A review of epidemic preparedness for influenza through local vaccine production: national security for Thailand
Identifieur interne : 000A54 ( Pmc/Corpus ); précédent : 000A53; suivant : 000A55A review of epidemic preparedness for influenza through local vaccine production: national security for Thailand
Auteurs : Punnee Pitisuttithum ; Ponthip WirachwongSource :
- Human Vaccines & Immunotherapeutics [ 2164-5515 ] ; 2019.
Abstract
Being vigilant of the potential for an influenza pandemic, the Global Action Plan for Influenza Vaccines (GAP) promoted the establishment and maintenance of local vaccine manufacturing capacity. In accordance with this, the Thai government has developed its national strategic plan for influenza pandemic preparedness including the plan for manufacturing influenza vaccine in Thailand. With the support of WHO, the Thai Government Pharmaceutical Organization (GPO) as the developed local production capacity of influenza vaccines. The H1N1 live attenuated influenza vaccine (LAIV) and H5N2 LAIV produced by GPO have been proven to be safe and immunogenic through clinical trials, followed by Thai FDA licensure for pandemic use. The GPO-produced H5N2 LAIV has been proven to have priming effects on an inactivated subunit H5N1 booster vaccine. This Thai local manufacturer is now expanding its capacity to Inactivated Influenza Vaccine (IIV), aiming for sustainable influenza vaccine production for national coverage.
Url:
DOI: 10.1080/21645515.2019.1638205
PubMed: 31335234
PubMed Central: 6816430
Links to Exploration step
PMC:6816430Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">A review of epidemic preparedness for influenza through local vaccine production: national security for Thailand</title><author><name sortKey="Pitisuttithum, Punnee" sort="Pitisuttithum, Punnee" uniqKey="Pitisuttithum P" first="Punnee" last="Pitisuttithum">Punnee Pitisuttithum</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University</institution>, Bangkok,<country>Thailand</country></nlm:aff></affiliation></author><author><name sortKey="Wirachwong, Ponthip" sort="Wirachwong, Ponthip" uniqKey="Wirachwong P" first="Ponthip" last="Wirachwong">Ponthip Wirachwong</name><affiliation><nlm:aff id="AFF0002"><institution>Research and Development Institute, Government Pharmaceutical Organization</institution>, Bangkok,<country>Thailand</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31335234</idno><idno type="pmc">6816430</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816430</idno><idno type="RBID">PMC:6816430</idno><idno type="doi">10.1080/21645515.2019.1638205</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000A54</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A54</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A review of epidemic preparedness for influenza through local vaccine production: national security for Thailand</title><author><name sortKey="Pitisuttithum, Punnee" sort="Pitisuttithum, Punnee" uniqKey="Pitisuttithum P" first="Punnee" last="Pitisuttithum">Punnee Pitisuttithum</name><affiliation><nlm:aff id="AFF0001"><institution>Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University</institution>, Bangkok,<country>Thailand</country></nlm:aff></affiliation></author><author><name sortKey="Wirachwong, Ponthip" sort="Wirachwong, Ponthip" uniqKey="Wirachwong P" first="Ponthip" last="Wirachwong">Ponthip Wirachwong</name><affiliation><nlm:aff id="AFF0002"><institution>Research and Development Institute, Government Pharmaceutical Organization</institution>, Bangkok,<country>Thailand</country></nlm:aff></affiliation></author></analytic><series><title level="j">Human Vaccines & Immunotherapeutics</title><idno type="ISSN">2164-5515</idno><idno type="eISSN">2164-554X</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>ABSTRACT</title><p>Being vigilant of the potential for an influenza pandemic, the Global Action Plan for Influenza Vaccines (GAP) promoted the establishment and maintenance of local vaccine manufacturing capacity. In accordance with this, the Thai government has developed its national strategic plan for influenza pandemic preparedness including the plan for manufacturing influenza vaccine in Thailand. With the support of WHO, the Thai Government Pharmaceutical Organization (GPO) as the developed local production capacity of influenza vaccines. The H1N1 live attenuated influenza vaccine (LAIV) and H5N2 LAIV produced by GPO have been proven to be safe and immunogenic through clinical trials, followed by Thai FDA licensure for pandemic use. The GPO-produced H5N2 LAIV has been proven to have priming effects on an inactivated subunit H5N1 booster vaccine. This Thai local manufacturer is now expanding its capacity to Inactivated Influenza Vaccine (IIV), aiming for sustainable influenza vaccine production for national coverage.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Iamsirithaworn, S" uniqKey="Iamsirithaworn S">S Iamsirithaworn</name></author><author><name sortKey="Akarasewi, P" uniqKey="Akarasewi P">P Akarasewi</name></author><author><name sortKey="Yingyong, T" uniqKey="Yingyong T">T Yingyong</name></author><author><name sortKey="Suthachana, S" uniqKey="Suthachana S">S Suthachana</name></author><author><name sortKey="Pittayawonganon, C" uniqKey="Pittayawonganon C">C Pittayawonganon</name></author><author><name sortKey="Ungchusak, K" uniqKey="Ungchusak K">K. Ungchusak</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Sasaki, S" uniqKey="Sasaki S">S Sasaki</name></author><author><name sortKey="Holmes, Th" uniqKey="Holmes T">TH Holmes</name></author><author><name sortKey="Albrecht, Ra" uniqKey="Albrecht R">RA Albrecht</name></author><author><name sortKey="Garcia Sastre, A" uniqKey="Garcia Sastre A">A Garcia-Sastre</name></author><author><name sortKey="Dekker, Cl" uniqKey="Dekker C">CL Dekker</name></author><author><name sortKey="He, Xs" uniqKey="He X">XS He</name></author><author><name sortKey="Greenberg, Hb" uniqKey="Greenberg H">HB. Greenberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Clements, Ml" uniqKey="Clements M">ML Clements</name></author><author><name sortKey="Murphy, Br" uniqKey="Murphy B">BR Murphy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Phonrat, B" uniqKey="Phonrat B">B Phonrat</name></author><author><name sortKey="Pitisuttithum, P" uniqKey="Pitisuttithum P">P Pitisuttithum</name></author><author><name sortKey="Chamnanchanunt, S" uniqKey="Chamnanchanunt S">S Chamnanchanunt</name></author><author><name sortKey="Puthavathana, P" uniqKey="Puthavathana P">P Puthavathana</name></author><author><name