Respiratory Viruses Slide Set

Prevention of Influenza Viruses Infection

G. Prevention

Vaccines against influenza have been around for 50 years. Despite this, the efficacy of influenza vaccines is still questioned, and the ability of vaccines to limit epidemic infection has not been proven.

1. Immunity to Influenza - the results of challenge studies indicated that immunity is induced by the host responses to the virus haemagglutinin (HA) and to neuraminidase (NA). Antibody against HA is the most important component in the protection against influenza viruses. In addition to conferring relative protection against infection, serum HI is reported both to reduce the severity of infection and decrease virus spreading in infected persons. Serum anti-neuraminidase Ab has also been shown to contribute protection against influenza infection. A generally held view is that serum HI antibody is more important in determining immunity than anti-neuraminidase antibody. It is clear that an influenza vaccine must contain both HA and NA antigens in a form which will stimulate the production of neutralizing antibody, local IgA antibody and possibly cellular immunity.

2. Types of vaccine

1. Whole virus vaccines - whole inactivated virus vaccines were the first influenza vaccines to be produced. The currently circulating strain of influenza is inoculated into embryonated eggs, harvested 2-3 days later and inactivated. this vaccine confers protection in 60-90% of vaccinees and the protection lasts for 1-5 years, depending on the vaccine strain and the age of the vaccinee. However, the subsequent infecting virus may show slow antigenic drift and the vaccine induced antibody will be less effective in conferring protection against the new strains.
   
2. Split virus vaccines - Because of the high incidence of reactions seen in vaccinees given whole, inactivated virus vaccine, attempts have been made to produce a vaccine which is less reactogenic but conserving immunogenicity. Split vaccines were prepared inactivated particles disrupted with detergents. These vaccines have been shown to induce fewer side effects in the vaccinees and are just are immunogenic as whole virus vaccine. Whole virus vaccine should not be used in children.
   
3. Subunit virus vaccines - subunit vaccines have been prepared which contained only the HA and NA antigens. These are used in aqueous suspension or may be absorbed to carriers such as alhydrogel. Volunteers given subunit vaccines experienced fewer reactions than those given whole virus vaccines and those given aqueous vaccine experienced fewer reactions than those given the absorbed subunit vaccine. therefore, the best vaccines available at present are the aqueous subunit vaccines, although some authorities have questioned the effectiveness of subunit vaccines.
   
4. Live attenuated vaccines - there is experimental evidence that immunization with live, attenuated influenza virus vaccines induce a solid immunity than do inactivated vaccines. Normal methods for attenuation, such as repeated passages and temperature adaptation require a long period to complete, and probably too long for the vaccine to become available for immunization against the current influenza strain. To circumvent this problem , already attenuated strains have been mixed with wild-type virus to produce recombinants which contain the RNA fragments which code for wild-type HA and NA, and all the other genetic material form the attenuated strain. These recombinants can be produced relatively quickly. When given intranasally, produced few side effects.

Although research to develop live attenuated vaccines has been pursued for 20 years, basic problems remains particularly in the area of purification. The vaccine must also be shown to be attenuated and safe. It is estimated that if the safeguards are to be satisfied, 2 years would be needed for the development of an attenuated vaccine. This makes their development impractical , since by the time the vaccine virus can be made available, the epidemic strain against which the vaccine has been prepared would have disappeared. For an attenuated vaccine to be a practical proposition, the development time must be down to 6-9 months.

3. Recommendations - At present, no live attenuated vaccine is available for general use. The vaccines that are currently available are produced from virus grown in embryonated eggs. The aqueous subunit vaccine is the most acceptable formulation. These vaccines produce few reactions and confer protection in 60-90% of vaccinees. Vaccination is recommended for the elderly and individuals at risk for severe infection. In addition, key personnel n industry and social and medical services. It is highly debatable whether the vaccine should be given to the general population. Influenza immunization is strongly recommended for adults and children with any of the following:

1. Chronic respiratory disease
2. Chronic heart disease
3. Chronic renal failure
4. Diabetes mellitus and other endocrine disorders
5. Immunosuppresion due to disease or treatment

Immunization is also recommended for residents of nursing homes and old peoples' homes and other long stay facilities where rapid spread is likely to follow. Two types of vaccines are available in the UK; "split virus vaccines", and "surface antigen" vaccine which contains highly purified HA and NA antigens prepared from disrupted virus particles. Both vaccines are suitable for use in children.

4. WHO Influenza Surveillance Program

The WHO has a network of around 110 influenza centres worldwide that regularly submit new influenza isolates to the 4 WHO collaborating centres (US, UK, Japan, Australia) for analysis. The aim is to detect  new and potentially dangerous strains of influenza at the earliest moment so that measures can be enacted in the event of a pandemic. The strains used in current influenza vaccines are supplied to the vaccine by the WHO. It is normally a trivalent vaccine: one H3N2, one H1N1 and one influenza A sutype. The sutypes selected are those that are normally the most antigencally diverse strains considered to have to greatest epidemic potential.

H. H5N1 Avian Influenza

The H5N1 avian influenza outbreak in Hong Kong 1997

In the latter half of 1997, an outbreak occurred in Hong Kong whereby 18 persons were infected by an avian influenza A, serotype H5N1. Of these 6 died, and 3 others were severely ill. The source of the outbreak was infected chickens and the outbreak stopped after all the chickens were slaughtered in the territory. Large-scale serological studies carried out showed that workers in the poultry industry were particularly at risk of infection although none complained of any symptoms. There was evidence of limited human to human transmission. It was postulated that the strain of avian influenza involved was unusually virulent; it had multiple basic amino acids near the cleavage site of the haemagglutinin protein, which as a result may render the haemagglutinin susceptible to a wider range of proteases. Since that outbreak, no more cases have occurred. In 1999, there were reports of human infections by avian influenza A H9N2 in Hong Kong and in Mainland China. However, all these cases were very mild and it is thought that the virus was unlikely to pose a large public health risk.
 

2003 Onwards

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 Europe and Africa. The WHO has put great priority and resources in the surveillance of H5N1 infections worldwide in the hope of averting or diminishing the impact of a pandemic should a pandemic capable strain emerges. http://www.who.int/csr/disease/avian_influenza/en/

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 although a few suspicious clustering of cases in families have occurred. It is thought an avian influenza may acquire this capability through either

1. Reassortment with human influenza viruses (1957 and 1968). Reassortments in 1957 (H1N1-H2N2), and 1968 (H2N2-H3N2) are thought to have occurred through an intermediary host such as the pig.

2. Gradual mutations, as suspected in the 1918 pandemic H1N1 strain. Direct infection of humans by H5N1 opens the possibility that reassortment can occur without an intermediary host.

Many experts believe that a pandemic was stopped in 1997 in Hong Kong 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

A large number of control measures have been implemented or recommended against avian H5N1 infection, at both the animal and human level. These include increased surveillance of livestock, increased biosecurity to prevent contact between livestock and migratory birds, and also vaccination of livestock. At the human level, there is increased surveillance, stockpiling of tamiflu, and also the development of candidate vaccines.

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.
 

Respiratory Viruses Slide Set