Giuseppe
Emeritus
Global influenza surveillance network: laboratory surveillance and response to pandemic H1N1 2009 (WHO, WER, edited)
[Original Full Document: LINK. EDITED.]
Weekly epidemiological record - 4 september 2009, 84th year - No. 36, 2009, 84, 361?372 (http://www.who.int/wer)
Global influenza surveillance network: laboratory surveillance and response to pandemic H1N1 2009
Background
In response to the spread of the new influenza A (H1N1) virus, WHO declared pandemic influenza Phase 6 on 11 June 2009(1) and organized a global response to this event with partners. Monitoring the evolution of the pandemic virus and sharing information for public health response have been key components of the global response. Under the coordination of WHO, the Global influenza surveillance network (GISN)(2) has made significant contributions to these efforts. This network comprises 5 WHO collaborating centres for reference and research on influenza (WHOCC), 4 essential regulatory laboratories (ERLs) and 128 institutions in 99 countries, that are recognized by WHO as national influenza centres (NICs).
From the start of the pandemic, regular teleconferences with the WHOCCs and ERLs have been held for periodic exchange and review of laboratory response and virological findings. This report provides a summary of the GISN?s response including pandemic H1N1 2009 diagnostic assays, circulating pandemic and seasonal viruses, antigenic and genetic characterization of the viruses, antiviral resistance monitoring, and vaccine virus and reagent development.
1. Diagnostic assays
Pandemic H1N1 2009 viruses were first detected in April 2009. Laboratories in GISN are conducting diagnostic assays for virus detection, virological surveillance and for clinical management.(3) The United States Centers for Disease Control and Prevention (CDC) has developed a real-time reverse transcriptase polymerase chain reaction (RT-PCR) diagnostic method for the detection of pandemic H1N1 2009 viruses and, to date, has distributed >600 PCR kits to laboratories in the USA and worldwide. Many institutions were able to acquire such assays following WHO/GISN timely announcement on the web.(4) Supplementary reagent kits for the haemagglutination inhibition (HI) test have been sent to laboratories in the USA and to 40 laboratories in 25 countries.
Many other institutes have developed real-time and conventional PCR assays as well as sequencing protocols for the detection and confirmation of pandemic H1N1 2009 virus. WHO is coordinating the development and use of these assays in GISN and strengthening laboratory capacity in various regions.
2. Monitoring the co-circulation of pandemic and seasonal influenza virus
Data on the number of specimens positive for pandemic (H1N1) 2009 and seasonal influenza viruses have been collected through FluNet, an internet-based data query and reporting tool developed by WHO to facilitate global influenza reporting,(5) as well as directly from the WHOCCs. During the pandemic period from 19 April (week 17) to 1 August 2009 (week 31), 60 655 specimens tested positive for influenza and were reported to Flu-Net by 73 countries, areas and territories. Of these, 35 585 (58.7%) specimens tested positive for pandemic H1N1 2009.
The proportion of pandemic H1N1 versus seasonal influenza viruses reported to FluNet increased from week 17 to week 31. Data from the reporting countries, areas and territories are shown in Fig 1. However, as not all countries experiencing pandemic H1N1 2009 activity reported to FluNet during this time period, the data should be interpreted cautiously.
From the start of the pandemic until 1 August 2009, 119 countries, areas and territories cumulatively shared 8042 clinical samples and 2000 virus isolates with WHOCCs. Of the total, 8062 specimens (clinical and isolates) were tested and 6153 (76.3%) tested positive for influenza. Of these positive specimens, 3586 (58.3%) were pandemic H1N1, 1990 (32.3%) were non-pandemic influenza A and 577 (9.4%) were influenza B. The proportions reported here may not be representative of influenza virus circulation in the submitting countries.
It is nevertheless clear from both the WHOCC and Flu-Net reporting systems that the pandemic H1N1 2009 virus is the predominant influenza virus circulating in many countries, including those in the Southern Hemisphere that are currently experiencing winter conditions.