sortKey="Ngaosuwankul, N" uniqKey="Ngaosuwankul N">N Ngaosuwankul</name></author><author><name sortKey="Louisirirotchanakul, S" uniqKey="Louisirirotchanakul S">S Louisirirotchanakul</name></author><author><name sortKey="Dhitavat, J" uniqKey="Dhitavat J">J Dhitavat</name></author><author><name sortKey="Thirapakpoomanunt, S" uniqKey="Thirapakpoomanunt S">S Thirapakpoomanunt</name></author><author><name sortKey="Chokevivat, V" uniqKey="Chokevivat V">V Chokevivat</name></author><author><name sortKey="Wibulpolprasert, S" uniqKey="Wibulpolprasert S">S Wibulpolprasert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Surichan, S" uniqKey="Surichan S">S Surichan</name></author><author><name sortKey="Wirachwong, P" uniqKey="Wirachwong P">P Wirachwong</name></author><author><name sortKey="Supachaturas, W" uniqKey="Supachaturas W">W Supachaturas</name></author><author><name sortKey="Utid, K" uniqKey="Utid K">K Utid</name></author><author><name sortKey="Theerasurakarn, S" uniqKey="Theerasurakarn S">S Theerasurakarn</name></author><author><name sortKey="Langsanam, P" uniqKey="Langsanam P">P Langsanam</name></author><author><name sortKey="Lakornrach, P" uniqKey="Lakornrach P">P Lakornrach</name></author><author><name sortKey="Nitisaporn, L" uniqKey="Nitisaporn L">L Nitisaporn</name></author><author><name sortKey="Chansikkakorn, C" uniqKey="Chansikkakorn C">C Chansikkakorn</name></author><author><name sortKey="Vangkanonta, W" uniqKey="Vangkanonta W">W Vangkanonta</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pitisuttithum, P" uniqKey="Pitisuttithum P">P Pitisuttithum</name></author><author><name sortKey="Boonnak, K" uniqKey="Boonnak K">K Boonnak</name></author><author><name sortKey="Chamnanchanunt, S" uniqKey="Chamnanchanunt S">S Chamnanchanunt</name></author><author><name sortKey="Puthavathana, P" uniqKey="Puthavathana P">P Puthavathana</name></author><author><name sortKey="Luvira, V" uniqKey="Luvira V">V Luvira</name></author><author><name sortKey="Lerdsamran, H" uniqKey="Lerdsamran H">H Lerdsamran</name></author><author><name sortKey="Kaewkungwal, J" uniqKey="Kaewkungwal J">J Kaewkungwal</name></author><author><name sortKey="Lawpoolsri, S" uniqKey="Lawpoolsri S">S Lawpoolsri</name></author><author><name sortKey="Thanachartwet, V" uniqKey="Thanachartwet V">V Thanachartwet</name></author><author><name sortKey="Silachamroon, U" uniqKey="Silachamroon U">U Silachamroon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kr, T" uniqKey="Kr T">T KR</name></author><author><name sortKey="Cj, L" uniqKey="Cj L">L CJ</name></author><author><name sortKey="Khurana, S" uniqKey="Khurana S">S Khurana</name></author><author><name sortKey="Manischewitz, J" uniqKey="Manischewitz J">J Manischewitz</name></author><author><name sortKey="Lr, K" uniqKey="Lr K">K LR</name></author><author><name sortKey="Ba, M" uniqKey="Ba M">M BA</name></author><author><name sortKey="Ra, K" uniqKey="Ra K">K RA</name></author><author><name sortKey="Kd, L" uniqKey="Kd L">L KD</name></author><author><name sortKey="Qin, J" uniqKey="Qin J">J Qin</name></author><author><name sortKey="Da, F" uniqKey="Da F">F DA</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Hum Vaccin Immunother</journal-id><journal-id journal-id-type="iso-abbrev">Hum Vaccin Immunother</journal-id><journal-id journal-id-type="publisher-id">KHVI</journal-id><journal-id journal-id-type="publisher-id">khvi20</journal-id><journal-title-group><journal-title>Human Vaccines & Immunotherapeutics</journal-title></journal-title-group><issn pub-type="ppub">2164-5515</issn><issn pub-type="epub">2164-554X</issn><publisher><publisher-name>Taylor & Francis</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31335234</article-id><article-id pub-id-type="pmc">6816430</article-id><article-id pub-id-type="publisher-id">1638205</article-id><article-id pub-id-type="doi">10.1080/21645515.2019.1638205</article-id><article-categories><subj-group subj-group-type="heading"><subject>Commentary</subject></subj-group></article-categories><title-group><article-title>A review of epidemic preparedness for influenza through local vaccine production: national security for Thailand</article-title><alt-title alt-title-type="running-authors">P. PITISUTTITHUM AND P. WIRACHWONG</alt-title><alt-title alt-title-type="running-title">HUMAN VACCINES & IMMUNOTHERAPEUTICS</alt-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">http://orcid.org/0000-0003-3215-2183</contrib-id><name><surname>Pitisuttithum</surname><given-names>Punnee</given-names></name><xref ref-type="corresp" rid="AN0001"></xref><xref ref-type="aff" rid="AFF0001"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wirachwong</surname><given-names>Ponthip</given-names></name><xref ref-type="aff" rid="AFF0002"><sup>b</sup></xref></contrib><aff id="AFF0001"><label>a</label><institution>Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University</institution>, Bangkok,<country>Thailand</country></aff><aff id="AFF0002"><label>b</label><institution>Research and Development Institute, Government Pharmaceutical Organization</institution>, Bangkok,<country>Thailand</country></aff></contrib-group><author-notes><corresp id="AN0001">CONTACT Punnee Pitisuttithum <email xlink:href="punnee.pit@mahidol.ac.th">punnee.pit@mahidol.ac.th</email><institution>Faculty of Tropical Medicine, Mahidol University</institution>, <addr-line>420/6 Ratchawithi road</addr-line>, Ratchathewi 10400, <country>Thailand</country></corresp></author-notes><pub-date pub-type="collection"><year>2019</year></pub-date><pub-date pub-type="epub"><day>5</day><month>9</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>5</day><month>9</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>15</volume><issue>10</issue><fpage seq="25">2440</fpage><lpage>2445</lpage><history><date date-type="received"><day>25</day><month>4</month><year>2019</year></date><date date-type="rev-recd"><day>14</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>22</day><month>6</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>The Author(s)</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/">http://creativecommons.org/licenses/by-nc-nd/4.0/</ext-link>), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="khvi-15-10-1638205.pdf"></self-uri><abstract><title>ABSTRACT</title><p>Being vigilant of the potential for an influenza pandemic, the Global Action Plan for Influenza Vaccines (GAP) promoted the establishment and maintenance of local vaccine manufacturing capacity. In accordance with this, the Thai government has developed its national strategic plan for influenza pandemic preparedness including the plan for manufacturing influenza vaccine in Thailand. With the support of WHO, the Thai Government Pharmaceutical Organization (GPO) as the developed local production capacity of influenza vaccines. The H1N1 live attenuated influenza vaccine (LAIV) and H5N2 LAIV produced by GPO have been proven to be safe and immunogenic through clinical trials, followed by Thai FDA licensure for pandemic use. The GPO-produced H5N2 LAIV has been proven to have priming effects on an inactivated subunit H5N1 booster vaccine. This Thai local manufacturer is now expanding its capacity to Inactivated Influenza Vaccine (IIV), aiming for sustainable influenza vaccine production for national coverage.