a high rate of STIs within the population of sex workers
Have sex with a ‘bridging’ population of their clients, who would then have sex with the general population and disseminate disease
Disproven in the case of HIV as the Praed Street Project actually found a low rate of HIV within the prostitutes they studied, and found they were more likely to use condoms with clients than with regular boyfriends/non-paying partners
What is R0
Basic reproductive number: the average number of secondary infections occurring from a single infected individual in a totally susceptible population.
What does R0 have to be for an epidemic to occur?
> 1
What is R(t)
the average number of secondary infections caused by a single individual at any point in time
R(t) = R0 (S/N) where S/N is the proportion of the population susceptible
What is the transmission rate
= pcSI/N where:
c = the contact rate
I/N = the proportion of population infectious
p = the probability of transmission when an infection individual contacts a susceptible
S = the number of susceptible individuals
How do the transmission rate and R(t) change over the course of an epidemic?
When we start, R(t) = R0, and R(t) is then declining over the course of the infection.
Transmission rate will increase as the proportion of population who are infectious increases and the contact rate increases, but then will decrease as the supply of susceptible individuals is depleted
What is a point/common source outbreak
where all cases have been exposed over a short time period and all infections occur within one incubation peak.
This will produce a single peak of cases.
An example would be food poisoning from a wedding buffet.
What is a Continuing source outbreak
where all cases have been exposed to an ongoing source of infection.
The infections occur randomly when compared to the incubation period.
An example would be Legionella from a contaminated air conditioning unit.
What is a propagated source outbreak
where the infection can spread from one person to another.
This produces multiple peaks, and infections occur over several incubation periods.
An example would be a measles outbreak at a school.
What is a mixed source outbreak
where there is both a common point source and secondary spreading from one person to another.
This produces multiple peaks with infections occurring over multiple incubation periods.
Is access to medicines a human right?
Yes:
ICCPR - art 6 - right to life
ICESCR art 12:
Health is a fundamental human right indispensable for the exercise of other human rights
Access to health care
UDHR art 3 - Access to health care
International Covenant on Economic, social and cultural rights - art 12 - the prevention, treatment, and control of epidemic, endemic, occupational, and other diseases
ICESCR GC 12 - To provide essential drugs as defined under the WHO Action Programme on Essential Drugs
What is the TRIPS agreement
came into force in the late 1990s
They provided preferential trading tariffs for members
However, member countries had to sign up to the whole thing - and one condition was intellectual property rights for pharmaceuticals
This was the result of lobbying by the pharmaceutical company - civil society wasn’t lobbying for as long, and healthcare professionals hadn’t really considered the issue
Tightening of patent protection and consequent diminishing production of generics led to a large global series of demonstrations around he prices of and access to medicines
Globalisation of patent rules
20 year patents on pharmaceutical products
As a result, all new drugs will be patented in all key generic producing countries e.g. India, Brazil, Thailand
Whilst the need for affordable newer drugs increases and the price discounts are insufficient
What are the industry strategies to provide access to medicines?
Tiered pricing
But the discounts aren’t enough and this isn’t as effective as generic competition
No solution to patent barriers for innovation e.g. paediatric formulations
Voluntary licences
Restrictions still limit the full effect of generic competition e.g. export
Rare and often a response to threats of legal action
How do India’s pharmaceutical patent laws work?
India’s patent law balances IP and public health - patents are not granted for new uses or new forms of existing medicines unless they demonstrate significant increases in efficacy
What do CIPR have to say about TRIPS and IP
“All the evidence we have examined suggests that [IP] plays hardly any role at all, except for those diseases where there is a large market in the developed world, for example diabetes or heart disease”
“There is no evidence that the implementation of the TRIPS agreement in developing countries will significantly boost R&D… Insufficient market incentives are the decisive factor”
Are newly patented drugs ‘breakthroughs’?
No -
Very little R&D for NTDs - in 1975-2004 only 1.3% of marketed chemicals
Only 5.9% of newly patented drugs in Canada from 1990-2004 met the criteria of being a ‘breakthrough drug’
68% of new products approved in France between 1981 and 2004 brought ‘nothing new’ over previously available preparations
WHA’s plan - Global Strategy and Plan of Action on Public Health, Innovation and Intellectual Property (2009)?
