Influenza virus surveillance, vaccine strain selection, and manufacture.

As outlined in other chapters, the influenza virus, existing laboratory diagnostic abilities, and disease epidemiology have several peculiarities that impact on the timing and processes for the annual production of influenza vaccines. The chapter provides an overview on the key biological and other factors that influence vaccine production. They are the reason for an "annual circle race" beginning with global influenza surveillance during the influenza season in a given year to the eventual supply of vaccines 12 months later in time before the next seasonal outbreak and so on. As influenza vaccines are needed for the Northern and Southern Hemisphere outbreaks in fall and spring, respectively, global surveillance and vaccine production has become a year round business. Its highlights are the WHO recommendations on vaccine strains in February and September and the eventual delivery of vaccine doses in time before the coming influenza season. In between continues vaccine strain and epidemiological surveillance, preparation of new high growth reassortments, vaccine seed strain preparation and development of standardizing reagents, vaccine bulk production, fill-finishing and vaccine release, and in some regions, clinical trials for regulatory approval.

Seasonal influenza vaccine provides priming for A/H1N1 immunization.

Mass vaccination against the 2009 A/H1N1 influenza virus, with different vaccine formulations, is being implemented globally. Because of the urgency with which the vaccine has been prepared, little information has been gathered on variables that influence the effectiveness of the vaccine. Specifically, it is not clear whether priming by previous infection with or vaccination against seasonal influenza affects the response to the vaccine. Similarly, the role of vaccine adjuvants in vaccine response is not known. To address these questions, we injected ferrets with seasonal influenza vaccine and then vaccinated with 2009 A/H1N1 vaccine with or without the oil-in-water adjuvant MF59. The results show that the seasonal flu vaccine, although it did not induce functional antibodies against the 2009 A/H1N1 virus, provided immunological priming and allowed production of protective antibodies to 2009 A/H1N1 after one dose of 2009 A/H1N1 vaccine. The vaccine given without adjuvant significantly reduced viral load in the lungs but did not protect from infection. Only the vaccine with adjuvant completely prevented both pulmonary and nasal infection.

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.

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.

SARS molecular detection external quality assurance.

Inactivated severe acute respiratory syndrome-associated coronavirus samples were used for an external quality assurance study within the World Health Organization SARS Reference and Verification Network and other reference institutions. Of 58 participants, 51 correctly detected virus in all samples > or =9,400 RNA copies per milliliter and none in negative samples. Commercial test kits significantly improved the outcome.

Newly discovered coronavirus as the primary cause of severe acute respiratory syndrome.

BACKGROUND: The worldwide outbreak of severe acute respiratory syndrome (SARS) is associated with a newly discovered coronavirus, SARS-associated coronavirus (SARS-CoV). We did clinical and experimental studies to assess the role of this virus in the cause of SARS. METHODS: We tested clinical and postmortem samples from 436 SARS patients in six countries for infection with SARS-CoV, human metapneumovirus, and other respiratory pathogens. We infected four cynomolgus macaques (Macaca fascicularis) with SARS-CoV in an attempt to replicate SARS and did necropsies on day 6 after infection. FINDINGS: SARS-CoV infection was diagnosed in 329 (75%) of 436 patients fitting the case definition of SARS; human metapneumovirus was diagnosed in 41 (12%) of 335, and other respiratory pathogens were diagnosed only sporadically. SARS-CoV was, therefore, the most likely causal agent of SARS. The four SARS-CoV-infected macaques excreted SARS-CoV from nose, mouth, and pharynx from 2 days after infection. Three of four macaques developed diffuse alveolar damage, similar to that in SARS patients, and characterised by epithelial necrosis, serosanguineous exudate, formation of hyaline membranes, type 2 pneumocyte hyperplasia, and the presence of syncytia. SARS-CoV was detected in pneumonic areas by virus isolation and RT-PCR, and was localised to alveolar epithelial cells and syncytia by immunohistochemistry and transmission electron microscopy. INTERPRETATION: Replication in SARS-CoV-infected macaques of pneumonia similar to that in human beings with SARS, combined with the high prevalence of SARS-CoV infection in SARS patients, fulfill the criteria required to prove that SARS-CoV is the primary cause of SARS.

The global agenda on influenza surveillance and control.

In collaboration with its many partners, WHO has developed a new Global Agenda on Influenza Surveillance and Control. The Global Agenda defines 17 priority activities that are critical to reducing the morbidity and mortality from annual influenza epidemics and preparing for the next pandemic. The Global Agenda will provide the foundation for global and national intervention plans, facilitate international coordination of prevention and control activities and contribute to renewed interest in epidemic influenza prevention and pandemic preparedness.