Control of Viral Diseases

Derek Wong
“Wong’s Virology” http://virology-online.com
 Terms
 Containment – to contain the disease as to prevent it from
becoming a worse problem. Containment is usually the only
option available for the majority of infectious diseases.
 Elimination – to eliminate the disease even though the
infectious agent may remain e.g. rabies and polio had been
eliminated in many countries, and probably SARS in 2003.
 Eradication – to eradicate the infectious agent altogether
worldwide e.g. smallpox
 Epidemiology (Gr.Studies upon people)

Study of health and disease as it occurs in the

community either in groups of person or the entire
population. It deals with
 Nature of the disease
 Distribution of the disease
 Causation of the disease
 Mode of transfer of the disease
 Prevention and control of the disease
Surveillance of Infectious
Diseases
 Strategies for Surveillance of
Infectious Diseases
 Notifiable diseases – make it a statutory duty for
physicians to notify the disease.
 Virus isolation or serologic evidence reported
through diagnostic laboratories
 Specific Epidemiological Studies e.g. hantavirus,
hand foot and mouth disease surveillance
Notifiable viral diseases (Hong Kong)
 Yellow fever
 Poliomyelitis
 Measles
 Mumps
 Rubella
 Rabies (Human and Animal)
 Viral Hepatitis
 Dengue fever
 Chicken Pox
 H5N1 influenza
 SARS
 Requirements for surveillance based on
clinical case

Occurrence of clinical illness

Sufficient severity to seek medical care

Availability of medical care

Capability of physicians to diagnose illness

Laboratory support of diagnosis

Reporting of disease to Health Department

Collection and analysis of data by Health Department
 Laboratory based surveillance
 Scientific source of information
 Coherent and consistent information on trends of
infection
 Qualitative detail information
Control Measures Available
Control Measures Available
To control the spread of the disease in the
population by
 Agent - removing the source of the agent by targeting
its reservoir
 Controlling its transmission
 Patient – immunization, prophylaxis, antiviral therapy.
 Removing the Source
 Every pathogen has a reservoir, which may be in humans, animals or
both. One may aim to remove the pathogen from the reservoir, or
remove the reservoir completely.
 Human Reservoir
 Isolating the patient
 Curing the patient completely
 Preventing infection in susceptible individuals by vaccination
 Animal Reservoir
 Isolating/observing the animal e.g. rabid dog
 Eradicate the animals involved e.g. slaughter of rabid dog, vector control
 Vaccinating the animals e.g. vaccination of dogs and foxes. It is very
difficult to vaccinate wild animals.
 Controlling its transmission
 Prophylactic chemotherapy or vaccination among
individuals exposed to or susceptible to infection.
 Contact tracing
 Improvement in hygiene and living standards
 Modification of lifestyle and behavior
 Health education
 Screening of potential sources of infection e.g. blood,
foods, water
 Controlling vectors that may be involved in transmission
Man-Arthropod-Man Cycle
Animal-Arthropod-Man Cycle
Examples of Arthropod Vectors

Aedes Aegyti
Assorted Ticks

Culex Mosquito Phlebotmine Sandfly

Vaccination
 Types of Vaccination Strategies
 There are two types of vaccination policies:
 Universal Vaccination – every person is vaccinated in the hope of
eliminating/eradicating the disease from the community
 Selective Vaccination – only individuals in particular risk groups
are vaccinated.
 Both policies are in use for rubella.
 The US started off with universal vaccination.
 The UK and HK started off with selective vaccination of primary
school girls but decided to switch to universal vaccination because
the uptake rate was not good enough.
 Characteristics of vaccines
The characteristics of the vaccine used is a major determinant on
the outcome of the vaccination strategy. Factors to consider
include
 Response rate
 Type of protection
 Duration of protection
 Local immunity
 Side effects
 Route of administration
 Stability
 Cost
 Developing a vaccination policy
The following questions should be asked when a vaccination policy
against a particular virus is being developed.

1. What proportion of the population should be immunized to

achieve eradication.
2. What is the best age to immunize?
3. How is this affected by birth rates and other factors
4. How does immunization affect the age distribution of susceptible
individuals, particularly those in age-classes most at risk of
serious disease?
5. How significant are genetic, social, or spatial heterogeneities in
susceptibility to infection?
6. How does this affect herd immunity?
Coverage Required for
eradication
 Basic concept is that of the basic rate of the infection R0.
 For most viral infections, R0 is the average number of secondary cases produced by a
primary case in a wholly susceptible population. Clearly, an infection cannot maintain
itself or spread if R0 is less than 1.
 R0 can be estimated from as B/(A-D);B = life expectancy, A = average age at which
infection is acquired, D = the characteristic duration of maternal antibodies.
 The larger the value of R0, the harder it is to eradicate the infection from the community
in question.
 A rough estimate of the level of immunization coverage required can be estimated in the
following manner: eradication will be achieved if the proportion immunized exceeds a
critical value pinc = 1-1/R0.
 Thus the larger the R0, the higher the coverage is required to eliminate the infection.
 Thus the global eradication of measles, with its R0 of 10 to 20 or more, is almost sure to
be more difficult to eradicate than smallpox, with its estimated R0 of 2 to 4.
Critical Coverage
Av Age of Epidemic Critical
infection Period Ro Coverage

