Key policy and programmatic factors to improve influenza vaccination rates based on the experience from four high-performing countries.

BACKGROUND: Many countries consistently fail to achieve the target influenza vaccine coverage rate (VCR) of 75% for populations at risk of complications, recommended by the World Health Organization and European Council. We aimed to identify factors for achieving a high VCR in the scope of four benchmark countries with high influenza VCRs: Australia, Canada, UK and USA. METHODS: Publicly available evidence was first reviewed at a global level and then for each of the four countries. Semi-structured interviews were then conducted with stakeholders meeting predefined criteria. Descriptive cluster analyses were performed to identify key factors and pillars for establishing and maintaining high VCRs. RESULTS: No single factor led to a high VCR, and each benchmark country used a different combination of tailored approaches to achieve a high vaccine coverage. In each country, specific triggers were important to stimulate changes that led to improved vaccine coverage. A total of 42 key factors for a successful influenza vaccination programme were identified and clustered into five pillars: (1) Health Authority accountability and strengths of the influenza programme, (2) facilitated access to vaccination, (3) healthcare professional accountability and engagement, (4) awareness of the burden and severity of disease and (5) belief in influenza vaccination benefit. Each benchmark country has implemented multiple factors from each pillar. CONCLUSION: A wide range of factors were identified from an evaluation of four high-performing benchmark countries, classified into five pillars, thus providing a basis for countries with lower VCRs to tailor their own particular solutions to improve their influenza VCR.

Vaccines for pandemic influenza. The history of our current vaccines, their limitations and the requirements to deal with a pandemic threat.

Fears of a potential pandemic due to A(H5N1) viruses have focussed new attention on our current vaccines, their shortcomings, and concerns regarding global vaccine supply in a pandemic. The bulk of current vaccines are inactivated split virus vaccines produced from egg-grown virus and have only modest improvements compared with those first introduced over 60 years ago. Splitting, which was introduced some years ago to reduce reactogenicity, also reduces the immunogenicity of vaccines in immunologically naïve recipients. The A(H5N1) viruses have been found poorly immunogenic and present other challenges for vaccine producers which further exacerbate an already limited global production capacity. There have been some recent improvements in vaccine production methods and improvements to immunogenicity by the development of new adjuvants, however, these still fall short of providing timely supplies of vaccine for all in the face of a pandemic. New approaches to influenza vaccines which might fulfil the demands of a pandemic situation are under evaluation, however, these remain some distance from clinical reality and face significant regulatory hurdles.

Avian influenza: a pandemic waiting in the wings?

Recent widespread outbreaks of avian influenza and, associated with these a growing number of human infections with a high mortality rate, have raised concerns that this might be the prelude to a severe pandemic of human influenza. As a background to these concerns the present article reviews influenza as a human disease, its origins and the involvement of other species, properties of the influenza viruses and the current status of influenza prevention and control.

A novel means of identifying the neuraminidase type of currently circulating human A(H1) influenza viruses.

With the recent emergence and spread of influenza A(H1N2) viruses which appear to have arisen by reassortment of circulating A(H1N1) and A(H3N2) strains, there is a need in epidemiological studies to determine the neuraminidase type in order to differentiate between influenza A(H1N2) and A(H1N1) strains. A fluorescence-based neuraminidase enzyme inhibition assay that has been developed to screen influenza viruses for potential resistance to the neuraminidase inhibitor drugs appears to be suitable for this purpose. When used with the neuraminidase inhibitor zanamivir the assay was able to provide a positive predictive value of 93.5% for the identification of neuraminidase type N1 or N2. This assay enables a large number of influenza A viruses to be screened at low cost to determine relative levels of A(H1N2) or A(H1N1) viruses circulating in the population.

Identification of a human influenza type B strain with reduced sensitivity to neuraminidase inhibitor drugs.

A total of 126 influenza B isolates isolated between 1998 and 2002 from Australasia and the Asia-Pacific region were tested for their sensitivity to the neuraminidase (NA) inhibitor drugs zanamivir and oseltamivir carboxylate using a fluorescence-based enzyme assay. The mean (+/-1 S.D.) 50% inhibitory concentration (IC50) of the influenza B viruses tested was 1.41+/-0.53 nM against zanamivir and 14.91+/-14.31 nM with oseltamivir carboxylate. However, a single type B isolate (B/Perth/211/2001) from an infant who had not been treated with either of the NA inhibitor drugs, showed a nine-fold lower sensitivity to zanamivir and a 14-fold lower sensitivity to oseltamivir carboxylate compared with the mean IC50 of influenza B strains. A decrease in sensitivity to oseltamivir carboxylate and RWJ-270201 was also seen in both: a chemiluminescent assay and a second different fluorescent assay. Sequence analysis of the haemagglutinin HA1 region and the neuraminidase gene of B/Perth/211/2001 revealed no amino acid changes in sites that have previously been reported to confer resistance to either of the NAI drugs. Further investigations are in progress to identify the basis for this reduced sensitivity.

