Two Live Attenuated Vaccines against Recent Low–and Highly Pathogenic H7N9 Influenza Viruses Are Safe and Immunogenic in Ferrets
Identifieur interne : 000F30 ( Ncbi/Merge ); précédent : 000F29; suivant : 000F31Two Live Attenuated Vaccines against Recent Low–and Highly Pathogenic H7N9 Influenza Viruses Are Safe and Immunogenic in Ferrets
Auteurs : Larisa Rudenko ; Irina Kiseleva ; Elena Krutikova ; Ekaterina Stepanova ; Irina Isakova-Sivak ; Svetlana Donina ; Andrey Rekstin ; Maria Pisareva ; Ekaterina Bazhenova ; Tatiana Kotomina ; Anastasia Katelnikova ; Arman Muzhikyan ; Valery Makarov ; Erin Grace Sparrow ; Guido TorelliSource :
- Vaccines [ 2076-393X ] ; 2018.
Abstract
Influenza H7N9 virus is a potentially pandemic subtype to which most people are immunologically naïve. To be better prepared for the potential occurrence of an H7N9 pandemic, in 2017 the World Health Organization recommended developing candidate vaccine viruses from two new H7N9 viruses, A/Guangdong/17SF003/2016 (A/GD) and A/Hong Kong/125/2017 (A/HK). This report describes the development of live attenuated influenza vaccine (LAIV) candidates against A/GD and A/HK viruses and study of their safety and immunogenicity in the ferret model in order to choose the most promising one for a phase I clinical trial. The A/HK-based vaccine candidate (A/17/HK) was developed by classical reassortment in eggs. The A/GD-based vaccine candidate (A/17/GD) was generated by reverse genetics. Ferrets were vaccinated with two doses of LAIV or phosphate-buffered saline. Both H7N9 LAIVs tested were safe for ferrets, as shown by absence of clinical signs, and by virological and histological data; they were immunogenic after a single vaccination. These results provide a compelling argument for further testing of these vaccines in volunteers. Since the A/HK virus represents the cluster that has caused the majority of human cases, and because the A/HK-based LAIV candidate was developed by classical reassortment, this is the preferred candidate for a phase I clinical trial.
Url:
DOI: 10.3390/vaccines6040074
PubMed: 30388790
PubMed Central: 6313887
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PMC:6313887Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Two Live Attenuated Vaccines against Recent Low–and Highly Pathogenic H7N9 Influenza Viruses Are Safe and Immunogenic in Ferrets</title>
<author><name sortKey="Rudenko, Larisa" sort="Rudenko, Larisa" uniqKey="Rudenko L" first="Larisa" last="Rudenko">Larisa Rudenko</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kiseleva, Irina" sort="Kiseleva, Irina" uniqKey="Kiseleva I" first="Irina" last="Kiseleva">Irina Kiseleva</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Krutikova, Elena" sort="Krutikova, Elena" uniqKey="Krutikova E" first="Elena" last="Krutikova">Elena Krutikova</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stepanova, Ekaterina" sort="Stepanova, Ekaterina" uniqKey="Stepanova E" first="Ekaterina" last="Stepanova">Ekaterina Stepanova</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Isakova Sivak, Irina" sort="Isakova Sivak, Irina" uniqKey="Isakova Sivak I" first="Irina" last="Isakova-Sivak">Irina Isakova-Sivak</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Donina, Svetlana" sort="Donina, Svetlana" uniqKey="Donina S" first="Svetlana" last="Donina">Svetlana Donina</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rekstin, Andrey" sort="Rekstin, Andrey" uniqKey="Rekstin A" first="Andrey" last="Rekstin">Andrey Rekstin</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pisareva, Maria" sort="Pisareva, Maria" uniqKey="Pisareva M" first="Maria" last="Pisareva">Maria Pisareva</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bazhenova, Ekaterina" sort="Bazhenova, Ekaterina" uniqKey="Bazhenova E" first="Ekaterina" last="Bazhenova">Ekaterina Bazhenova</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kotomina, Tatiana" sort="Kotomina, Tatiana" uniqKey="Kotomina T" first="Tatiana" last="Kotomina">Tatiana Kotomina</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Katelnikova, Anastasia" sort="Katelnikova, Anastasia" uniqKey="Katelnikova A" first="Anastasia" last="Katelnikova">Anastasia Katelnikova</name>
<affiliation><nlm:aff id="af2-vaccines-06-00074">Institute of Preclinical Research Ltd., St. Petersburg 188663, Russia;<email>katelnikova.ae@doclinika.ru</email>
(A.K.);<email>mancho1@yandex.ru</email>
(A.M.);<email>makarov.vg@doclinika.ru</email>
(V.M.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Muzhikyan, Arman" sort="Muzhikyan, Arman" uniqKey="Muzhikyan A" first="Arman" last="Muzhikyan">Arman Muzhikyan</name>
<affiliation><nlm:aff id="af2-vaccines-06-00074">Institute of Preclinical Research Ltd., St. Petersburg 188663, Russia;<email>katelnikova.ae@doclinika.ru</email>