</p></abstract><kwd-group kwd-group-type="author"><title>KEYWORDS</title><kwd>Influenza vaccine</kwd><kwd>live attenuated</kwd><kwd>national security</kwd></kwd-group><counts><fig-count count="2"></fig-count><table-count count="4"></table-count><ref-count count="11"></ref-count><page-count count="6"></page-count></counts></article-meta></front><body><sec id="S0001"><title>Current situation of influenza pandemic risk and the 2009 H1N1 pandemic</title><p>Since the first human infection of highly pathogenic H5N1 avian influenza in Hong Kong in 1997, sporadic cases have been reported off and on in several countries including in Thailand in 2004. In fact, as of May 2019, there have been 861 confirmed human infections including 455 deaths from avian influenza A(H5N1) reported from 17 countries.<sup><xref rid="CIT0001">1</xref></sup> Moreover, since March 2013 when the avian influenza A(H7N9) infection was first detected in humans, a total of 1,567 laboratory-confirmed human infections including at least 615 deaths (mainly from China) have been reported to the World Health Organization (WHO).</p><p>In 2006, with growing concern that avian influenza viruses could mutate to become transmissible between humans and cause a pandemic, the Global Action Plan for Influenza Vaccines (GAP) was launched by WHO. At the time of launching GAP, egg-based vaccine production had the capacity to produce about 350 million doses of inactivated trivalent vaccine containing 15 µg of hemagglutinin (HA) per dose per year, or with optimization (working three shifts/24 h) up to 500 million doses. Even if manufacturers were to optimize output and expand vaccine production-capacity in the following 2–3 years, it was predicated that by 2009 the estimated maximum production capacity would be 780 million doses of inactivated trivalent vaccine and 2,340 million doses of monovalent pandemic influenza vaccine.<sup><xref rid="CIT0002">2</xref></sup> Therefore, one of the major approaches to increasing supplies of pandemic influenza vaccine was capacity building and infrastructure strengthening or new production facilities in developing and/or industrialized countries; several developing country vaccine manufacturers participated in the GAP technology transfer programme, including the Government Pharmaceutical Organization (GPO), Thailand which signed an agreement with WHO in 2007.</p><p>At the time of the influenza A(H1N1) pandemic in 2009, the first imported case of pandemic H1N1 in Thailand was in early May 2009. By the second week of June 2009, there were two influenza outbreak notifications in the central region of Thailand, and then only a few weeks later the influenza virus spread throughout the country.<sup><xref rid="CIT0003">3</xref></sup> At that time, there was no commitment to supplying inactivated influenza vaccines to Thailand during potential pandemics and there was no domestic production of bulk influenza vaccines. In fact, prior to 2007, there was no experience in egg-based vaccine production. By 2010, Thailand was importing 2.1 million doses of seasonal influenza vaccine: GPO-MBP, a joint venture between the Government Pharmaceutical Organization (GPO) and Sanofi Pasteur, supplied approximately 800,000 doses of seasonal influenza vaccine by formulating and filling imported bulk, and the remaining 1.3 million doses were imported as finished products.</p><p>In 2005, the Thai government issued the first national pandemic influenza preparedness plans in response to the highly pathogenic avian influenza outbreak in 2004. The second national strategic plan was issued for the year 2008–2010. The first national strategic plan for influenza pandemic preparedness (2005–2007) focused on supporting research and development of vaccines and antivirals during outbreaks.<sup><xref rid="CIT0004">4</xref></sup> In the second national strategic plan (2008–2010), it was emphasized that Thailand would set up a local industrial-scale manufacture plant for egg-based pandemic influenza vaccines and train personnel for industrial-scale vaccine research and development processes.<sup><xref rid="CIT0005">5</xref></sup></p><p>With the support from WHO and the Biomedical Advanced Research and Development Authority (BARDA), the GPO has been able to develop live attenuated influenza vaccine (LAIV) for potential pandemic vaccines (H1N1 and H5N2 LAIV) and inactivated influenza vaccine for seasonal use.</p><p>In 2009, the Thai Government Pharmaceutical Organization (GPO) decided to focus on development of LAIV because of the potential advantages of LAIVs compared to IIVs: LAIVs manufacturing does not require down-stream processing and the harvested vaccines can be simply packaged; confer high yields (20–50 doses of monovalent vaccine per an egg) compared to the IIVs; delivered needle-free (intra-nasal spray application) which can be facilitated in resource-poor settings; and induce a broad-immune responses including mucosal, systemic and cross-reactive responses.<sup><xref rid="CIT0006">6</xref>,<xref rid="CIT0007">7</xref></sup> In May 2009, there was a sub-license agreement with WHO to obtain Russian LAIV technology from the Institute of Experimental Medicine (IEM), Saint Petersburg, Russia. After receiving the influenza A H1N1 (2009) pre-master seed from Russia through the support of WHO, the first pLAIV vaccine concentrate was harvested, and the first pLAIV clinical lot was filled in late August 2009. Based on the WHO recommendations for production and quality control of LAIV, the GMP-certified pilot plant was built at Silapakorn University in Bangkok, Thailand.<sup><xref rid="CIT0008">8</xref></sup> Some initial obstacles were encountered such as a lower yield of doses than expected, the need to import a huge number of specific pathogen-free (SPF) eggs and longer time for the optimization processes.<sup><xref rid="CIT0009">9</xref></sup> The H1N1 monovalent vaccine was shown to be safe and immunogenic, fulfilling the criteria for licensure for emergency use.