Susceptibility of human influenza viruses from Australasia and South East Asia to the neuraminidase inhibitors zanamivir and oseltamivir.

Human influenza viruses isolated from Australasia (Australia and New Zealand) and South East Asia were analysed to determine their sensitivity to the NA inhibitor drugs, zanamivir and oseltamivir. A total of 532 strains isolated between 1998 and 2002 were tested using a fluorescence-based assay to measure the relative inhibition of NA activity over a range of drug concentrations. Based on median IC50 values, influenza A viruses (with neuraminidase subtypes N1 and N2) were more sensitive to both the NA inhibitors than were influenza B strains. Influenza A viruses with a N1 subtype and influenza B strains both demonstrated a greater sensitivity to zanamivir than to oseltamivir carboxylate, whereas influenza A strains with a N2 subtype were more susceptible to oseltamivir carboxylate. For each of the neuraminidase types, IC50 values for viruses from Australasia and South East Asia were found to be comparable. Based on the data prior to and following the licensing of the drugs into the respective regions, the use of the NA inhibitors did not appear to have a significant impact on the susceptibility of the viruses tested to zanamivir or oseltamivir carboxylate.

In vitro generation and characterisation of an influenza B variant with reduced sensitivity to neuraminidase inhibitors.

A contemporary influenza type B virus was passaged in vitro in the presence of increasing concentrations of the neuraminidase inhibitors, zanamivir and oseltamivir carboxylate (0.1-1000 microM over nine passages). After the fifth passage in the presence of zanamivir (10 microM), the virus acquired a Glu 119 Asp neuraminidase mutation (influenza A N2 subtype numbering) in the enzyme active site. After a further three passages, in which growth occurred in 100 microM of zanamivir, a Gln 218 Lys mutation (A (H3) numbering) in the HA1 domain of the haemagglutinin was found. In a fluorescence-based neuraminidase inhibition assay, viruses with the Glu 119 Asp NA mutation had a 32,000-fold reduction in sensitivity to the NA inhibitor zanamivir compared to the wild-type virus, while the mutation resulted in a 105-fold reduction in sensitivity to oseltamivir carboxylate. Viruses grown in the presence of 1000 microM oseltamivir carboxylate did not acquire any neuraminidase mutations but did have a His 103 Gln substitution (A (H3) numbering) in the HA1 region of the haemagglutinin which was demonstrated to significantly reduce receptor binding strength in vitro. Tissue culture assays demonstrated that the HA mutation caused a seven-fold reduction in sensitivity to oseltamivir carboxylate, and a 90-fold reduction in sensitivity to zanamivir.

Concurrent summer influenza and pertussis outbreaks in a nursing home in Sydney, Australia.

OBJECTIVE: To report on the investigation of a summer outbreak of acute respiratory illness among residents of a Sydney nursing home. DESIGN: An epidemiologic and microbiological investigation of the resident cohort at the time of the outbreak and medical record review 5 months later. SETTING: A nursing home located in Sydney, Australia, during February to July 1999. PATIENTS: The cohort of residents present in the nursing home at the time of the outbreak. INTERVENTIONS: Public health interventions included recommendations regarding hygiene, cohorting of residents and staff, closure to further admissions, and prompt reporting of illness; and virologic and serologic studies of residents. RESULTS: Of the 69 residents (mean age, 85.1 years), 35 fulfilled the case definition of acute respiratory illness. Influenza A infection was confirmed in 19 residents, and phylogenetic analysis of the resulting isolate, designated H3N2 A/Sydney/203/99, showed that it differed from strains isolated in eastern Australia during the same period. Serologic evidence of Bordetella infection was also found in 10 residents; however, stratified epidemiologic analysis pointed to influenza A as the cause of illness. CONCLUSIONS: The investigation revealed an unusual summer outbreak of influenza A concurrent with subclinical pertussis infection. Surveillance of acute respiratory illness in nursing homes throughout the year, rather than solely during epidemic periods, in combination with appropriate public health laboratory support, would allow initiation of a timely public health response to outbreaks of acute respiratory illness in this setting.

Influenza vaccine strain selection and recent studies on the global migration of seasonal influenza viruses.

