Control of Viral Diseases

Derek Wong
Wongs Virology http://virologyonline.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

individuals exposed to or susceptible to infection.

among

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

Culex Mosquito

Assorted Ticks

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.

2.
3.
4.

5.

6.

What proportion of the population should be immunized to

achieve eradication.
What is the best age to immunize?
How is this affected by birth rates and other factors
How does immunization affect the age distribution of susceptible
individuals, particularly those in age-classes most at risk of
serious disease?
How significant are genetic, social, or spatial heterogeneities in
susceptibility to infection?
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
infection

Epidemic
Period

Ro

Critical
Coverage

Measles

4-5

15-17

92-95

Pertussis

4-5

3-4

15-17

92-95

Mumps

6-7

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 relatives
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

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

4. 35

2. 03

4. 03

18. 27

41. 67

74. 34

93. 41

95. 68

93. 75

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

Posi t i ve Rat e
Tot al Number of Sera

Day Di ff 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

death
s

cases

death
s

cases

death
s

cases

death
s

cases

death
s

cases

death
s

cases

death
s

Azerbaijan

Cambodia

China

13

30

20

Djibouti

Egypt

18

10

25

47

20

Indonesia

20

13

55

45

42

37

15

12

132

107

Iraq

Laos

Myanmar

Nigeria

Pakistan

Thailand

17

12

25

17

Turkey

12

12

Total

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 illprepared 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.