(A.K.);<email>mancho1@yandex.ru</email>
(A.M.);<email>makarov.vg@doclinika.ru</email>
(V.M.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Makarov, Valery" sort="Makarov, Valery" uniqKey="Makarov V" first="Valery" last="Makarov">Valery Makarov</name>
<affiliation><nlm:aff id="af2-vaccines-06-00074">Institute of Preclinical Research Ltd., St. Petersburg 188663, Russia;<email>katelnikova.ae@doclinika.ru</email>
(A.K.);<email>mancho1@yandex.ru</email>
(A.M.);<email>makarov.vg@doclinika.ru</email>
(V.M.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sparrow, Erin Grace" sort="Sparrow, Erin Grace" uniqKey="Sparrow E" first="Erin Grace" last="Sparrow">Erin Grace Sparrow</name>
<affiliation><nlm:aff id="af3-vaccines-06-00074">World Health Organization, 1211 Geneva, Switzerland;<email>sparrowe@who.int</email>
(E.G.S.);<email>torellig@who.int</email>
(G.T.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Torelli, Guido" sort="Torelli, Guido" uniqKey="Torelli G" first="Guido" last="Torelli">Guido Torelli</name>
<affiliation><nlm:aff id="af3-vaccines-06-00074">World Health Organization, 1211 Geneva, Switzerland;<email>sparrowe@who.int</email>
(E.G.S.);<email>torellig@who.int</email>
(G.T.)</nlm:aff>
</affiliation>
</author>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Two Live Attenuated Vaccines against Recent Low–and Highly Pathogenic H7N9 Influenza Viruses Are Safe and Immunogenic in Ferrets</title>
<author><name sortKey="Rudenko, Larisa" sort="Rudenko, Larisa" uniqKey="Rudenko L" first="Larisa" last="Rudenko">Larisa Rudenko</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kiseleva, Irina" sort="Kiseleva, Irina" uniqKey="Kiseleva I" first="Irina" last="Kiseleva">Irina Kiseleva</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Krutikova, Elena" sort="Krutikova, Elena" uniqKey="Krutikova E" first="Elena" last="Krutikova">Elena Krutikova</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Stepanova, Ekaterina" sort="Stepanova, Ekaterina" uniqKey="Stepanova E" first="Ekaterina" last="Stepanova">Ekaterina Stepanova</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Isakova Sivak, Irina" sort="Isakova Sivak, Irina" uniqKey="Isakova Sivak I" first="Irina" last="Isakova-Sivak">Irina Isakova-Sivak</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Donina, Svetlana" sort="Donina, Svetlana" uniqKey="Donina S" first="Svetlana" last="Donina">Svetlana Donina</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rekstin, Andrey" sort="Rekstin, Andrey" uniqKey="Rekstin A" first="Andrey" last="Rekstin">Andrey Rekstin</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Pisareva, Maria" sort="Pisareva, Maria" uniqKey="Pisareva M" first="Maria" last="Pisareva">Maria Pisareva</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Bazhenova, Ekaterina" sort="Bazhenova, Ekaterina" uniqKey="Bazhenova E" first="Ekaterina" last="Bazhenova">Ekaterina Bazhenova</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Kotomina, Tatiana" sort="Kotomina, Tatiana" uniqKey="Kotomina T" first="Tatiana" last="Kotomina">Tatiana Kotomina</name>
<affiliation><nlm:aff id="af1-vaccines-06-00074">Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Katelnikova, Anastasia" sort="Katelnikova, Anastasia" uniqKey="Katelnikova A" first="Anastasia" last="Katelnikova">Anastasia Katelnikova</name>
<affiliation><nlm:aff id="af2-vaccines-06-00074">Institute of Preclinical Research Ltd., St. Petersburg 188663, Russia;<email>katelnikova.ae@doclinika.ru</email>
(A.K.);<email>mancho1@yandex.ru</email>
(A.M.);<email>makarov.vg@doclinika.ru</email>
(V.M.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Muzhikyan, Arman" sort="Muzhikyan, Arman" uniqKey="Muzhikyan A" first="Arman" last="Muzhikyan">Arman Muzhikyan</name>
<affiliation><nlm:aff id="af2-vaccines-06-00074">Institute of Preclinical Research Ltd., St. Petersburg 188663, Russia;<email>katelnikova.ae@doclinika.ru</email>
(A.K.);<email>mancho1@yandex.ru</email>
(A.M.);<email>makarov.vg@doclinika.ru</email>
(V.M.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Makarov, Valery" sort="Makarov, Valery" uniqKey="Makarov V" first="Valery" last="Makarov">Valery Makarov</name>
<affiliation><nlm:aff id="af2-vaccines-06-00074">Institute of Preclinical Research Ltd., St. Petersburg 188663, Russia;<email>katelnikova.ae@doclinika.ru</email>
(A.K.);<email>mancho1@yandex.ru</email>
(A.M.);<email>makarov.vg@doclinika.ru</email>
(V.M.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Sparrow, Erin Grace" sort="Sparrow, Erin Grace" uniqKey="Sparrow E" first="Erin Grace" last="Sparrow">Erin Grace Sparrow</name>