3. Monitoring the evolution of the pandemic H1N1 2009 virus: antigenic and genetic characterization
Studies on the virological characteristics of the pandemic H1N1 2009 virus are being carried out by GISN to monitor the evolution of the virus. A number of pandemic H1N1 2009 clinical specimens and isolates from affected countries have also been shared with the WHOCCs for detailed virus characterization. From April to 1 August 2009, 119 shipments from 56 countries, areas and territories to the WHOCCs were received with facilitation by the WHO global influenza shipment fund project.(6) Representative pandemic HIN1 2009 virus isolates from many countries have been analysed both antigenically and genetically by the WHOCCs. All viruses tested to date are antigenically similar to the A/California/7/2009 vaccine virus, as revealed by the HI test using ferret antisera. Viruses that have been sequenced are all closely related to the A/California/7/2009, virus with very minor genetic variation. Complete genome sequencing has shown no evidence of reassortment with other influenza viruses.
Serological studies conducted at the WHOCCs suggest that a proportion of older adults have some level of cross-reactive neutralizing antibodies to the pandemic H1N1 2009 virus. Data from a study in Japan showed that 40% of 30 elderly persons (aged 72?103 years; average 83 years) had neutralizing antibody titers of >40 against the pandemic virus. Data from the USA showed that children and younger adults aged <30 years had little or no cross-reactive antibodies to human infection with pandemic A (H1N1) 2009 influenza virus, but that cross-reactive neutralizing antibody titers of ≥80 were detected in approximately one third of older adults (aged >60 years) tested.
Based on the data generated thus far, vaccination with recent seasonal trivalent influenza vaccines, including the 2008?2009 vaccine that contained the A/Brisbane/59/2007-like H1N1 component, did not result in a boost of cross-reactive antibodies to the pandemic H1N1 2009 virus in any age group.
4. Antiviral resistance monitoring
GISN is actively monitoring the susceptibility of emerging influenza viruses to antiviral drugs. In general, the pandemic H1N1 2009 viruses are resistant to M2 inhibitors (amantadine and rimantadine) but sensitive to neuraminidase inhibitors (oseltamivir and zanamivir). Of >2000 virus isolates from 119 countries and 180 clinical specimens evaluated from the USA, only 12 oseltamivir-resistant isolates of pandemic virus have been reported (from Canada, China, Denmark, Hong Kong Special Administrative Region of China, Japan, Singapore and the USA). All the patients experienced typical influenza-like illness and all subsequently recovered without complication. The cases were all sporadic, and resistant viruses have not been detected in close contacts of these individuals. All the resistant viruses remain sensitive to zanamivir. These findings serve as the scientific base for formulating national and global policy on the use of antiviral drugs against pandemic H1N1 2009 virus infections.(7)
5. Vaccine virus and reagent development
WHOCCs and ERLs have helped to pioneer techniques for influenza vaccine virus development over the years. In addition to undertaking studies on antigenic and genetic characterization of virus isolates and providing advice to WHO concerning vaccine virus selection, they develop classical and reverse genetics-based reassortant candidate vaccine viruses for influenza vaccine production.
a. Pandemic candidate vaccine virus recommendation
Based on the antigenic and genetic analysis, on 26 May 2009, WHO recommended A/California/7/2009-like virus for pandemic vaccine development.(8)
b. Pandemic vaccine virus and reagents development
Since the beginning of the current pandemic, WHOCCs, ERLs, partner institutions, in coordination and collaboration with vaccine manufacturers, have been making continuous efforts in the development of candidate pandemic vaccine viruses. To date, 10 reassortants and 4 wild-type vaccine viruses have been distributed to manufacturers and research institutions for vaccine development.(9, 10)
Reagents are being developed by WHO ERLs in close collaboration with the vaccine manufacturers and distributed for testing of the potency of the developed vaccines.(11)
6. Information exchange
A number of guidance documents and recommendations have been prepared by WHO in collaboration with GISN and published on the WHO web site,(12) in areas including information for laboratory diagnosis, storage, transport and shipment of specimens, the characteristics of the pandemic H1N1 2009 viruses and recommendations for vaccine development, as well as the status of vaccine virus development and availability of reagents for vaccine potency.