<sup><xref rid="CIT0008">8</xref></sup></p><sec id="S0001-S2001"><title>GPO-manufactured live attenuated influenza H5 candidate vaccine</title><p>GPO had received master donor seed H5N2 candidate vaccine strain (A/17/turkey/Turkey/05/133) from WHO. The product was assessed in preclinical and nonclinical studies and then moved to a phase I clinical trial. After a safety interim analysis, the Data Safety Monitoring Board agreed to move into a phase II study in healthy participants.</p><p><bold>1. Phase I Safety and Immunogenicity of Live Attenuated Influenza H5 Candidate Vaccine Strain A/17/turkey/Turkey/05/133 (H5N2) in Healthy Thai Volunteers</bold></p><p>This was a double-blind randomized study in 24 participants aged 18–45 years in 2012, 16 and 8 participants received vaccines and placebo, respectively. The Primary objective was to evaluate safety and reactogenicity of candidate H5 LAIV (strain H5N2) manufactured by GPO in healthy Thais with the humoral immune response by using hemagglutination inhibition (HAI) test and microneutralization assay as a secondary objective. Viral shedding and the stability of the viral strain were measured by polymerase chain reaction (PCR). The vaccine used the cold-adapted temperature-sensitive (<italic>ca-ts</italic>) live attenuated H5 candidate strain. The A/17/turkey/Turkey/05/133 (H5N2) vaccine was administered with 0.25 ml to each nostril by nasal spray on day 1 and day 21. The safety and immunogenicity monitoring were done up to 60 days. Participants were kept isolation and were discharged when nasal swabs were negative to ensure that there was no risk to the environment.</p><p>The A/17/turkey/Turkey/05/133 H5N2 candidate vaccine was safety and immunogenic. There were a total of 51 adverse events by systemic organ classes, 35 adverse events were reported from the vaccine group (16 participants), and 16 events were from the placebo group (8 participants). The most frequent adverse events were respiratory/thoracic/mediastinal disorders both in the vaccine group (16 events) and the placebo group (6 events), followed by gastrointestinal disorders in the vaccine group (6 events) and the placebo group (4 events). Among the total of 47 local reactions (24 after 1<sup>st</sup> immunization and 23 after 2<sup>nd</sup> immunization), 31 were from the vaccine group and 16 were from the placebo group. After the 1<sup>st</sup> immunization, the most frequent local reaction in vaccine group was stiffness of the nose (6 events), while placebo group reported only 1 event of the stiffness of the nose after the 1<sup>st</sup> immunization. After the 2<sup>nd</sup> immunization on day 21, the most frequent local reactions in the vaccine group were stiffness of the nose (6 events) and scratchy throat (4 events).</p><sec id="S0001-S2001-S3001"><title>Viral shedding and viral strain stability results</title><p>At the 1<sup>st</sup> immunization, 14 vaccinees out of 16 showed positive PCR results, and 10 vaccinees persisted to day 3. After the 2nd immunization, 13 out of 15 vaccinees had positive PCR results on day 1, and 5 vaccinees persisted up to day 3 following the 2nd immunization. One vaccinee’s nasal swab had positive PCR results up to day 5 after the 2nd immunization. The nasal swab culture in eggs showed fewer positive results: 5 out of 16 vaccinees’ nasal swab were culture-positive after the 1<sup>st</sup> immunization and no one had positive culture after day 1. Only one vaccinee’s nasal swab was culture-positive on day 1 after the 2<sup>nd</sup> immunization. No influenza virus was isolated from Madin-Darby Canine Kidney epithelial (MDCK) cell cultures. There were nucleotide/amino acid changes in <italic>NP, NA</italic>, and <italic>PB1</italic> genes but not in <italic>PA, PB2, M, NS</italic>, and <italic>HA</italic> genes.</p><p><bold>2. Phase II Safety and Immunogenicity of Live Attenuated Influenza H5 candidate vaccine strain A/17/turkey/Turkey/05/133 (H5N2) in healthy Thai volunteers</bold></p><p>This was a double-blind randomized placebo-controlled study using the same dose as in phase I study. The study was conducted from January to June 2013. The purpose of this study was to evaluate the immune response and safety of live attenuated influenza H5 vaccine candidate strain A/17/turkey/Turkey/05/133 (H5N2) manufactured by GPO in healthy Thais. One hundred and fifty participants (100 vaccinees and 50 placebos) aged 18–49 years were enrolled. Due to limited space in the isolation ward of the clinical trial unit, Participants were separated in 4 batches; Batch 1: 36 participants (24 vaccinees and 12 placebos) Batch 2: 38 participants (25 vaccinees and 13 placebos) Batch 3: 38 participants (25 vaccinees and 13 placebos) Batch 4: 38 participants (26 vaccinees and 12 placebos). Each batch was admitted to the isolation ward for 5 days after each immunization mainly for safety assessment and to ensure that there was no risk to contaminate the external environment with the vaccine strain. Two doses of live attenuated influenza H5 vaccine candidate strain A/17/turkey/Turkey/05/133 (H5N2) were given by intranasal route on days 1 and 28. Follow up for nasal swab culture was done on days 2, 3, 5 and participants were discharged if culture-negative. Anyone who was still positive for nasal shedding on day 3 was given oseltamivir. Blood withdrawal was done on days 1 and 28 before immunization and on days 49 and 60, to measure immune responses by HAI, microneutralization, and serum IgG and IgA ELISA. 45 participants were randomized for nasal wash specimen on days 1, 14, 28 and 49. The trial could be terminated by any of those followings: If subject experienced disability or severe adverse event or death which was definitely related to the study vaccine in the investigator’s opinion; Data and Safety Monitoring Board (DSMB) judges to terminate the trial. The detailed information about the vaccine and the study procedure was previously described.<sup><xref rid="CIT0010">10</xref></sup></p></sec><sec id="S0001-S2001-S3002"><title>Characteristics of screened volunteers</title><p>Between Feb 4, 2013, and Feb 28, 2013, 256 individuals were screened, of whom 152 participants were enrolled and 104 were excluded because of abnormal laboratory tests, abnormal chest x-rays, and medical history.<sup><xref rid="CIT0010">10</xref></sup> The characteristics of the screen-failed and enrolled participants were not statistically different in terms of age, height, weight and gender composition (<xref rid="T0001">Table 1</xref>).