Measles 4-5 2 15-17 92-95

Pertussis 4-5 3-4 15-17 92-95

Mumps 6-7 3 10-12 90-92

Rubella 9-10 3-5 7-8 85-87

Diptheria 11-14 4-6 5-6 80-85

Polio 12-15 3-5 5-6 80-85

Eradication of Small Pox
 Eradication of Smallpox - 1
 Smallpox was transmitted by respiratory route from lesions in the respiratory tract of
patients in the early stage of the disease
 During the 12 day incubation period, the virus was distributed initially to the internal
organs and then to the skin.
 Variola major caused severe infections with 20-50% mortality, variola minor with <1%
mortality
 Management of outbreaks depended on the isolation of infected individuals and the
vaccination of close contacts.
 Smallpox was eradicated from most countries in Europe and the US by 1940s. By the
1960s, smallpox remained a serious problem in the Indian subcontinent, Indonesia and
much of Africa.
 The WHO listed smallpox as the top on the list for eradication in 1967.
 Eradication of Smallpox - 2
The initial strategy was separated into 3 phases;
 Attack phase - This applied to areas where the incidence of smallpox exceeded 5
cases per 100,000 and where vaccination coverage was less than 80%. Attention
was given to mass vaccination and improvement in case surveillance and
reporting. This phase lasted from 1967-1973. A large amount of financial
resoureces were provided for setting up surveillance centres and reference centres.
Priority was given to Brazil, sub-saharan African, S.Asia and Africa.
 Consolidation Phase - In areas where the incidence was less than 5 cases per
100,000 and vaccination coverage exceeded 80%, the objective was the
elimination of smallpox. Vaccination uptake was to be maintained and
surveillance improved. Facilities should be made available for isolation.
 Maintenance Phase - once smallpox had been eliminated, it was essential it was
not reintroduced. This phase was entered in 1978. In 1980, the world was declared
to be free of smallpox.
 Eradication of Smallpox - 3
 It soon became clear that smallpox could not be eradicated with mass vaccination alone.
In some countries, it was not possible to achieve a smallpox vaccination uptake rate of
80%.
 Therefore more attention was paid to case tracing and isolation procedures. Experience
in West Africa and Indonesia had shown that smallpox can be eliminated without mass
vaccination, provided that a high rate of case detection was achieved.
 The Indian subcontinent was a special problem because of its large size and population.
It provided a reservoir for variola major infection. Extra attention was paid to search out
unnotified cases that proved to be highly effective. The last cases of variola major
occurred in the Indian subcontinent in 1975.
 The last case of variola minor occurred in Somalia in 1977. The last cases of smallpox
occurred in a Birmingham laboratory in 1979.
 It was estimated that the smallpox eradication campaign costed US $312 million. If
smallpox had not been eradicated, routine efforts to control smallpox would have costed
US $1000 million.
 Features that made Smallpox
an eradicable disease
 1. A severe disease with morbidity and mortality
 2. Considerable savings to developed non-endemic countries
 3. Eradication from developed countries demonstrated its feasibility
 4. No cultural or social barriers to case tracing and control
 5. Long incubation period
 6. Infectious only after incubation period
 7. Low communicability
 8. No carrier state
 9. Subclinical infections not a source of infection
 10. Easily diagnosed
 11. No animal reservoir
 12. Infection confers long-term immunity
 13. one stable serotype
 14. Effective vaccine available
The SARS Crisis
 Key Events
 Early Feb 2003 – Guandong province reported 305 cases and 5 deaths
caused by atypical pneumonia of unknown cause.
 19th Feb – WHO influenza network activated emergency pandemic
plans after receiving a report from Hong Kong confirming a case of
Influenza H5N1 infection.
 21st Feb – Prof Liu Jian Lung came to Hong Kong to attend a
relative’s wedding. He stayed at Rm 911 of the Metropole Hotel. Six
people were infected and they carried the infection to the rest of Hong
Kong, Vietnam and Canada.
 Early March - Carlo Urbani identified SARS as a unique clinical entity
in patients who had been infected by Johnny Chen in a Vietnam
hospital. WHO was put on alert. Urbani himself later became infected
and died.
 Discovery of the Virus
 18th-20th March – Paramyxovirus RNA and particles reported by
CUHK and other laboratories in Germany and Canada.
 21st March – HKU reported isolating an unknown virus from 2
patients with SARS in FRhK4 cells, and demonstrated a rising
antibody response against this virus by IF in patients with SARS.
Furthermoe, EM revealed virus-like particles in lung autopsies.
 22nd March – CDC isolated a virus that caused a CPE in Vero E6 cells
from a patient from Thailand and showed coronavirus-like particles on
electron microscopy. Serum from SARS patients were sent by the
GVU to the CDC for confirmation. GVU visualized coronavirus
particles in faeces of a mouse that had been inoculated (this was
proved later not to be SARS-CoV)
 23rd March – CDC identified the new agent as a coronavirus and gave
sequences of initial primers to collaborating laboratories.
 The SARS associated virus
A Coronavirus
Enveloped single-stranded RNA virus
Virions 80-100 nm in diameter.
Pleomorphic morphology. Characterised
by surface spikes giving a crown-like
appearance. (Not seen in SARS agent)
There are two known serogroups of
coronaviruses: OC43 and 229E, but the
SARS agent do not belong to either.
Genome 29000 bases, appears to be a
completely new coronavirus
 Virological Aspects
 Incubation period:- mean 6.37 (95% CI 5.29-7.75)
 Risk of transmission is greatest around day 10 of illness.
 No evidence that patients can transmit infection 10 days after fever has
resolved.
 Children are rarely affected by SARS
 The implications of the Metropole Hotel are not yet fully understood.
 Risk of in-flight transmission – 5 international flights had been
associated with the transmission of SARS. No evidence of in-flight
transmission after the 27 March advisory.
 Positive Rate of Listed Cases(Sample Distribution) dated 30th Oct 2003
% Positive Rate
110
Total Number of Sera
100
NPA
90
Faeces
80
70
60
50
40
30
20
10
0
<=0 1- 3 4- 6 7- 9 10- 12 13- 15 16- 18 19- 21 22- 24
Pos i t i ve Rat e 4. 35 2. 03 4. 03 18. 27 41. 67 74. 34 93. 41 95. 68 93. 75
Tot al Number of Ser a 69 413 686 883 1003 1155 1337 1476 1572
NPA 34. 6 45. 2 58. 4 59. 7 41. 9 39. 1 12. 5 20 10
Faeces 12. 5 28. 3 46. 9 70. 3 68. 2 54. 2 38. 5 48. 3 11. 6