<affiliation><nlm:aff id="af3-vaccines-06-00074">World Health Organization, 1211 Geneva, Switzerland;<email>sparrowe@who.int</email>
(E.G.S.);<email>torellig@who.int</email>
(G.T.)</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Torelli, Guido" sort="Torelli, Guido" uniqKey="Torelli G" first="Guido" last="Torelli">Guido Torelli</name>
<affiliation><nlm:aff id="af3-vaccines-06-00074">World Health Organization, 1211 Geneva, Switzerland;<email>sparrowe@who.int</email>
(E.G.S.);<email>torellig@who.int</email>
(G.T.)</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Vaccines</title>
<idno type="eISSN">2076-393X</idno>
<imprint><date when="2018">2018</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Influenza H7N9 virus is a potentially pandemic subtype to which most people are immunologically naïve. To be better prepared for the potential occurrence of an H7N9 pandemic, in 2017 the World Health Organization recommended developing candidate vaccine viruses from two new H7N9 viruses, A/Guangdong/17SF003/2016 (A/GD) and A/Hong Kong/125/2017 (A/HK). This report describes the development of live attenuated influenza vaccine (LAIV) candidates against A/GD and A/HK viruses and study of their safety and immunogenicity in the ferret model in order to choose the most promising one for a phase I clinical trial. The A/HK-based vaccine candidate (A/17/HK) was developed by classical reassortment in eggs. The A/GD-based vaccine candidate (A/17/GD) was generated by reverse genetics. Ferrets were vaccinated with two doses of LAIV or phosphate-buffered saline. Both H7N9 LAIVs tested were safe for ferrets, as shown by absence of clinical signs, and by virological and histological data; they were immunogenic after a single vaccination. These results provide a compelling argument for further testing of these vaccines in volunteers. Since the A/HK virus represents the cluster that has caused the majority of human cases, and because the A/HK-based LAIV candidate was developed by classical reassortment, this is the preferred candidate for a phase I clinical trial.</p>
</div>
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</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Vaccines (Basel)</journal-id>
<journal-id journal-id-type="iso-abbrev">Vaccines (Basel)</journal-id>
<journal-id journal-id-type="publisher-id">vaccines</journal-id>
<journal-title-group><journal-title>Vaccines</journal-title>
</journal-title-group>
<issn pub-type="epub">2076-393X</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">30388790</article-id>
<article-id pub-id-type="pmc">6313887</article-id>
<article-id pub-id-type="doi">10.3390/vaccines6040074</article-id>
<article-id pub-id-type="publisher-id">vaccines-06-00074</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Two Live Attenuated Vaccines against Recent Low–and Highly Pathogenic H7N9 Influenza Viruses Are Safe and Immunogenic in Ferrets</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Rudenko</surname>
<given-names>Larisa</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
<xref ref-type="author-notes" rid="fn1-vaccines-06-00074">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kiseleva</surname>
<given-names>Irina</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
<xref ref-type="author-notes" rid="fn1-vaccines-06-00074">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Krutikova</surname>
<given-names>Elena</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-8670-8645</contrib-id>
<name><surname>Stepanova</surname>
<given-names>Ekaterina</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
<xref rid="c1-vaccines-06-00074" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2801-1508</contrib-id>
<name><surname>Isakova-Sivak</surname>
<given-names>Irina</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-6502-8341</contrib-id>
<name><surname>Donina</surname>
<given-names>Svetlana</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rekstin</surname>
<given-names>Andrey</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Pisareva</surname>
<given-names>Maria</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bazhenova</surname>
<given-names>Ekaterina</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kotomina</surname>
<given-names>Tatiana</given-names>
</name>
<xref ref-type="aff" rid="af1-vaccines-06-00074">1</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-3203-9869</contrib-id>
<name><surname>Katelnikova</surname>
<given-names>Anastasia</given-names>
</name>
<xref ref-type="aff" rid="af2-vaccines-06-00074">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Muzhikyan</surname>
<given-names>Arman</given-names>
</name>
<xref ref-type="aff" rid="af2-vaccines-06-00074">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Makarov</surname>