<table-wrap id="T0001" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1080/21645515.2019.1638205-T0001</object-id><label>Table 1.</label><caption><p>Baseline characteristics of screen-failed and enrolled participants in the phase II trial conducted in Thailand.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment><table frame="hsides" rules="groups"><colgroup><col width="1*" align="left"></col><col width="1*" align="center"></col><col width="1*" align="center"></col><col width="1*" align="char" char="."></col></colgroup><thead><tr><th align="left"> </th><th align="center">Enrolled fail<hr></hr></th><th align="center">Enrolled participants<hr></hr></th><th align="char" char="."> </th></tr><tr><th align="left"> <hr></hr></th><th align="center">(N = 104)<hr></hr></th><th align="center">(N = 152)<hr></hr></th><th align="char" char="."> <hr></hr></th></tr><tr><th align="left">Personal data</th><th align="center">n (%)</th><th align="center">n (%)</th><th align="center" char=".">P-value</th></tr></thead><tbody><tr><td align="left">Sex</td><td align="center"> </td><td align="center"> </td><td align="char" char="."> </td></tr><tr><td align="left"> – Male</td><td align="center">42(40.38%)</td><td align="center">60(39.47%)</td><td align="char" char=".">0.884</td></tr><tr><td align="left"> – Female</td><td align="center">62(59.62%)</td><td align="center">92(60.53%)</td><td align="char" char="."> </td></tr><tr><td align="left">Age (years)</td><td align="center"> </td><td align="center"> </td><td align="char" char="."> </td></tr><tr><td align="left"> – Mean ± SD</td><td align="center">31.20 ± 9.00</td><td align="center">31.27 ± 8.54</td><td align="char" char=".">0.948</td></tr><tr><td align="left">Height (cm.)</td><td align="center"> </td><td align="center"> </td><td align="char" char="."> </td></tr><tr><td align="left"> – Mean ± SD</td><td align="center">162.3 ± 8.46</td><td align="center">162.1 ± 7.93</td><td align="char" char=".">0.893</td></tr><tr><td align="left">Weight (kg.)</td><td align="center"> </td><td align="center"> </td><td align="char" char="."> </td></tr><tr><td align="left"> – Mean ± SD</td><td align="center">61.53 ± 13.69</td><td align="center">58.98 ± 9.36</td><td align="char" char=".">0.102</td></tr></tbody></table></table-wrap></p></sec><sec id="S0001-S2001-S3003"><title>Safety results</title><p>There was a total of 138 adverse events: 95 events from 101 vaccinees and 43 events from 51 placebos. Eighty (84%) of 95 events in the vaccine group and 32 (78%) of 43 events in the placebo group were reported as probably related to vaccination.<sup><xref rid="CIT0010">10</xref></sup> There was no adverse event reported as definitely related to vaccination.</p><p>The most frequent adverse event reported according to the organ classes was of respiratory, thoracic and mediastinal disorders both in vaccine group (36.84%) and placebo group (23.26%), and the second most frequent adverse event was of infections and infestations both in vaccine group (15.79%) and placebo group (18.6%) (<xref rid="F0001">Figure 1</xref>). The most frequent systemic reaction was post-nasal drippings in both groups after the first immunization (<xref rid="F0002">Figure 2</xref>).<fig id="F0001" fig-type="figure" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1080/21645515.2019.1638205-F0001</object-id><label>Figure 1.</label><caption><p>Adverse events by systemic organ classes (%by each group) either receiving H5N2 LAIV vaccine or placebo.</p></caption><graphic specific-use="web-only" content-type="color" xlink:href="khvi-15-10-1638205-g001"></graphic></fig><fig id="F0002" fig-type="figure" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1080/21645515.2019.1638205-F0002</object-id><label>Figure 2.</label><caption><p>Systemic reactions (%) after 1st and 2nd immunization with H5N2 LAIV vaccine or placebo.</p></caption><graphic specific-use="web-only" content-type="color" xlink:href="khvi-15-10-1638205-g002"></graphic></fig></p></sec><sec id="S0001-S2001-S3004"><title>Immune responses</title><p>Humoral immune response was measured using hemagglutination inhibition test (HAI), microneutralization assay (MN), serum IgA and serum IgG. On day 21, 14 of 100 (14%) of participants in the vaccine group had a fourfold or greater rise of antibodies by at least one of HAI, MN, IgA or IaG assays. On days 49 and 60, 36 (36%) and 53 (53%) out of 100 vaccinees, respectively, showed a 4-fold or greater increase of antibodies with at least one of these four assays, while no 4-fold or greater rise was observed in the placebo group on any days.</p><p>H5N2 LAIV also induced local antibody responses and cellular immune responses in cytotoxic T cells, different T-helper cell populations, and virus-specific immune memory cells. A recent study conducted in the US by K. Subbarao showed that influenza A(H5N1) pLAIV recipients with poor primary immune responses were actually having a long-lasting immunity and could be boosted with inactivated influenza H5N1 vaccine at 52, 54 or 56 months after the immunization by pLAIV.<sup><xref rid="CIT0011">11</xref></sup></p><p><bold>3. Evaluation of Priming Effects of H5N2 pLAI Vaccine on the Subsequent Response to Inactivated H5N1 Vaccine</bold> (“OrniFlu”, Federal State Scientific-Industrial Company Microgen for Immunobiological Medicines, Ministry of Health, Russia)<sup><xref rid="CIT0010">10</xref></sup></p><p>This study aimed to evaluate the effect of H5N2 LAIV priming on an inactivated subunit H5N1 booster vaccine with an approximate 1 year of the prime-boost interval.</p></sec><sec id="S0001-S2001-S3005"><title>Materials and methods of the study</title><p>The booster vaccine used was subunit aluminum hydroxide adsorbed influenza vaccine containing HA and NA proteins from the influenza virus A/turkey/Turkey/1/05 (H5N1). Sixty participants (40 vaccinees, 20 placebos from the previous phase II study) have been enrolled and received one dose of the H5 inactivated influenza vaccine (IIV) 1 year after the H5N2 vaccination. The total follow-up time was 90 days.</p></sec><sec id="S0001-S2001-S3006"><title>Immune responses</title><p>In the vaccinated group who had been previously immunized with two doses of H5N2 LAIV 1 year before the booster vaccination, 39 (98%) of 40 participants developed a four-fold or greater rise of antibody titres against the strain A/turkey/Turkey/05/133 in HAI assay and 38 (95%) of 40 in MN assay on day 7. All participants had a four-fold or greater increase in antibody titers (peak GMT) against A/turkey/Turkey/05/133 and A/Thailand/1(KAN-1)/04 (similar to wild type H5 virus which was circulated in Thailand) in both HAI and MN on day 28 (<xref rid="T0002">Tables 2</xref>–<xref rid="T0004">4</xref>). While in the control group who had received placebo, the four-fold or greater increase was observed in 3 (15%) of 20 participants in HAI assay and MN assay on day 7 (both <italic>p</italic> < .0001 vs. vaccine group) on day 28, 14 (70%) or 20 participants and 15 (75%) of 20 participants in the control group developed four-fold or greater increase in antibody titer by HAI assay and MN assay, respectively.<sup><xref rid="CIT0010">10</xref></sup> These data show the boosting effect from the priming dose of vaccine.<table-wrap id="T0002" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1080/21645515.2019.1638205-T0002</object-id><label>Table 2.