Annual influenza epidemics in humans affect 5-15% of the population, causing an estimated half million deaths worldwide per year [Stohr K. Influenza-WHO cares. Lancet Infectious Diseases 2002;2(9):517]. The virus can infect this proportion of people year after year because the virus has an extensive capacity to evolve and thus evade the immune response. For example, since the influenza A(H3N2) subtype entered the human population in 1968 the A(H3N2) component of the influenza vaccine has had to be updated almost 30 times to track the evolution of the viruses and remain effective. The World Health Organization Global Influenza Surveillance Network (WHO GISN) tracks and analyzes the evolution and epidemiology of influenza viruses for the primary purpose of vaccine strain selection and to improve the strain selection process through studies aimed at better understanding virus evolution and epidemiology. Here we give an overview of the strain selection process and outline recent investigations into the global migration of seasonal influenza viruses.

The global circulation of seasonal influenza A (H3N2) viruses.

Antigenic and genetic analysis of the hemagglutinin of approximately 13,000 human influenza A (H3N2) viruses from six continents during 2002-2007 revealed that there was continuous circulation in east and Southeast Asia (E-SE Asia) via a region-wide network of temporally overlapping epidemics and that epidemics in the temperate regions were seeded from this network each year. Seed strains generally first reached Oceania, North America, and Europe, and later South America. This evidence suggests that once A (H3N2) viruses leave E-SE Asia, they are unlikely to contribute to long-term viral evolution. If the trends observed during this period are an accurate representation of overall patterns of spread, then the antigenic characteristics of A (H3N2) viruses outside E-SE Asia may be forecast each year based on surveillance within E-SE Asia, with consequent improvements to vaccine strain selection.

The influenza viruses.

Human epidemic influenza is caused by influenza type A and B viruses, which continually undergo antigenic change in their surface antigens, haemagglutinin (H) and neuraminidase (N). Influenza epidemics are the consequence of small, ongoing antigenic changes known as "antigenic drift", which occurs in both influenza types. Pandemic influenza occurs at irregular and unpredictable intervals, and is the result of a major antigenic change known as "antigenic shift", which occurs only in influenza A. Aquatic birds are the evolutionary hosts of influenza viruses; they harbour many distinct forms or subtypes of influenza A, which are usually present as harmless gut infections. Antigenic shift involves the evolution of a new human influenza A virus through the acquisition of a new haemagglutinin gene encoding a different subtype from an avian influenza, or by the adaptation of an avian virus, causing it to become transmissible between humans. Two subtypes of avian influenza, H5 and H7, can cause severe infections when introduced into domestic poultry. Recently, influenza A/H5N1 viruses have caused widespread outbreaks, starting in Asia and spreading widely to other regions. Avian influenza viruses do not readily infect humans. However, during the past 3 years, more than 250 cases of H5N1 infection of humans have occurred, with associated mortality approaching 60%. It is feared that a new pandemic of human influenza may emerge from this.

Reactogenicity and immunogenicity of an inactivated influenza vaccine administered by intramuscular or subcutaneous injection in elderly adults.

In many countries there is no clear recommendation regarding the preferred route of administration of inactivated influenza vaccines. In a randomised, observer blind study of 720 elderly subjects, a split, trivalent influenza vaccine was significantly more immunogenic for both A strains (H3N2 and H1N1, p = 0.0016 and 0.003, respectively) when given intramuscularly compared to subcutaneously. This difference was due entirely to a gender effect, with females in the intramuscular (IM) group having a significantly greater serological response than females in the subcutaneous (SC) group for both of these strains. Similar results were seen with local adverse effects. These data suggest that vaccination practices that ensure intramuscular injection are required for optimal administration of influenza vaccines in the elderly.

Report of the second meeting on the development of influenza vaccines that induce broad-spectrum and long-lasting immune responses, World Health Organization, Geneva, Switzerland, 6-7 December 2005.

New influenza vaccines that induce broad-spectrum and long-lasting immune responses and provide protection against divergent influenza viruses could overcome problems with the current vaccination strategy, based on annual intervention, better suit the needs of developing countries and contribute to epidemic and potential pandemic control. The World Health Organization held a consultation to review the current status of research in the area of influenza vaccines and to establish a research agenda for the development of such influenza vaccine. The main conclusions and recommendations from this consultation are presented below.

Neuraminidase inhibitor-resistant and -sensitive influenza B viruses isolated from an untreated human patient.

An influenza B virus from an infant with no history of treatment or contact with neuraminidase inhibitors demonstrated a significant reduction in sensitivity to these drugs. Here, we describe the analysis of a mixed viral population that contained a novel D197E amino acid substitution that was responsible for this reduction.