<given-names>Valery</given-names>
</name>
<xref ref-type="aff" rid="af2-vaccines-06-00074">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-3912-2550</contrib-id>
<name><surname>Sparrow</surname>
<given-names>Erin Grace</given-names>
</name>
<xref ref-type="aff" rid="af3-vaccines-06-00074">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Torelli</surname>
<given-names>Guido</given-names>
</name>
<xref ref-type="aff" rid="af3-vaccines-06-00074">3</xref>
</contrib>
</contrib-group>
<aff id="af1-vaccines-06-00074"><label>1</label>
Institute of Experimental Medicine, St. Petersburg 197376, Russia;<email>vaccine@mail.ru</email>
(L.R.);<email>irina.v.kiseleva@mail.ru</email>
(I.K.);<email>krutikova.iem@mail.ru</email>
(E.K.);<email>isakova.sivak@gmail.com</email>
(I.I.-S.);<email>sveta.donina@gmail.com</email>
(S.D.);<email>arekstin@yandex.ru</email>
(A.R.);<email>maria.pisareva@influenza.spb.ru</email>
(M.P.);<email>sonya.01.08@mail.ru</email>
(E.B.);<email>tstretiak@gmail.com</email>
(T.K.)</aff>
<aff id="af2-vaccines-06-00074"><label>2</label>
Institute of Preclinical Research Ltd., St. Petersburg 188663, Russia;<email>katelnikova.ae@doclinika.ru</email>
(A.K.);<email>mancho1@yandex.ru</email>
(A.M.);<email>makarov.vg@doclinika.ru</email>
(V.M.)</aff>
<aff id="af3-vaccines-06-00074"><label>3</label>
World Health Organization, 1211 Geneva, Switzerland;<email>sparrowe@who.int</email>
(E.G.S.);<email>torellig@who.int</email>
(G.T.)</aff>
<author-notes><corresp id="c1-vaccines-06-00074"><label>*</label>
Correspondence: <email>fedorova.iem@gmail.com</email>
; Tel.: +7-812-234-4292</corresp>
<fn id="fn1-vaccines-06-00074"><label>†</label>
<p>These authors contributed equally to this work as first authors.</p>
</fn>
</author-notes>
<pub-date pub-type="epub"><day>01</day>
<month>11</month>
<year>2018</year>
</pub-date>
<pub-date pub-type="collection"><month>12</month>
<year>2018</year>
</pub-date>
<volume>6</volume>
<issue>4</issue>
<elocation-id>74</elocation-id>
<history><date date-type="received"><day>30</day>
<month>8</month>
<year>2018</year>
</date>
<date date-type="accepted"><day>27</day>
<month>9</month>
<year>2018</year>
</date>
</history>
<permissions><copyright-statement>© 2018 by the World Health Organization.</copyright-statement>
<copyright-year>2018</copyright-year>
<license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the terms of the Creative Commons Attribution IGO License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/3.0/igo/legalcode">http://creativecommons.org/licenses/by/3.0/igo/legalcode</ext-link>
), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any reproduction of this article there should not be any suggestion that WHO or this article endorse any specific organization or products. The use of the WHO logo is not permitted. This notice should be preserved along with the article’s original URL.</license-p>
</license>
</permissions>
<abstract><p>Influenza H7N9 virus is a potentially pandemic subtype to which most people are immunologically naïve. To be better prepared for the potential occurrence of an H7N9 pandemic, in 2017 the World Health Organization recommended developing candidate vaccine viruses from two new H7N9 viruses, A/Guangdong/17SF003/2016 (A/GD) and A/Hong Kong/125/2017 (A/HK). This report describes the development of live attenuated influenza vaccine (LAIV) candidates against A/GD and A/HK viruses and study of their safety and immunogenicity in the ferret model in order to choose the most promising one for a phase I clinical trial. The A/HK-based vaccine candidate (A/17/HK) was developed by classical reassortment in eggs. The A/GD-based vaccine candidate (A/17/GD) was generated by reverse genetics. Ferrets were vaccinated with two doses of LAIV or phosphate-buffered saline. Both H7N9 LAIVs tested were safe for ferrets, as shown by absence of clinical signs, and by virological and histological data; they were immunogenic after a single vaccination. These results provide a compelling argument for further testing of these vaccines in volunteers. Since the A/HK virus represents the cluster that has caused the majority of human cases, and because the A/HK-based LAIV candidate was developed by classical reassortment, this is the preferred candidate for a phase I clinical trial.</p>
</abstract>
<kwd-group><kwd>H7N9</kwd>
<kwd>avian influenza</kwd>
<kwd>pandemic threat</kwd>
<kwd>live attenuated influenza vaccine</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="vaccines-06-00074-f001" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Experimental groups and study design.</p>
</caption>
<graphic xlink:href="vaccines-06-00074-g001"></graphic>
</fig>