Ensure intellectual property rights do not prevent access
Examine feasibility of voluntary patent pools
Exploratory discussions on biomedical R&D treaty
Addressing de-linkage of the costs of R&D and the price of health products
Explore the award of prizes
How does the patent pool work
Negotiates with patent holders for licences to be available in the pool
Manufacturers then seek a license from the pool to produce a generic drug and pay royalties to the patent holder
How does MSF’s push pull pool campaign work?
for TB:
Finance R&D through grants (push)
Incentivise R&D achievements with milestone prizes (pull)
Share intellectual property to enable collaboration and fair licensing of successful medicines (pooling)
Brazilian study found that visceral leishmaniasis is 6x higher in households without regular refuse collection compared to those with
(Costa et al 2005)
immigrants to Canada - over 36% of participants were susceptible to M, M, or R
Greenaway et al 2007
Give some stats on the state of water provision globally
1.1 billion people lack improved water supply - 17% of the global population
2/3rds of these people live in Asia
World’s population is growing which is putting more pressure on water systems
Urban population is growing, meaning pressures are often very localised; however:
Opportunity to put in place traditional engineering solutions and tax city-dwellers
Internationally, in cities you are better off in terms of water and sanitation than you would be in a rural area
Give some stats about global sanitation provision
Mostly doing worse with sanitation than we are with clean water provision, and this is where most of the disease risk is
2.6 billion people lack improved sanitation - 42% of the global population
More than half live in China or India
69% lack access in rural areas, 22% lack access in urban areas
40% of the world’s hospital beds are occupied by people with enteric infections
Specifications for a sanitation system
No contact by humans with waste materials within the system
No access to the waste materials for insects and animals
No offensive odours or insect nuisance
No unacceptable contamination of groundwater that may pollute springs or wells
No unacceptable contamination of surface water
No unacceptable contamination of surface soil
Simple and inexpensive construction, use, and maintenance
Modesty needs and personal cleansing practices of users are catered for
Things to consider when designing a sanitation system
What is the soil like
How many people will use it, distance between dwellings, interval of emptying
Sanitation ladder - not too technological too soon
Is there water regularly available to flush with?
How will they maintain the system?
Why is drug resistance e.g. in pneumonia a problem
Increased difficulty in control of infectious diseases
Reduced effectiveness of treatment -> longer period of infectiousness -> increased risk of transmission
Growth of global trade and travel allows rapid spread to distant countries
Increased healthcare costs
More expensive therapies required when first line treatments no longer work
Longer duration of illness and treatment
Increased mortality
Failure to respond to standard treatment leads to prolonged illness and greater risk of death
What can we do about antimicrobial resistance in pneumonia
Vaccinate
Local/national/international surveillance projects
Campaigns promoting judicious use of antimicrobials
Start smart and focus (UK)
Get smart (US)
WHO
R&D of novel therapeutics
Why is it feasible to eradicate polio
Effective vaccine
No natural non-human reservoir
Coverage of vaccination improving
Political will
Summarise the OPV
Cheaper
Easier to administer
Secondarily immunises household contacts
Mucosal immunity
Lower rate of seroconversion in developing countries - interference by other infections and diarrhoeal disease
Vaccine Associated Paralytic Poliomylitis (rarely) as OPV is similar to the wild type poliovirus
Summarise the IPV
Older
Injected
Induces good humoral immunity against paralysis
Much more limited impact on mucosal immunity against infection
Challenges to polio eradication?
Effectiveness of OPV
Reaching the communities who need the vaccine
Public and political support for vaccination
Schistosomiasis life cycle
Aquatic snail releases cercaria
Enters via unbroken human skin
Circulates to the liver; pairs up, migrates, lays eggs in blood vessels
Egg rotates in capillaries and bursts open via its spine
Escapes to the bladder or the intestine
If the person defecates in water, the eggs will hatch and the larva will find a snail
If it does, it takes over the snail as an intermediate host
And then multiple through the larval stages
A month later, produces a free swimming larva (cercaria)
Whole lifecycle takes over 2 months
How does schisto cause disease?
Not all eggs get out of the body - some get washed to the liver, get stuck there, and die. Then the body recognises them, attacks them, and a scar is formed. Eventually the liver gets entirely blocked and fibrotic, and as much as 20-25 years later there is death, usually due to oesophageal varices and haematemesis
Why is schisto especially bad for women?