Day Di f f erence
 Epidemiological Aspects
 Incubation around 6 days.
 Spread by droplets – no evidence it is an airborne disease. Uncertain
whether faecal-oral spread can occur.
 Health care workers were at special risk, especially those involved in
procedures that may generate aerosols. In some cases, transmission to
health care workers occurred despite that the staff was wearing full
protection.
 Risk of transmission is greatest at around day 10 of illness
 No evidence that patients can transmit infection 10 days after fever has
resolved.
 Children are rarely affected by SARS
 Super Spreading Events
 Some infected individuals have spread the infection to large numbers
of people. They were originally called superspreaders but WHO now
prefer to call them superspreading events.
 In Hong Kong, 3 superspreading events occurred:
 Metropole Hotel – the mechanism is not completely understood.
 Prince of Wales Hospital – the use of a nebulizer by the patient was
responsible.
 Amoy Garden – this was a unique event. The index patient was a 33-yr
old man with chronic renal disease treated at PWH. He visited Amoy
Garden frequently and had diarrhoea over a 3-day period. Dry U-traps in
bathroom floors allowed contaminated sewage droplets to enter
households.
 Control Measure Taken
 PPE provided for hospital staff, patients and visitors to hospitals. In
the later stages, hospitals were closed to visitors and all patients had to
wear masks.
 Home quarantine for contact cases.
 DH supervised cleaning and disinfection of the workplaces and homes
of those infected.
 Residents of Amoy Garden Block E were first quarantines before
transfer to a camp.
 Public education campaigns for workplace ad personal hygiene
 Schools were closed.
 Future Control Measures
 Better drugs should be available
 Anti-viral prophylaxis
 Vaccines
 More sensitive diagnostic tests would enable the early
detection of cases.
 Better surveillance system
 Better contingency procedures
 Better education and facilities.
H5N1 Avian Influenza
 H5N1 Avian Influenza
 First human infection by a highly pathogenic H5N1 avian influenza was
reported in Hong Kong in 1997. 18 persons were infected with 6 deaths. The
outbreak was eventually controlled after culling all the chickens.
 The virus resurfaced in Feb 2003 to cause 2 infections (one fatal) in a Hong
Kong family who had recently traveled to China. It began to cause outbreaks
in the rest of Asia that year that were unnoticed.
 In 2004, Vietnam and Thailand started reporting human infections, followed
by Cambodia, Indonesia and China in 2005. The strains exhibited divergence
in these localities.
 It is now thought that highly pathogenic H5N1 is now firmly endemic Asia
and has also spread to Russia and Southern Europe.
 It is thought that the virus is carried by migratory birds.
Human Cases Reported to the WHO as of April 2008