Rapid communication and information exchange is being facilitated among WHO/GISN, key partners and influenza experts worldwide by holding global teleconferences to strengthen the current understanding of the virological characteristics of the pandemic H1N1 2009 virus. The first global teleconference was held on 15 July 2009 with participation from WHOCCs, H5 reference laboratories, NICs, research institutions, laboratory experts of the Organisation Mondiale de la Sant? Animale (OIE) and Food and Agriculture Organization (FAO), WHO Regional Offices and WHO headquarters. Regular teleconferences are planned in the future.
7. Summary
Under the coordination and leadership of WHO, the GISN laboratories have made important contributions and will continue to support the global response to pandemic H1N1 2009 through monitoring of the virus: its spread, evolution and biological behavior, which have been the scientific foundation for many other response measures, for example the use of antiviral drugs and the development of vaccine.
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(1) See http://www.who.int/mediacentre/news/statements/2009/h1n1_pandemic_phase6_20090611/en/index.html
(2) See http://www.who.int/csr/disease/influenza/influenzanetwork/en/index.html
(3) See http://www.who.int/csr/resources/publications/swineflu/diagnostic_recommendations/en/index.html
(4) See http://www.who.int/csr/resources/publications/swineflu/realtimeptpcr/en/index.html
(5) See http://www.who.int/flunet
(6) See http://www.euro.who.int/Document/INF/flu_samples_ship_instructions.pdf
(7) See http://www.who.int/csr/resources/publications/swineflu/h1n1_use_antivirals_20090820/en/index.html
(8) See http://www.who.int/csr/resources/publications/swineflu/H1N1Vaccinevirusrecommendation26May2009.pdf
(9) See http://www.who.int/csr/resources/publications/swineflu/summary_candidate_vaccine.pdf
(10) See http://www.who.int/csr/resources/publications/swineflu/nibrg_121xp/en/index.html
(11) See http://www.who.int/csr/resources/publications/swineflu/vaccine_potency_reagents/en/index.html
(12) See http://www.who.int/csr/disease/swineflu/guidance/laboratory/en/index.html
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[Original Full Document: LINK. EDITED.]
Weekly epidemiological record - 4 september 2009, 84th year - No. 36, 2009, 84, 361?372 (http://www.who.int/wer)
Global influenza surveillance network: laboratory surveillance and response to pandemic H1N1 2009
Background
In response to the spread of the new influenza A (H1N1) virus, WHO declared pandemic influenza Phase 6 on 11 June 2009(1) and organized a global response to this event with partners. Monitoring the evolution of the pandemic virus and sharing information for public health response have been key components of the global response. Under the coordination of WHO, the Global influenza surveillance network (GISN)(2) has made significant contributions to these efforts. This network comprises 5 WHO collaborating centres for reference and research on influenza (WHOCC), 4 essential regulatory laboratories (ERLs) and 128 institutions in 99 countries, that are recognized by WHO as national influenza centres (NICs).
From the start of the pandemic, regular teleconferences with the WHOCCs and ERLs have been held for periodic exchange and review of laboratory response and virological findings. This report provides a summary of the GISN?s response including pandemic H1N1 2009 diagnostic assays, circulating pandemic and seasonal viruses, antigenic and genetic characterization of the viruses, antiviral resistance monitoring, and vaccine virus and reagent development.
1. Diagnostic assays
Pandemic H1N1 2009 viruses were first detected in April 2009. Laboratories in GISN are conducting diagnostic assays for virus detection, virological surveillance and for clinical management.(3) The United States Centers for Disease Control and Prevention (CDC) has developed a real-time reverse transcriptase polymerase chain reaction (RT-PCR) diagnostic method for the detection of pandemic H1N1 2009 viruses and, to date, has distributed >600 PCR kits to laboratories in the USA and worldwide. Many institutions were able to acquire such assays following WHO/GISN timely announcement on the web.(4) Supplementary reagent kits for the haemagglutination inhibition (HI) test have been sent to laboratories in the USA and to 40 laboratories in 25 countries.