Anaemia -> poor birth outcomes
Female genital schistosomiasis: lesions on cervix which increase the HIV/AIDS risk
Why is schistosomiasis so serious/some stats on the burden
2nd most prevalent infectious disease behind malaria
200,000 deaths/year in SSA
Affects 74 tropical countries in Africa, Caribbean, South America, East Asia, and the Middle East
62% of the burden occurs in 10 countries in Africa
Worldwide 700 million people at risk
207 million people infected
What are the main interventions for schistosomiasis
Mass drug administration to school children and others considered at risk
Health education and behaviour change
Snail control
Improve water and sanitation
Describe chemical snail control
Spraying water bodies with molluscicides
Effective on small water bodies
However, unless carried out intensely and in conjunction with MDA, only a short term solution as rapid re-colonisation can occur
Describe environmental snail control
Reduces the numbers, or in some cases wipes out snail populations
Thomas and Tait (1984): altering light, water chemistry, water flow, sediment type, seasonal drying, aquatic and sub-aquatic plants, introducing other snail species and management of irrigation schemes
Unless there is long-term commitment from rural communities, the rapid reintroduction of the species is inevitable
Describe biological snail control
Introduce pathogens, parasites, predators, competitors, genetic manipulation
Ideas still in early stages and can be complicated to implement
Due to overfishing of mollusc eating fish, some areas of Lake Malawi have seen an increase in schisto cases
Small community owned projects have implemented fishing boundaries to try and re-establish the fish population to reduce schisto
Which water/sanitation strategies are important for schistosomiasis
77% reduction in severity and intensity of schistosomiasis can be gained with improved water and sanitation facilities - but just because they are introduced, doesn’t mean they will be maintained
Accessible urinals close by river/pond
Safe laundry area near river/pond
What is the point of monitoring a schisto programme
Assesses impact - has the program been successful
Provides feedback to:
Affected communities to increase ownership and compliance
Donors to show progress towards objectives and justify continued funding
Enable programme adaptation
Generate scientific data on the factors influencing treatment programme success
Assess whether financial resources are being used appropriately
Advocate for future funding and programme support
What are some non-PCT schistosomiasis interventions
Competitors and predators
Improved drainage
Waterflow
Water level fluctuations
How can competitors and predators help schisto
Brown and DeVries (1985) - fish predators can dramatically alter the population dynamics of a single snail species
How does improved drainage affect schisto
R Slootweg and R Keyzer - reducing schistosomiasis infection risks through improved drainage
Reconstruction of the depression zone along the village diminished risk of schistosomiasis transmission considerably
However, a potential transmission site with low numbers of snails remains present near the dam at a far distance from the village
How does improved waterflow affect schisto
Snails are not found where the water flow velocity exceeds 0.3 m/s except when aquatic vegetation provides them with refuge from the current
High water flow velocities are well tolerated in cement-lined canals
Periodically flush canal sections between the check structures
High water velocity not only removes snails by washing them away or leaving them stranded high on the canal banks, it also scours silt deposits
How does improved water level fluctuations affect schisto
Important in small canals
Periodic removal of aquatic plants from canals also reduces friction to the water flow, which increases conveyance efficiencies in the irrigation system
In Egypt and Sudan, control of aquatic plants in canals has been applied as an effective method of snail control
What health education can you do for schisto
Inform, motivate, train and encourage communities and their leaders to play a major role in improving their own health
Studies reveal many think it is an STI
In some countries, it is seen as a coming of age when a boy’s urine is red
What are the 5 specific objectives of schisto health education
Control of transmission through changes in water contact behaviour
Improved environmental sanitation through the control of urinary and faecal contamination of snail habitats
Compliance in chemotherapy
Assistance and cooperation with snail control programs
The promotion of health-promoting behaviour and community motivation to sustain these programs, together with increasing self reliance in health activities
Give an example of a time that pressures for more water supply led to schistosomiasis
The dam in senegal - OMVS
Why did the OMVS dam get built
Increasing populations in resource poor setting and demand of food leads to construction of dams and irrigation schemes
This can cause transmission intensification or the introduction of diseases into previous non-endemic areas, as in Senegal
1970s - governments of Senegal, Mali an dMauritania established the OMVS to develop and use the resources of the Senegal river
Integrated development scheme was designed leading to the construction of two dams and a barrage at Diama
1976 - USAID and OMVS signed an agreement for a multidisciplinary assessment of the environment to see what the impact would be of the project
What conclusions did the USAID study of the OMVS dam have
S haematobium in the delta was at a very low level
S mansoni did not occur