</label><caption><p>Comparing seroconversion rates of 4 fold-rising between previously vaccinated with LAIV H5N2 and naïve subjects by hemagglutinin-inhibition assay (HAI) at day 1, 7, 28 and 90 (Test Virus: A/17turkey/05/133 (H5N2)).</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment><table frame="hsides" rules="groups"><colgroup><col width="1*" align="left"></col><col width="1*" align="left"></col><col width="1*" align="left"></col><col width="1*" align="center"></col></colgroup><thead><tr><th align="left">Day</th><th align="center">Group</th><th align="left"> </th><th align="center">4-fold rising<break></break>N (%)</th></tr></thead><tbody><tr><td align="left">Day 1</td><td align="left">Vaccinated (N = 40)</td><td align="left"> </td><td align="center">0(0.00)</td></tr><tr><td align="left"> </td><td align="left">Naïve (N = 20)</td><td align="left"> </td><td align="center">0(0.00)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">p- vale = -[3]</td><td align="center"> </td></tr><tr><td align="left">Day 7</td><td align="left">Vaccinated (N = 40)</td><td align="left"> </td><td align="center">39(97.50)</td></tr><tr><td align="left"> </td><td align="left">Naïve (N = 20)</td><td align="left"> </td><td align="center">3(15.00)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">p- vale = <0.0001 [2]α</td><td align="center"> </td></tr><tr><td align="left">Day 28</td><td align="left">Vaccinated (N = 40)</td><td align="left"> </td><td align="center">40(100.00)</td></tr><tr><td align="left"> </td><td align="left">Naïve (N = 20)</td><td align="left"> </td><td align="center">14(70.00)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">p- vale = <0.0008 [1]α</td><td align="center"> </td></tr><tr><td align="left">Day 90</td><td align="left">Vaccinated (N = 40), (n = 39)</td><td align="left"> </td><td align="center">39(97.50)</td></tr><tr><td align="left"> </td><td align="left">Naïve (N = 20)</td><td align="left"> </td><td align="center">15(75.00)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">p- vale = <0.0031 [1]α</td><td align="center"> </td></tr></tbody></table><table-wrap-foot><fn><p>SID 93014 in previously vaccinated with LAIV H5N2 group got missing data at day 90 both in HIA and micro NT.</p></fn><fn><p>[1] Overall <italic>p</italic>-value (2-sided) based on Fisher’s exact test.</p></fn><fn><p>[2] Overall <italic>p</italic>-value (2-sided) based on Chi-square test.</p></fn><fn><p>[3] No statistic was considered.</p></fn><fn><p>- Intention to Treat (ITT)</p></fn><fn><p>α – significant difference</p></fn></table-wrap-foot></table-wrap><table-wrap id="T0003" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1080/21645515.2019.1638205-T0003</object-id><label>Table 3.</label><caption><p>Comparing seroconversion rates of 4 fold rising between previously vaccinated with LAIV H5N2 and naïve subjects by hemagglutinin-inhibition assay (HAI) at day 1, 7, 28 and 90 (Test virus: rg-H5N1-KAN-1).</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment><table frame="hsides" rules="groups"><colgroup><col width="1*" align="left"></col><col width="1*" align="left"></col><col width="1*" align="left"></col><col width="1*" align="center"></col></colgroup><thead><tr><th align="left">Day</th><th align="center">Group</th><th align="left"> </th><th align="center">4-fold rising<break></break>N (%)</th></tr></thead><tbody><tr><td align="left">Day 1</td><td align="left">Vaccinated (N = 40)</td><td align="left"> </td><td align="center">0(0.00)</td></tr><tr><td align="left"> </td><td align="left">Naïve (N = 20)</td><td align="left"> </td><td align="center">0(0.00)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">p- vale = -[3]</td><td align="center"> </td></tr><tr><td align="left">Day 7</td><td align="left">Vaccinated (N = 40)</td><td align="left"> </td><td align="center">35(87.50)</td></tr><tr><td align="left"> </td><td align="left">Naïve (N = 20)</td><td align="left"> </td><td align="center">0(0.00)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">p- vale = <0.0001 [2]</td><td align="center"> </td></tr><tr><td align="left">Day 28</td><td align="left">Vaccinated (N = 40)</td><td align="left"> </td><td align="center">40(100.00)</td></tr><tr><td align="left"> </td><td align="left">Naïve (N = 20)</td><td align="left"> </td><td align="center">3(15.00)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">p- vale = <0.0001 [2]</td><td align="center"> </td></tr><tr><td align="left">Day 90</td><td align="left">Vaccinated (N = 40), (n = 39)</td><td align="left"> </td><td align="center">38(95.00)</td></tr><tr><td align="left"> </td><td align="left">Naïve (N = 20)</td><td align="left"> </td><td align="center">4(20.00)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">p- vale = <0.0001 [1]</td><td align="center"> </td></tr></tbody></table><table-wrap-foot><fn><p>SID 93014 in previously vaccinated with LAIV H5N2 group got missing data at day 90 both in HIA and micro NT.</p></fn><fn><p>[1] Overall <italic>p</italic>-value (2-sided) based on Fisher’s exact test.</p></fn><fn><p>[2] Overall <italic>p</italic>-value (2-sided) based on Chi-square test.</p></fn><fn><p>[3] No statistic was considered.</p></fn><fn><p>- Intention to Treat (ITT)</p></fn></table-wrap-foot></table-wrap><table-wrap id="T0004" orientation="portrait" position="float"><object-id pub-id-type="doi">10.1080/21645515.2019.1638205-T0004</object-id><label>Table 4.</label><caption><p>Geometric mean of immune response by previously vaccinated with LAIV H5N2 and naïve subjects.</p></caption><pmc-comment>OASIS TABLE HERE</pmc-comment><table frame="hsides" rules="groups"><colgroup><col width="1*" align="left"></col><col width="1*" align="left"></col><col width="1*" align="left"></col><col width="1*" align="center"></col><col width="1*" align="center"></col><col width="1*" align="center"></col></colgroup><thead><tr><th align="left">Antibody assay</th><th align="center">Test virus</th><th align="center">Study group</th><th align="center">Day 1 GMT (95% CI)</th><th align="center">Day 7 GMT (95% CI)</th><th align="center">Day 28 GMT (95% CI)</th></tr></thead><tbody><tr><td align="left">HAI Assay</td><td align="left">A17/turkey/Turkey/05/133</td><td align="left">Previously vaccinated</td><td align="center">3.92 (3.24, 4.75)</td><td align="center">211.12 (134.45, 331.52)</td><td align="center">566.89 (436.97, 735.44)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">Naïve</td><td align="center">2.59 (2.41, 2.78)</td><td align="center">3.66 (2.60, 5.15)</td><td align="center">25.49 (11.82, 54.96)</td></tr><tr><td align="left"> </td><td align="left"> </td><td colspan="2" align="center">P – value = 0.0011<sup>[5]</sup>α</td><td align="center">< 0.0001<sup>[5]</sup>α</td><td align="center">< 0.0001<sup>[5]</sup>α</td></tr><tr><td align="left"> </td><td align="left">A/Thailand/1(KAN-1)/04</td><td align="left">Previously vaccinated</td><td align="center">2.59 (2.46, 2.72)</td><td align="center">32.49 (22.01, 47.96)</td><td align="center">98.49 (75.44, 128.58)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">Naïve</td><td align="center">2.5 (-)</td><td align="center">2.77 (2.46, 3.12)</td><td align="center">5.18 (2.90, 9.25)</td></tr><tr><td align="left"> </td><td align="left"> </td><td colspan="2" align="center">P – value = 0.3254<sup>[5]</sup></td><td align="center">< 0.0001<sup>[5]</sup>α</td><td align="center">< 0.0001<sup>[5]</sup>α</td></tr><tr><td align="left">Micro NT</td><td align="left">A17/turkey/Turkey/05/133</td><td align="left">Previously vaccinated</td><td align="center">8.56 (6.48, 11.29)</td><td