Many other institutes have developed real-time and conventional PCR assays as well as sequencing protocols for the detection and confirmation of pandemic H1N1 2009 virus. WHO is coordinating the development and use of these assays in GISN and strengthening laboratory capacity in various regions.
2. Monitoring the co-circulation of pandemic and seasonal influenza virus
Data on the number of specimens positive for pandemic (H1N1) 2009 and seasonal influenza viruses have been collected through FluNet, an internet-based data query and reporting tool developed by WHO to facilitate global influenza reporting,(5) as well as directly from the WHOCCs. During the pandemic period from 19 April (week 17) to 1 August 2009 (week 31), 60 655 specimens tested positive for influenza and were reported to Flu-Net by 73 countries, areas and territories. Of these, 35 585 (58.7%) specimens tested positive for pandemic H1N1 2009.
The proportion of pandemic H1N1 versus seasonal influenza viruses reported to FluNet increased from week 17 to week 31. Data from the reporting countries, areas and territories are shown in Fig 1. However, as not all countries experiencing pandemic H1N1 2009 activity reported to FluNet during this time period, the data should be interpreted cautiously.
From the start of the pandemic until 1 August 2009, 119 countries, areas and territories cumulatively shared 8042 clinical samples and 2000 virus isolates with WHOCCs. Of the total, 8062 specimens (clinical and isolates) were tested and 6153 (76.3%) tested positive for influenza. Of these positive specimens, 3586 (58.3%) were pandemic H1N1, 1990 (32.3%) were non-pandemic influenza A and 577 (9.4%) were influenza B. The proportions reported here may not be representative of influenza virus circulation in the submitting countries.
It is nevertheless clear from both the WHOCC and Flu-Net reporting systems that the pandemic H1N1 2009 virus is the predominant influenza virus circulating in many countries, including those in the Southern Hemisphere that are currently experiencing winter conditions.
3. Monitoring the evolution of the pandemic H1N1 2009 virus: antigenic and genetic characterization
Studies on the virological characteristics of the pandemic H1N1 2009 virus are being carried out by GISN to monitor the evolution of the virus. A number of pandemic H1N1 2009 clinical specimens and isolates from affected countries have also been shared with the WHOCCs for detailed virus characterization. From April to 1 August 2009, 119 shipments from 56 countries, areas and territories to the WHOCCs were received with facilitation by the WHO global influenza shipment fund project.(6) Representative pandemic HIN1 2009 virus isolates from many countries have been analysed both antigenically and genetically by the WHOCCs. All viruses tested to date are antigenically similar to the A/California/7/2009 vaccine virus, as revealed by the HI test using ferret antisera. Viruses that have been sequenced are all closely related to the A/California/7/2009, virus with very minor genetic variation. Complete genome sequencing has shown no evidence of reassortment with other influenza viruses.
Serological studies conducted at the WHOCCs suggest that a proportion of older adults have some level of cross-reactive neutralizing antibodies to the pandemic H1N1 2009 virus. Data from a study in Japan showed that 40% of 30 elderly persons (aged 72?103 years; average 83 years) had neutralizing antibody titers of >40 against the pandemic virus. Data from the USA showed that children and younger adults aged <30 years had little or no cross-reactive antibodies to human infection with pandemic A (H1N1) 2009 influenza virus, but that cross-reactive neutralizing antibody titers of ≥80 were detected in approximately one third of older adults (aged >60 years) tested.
Based on the data generated thus far, vaccination with recent seasonal trivalent influenza vaccines, including the 2008?2009 vaccine that contained the A/Brisbane/59/2007-like H1N1 component, did not result in a boost of cross-reactive antibodies to the pandemic H1N1 2009 virus in any age group.