Highest schisto prevalences were found in the nomadic tribes disseminating the disease throughout the region
Explanations given:
Low density human population of the delta
Little contact of the population with snail infested waters
Possibility that the strain of the snail in the delta is an inefficient intermediate host for the strain of S. haematobium in the Senegal River Basin
Waters are harmful to schistosome larvae (miracidia) because the river water is acidic with a pH of 6 or below
What happened after the Senegal dam was completed
Completed in 1985 - in 1988 S mansoni was reported in stool examinations 130km from the dam
In 1989, 49% of stool samples were positive
Children were reporting blood in their urine
90% of the Wolof ethnic group were positive for S haematobium and 87% of another 382 sampled
By 1990, 60% were positive
By 1994, there was splenomegaly, and hepatomegaly in 36% of the population
Which factors contributed to the advent of schistosomiasis in Senegal after the dam
Physical and chemical changes in the water and environment leading to an increase in snail hosts
Stopped sea water reaching areas further up the river
Increase in Biomphalaria prefer and Bulinus globules
Reduced adverse effects of salinity on the parasite
Increase in the irrigated areas
Stability of water levels
What actions were taken to get rid of schistosomiasis at the senegal dam
Treatment with PZY but only 18% of those treated were cured
Rapid reinfection
Presence of immature worms
Low levels of antischistosome immunity
Resistance/tolerance ot PZQ
Larger average biomass of parasite, therefore less likely to work
Further intervention - prawns
Treatment with a double dose of PZQ, spaced 3 weeks apart
6 weeks earlier, released prawns into the water point and they consumed a huge number of snails
The disease did not build up and build back very quickly
AT the 6 month point he average parasite egg burden of 31 eggs at baseline had fallen to less than 1
At 12 months, the difference in egg burden was not as dramatic
Explain the main results of the study of schistosomiasis variation in China
The study examined schistosomiasis in hilly and marshland regions, which both have populations of humans, but the marshland has more cattle (kept by the humans) and the hilly regions have a large rodent population
Rodents were by far the most common host for schistosomiasis in the hilly regions, but were very rarely hosts in the marshland regions
Opposite was true of cattle
Additionally, there was a difference in the timing of cercarial release (when schistosomes would be aiming to infect a host)
In the marshland, cercarial release was in the early morning, before the heat of the day, when people would take their cattle to water
In the hilly regions, it was in the evening.
Therefore, it was clear that schistosomiasis was behaving in different ways in the two regions.
They study then examined the phylogenetic tree of schistosomiasis and found that those in the hilly and in the marshland regions formed two distinct families
Overall, the study showed that schistosomes exhibited variability in their genotype and phenotype which maximised their opportunities for infection and transmission in changing environments.
Explain the arguments for PZQ resistance in schistosomiasis
Resistance to all veterinary antihelminthics
Can select for PZQ resistance in animal models
Isolation of parasites with reduced sensitivity in Egypt
Parasite evolution over short time periods
Non-random mating amongst schistosomes
Current/recent MDA programmes are highly successful - strong selective pressures
Currently reliant on a single drug
Monitoring is difficult - no (informative or non-informative) molecular markers available, lack of mechanistic knowledge of PZQ action
Could rare resistance conferring alleles be already present in untreated populations?
Are rare resistance-conferring alleles the only parasite strategy involved in apparent ‘PZQ treatment failures’?
Explain the arguments against PZQ resistance in schistosomiasis
No evidence from China Probably no drug resistance in Senegal No increase 10 years later in Egypt Predicted large refugia Long generation time in human host
What are the genetic consequences of MDA on schistosomiasis?
No molecular markers for PZQ yet
Significant genetic ‘bottleneck’ was produced by MDA on schistosome population genetics
Hence, the ‘effective reservoir’ may be smaller than previously thought
Continued significant reductions in diversity may reduce the schistosomes’ ability to adapt and survive any future novel environmental selective pressures to which they might be exposed
Or, there may be increased success of a small number of potentially resistant alleles
Would treating everyone in the world with PZQ eradicate schistosomiasis?
If you treated everyone in the world with PZQ at the same time you wouldn’t eradicate schistosomiasis
Some would be in the other life cycle stages, not in humans, and the juvenile worms are tolerant to PZQ
There would still be a degree of refugia
Schoolchildren get treated because they are infected with the greatest intensity, but this still leaves infections in older people
How common is onchocerciasis and how has this changed
Also known as river blindness
Very common 60 years ago, with about 50% of people over the age of 40 blind in some areas
Today, virtually no blindness due to onchocerciasis but there are still many people infected especially in Western Central Africa and they have to be treated once a year to prevent the blindness
Explain the life cycle of onchocerciasis/how does it cause disease
Parasite
Host is the blackfly, which breeds in fast moving water
This is why it’s common next to rivers (river blindness……….)
