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Genetic stability of live attenuated vaccines against potentially pandemic influenza viruses.
Vaccine. 2015 Dec 08; 33(49):7008-14.V

Abstract

BACKGROUND

Ensuring genetic stability is a prerequisite for live attenuated influenza vaccine (LAIV). This study describes the results of virus shedding and clinical isolates' testing of Phase I clinical trials of Russian LAIVs against potentially pandemic influenza viruses in healthy adults.

METHODS

Three live attenuated vaccines against potentially pandemic influenza viruses, H2N2 LAIV, H5N2 LAIV and H7N3 LAIV, generated by classical reassortment in eggs, were studied. For each vaccine tested, subjects were randomly distributed into two groups to receive two doses of either LAIV or placebo at a 3:1 vaccine/placebo ratio. Nasal swabs were examined for vaccine virus shedding by culturing in eggs and by PCR. Vaccine isolates were tested for temperature sensitivity and cold-adaptation (ts/ca phenotypes) and for nucleotide sequence.

RESULTS

The majority of nasal wash positive specimens were detected on the first day following vaccination. PCR method demonstrated higher sensitivity than routine virus isolation in eggs. None of the placebo recipients had detectable vaccine virus replication. All viruses isolated from the immunized subjects retained the ts/ca phenotypic characteristics of the master donor virus (MDV) and were shown to preserve all attenuating mutations described for the MDV. These data suggest high level of vaccine virus genetic stability after replication in humans. During manufacture process, no additional mutations occurred in the genome of H2N2 LAIV. In contrast, one amino acid change in the HA of H7N3 LAIV and two additional mutations in the HA of H5N2 LAIV manufactured vaccine lot were detected, however, they did not affect their ts/ca phenotypes.

CONCLUSIONS

Our clinical trials revealed phenotypic and genetic stability of the LAIV viruses recovered from the immunized volunteers. In addition, no vaccine virus was detected in the placebo groups indicating the lack of person-to-person transmission. LAIV TRIAL REGISTRATION at ClinicalTrials.gov: H7N3-NCT01511419; H5N2-NCT01719783; H2N2-NCT01982331.

Authors+Show Affiliations

Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street , St Petersburg 197376, Russia. Electronic address: irina.v.kiseleva@mail.ru.Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street , St Petersburg 197376, Russia.Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street , St Petersburg 197376, Russia.Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street , St Petersburg 197376, Russia.Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street , St Petersburg 197376, Russia.Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street , St Petersburg 197376, Russia.Department of Molecular Virology, Institute of Influenza, St Petersburg 197376, Russia.Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street , St Petersburg 197376, Russia.PATH, Seattle, Washington, 98121, USA.Department of Virology, Institute of Experimental Medicine, 12 Acad. Pavlov Street , St Petersburg 197376, Russia.

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26432909

Citation

Kiseleva, Irina, et al. "Genetic Stability of Live Attenuated Vaccines Against Potentially Pandemic Influenza Viruses." Vaccine, vol. 33, no. 49, 2015, pp. 7008-14.
Kiseleva I, Dubrovina I, Fedorova E, et al. Genetic stability of live attenuated vaccines against potentially pandemic influenza viruses. Vaccine. 2015;33(49):7008-14.
Kiseleva, I., Dubrovina, I., Fedorova, E., Larionova, N., Isakova-Sivak, I., Bazhenova, E., Pisareva, M., Kuznetsova, V., Flores, J., & Rudenko, L. (2015). Genetic stability of live attenuated vaccines against potentially pandemic influenza viruses. Vaccine, 33(49), 7008-14. https://doi.org/10.1016/j.vaccine.2015.09.050
Kiseleva I, et al. Genetic Stability of Live Attenuated Vaccines Against Potentially Pandemic Influenza Viruses. Vaccine. 2015 Dec 8;33(49):7008-14. PubMed PMID: 26432909.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic stability of live attenuated vaccines against potentially pandemic influenza viruses. AU - Kiseleva,Irina, AU - Dubrovina,Irina, AU - Fedorova,Ekaterina, AU - Larionova,Natalie, AU - Isakova-Sivak,Irina, AU - Bazhenova,Ekaterina, AU - Pisareva,Maria, AU - Kuznetsova,Victoria, AU - Flores,Jorge, AU - Rudenko,Larisa, Y1 - 2015/10/02/ PY - 2015/02/10/received PY - 2015/09/04/revised PY - 2015/09/14/accepted PY - 2015/10/4/entrez PY - 2015/10/4/pubmed PY - 2016/8/21/medline KW - Genetic stability KW - Influenza KW - Live attenuated influenza vaccine KW - Pre-pandemic vaccine KW - Vaccine virus shedding SP - 7008 EP - 14 JF - Vaccine JO - Vaccine VL - 33 IS - 49 N2 - BACKGROUND: Ensuring genetic stability is a prerequisite for live attenuated influenza vaccine (LAIV). This study describes the results of virus shedding and clinical isolates' testing of Phase I clinical trials of Russian LAIVs against potentially pandemic influenza viruses in healthy adults. METHODS: Three live attenuated vaccines against potentially pandemic influenza viruses, H2N2 LAIV, H5N2 LAIV and H7N3 LAIV, generated by classical reassortment in eggs, were studied. For each vaccine tested, subjects were randomly distributed into two groups to receive two doses of either LAIV or placebo at a 3:1 vaccine/placebo ratio. Nasal swabs were examined for vaccine virus shedding by culturing in eggs and by PCR. Vaccine isolates were tested for temperature sensitivity and cold-adaptation (ts/ca phenotypes) and for nucleotide sequence. RESULTS: The majority of nasal wash positive specimens were detected on the first day following vaccination. PCR method demonstrated higher sensitivity than routine virus isolation in eggs. None of the placebo recipients had detectable vaccine virus replication. All viruses isolated from the immunized subjects retained the ts/ca phenotypic characteristics of the master donor virus (MDV) and were shown to preserve all attenuating mutations described for the MDV. These data suggest high level of vaccine virus genetic stability after replication in humans. During manufacture process, no additional mutations occurred in the genome of H2N2 LAIV. In contrast, one amino acid change in the HA of H7N3 LAIV and two additional mutations in the HA of H5N2 LAIV manufactured vaccine lot were detected, however, they did not affect their ts/ca phenotypes. CONCLUSIONS: Our clinical trials revealed phenotypic and genetic stability of the LAIV viruses recovered from the immunized volunteers. In addition, no vaccine virus was detected in the placebo groups indicating the lack of person-to-person transmission. LAIV TRIAL REGISTRATION at ClinicalTrials.gov: H7N3-NCT01511419; H5N2-NCT01719783; H2N2-NCT01982331. SN - 1873-2518 UR - https://www.unboundmedicine.com/medline/citation/26432909/Genetic_stability_of_live_attenuated_vaccines_against_potentially_pandemic_influenza_viruses_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0264-410X(15)01326-2 DB - PRIME DP - Unbound Medicine ER -