<fig id="vaccines-06-00074-f002" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>Changes in body weight of ferrets after administration of H7N9 LAIV expressed as % of initial body weight (mean + SEM): (<bold>A</bold>
) First vaccination; (<bold>B</bold>
) second vaccination.</p>
</caption>
<graphic xlink:href="vaccines-06-00074-g002"></graphic>
</fig>
<fig id="vaccines-06-00074-f003" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>Clinical signs in ferrets after administration of H7N9 LAIV (group medians of sums of scores): (<bold>A</bold>
) First vaccination; (<bold>B</bold>
) second vaccination.</p>
</caption>
<graphic xlink:href="vaccines-06-00074-g003"></graphic>
</fig>
<fig id="vaccines-06-00074-f004" orientation="portrait" position="float"><label>Figure 4</label>
<caption><p>Body temperature of ferrets after vaccination with H7N9 LAIV (mean + SEM): (<bold>A</bold>
) First vaccination; (<bold>B</bold>
) second vaccination.</p>
</caption>
<graphic xlink:href="vaccines-06-00074-g004"></graphic>
</fig>
<fig id="vaccines-06-00074-f005" orientation="portrait" position="float"><label>Figure 5</label>
<caption><p>Microscopic analysis of trachea and lung pathology. Representative hematoxylin and eosin-stained trachea and lung sections of ferrets inoculated with one dose of A/17/GD LAIV (<bold>A</bold>
,<bold>D</bold>
), A/17/HK LAIV (<bold>B</bold>
,<bold>E</bold>
) or PBS (<bold>C</bold>
,<bold>F</bold>
): (<bold>A</bold>
–<bold>C</bold>
) trachea slices; magnification 200×. There are no pathological changes. (<bold>D</bold>
–<bold>F</bold>
) lung slices; magnification 100×. Red arrows indicate lymphocytic infiltration. (<bold>D</bold>
) mild lymphocytic infiltration associated with hyperplasia of peribronchial lymphoid tissue. (<bold>E</bold>
) moderate lymphocytic infiltration associated with hyperplasia of peribronchial lymphoid tissue. (<bold>F</bold>
) mild lymphocytic infiltration associated with hyperplasia of peribronchial lymphoid tissue.</p>
</caption>
<graphic xlink:href="vaccines-06-00074-g005"></graphic>
</fig>
<fig id="vaccines-06-00074-f006" orientation="portrait" position="float"><label>Figure 6</label>
<caption><p>Homologous and heterologous antibody titers in ferrets given two doses of H7N9 LAIV intranasally at 28 days interval. Individual data and geometric means are shown. Test of Wilcoxon was used for comparison of antibody GMTs. (<bold>A</bold>
) HAI antibody titers. (<bold>B</bold>
) Serum IgG antibody titers. (<bold>C</bold>
) Serum IgA antibody titers. (<bold>D</bold>
) Secretory IgA antibody titers in nasal washes.</p>
</caption>
<graphic xlink:href="vaccines-06-00074-g006"></graphic>
</fig>
<table-wrap id="vaccines-06-00074-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">vaccines-06-00074-t001_Table 1</object-id>
<label>Table 1</label>
<caption><p>A list of viruses used in the study.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Virus</th>
<th colspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Genome Composition</th>
<th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Comment</th>
</tr>
<tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Surface Antigens HA and NA</th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Internal Protein Genes</th>
</tr>
</thead>
<tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">Len/17 (H2N2)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Len/17</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Len/17</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Master donor virus for LAIV</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">A/HK WT (H7N9)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">A/HK WT</td>
<td align="center" valign="middle" rowspan="1" colspan="1">A/HK WT</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Human isolate (avian influenza virus)</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">A/17/HK (H7N9)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">A/HK WT</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Len/17</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LAIV reassortant virus obtained by classical reassortment in eggs</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">A/17/GD (H7N9)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">A/GD WT modified *</td>
<td align="center" valign="middle" rowspan="1" colspan="1">Len/17</td>
<td align="center" valign="middle" rowspan="1" colspan="1">LAIV reassortant virus obtained by reverse genetics</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A/17/AH (H7N9)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A/AH WT</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Len/17</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LAIV reassortant virus obtained by classical reassortment in eggs</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p><bold>*</bold>