4. Antiviral resistance monitoring
GISN is actively monitoring the susceptibility of emerging influenza viruses to antiviral drugs. In general, the pandemic H1N1 2009 viruses are resistant to M2 inhibitors (amantadine and rimantadine) but sensitive to neuraminidase inhibitors (oseltamivir and zanamivir). Of >2000 virus isolates from 119 countries and 180 clinical specimens evaluated from the USA, only 12 oseltamivir-resistant isolates of pandemic virus have been reported (from Canada, China, Denmark, Hong Kong Special Administrative Region of China, Japan, Singapore and the USA). All the patients experienced typical influenza-like illness and all subsequently recovered without complication. The cases were all sporadic, and resistant viruses have not been detected in close contacts of these individuals. All the resistant viruses remain sensitive to zanamivir. These findings serve as the scientific base for formulating national and global policy on the use of antiviral drugs against pandemic H1N1 2009 virus infections.(7)
5. Vaccine virus and reagent development
WHOCCs and ERLs have helped to pioneer techniques for influenza vaccine virus development over the years. In addition to undertaking studies on antigenic and genetic characterization of virus isolates and providing advice to WHO concerning vaccine virus selection, they develop classical and reverse genetics-based reassortant candidate vaccine viruses for influenza vaccine production.
a. Pandemic candidate vaccine virus recommendation
Based on the antigenic and genetic analysis, on 26 May 2009, WHO recommended A/California/7/2009-like virus for pandemic vaccine development.(8)
b. Pandemic vaccine virus and reagents development
Since the beginning of the current pandemic, WHOCCs, ERLs, partner institutions, in coordination and collaboration with vaccine manufacturers, have been making continuous efforts in the development of candidate pandemic vaccine viruses. To date, 10 reassortants and 4 wild-type vaccine viruses have been distributed to manufacturers and research institutions for vaccine development.(9, 10)
Reagents are being developed by WHO ERLs in close collaboration with the vaccine manufacturers and distributed for testing of the potency of the developed vaccines.(11)
6. Information exchange
A number of guidance documents and recommendations have been prepared by WHO in collaboration with GISN and published on the WHO web site,(12) in areas including information for laboratory diagnosis, storage, transport and shipment of specimens, the characteristics of the pandemic H1N1 2009 viruses and recommendations for vaccine development, as well as the status of vaccine virus development and availability of reagents for vaccine potency.
Rapid communication and information exchange is being facilitated among WHO/GISN, key partners and influenza experts worldwide by holding global teleconferences to strengthen the current understanding of the virological characteristics of the pandemic H1N1 2009 virus. The first global teleconference was held on 15 July 2009 with participation from WHOCCs, H5 reference laboratories, NICs, research institutions, laboratory experts of the Organisation Mondiale de la Sant? Animale (OIE) and Food and Agriculture Organization (FAO), WHO Regional Offices and WHO headquarters. Regular teleconferences are planned in the future.
7. Summary
Under the coordination and leadership of WHO, the GISN laboratories have made important contributions and will continue to support the global response to pandemic H1N1 2009 through monitoring of the virus: its spread, evolution and biological behavior, which have been the scientific foundation for many other response measures, for example the use of antiviral drugs and the development of vaccine.
-
(1) See http://www.who.int/mediacentre/news/statements/2009/h1n1_pandemic_phase6_20090611/en/index.html
(2) See http://www.who.int/csr/disease/influenza/influenzanetwork/en/index.html
(3) See http://www.who.int/csr/resources/publications/swineflu/diagnostic_recommendations/en/index.html
(4) See http://www.who.int/csr/resources/publications/swineflu/realtimeptpcr/en/index.html
(5) See http://www.who.int/flunet
(6) See http://www.euro.who.int/Document/INF/flu_samples_ship_instructions.pdf
(7) See http://www.who.int/csr/resources/publications/swineflu/h1n1_use_antivirals_20090820/en/index.html
(8) See http://www.who.int/csr/resources/publications/swineflu/H1N1Vaccinevirusrecommendation26May2009.pdf
(9) See http://www.who.int/csr/resources/publications/swineflu/summary_candidate_vaccine.pdf
(10) See http://www.who.int/csr/resources/publications/swineflu/nibrg_121xp/en/index.html
(11) See http://www.who.int/csr/resources/publications/swineflu/vaccine_potency_reagents/en/index.html
(12) See http://www.who.int/csr/disease/swineflu/guidance/laboratory/en/index.html
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