2003 2004 2005 2006 2007 2008 Total

Country

cases deaths cases deaths cases deaths cases deaths cases deaths cases deaths cases deaths

Azerbaijan 0 0 0 0 0 0 8 5 0 0 0 0 8 5

Cambodia 0 0 0 0 4 4 2 2 1 1 0 0 7 7

China 1 1 0 0 8 5 13 8 5 3 3 3 30 20

Djibouti 0 0 0 0 0 0 1 0 0 0 0 0 1 0

Egypt 0 0 0 0 0 0 18 10 25 9 4 1 47 20

Indonesia  0 0 0 0 20 13 55 45 42 37 15 12 132 107

Iraq 0 0 0 0 0 0 3 2 0 0 0 0 3 2

Laos 0 0 0 0 0 0 0 0 2 2 0 0 2 2

Myanmar 0 0 0 0 0 0 0 0 1 0 0 0 1 0

Nigeria 0 0 0 0 0 0 0 0 1 1 0 0 1 1

Pakistan 0 0 0 0 0 0 0 0 3 1 0 0 3 1

Thailand 0 0 17 12 5 2 3 3 0 0 0 0 25 17

Turkey 0 0 0 0 0 0 12 4 0 0 0 0 12 4

Total 4 4 46 32 98 43 115 79 88 59 27 21 378 238

 Risks of a pandemic
 The present H5N1 strains do not have the ability to transmit efficiently
between humans. To date, there had been no certain cases of human to
human transmission.
 It is thought an avian influenza may acquire this capability through
either 1. Reassortment with human influenza viruses (1957 and 1968),
or 2. gradual mutations ?1918.
 Reassortments in 1957 (H1N1-H2N2), and 1968 (H2N2-H3N2) are
thought to have occurred through an intermediary host such as the pig.
 Direct infection of humans by H5N1 opens the possibility that
reassortment can occur without an intermediary host.
 Therefore many experts believe that a pandemic was stopped in 1997
by the culling of chickens.
 The bottom line is that nobody knows when and if a pandemic will
arise out of the current H5N1 outbreaks.
 Control Measures - 1
 It would not be possible to control infection in migratory birds. Therefore
measures should be taken at reducing the risk of infection in poultry where
there is much more contact with humans.
 Measures should be taken to reduce the contact between poultry and migratory
birds through increased biosecurity
 Vaccination of poultry is controversial but is now practiced in Hong Kong
 Surveillance and laboratory diagnosis of infection in poultry should be
strenghened. Where infection is detected, prompt culling of the herd is
essential.
 Control of infection in poultry is complicated by the fact that ducks can
excrete the virus silently.
 Steps such as a central slaughtering facility would reduce the risk of contact
with humans.
 Control Measures - 2
 Prototype H5 vaccines are now available but it is uncertain whether they
will be protective against a future pandemic capable strain.
 It is possible that the present H3N2/H1N1 may have some degree of
cross protectivity against H5N1
 Tamiflu is currently the most effective drug against influenza and
countries are urged to stockpile it as a part of pandemic planning.
 It is essential that facilities for the surveillance and laboratory diagnosis
of avian influenza are upgraded.
 Where human cases occurred, prompt identification, isolation and
treatment of contacts is essential.
 Pandemic Planning
 In August 2005, WHO sent all countries a document outlining recommended
strategic actions for responding to the avian influenza pandemic threat.
Recommended actions aim to strengthen national preparedness, reduce
opportunities for a pandemic virus to emerge, improve the early warning
system, delay initial international spread, and accelerate vaccine development.
 Despite an advance warning that has lasted almost two years, the world is ill-
prepared to defend itself during a pandemic. WHO has urged all countries to
develop preparedness plans, but only around 40 have done so.
 WHO has further urged countries with adequate resources to stockpile
antiviral drugs nationally for use at the start of a pandemic. Around 30
countries are purchasing large quantities of these drugs, but the manufacturer
has no capacity to fill these orders immediately.
 On present trends, most developing countries will have no access to vaccines
and antiviral drugs throughout the duration of a pandemic.