polybasic HA cleavage site deleted and K292R mutation introduced into NA protein; A/HK WT: A/Hong Kong/125/2017 (H7N9); A/GD WT: A/Guangdong/17FS003/2016 (H7N9); A/AH WT: A/Anhui/1/2013 (H7N9).</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="vaccines-06-00074-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">vaccines-06-00074-t002_Table 2</object-id>
<label>Table 2</label>
<caption><p>Vaccine virus in lungs and nasal washes of ferrets, as measured by PCR and by culture in embryonated chicken eggs.</p>
</caption>
<table frame="hsides" rules="groups"><tbody><tr><td colspan="5" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1"><bold>Culture in Chicken Eggs (lg EID<sub>50</sub>
/mL)</bold>
</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>Day after First Vaccination</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>A/17/HK</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>A/17/GD</bold>
</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Nasal Washes</bold>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Lung Tissue</bold>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Nasal Washes</bold>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Lung Tissue</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.45 ± 0.243 (8/8)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">n.d. <sup>1</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.39 ± 0.242 (8/8)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.38 ± 0.161 (8/8)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">< 1.5 <sup>2</sup>
(0/3)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.04 ± 0.254 (8/8)</td>
<td align="center" valign="middle" rowspan="1" colspan="1"><1.5 (0/3)</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.86 ± 0.289 (5/5)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3.40 ± 0.391 (5/5)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>Day after Second Vaccination</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>A/17/HK</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>A/17/GD</bold>
</td>
</tr>
<tr><td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Nasal Washes</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Nasal washes</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td colspan="2" align="center" valign="middle" rowspan="1"><1.5 (0/5)</td>
<td colspan="2" align="center" valign="middle" rowspan="1"><1.5 (0/5)</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td colspan="2" align="center" valign="middle" rowspan="1"><1.5 (0/5)</td>
<td colspan="2" align="center" valign="middle" rowspan="1"><1.5 (0/5)</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><1.5 (0/5)</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><1.5 (0/5)</td>
</tr>
<tr><td colspan="5" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>PCR (RT–qPCR/mL)</bold>
</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>Day after First Vaccination</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>A/17/HK</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>A/17/GD</bold>
</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Nasal Washes</bold>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Lung Tissue</bold>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Nasal Washes</bold>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Lung Tissue</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.690 ± 0.240 (8/8)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">n.d. <sup>1</sup>
</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.731 ± 0.151 (8/8)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">n.d.</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.239 ± 0.160 (8/8)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.525 ± 0.625 (3/3)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">4.817 ± 0.114 (8/8)</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.423 (1/3)</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5.207 ± 0.254 (5/5)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4.261 ± 0.681 (5/5)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>Day after Second Vaccination</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>A/17/HK</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>A/17/GD</bold>
</td>
</tr>
<tr><td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Nasal Washes</bold>
</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><bold>Nasal Washes</bold>
</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td colspan="2" align="center" valign="middle" rowspan="1">3.371 (1/5)</td>
