Control of Viral Diseases

1. Control of Viral Diseases Derek Wong “Wong’s Virology” http://virology-online.com

2. 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

3. 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

4. Surveillance of Infectious Diseases

5. 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

6. Notifiable viral diseases (Hong Kong) • Yellow fever • Poliomyelitis • Measles • Mumps • Rubella • Rabies (Human and Animal) • Viral Hepatitis • Dengue fever • Chicken Pox • H5N1 influenza • SARS

7. 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

8. Laboratory based surveillance • Scientific source of information • Coherent and consistent information on trends of infection • Qualitative detail information

9. Control Measures Available

10. 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.

11. 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.

12. 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

13. Man-Arthropod-Man Cycle

14. Animal-Arthropod-Man Cycle

15. Examples of Arthropod Vectors Aedes Aegyti Assorted Ticks Phlebotmine Sandfly Culex Mosquito

16. Vaccination

17. 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.

18. 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

19. Developing a vaccination policy The following questions should be asked when a vaccination policy against a particular virus is being developed. • 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?

20. 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.

21. 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

22. Eradication of Small Pox

23. 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.

24. 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.

25. 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.

26. 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

27. The SARS Crisis

28. 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.

29. 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.

30. 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

31. 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.

33. 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

34. 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.

35. 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.

36. 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.

37. H5N1 Avian Influenza

38. 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.

39. Human Cases Reported to the WHO as of April 2008

40. 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.

41. 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.

42. 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.

43. 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.