The adult worm lives in the human body and gives birth to live larvae
These circulate in the skin waiting to be picked up by a biting blackly
They develop in the blackfly, which infects a human when it bites them
The larvae circulate around the skin and cause intense itching
They also circulate across the retina, and if they do this over a period of time they damage the retina and people go blind
Life cycle of trachoma?
Flies carrying the microorganism land on children’s eyes, to feed on discharge
Women who take care of children also get the infection
Flies that breed in human faeces spread the disease to others
Dirty hands or face cloths also spread the disease
Bacterium produces a characteristic roughening of the inner surface of the eyelids
Incubation period is 5-12 days
Patients experience symptoms of conjunctivitis or irritation, like pink eye
What happens in active trachoma
Usually seen in children, especially pre-school
Characterised by white lumps in the under surface of the upper eyelid (conjunctival follicles or lymphoid germinal centres)
Non-specific inflammation and thickening often associated with papillae
Follicles may also appear at the junction of the cornea and the sclera (limbal follicles)
Active trachoma will often be irritating and have a watery discharge
Bacterial secondary infection may occur and cause a purulent discharge
What is cicatricial trachoma
Later structural changes - Includes scarring in the eyelid (tarsal conjunctive) which leads to distortion of the eyelid with buckling of the lid (tarsus) so that the lashes rub on the eye (trichiasis)
These lashes will lead to corneal opacities and scarring and then to blindness
How common is trachoma/what’s the burden
Children are the most susceptible to infection, but the blinding and more serious symptoms tend to be in adulthood
Serious public health problem
Affects the poorest populations in 46 endemic countries
146 million active cases, mainly among children and women
Almost 6 million people are blind or visually disabled due to trachoma
WHO estimates an annual productivity loss of $2.9 billion in 1995, adjusted to $3.5 billion in 2003
Not just Africa - also seen in indigenous populations of Australia
How is trachoma transmitted?
Person to person via dirty hands and clothing, but also flies
Direct contact with eye, nose, and throat secretions from affected individuals or contact with fomites
Mechanical transmission (flies)
Environmental risk factors
What are the risk factors for trachoma?
Lack of water Absence of latrines or toilets Poverty in general Flies Close proximity to cattle Crowding And more
What did the WHO recommend for trachoma?
Annual mass treatment for at least 3 years with 80% population coverage target
Based on expert opinion - no data at the time
May eliminate infection in mesoendemic communities, but the same efforts in hyperendemic communities seem to only cause a decline in active trachoma - not a reduction to 0% - even after multiple years of treatment
What did the PRET surveys in Gambia find?
Partnership for the Rapid Elimination of Trachoma - Gambia
Found that 1 round of treatment reduces TF below the elimination threshold, and further rounds were redundant
Would be better to do one high coverage (>90%) round of treatment to reduce prevalence
However, this isn’t always attainable therefore other measures may be taken
What is SAFE?
Trachoma strategy: Surgery for trichiasis Antibiotics Facial cleanliness Environmental improvement
What is the role of surgery in trachoma
Reduces risk of progressive corneal opacification
Needs training of surgeons and other staff to carry it out - not enough capacity at present
RCT in Gambia found uptake was 45% higher when the surgery was village based and no difference in success of treatment, cost to patient was lower
Uptake is low - lack of knowledge, cost, fear, inaccessibility
Trichiasis recurrence 20% at one year and 62% at three years
New strategies needed due to high rates of reinfection
What is the role of antibiotics in trachoma
Lower the relative risk but not much effect on the individual case
Control programs use them because:
Treat individual infections and reduce risk of developing scarring
Limit transmission to others
Mass treatment with topical tetracycline not feasible - twice a day for many weeks
Single dose azithromycin received better and based on studies, safe MDA strategies were developed
Pfizer donated
This is a good method but resources are lost treating those not infected, therefore rapid diagnostic tests being developed
What is the role of facial cleanliness/environmental improvement in trachoma
To prevent transmission rather than treat trichiasis or infection
Gambia study - households who put a higher proportion of water towards hygiene had a reduced risk of trachoma
RCT of hygiene promotion narrowly failed by WHO said it was compelling enough to warrant inclusion in the strategy
What can be done about eye seeking flies in trachoma
Not included in SAFE as no evidence that investment would have an impact on transmission
Identifies putative vector Musca sorbens
A large RCT which tested fly control, insecticide and provision of household latrines to reduce breeding materials significantly reduced contact between flies and eyes
Does water have a role in trachoma?