align="center">528.93 (333.88, 837.91)</td><td align="center">1,395.8 (1,040.8, 1,872.0)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">Naïve</td><td align="center">2.68 (2.42, 2.96)</td><td align="center">3.42 (2.47, 4.72)</td><td align="center">17.41 (9.05, 33.48)</td></tr><tr><td align="left"> </td><td align="left"> </td><td colspan="2" align="center">P – value = < 0.0001<sup>[5]</sup>α</td><td align="center">< 0.0001<sup>[5]</sup>α</td><td align="center">< 0.0001<sup>[5]</sup>α</td></tr><tr><td align="left"> </td><td align="left">A/Thailand/1 (KAN-1)/04</td><td align="left">Previously vaccinated</td><td align="center">2.5 (-)</td><td align="center">25.49 (17.90, 36.30)</td><td align="center">52.78 (38.92, 71.57)</td></tr><tr><td align="left"> </td><td align="left"> </td><td align="left">Naïve</td><td align="center">2.5 (-)</td><td align="center">2.5 (-)</td><td align="center">3.19 (2.50, 4.06)</td></tr><tr><td align="left"> </td><td align="left"> </td><td colspan="2" align="center">P – value = 1.0000<sup>[5]</sup></td><td align="center"><0.0001<sup>[5]</sup>α</td><td align="center"><0.0001<sup>[5]</sup>α</td></tr></tbody></table><table-wrap-foot><fn><p>SID 93014 in previously vaccinated with LAIV H5N2 group got missing data at day 90 both in HIA and micro NT.</p></fn><fn><p>[4] Overall <italic>p</italic>-value (2-sided) based on Independence T-test.</p></fn><fn><p>[5] Overall <italic>p</italic>-value (2-sided) based on Wilcoxon rank sum test.</p></fn><fn><p>- Antibody titers were compared between study groups.</p></fn><fn><p>- Intention to Treat (ITT)</p></fn><fn><p>α – significant difference</p></fn></table-wrap-foot></table-wrap></p><p>All participants in the previously vaccinated group developed a four-fold or greater increase in HAI and neutralizing cross-reactive antibody titers against clade one H5N1 virus (A/Thailand/1 [KAN-1]/04) on day 28. Almost all (95–100%) of the participants in the previously vaccinated group developed a four-fold or greater increase in the antibody against clade 2.1.3.2 H5N1 (A/Indonesia/05/05) and clade 2.3.4 H5N1 (A/Lao/Nong Khai/1/07) viruses on day 28. The detailed results are described in our previous report.<sup><xref rid="CIT0010">10</xref></sup></p></sec></sec></sec><sec id="S0002"><title>Efforts in manufacturing inactivated influenza vaccines (IIVs)</title><p>Following experience with the successful clinical trials of the H5N2 live-attenuated influenza vaccine and obtaining the licensure for its pandemic use from the Thai FDA, the GPO is conducting clinical trials and scaling up the production of IIVs.</p><p>The results of the phase I trial using IIVs manufactured by GPO showed the vaccine was safe and immunogenic (personal communication). The seroconversion rate of participants who had received the GPO trivalent-inactivated influenza vaccine 21 days later were 85%, 45%, and 95% against H1, H3, and flu B using HAI antibody assay, respectively. The results of phase II/III trial involving approximately 900 participants are underway.</p></sec><sec id="S0003"><title>Summary</title><p>The Thai government has developed its local vaccine manufacturer (the GPO) to be able to manufacture its own influenza vaccines as a part of the strategy of self-reliance and sustainability for national security. GPO’s vaccine manufacturing plant is in the process of validation and is being built with a budget of 1,116.19 million Baht.</p><p>The goal of the vaccine manufacturing plant is in the first instance to have the capacity to produce 2 million doses of seasonal influenza vaccines, then to increase to 10 million doses in the near future and eventually to be able to increase up to 60 million doses during epidemics/outbreaks. Furthermore, it is looking forward to becoming one of the key players in vaccine manufacturing in ASEAN and then to expanding its products into animal vaccines and biological products to be able to be a world-class key player of vaccines & biological products.</p></sec></body><back><sec><title>Acknowledgments</title><p>We would like to thank Marie-Paule Kieny, Larisa Rudenko, Martin Friede, Erin Grace Sparrow, Guido Torelli from WHO, Sit Thirapakpoomanunt, Suwit Wibulpolprasert, the Oversight Committee and staff of vaccine production of the Thai Government Pharmaceutical Organization (GPO), the Ministry of Public Health, Thailand, for their contributions to the Influenza Vaccine study; all the study volunteers for their participation; WHO for technical and financial support provided through a grant from US BARDA; the Institute of Experimental Medicine, St Petersburg, Russia for providing the master seed and performing the immune response assay in part 1 of the study; Microgen (Moscow, Russia) for providing the inactivated influenza vaccine used in part 2; the clinical and nursing staff at the Vaccine Trial Centre, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; and the laboratory staff at the Department of Microbiology, Siriraj Hospital, Mahidol University.</p></sec><sec id="S0004"><title>Disclosure of potential conflicts of interest</title><p>No potential conflicts of interest were disclosed.</p></sec><ref-list><title>References</title><ref id="CIT0001"><label>1.</label><mixed-citation publication-type="book"><person-group person-group-type="author"><collab>WHO</collab></person-group><source>Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2003–2018</source>. Geneva, Switzerland: WHO/GIP; <year>2018</year>.</mixed-citation></ref><ref id="CIT0002"><label>2.</label><mixed-citation publication-type="book"><person-group person-group-type="author"><collab>WHO</collab></person-group><source>Global pandemic influenza action plan to increase vaccine supply</source>. <publisher-loc>Geneva, Switzerland</publisher-loc>: <publisher-name>WHO</publisher-name>; <year>2006</year>.</mixed-citation></ref><ref id="CIT0003"><label>3.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Iamsirithaworn</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Akarasewi</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Yingyong</surname><given-names>T</given-names></name>, <name name-style="western"><surname>Suthachana</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Pittayawonganon</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Ungchusak</surname><given-names>K.</given-names></name></person-group><article-title>Three waves of the 2009 H1N1 influenza pandemic in Thailand</article-title>. <source>Siriraj Med J</source>. <year>2011</year>;<volume>63</volume>:<fpage>64</fpage>–<lpage>67</lpage>.</mixed-citation></ref><ref id="CIT0004"><label>4.</label><mixed-citation publication-type="book"><source>The National Committee on Avian Influenza Control. National Strategic Plan for Avian Influenza Control and Influenza Pandemic Preparedness in Thailand. 2005–2007</source>. Bangkok, <publisher-loc>Thailand</publisher-loc>: <publisher-name>The Ministry of Public Health</publisher-name>; <year>2005</year>.</mixed-citation></ref><ref id="CIT0005"><label>5.</label><mixed-citation publication-type="book"><person-group person-group-type="author"><collab>Executive Committee for Prevention and Control of Avian Influenza and Preparedness for Influenza Pandemic</collab></person-group><source>The second national strategic plan for prevention and control of avian influenza and preparedness for influenza pandemic</source>. Bangkok, <publisher-loc>Thailand</publisher-loc>: <publisher-name>The Ministry of Public Health</publisher-name>; <year>2008</year>.