Detection of influenza viruses resistant to neuraminidase inhibitors in global surveillance during the first 3 years of their use.

Emergence of influenza viruses with reduced susceptibility to neuraminidase inhibitors (NAIs) develops at a low level following drug treatment, and person-to-person transmission of resistant virus has not been recognized to date. The Neuraminidase Inhibitor Susceptibility Network (NISN) was established to follow susceptibility of isolates and occurrence of NAI resistance at a population level in various parts of the world. Isolates from the WHO influenza collaborating centers were screened for susceptibilities to oseltamivir and zanamivir by a chemiluminescent enzyme inhibition assay, and those considered potentially resistant were analyzed by sequence analysis of the neuraminidase genes. During the first 3 years of NAI use (1999 to 2002), 2,287 isolates were tested. Among them, eight (0.33%) viruses had a >10-fold decrease in susceptibility to oseltamivir, one (0.22%) in 1999 to 2000, three (0.36%) in 2000 to 2001, and four (0.41%) in 2001 to 2002. Six had unique changes in the neuraminidase gene compared to neuraminidases of the same subtype in the influenza sequence database. Although only one of the mutations had previously been recognized in persons receiving NAIs, none were from patients who were known to have received the drugs. During the 3 years preceding NAI use, no resistant variants were detected among 1,054 viruses. Drug use was relatively stable during the period, except for an approximate 10-fold increase in oseltamivir use in Japan during the third year. The frequency of variants with decreased sensitivity to the NAIs did not increase significantly during this period, but continued surveillance is required, especially in regions with higher NAI use.

A comparison of a rapid test for influenza with laboratory-based diagnosis in a paediatric population.

The rapid and accurate detection of influenza A and B in a hospital setting is useful to confirm infection, exclude other diseases and assist in the management of patient illness including the possible use of specific antiviral therapy. We evaluated the use of the Directigen Flu A+B in a paediatric hospital laboratory in comparison with the established diagnostic tests direct immunofluorescence, viral culture and reverse transcriptase-polymerase chain reaction. A total of 193 respiratory specimens were examined and the Directigen test detected positive samples with an 80.8 per cent sensitivity and a specificity of 100 per cent. This study confirms other paediatric studies which have found the Directigen Flu A+B to be less sensitive than traditional laboratory tests but nevertheless to have a potential role in patient management especially when a positive result is obtained.

The epidemiology and clinical impact of pandemic influenza.

It is impossible to predict when the next pandemic of influenza will occur; however, it is almost 35 years since the last pandemic, and the longest inter-pandemic interval recorded with certainty is 39 years. The next pandemic virus is likely to emerge in southeast Asia, as have two of the last three pandemic viruses. Complete global spread is likely to occur in 6 months or less, due to increased travel and urbanisation. It is likely that the usual inter-pandemic pattern of age-specific mortality will deviate temporarily towards higher mortality in younger adults. The extent to which this will happen is unclear, as the shift was extreme in 1918-1919 but less so in subsequent pandemics. Nevertheless, this may have important implications for the protection of essential workers such as health care, emergency service and military personnel. The extent to which elderly persons will be affected will depend upon previous exposure to similar influenza viruses. It is impossible to predict the likely increase in excess mortality that will occur when a new pandemic virus emerges. However, whilst mortality on the scale experienced in 1918-1919 is probably unlikely, there was a high level of mortality among those infected with the A/H5N1 virus in 1997, so it cannot be assumed that a future pandemic will be as mild as those in 1957-1958 or 1968-1969. There is likely to be more than one wave of infection and health services in most countries will be hard pressed to provide vaccines or to manage populations with clinical attack rates of approximately 25-30% and concomitant increases in demand for both primary and secondary health care services.

Surveillance for neuraminidase inhibitor resistance in human influenza viruses from Australia.

Two hundred and forty-five human influenza A and B viruses isolated in Australia between 1996 and 2003 were tested for their sensitivity to the NA inhibitor drugs, zanamivir and oseltamivir using a fluorescence-based neuraminidase inhibition assay. Based on mean IC50 values, influenza A viruses (with neuraminidase subtypes N1 and N2) were more sensitive to both the NA inhibitors than were influenza B strains. Influenza A viruses with a N1 subtype and influenza B strains both demonstrated a greater sensitivity to zanamivir than to oseltamivir carboxylate, whereas influenza A strains with a N2 subtype were more susceptible to oseltamivir carboxylate. A comparison of IC50 values for viruses isolated before and after the release of the NA inhibitors in Australia, found there was no significant difference in the sensitivity of strains to either neuraminidase inhibitor and none of the isolates tested showed clinically significant resistance.