No studies looking directly at water and trachoma
Several studies show families living further from water are at a greater risk
Trachoma has also been found to disappear where water has become available even in the absence of an antibiotic based programme
Why has the SAFE strategy for trachoma been successful?
Strategy clear and understandable
Measurable progress
Regular meetings between actors to share achievements and ideas
Delivery of services is performed effectively and inexpensively by non-specialists
Success of each part encourages communities to buy into the rest of it
Mass treatment (single dose azithromycin) is effective, feasible, and popular
Azithromycin is well tolerated, relatively free from side effects and has additional benefits - effective against malaria as well as resp and skin infections
No resistance yet
Donated and shipped to endemic countries by Pfizer
Advocacy by NGOs and WHO has led to governmental commitment in some countries
Strong NGO involvement
Intersectoral programmes - improving water supplies and sanitation while providing eye care
What does guinea worm do
parasite that infects humans through water.
The intermediate host is the water flea.
People are infected when they drink unfiltered water from a pond or stream.
Once in the stomach, the larvae come out and grow.
After a year, they are 1m in length and the worm then travels around the body.
When the female worm is ready to give birth, she forms a blister around the foot.
When the worm begins to the protrude from the body the blister becomes painful and burns.
The person will then go to a pond to relieve the sensation, and the larvae will come out to infect water fleas again.
How common is guinea worm?
30 years ago, there were approximately 2 million sufferers - in 2014 there are only about 150 cases globally and most are limited to Southern Sudan.
Why can guinea worm be eradicated?
only humans can have guinea worm (there is no animal reservoir) and the water fleas can only transmit it to humans by mistake - i.e. if we can get people to stop drinking unfiltered/unclean water then we can stop transmission.
The reductions so far have been made due to water and sanitation improvements, filtering water, health education, and case management so obviously this are effective and just need to be spread into the final few communities with guinea worm.
There are multiple organisations pushing for eradication including the WHO, Bill & Melinda Gates Foundation and the Carter Centre.
Summarise dengue fever
Asymptomatic or undifferentiated fever
Virus incubates for 2-7 days then fever
Headache, muscle and joint pain, self limiting, 1 week
Summarise dengue haemorrhagic fever
4 grades (1-4) Capillary leakage, thrombocytopenia, altered haemostasis, liver damage, bleeding
Summarise dengue shock syndrome
Massive fluid loss (pleural effusion) can result in shock
Ascites
Bleeding
Hepatomegaly
What is the burden of dengue
390 million dengue infected individuals per year of which 96 million showed symptoms
2.5 billion (2/5 of the world’s population) are at risk
What are the immune responses to dengue
E is a major target of neutralising and protective antibodies
NS1 is a target of protective antibodies
NS1-specific antibodies lead to ADCC and complement mediated cytotoxicity
NS3 is a major target of T cells (CD4 and CD8)
The IFN response is important
Neutralising antibodies are long-lived
Cross-reactive neutralising antibodies decline rapidly after infection
Protection is thought to be life-long for homotypic virus, but last only a few months for heterotypic virus
Serotype-specific and cross-reactive T cells are detected after infection
What is the immunopathogenesis in dengue
Observations that viral load is higher in DHF than DF and that there is leakage of cytokines/chemokines/mediators and/or damage of endothelial cells in DHF
The hypothesis is that increased viral load leads to antibody dependent enhancement (ADE) and cross-reactive T cells
Explain antibody dependent enhancement
Shown in monkeys
Sequential infections of different serotypes compared to the primary serotype
Some showed increased (10-fold) viraemia
Animals given dengue immune serum and then when challenged had higher viraemia than those given non-immune serum
Good animal model is lacking
More cytokine production and less degranulation in DHF compared to DF
What is the hypothesis about the leakage/increased vascular permeability in dengue
Endothelial cells were readily infected by dengue virus in vitro
However, only viral antigen found on endothelial cells in vivo
Cytokines/chemokines/mediator effect is preferable because patients quickly recover from the disease without any sequel
TNFalpha, lots of interleukins, complement fragments/complexes were al higher in DHF than DF
What are the criteria for a dengue vaccine?
Equal protective responses against all 4 serotypes
Need ‘all or nothing’
One strong dose for immediate effect
Boosting needs to ensure that Ab levels do not drop and also that they all decline at equal rates