</mixed-citation></ref><ref id="CIT0006"><label>6.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Sasaki</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Holmes</surname><given-names>TH</given-names></name>, <name name-style="western"><surname>Albrecht</surname><given-names>RA</given-names></name>, <name name-style="western"><surname>Garcia-Sastre</surname><given-names>A</given-names></name>, <name name-style="western"><surname>Dekker</surname><given-names>CL</given-names></name>, <name name-style="western"><surname>He</surname><given-names>XS</given-names></name>, <name name-style="western"><surname>Greenberg</surname><given-names>HB.</given-names></name></person-group><article-title>Distinct cross-reactive B-cell responses to live attenuated and inactivated influenza vaccines</article-title>. <source>J Infect Dis</source>. <year>2014</year>;<volume>210</volume>:<fpage>865</fpage>–<lpage>74</lpage>. doi:<pub-id pub-id-type="doi">10.1093/infdis/jiu190</pub-id>.<pub-id pub-id-type="pmid">24676204</pub-id></mixed-citation></ref><ref id="CIT0007"><label>7.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Clements</surname><given-names>ML</given-names></name>, <name name-style="western"><surname>Murphy</surname><given-names>BR</given-names></name></person-group><article-title>Development and persistence of local and systemic antibody responses in adults given live attenuated or inactivated influenza A virus vaccine</article-title>. <source>J Clin Microbiol</source>. <year>1986</year>;<volume>23</volume>:<fpage>66</fpage>–<lpage>72</lpage>.<pub-id pub-id-type="pmid">3700610</pub-id></mixed-citation></ref><ref id="CIT0008"><label>8.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Phonrat</surname><given-names>B</given-names></name>, <name name-style="western"><surname>Pitisuttithum</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Chamnanchanunt</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Puthavathana</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Ngaosuwankul</surname><given-names>N</given-names></name>, <name name-style="western"><surname>Louisirirotchanakul</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Dhitavat</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Thirapakpoomanunt</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Chokevivat</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Wibulpolprasert</surname><given-names>S</given-names></name></person-group><article-title>Safety and immune responses following administration of H1N1 live attenuated influenza vaccine in Thais</article-title>. <source>Vaccine</source>. <year>2013</year>;<volume>31</volume>:<fpage>1503</fpage>–<lpage>09</lpage>. doi:<pub-id pub-id-type="doi">10.1016/j.vaccine.2012.12.082</pub-id>.<pub-id pub-id-type="pmid">23318149</pub-id></mixed-citation></ref><ref id="CIT0009"><label>9.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Surichan</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Wirachwong</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Supachaturas</surname><given-names>W</given-names></name>, <name name-style="western"><surname>Utid</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Theerasurakarn</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Langsanam</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Lakornrach</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Nitisaporn</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Chansikkakorn</surname><given-names>C</given-names></name>, <name name-style="western"><surname>Vangkanonta</surname><given-names>W</given-names></name>, et al</person-group><article-title>Development of influenza vaccine production capacity by the government pharmaceutical organization of Thailand: addressing the threat of an influenza pandemic</article-title>. <source>Vaccine</source>. <year>2011</year>;<volume>29</volume>(<issue>Suppl 1</issue>):<fpage>A29</fpage>–<lpage>A33</lpage>. doi:<pub-id pub-id-type="doi">10.1016/j.vaccine.2011.04.120</pub-id>.<pub-id pub-id-type="pmid">21684425</pub-id></mixed-citation></ref><ref id="CIT0010"><label>10.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>Pitisuttithum</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Boonnak</surname><given-names>K</given-names></name>, <name name-style="western"><surname>Chamnanchanunt</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Puthavathana</surname><given-names>P</given-names></name>, <name name-style="western"><surname>Luvira</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Lerdsamran</surname><given-names>H</given-names></name>, <name name-style="western"><surname>Kaewkungwal</surname><given-names>J</given-names></name>, <name name-style="western"><surname>Lawpoolsri</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Thanachartwet</surname><given-names>V</given-names></name>, <name name-style="western"><surname>Silachamroon</surname><given-names>U</given-names></name>, et al</person-group><article-title>Safety and immunogenicity of a live attenuated influenza H5 candidate vaccine strain A/17/turkey/Turkey/05/133 H5N2 and its priming effects for potential pre-pandemic use: a randomised, double-blind, placebo-controlled trial</article-title>. <source>Lancet Infect Dis</source>. <year>2017</year>;<volume>17</volume>:<fpage>833</fpage>–<lpage>42</lpage>. doi:<pub-id pub-id-type="doi">10.1016/S1473-3099(17)30240-2</pub-id>.<pub-id pub-id-type="pmid">28533093</pub-id></mixed-citation></ref><ref id="CIT0011"><label>11.</label><mixed-citation publication-type="journal"><person-group person-group-type="author"><name name-style="western"><surname>KR</surname><given-names>T</given-names></name>, <name name-style="western"><surname>CJ</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Khurana</surname><given-names>S</given-names></name>, <name name-style="western"><surname>Manischewitz</surname><given-names>J</given-names></name>, <name name-style="western"><surname>LR</surname><given-names>K</given-names></name>, <name name-style="western"><surname>BA</surname><given-names>M</given-names></name>, <name name-style="western"><surname>RA</surname><given-names>K</given-names></name>, <name name-style="western"><surname>KD</surname><given-names>L</given-names></name>, <name name-style="western"><surname>Qin</surname><given-names>J</given-names></name>, <name name-style="western"><surname>DA</surname><given-names>F</given-names></name>, et al</person-group><article-title>A live attenuated influenza A(H5N1) vaccine induces long-term immunity in the absence of a primary antibody response</article-title>. <source>J Infect Dis</source>. <year>2014</year>;<volume>209</volume>:<fpage>1860</fpage>–<lpage>69</lpage>. doi:<pub-id pub-id-type="doi">10.1093/infdis/jiu123</pub-id>.<pub-id pub-id-type="pmid">24604819</pub-id></mixed-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/PandemieGrippaleV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000A54 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000A54 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= PandemieGrippaleV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:6816430
|texte= A review of epidemic preparedness for influenza through local vaccine production: national security for Thailand
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:31335234" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a PandemieGrippaleV1
| This area was generated with Dilib version V0.6.34. |  |