<td colspan="2" align="center" valign="middle" rowspan="1">3.481 (1/5)</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td colspan="2" align="center" valign="middle" rowspan="1"><1.5 <sup>2</sup>
(0/5)</td>
<td colspan="2" align="center" valign="middle" rowspan="1"><1.5 (0/5)</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><1.5 (0/5)</td>
<td colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1"><1.5 (0/5)</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p><sup>1</sup>
n.d.: not determined. <sup>2</sup>
Estimated threshold limit value.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="vaccines-06-00074-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">vaccines-06-00074-t003_Table 3</object-id>
<label>Table 3</label>
<caption><p>Semiquantitative analysis of lung tissue and bronchial tree in male ferrets, day 3 post vaccination.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th rowspan="3" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Histopathological Parameters</th>
<th colspan="9" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Score of Histopathological Changes</th>
</tr>
<tr><th colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">A/17/GD</th>
<th colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">A/17/HK</th>
<th colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">PBS</th>
</tr>
<tr><th colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">(Group 1)</th>
<th colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">(Group 2)</th>
<th colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">(Group 3)</th>
</tr>
</thead>
<tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">Animal index number</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Exudate in lung lumen</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Hypertrophy of bronchial epithelium</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Hyperplasia of bronchial epithelium</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Necrosis of bronchial epithelium</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Exudate in bronchiole lumen</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Hypertrophy of bronchoalveolar epithelium</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Hyperplasia of bronchoalveolar epithelium</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Necrosis of bronchoalveolar epithelium</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Bronchitis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Peribronchitis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Bronchiolitis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Peribronchiolitis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Perivasculitis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Vasculitis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Interstitial infiltrate</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Alveolitis</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Hyperemia of alveolar septum</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Alveolar emphysema</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Alveolar hemorrhages</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">Total points per animal</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">15</td>
<td align="center" valign="middle" rowspan="1" colspan="1">9</td>
<td align="center" valign="middle" rowspan="1" colspan="1">14</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Median</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">9</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">7</td>
<td colspan="3" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">5</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>0: no changes; 1: minimum changes; 2: moderate changes; 3: pronounced changes. Statistically significant differences were not found (Kruskal–Wallis test, <italic>p</italic>
> 0.05).</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="vaccines-06-00074-t004" orientation="portrait" position="float"><object-id pub-id-type="pii">vaccines-06-00074-t004_Table 4</object-id>
<label>Table 4</label>
<caption><p>Homologous and heterologous antibody immune responses of healthy volunteers after vaccination with A/17/AH (H7N9) LAIV.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th rowspan="3" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Assay</th>
<th rowspan="3" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">H7N9 Virus</th>
<th colspan="3" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">After First Vaccination</th>
<th colspan="3" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">After Second Vaccination</th>
</tr>
<tr><th colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Seroconversion</th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GMT Rise</th>
