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.

Influenza A (H1N1 09): public health lessons and questions.

Influenza A (H1N1 09) has been in Australia for 2 months and, in a world that had been preparing for a potentially dramatic outbreak due to H5 avian influenza, it has challenged global and national planning assumptions, definitions of pandemic influenza and our public health interventions. It has also highlighted how much we have yet to learn about both pandemic and seasonal influenza.

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.

Improving the selection and development of influenza vaccine viruses - Report of a WHO informal consultation on improving influenza vaccine virus selection, Hong Kong SAR, China, 18-20 November 2015.

Since 2010 the WHO has held a series of informal consultations to explore ways of improving the currently highly complex and time-pressured influenza vaccine virus selection and development process. In November 2015 experts from around the world met to review the current status of efforts in this field. Discussion topics included strengthening influenza surveillance activities to increase the availability of candidate vaccine viruses and improve the extent, timeliness and quality of surveillance data. Consideration was also given to the development and potential application of newer laboratory assays to better characterize candidate vaccine viruses, the potential importance of antibodies directed against influenza virus neuraminidase, and the role of vaccine effectiveness studies. Advances in next generation sequencing and whole genome sequencing of influenza viruses were also discussed, along with associated developments in synthetic genomics technologies, evolutionary analysis and predictive mathematical modelling. Discussions were also held on the late emergence of an antigenic variant influenza A(H3N2) virus in mid-2014 that could not be incorporated in time into the 2014-15 northern hemisphere vaccine. There was broad recognition that given the current highly constrained influenza vaccine development and production timeline it would remain impossible to incorporate any variant virus which emerged significantly long after the relevant WHO biannual influenza vaccine composition meetings. Discussions were also held on the development of pandemic and broadly protective vaccines, and on associated regulatory and manufacturing requirements and constraints. With increasing awareness of the health and economic burdens caused by seasonal influenza, the ever-present threat posed by zoonotic influenza viruses, and the significant impact of the 2014-15 northern hemisphere seasonal influenza vaccine mismatch, this consultation provided a very timely opportunity to share developments and exchange views. In all areas, a renewed and strengthened emphasis was placed on developing concrete and measurable actions and identifying the key stakeholders responsible for their implementation.

Geographic representativeness for sentinel influenza surveillance: implications for routine surveillance and pandemic preparedness.

OBJECTIVE: To review the guidelines for geographic representativeness applied to sentinel influenza surveillance as proposed in the Framework for an Australian Influenza Pandemic Plan (1999). METHODS: The number of sentinel practices, participating general practitioners and their consultation rates per 100,000 population, by region, were described for the Victorian sentinel surveillance system for 2003 and 2004. Influenza-like illness rates per 1,000 consultations were calculated for all participating practices and for a subset of regular participators. Indicators of seasonal influenza activity, set according to predefined thresholds, were compared in the two groups. RESULTS: During these two influenza seasons, a subset of approximately one-quarter (27%) of participating practices provided almost half (45%) of the patient swabs and detected the same level of influenza activity over two influenza seasons as all participating practices. However, this subset of GPs recorded only 0.3% of all GP consultations in Victoria in 2004. CONCLUSIONS: There should be an updated, evidence-based strategy for interpandemic influenza based on the number of general practice consultations. Requirements for surveillance during various pandemic phases also need to be reviewed.

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.

Neuraminidase inhibitor susceptibility network position statement: antiviral resistance in influenza A/H5N1 viruses.

The emerging epidemic of H5N1 avian influenza virus with spillover into the human population in Asia has provoked intense concern globally about the potential of these particularly pathogenic viruses to evolve with the capacity for human-to-human transmission with a consequent pandemic. The availability of antiviral drugs with activity against influenza A viruses and the recognition of drug-resistant variants to these drugs prompted the following report by a select group of the global experts--members of the Neuraminidase Inhibitor Susceptibility Network--on the best use of the available drugs, both for prophylaxis and treatment. The editors of Antiviral Therapy are pleased to be able to provide this document in an expeditious manner.

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.

Rapid detection and simultaneous subtype differentiation of influenza A viruses by real time PCR.

A real time RT-PCR, using the LightCycler, was developed and compared with rapid antigen enzyme immunoassay (AgEIA) and enhanced virus culture for rapid detection of influenza A viruses in stored and prospectively collected respiratory specimens. Specific hybridization probes were used for simultaneous detection and differentiation between H1N1 and H3N2 subtypes. The sensitivity of the RT-PCR for influenza A H1N1 was 120 copies and H3N2 350 copies of in vitro transcribed RNA. A specimen was considered positive for influenza A when it was culture positive or at least two methods yielded a positive test result. Using these criteria, with stored samples, the RT-PCR sensitivity, specificity, positive and negative predictive values were 82.9, 95.5, 98.9 and 52.5%, respectively. In specimens collected prospectively the RT-PCR sensitivity, specificity, positive and negative predictive values were 100, 87.9, 82.8 and 100%, respectively. There was complete concordance with subtype differentiation by hybridization probe melting temperature analysis and haemagglutination inhibition assay.

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.