<th colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Seroconversion</th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GMT Rise</th>
</tr>
<tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">No.</th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">%</th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">No.</th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">%</th>
<th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></th>
</tr>
</thead>
<tbody><tr><td rowspan="3" align="center" valign="middle" colspan="1">HAI</td>
<td align="center" valign="middle" rowspan="1" colspan="1">A/17/AH</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">10.3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.7</td>
<td align="center" valign="middle" rowspan="1" colspan="1">19</td>
<td align="center" valign="middle" rowspan="1" colspan="1">65.5</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.4</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">A/17/GD</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.3</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A/17/HK</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.0</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">MN</td>
<td align="center" valign="middle" rowspan="1" colspan="1">A/17/AH</td>
<td align="center" valign="middle" rowspan="1" colspan="1">14</td>
<td align="center" valign="middle" rowspan="1" colspan="1">48.0</td>
<td align="center" valign="middle" rowspan="1" colspan="1">3.4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">21</td>
<td align="center" valign="middle" rowspan="1" colspan="1">72.4</td>
<td align="center" valign="middle" rowspan="1" colspan="1">5.5</td>
</tr>
<tr><td align="center" valign="middle" rowspan="1" colspan="1">A/17/GD</td>
<td align="center" valign="middle" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" rowspan="1" colspan="1">6.9</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.3</td>
<td align="center" valign="middle" rowspan="1" colspan="1">7</td>
<td align="center" valign="middle" rowspan="1" colspan="1">24.1</td>
<td align="center" valign="middle" rowspan="1" colspan="1">1.6</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A/17/HK</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d. <sup>1</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">n.d.</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p><sup>1</sup>
n.d.: not determined.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list></list>
<tree><noCountry><name sortKey="Bazhenova, Ekaterina" sort="Bazhenova, Ekaterina" uniqKey="Bazhenova E" first="Ekaterina" last="Bazhenova">Ekaterina Bazhenova</name>
<name sortKey="Donina, Svetlana" sort="Donina, Svetlana" uniqKey="Donina S" first="Svetlana" last="Donina">Svetlana Donina</name>
<name sortKey="Isakova Sivak, Irina" sort="Isakova Sivak, Irina" uniqKey="Isakova Sivak I" first="Irina" last="Isakova-Sivak">Irina Isakova-Sivak</name>
<name sortKey="Katelnikova, Anastasia" sort="Katelnikova, Anastasia" uniqKey="Katelnikova A" first="Anastasia" last="Katelnikova">Anastasia Katelnikova</name>
<name sortKey="Kiseleva, Irina" sort="Kiseleva, Irina" uniqKey="Kiseleva I" first="Irina" last="Kiseleva">Irina Kiseleva</name>
<name sortKey="Kotomina, Tatiana" sort="Kotomina, Tatiana" uniqKey="Kotomina T" first="Tatiana" last="Kotomina">Tatiana Kotomina</name>
<name sortKey="Krutikova, Elena" sort="Krutikova, Elena" uniqKey="Krutikova E" first="Elena" last="Krutikova">Elena Krutikova</name>
<name sortKey="Makarov, Valery" sort="Makarov, Valery" uniqKey="Makarov V" first="Valery" last="Makarov">Valery Makarov</name>
<name sortKey="Muzhikyan, Arman" sort="Muzhikyan, Arman" uniqKey="Muzhikyan A" first="Arman" last="Muzhikyan">Arman Muzhikyan</name>
<name sortKey="Pisareva, Maria" sort="Pisareva, Maria" uniqKey="Pisareva M" first="Maria" last="Pisareva">Maria Pisareva</name>
<name sortKey="Rekstin, Andrey" sort="Rekstin, Andrey" uniqKey="Rekstin A" first="Andrey" last="Rekstin">Andrey Rekstin</name>
<name sortKey="Rudenko, Larisa" sort="Rudenko, Larisa" uniqKey="Rudenko L" first="Larisa" last="Rudenko">Larisa Rudenko</name>
<name sortKey="Sparrow, Erin Grace" sort="Sparrow, Erin Grace" uniqKey="Sparrow E" first="Erin Grace" last="Sparrow">Erin Grace Sparrow</name>
<name sortKey="Stepanova, Ekaterina" sort="Stepanova, Ekaterina" uniqKey="Stepanova E" first="Ekaterina" last="Stepanova">Ekaterina Stepanova</name>
<name sortKey="Torelli, Guido" sort="Torelli, Guido" uniqKey="Torelli G" first="Guido" last="Torelli">Guido Torelli</name>
</noCountry>
</tree>
</affiliations>
</record>
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