Development of reassortant influenza vaccines: classical reassortment or reverse genetics?

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Abstract

An important feature of influenza vaccines, which distinguishes them from other immunobiological preparations, is that they have no fixed composition. Due to the constant influenza virus antigenic variability, production facilities require timely supply with relevant vaccine strains undoable due to the lack of proper method for the convenient, rapid and uninterrupted development of vaccine strains. Among the licensed influenza vaccines, classical inactivated and live influenza vaccines hold a special place. They are based on reassortant vaccine strains obtained by crossing currently circulating influenza virus with the so-called donor strain (cold-adapted attenuation donor for live influenza vaccines or high yield donor for inactivated vaccines). Vaccine strains for licensed live attenuated influenza vaccines are reassortants with the so-called 6:2 genome formula — two genes encoding hemagglutinin and neuraminidase (HA and NA) belong to the current epidemic virus, and six genes encoding internal proteins (PB2, PB1, PA, NP, M and NS) — to cold-adapted master donor virus. There is a very limited number of donors of attenuation. In Russia, there are cold-adapted viruses A/Leningrad/134/17/57 (H2N2) and B/USSR/60/69; in the USA (MedImmune) there are viruses A/Ann Arbor/6/60ca (H2N2) and B/Ann Arbor/1/66ca. MedImmune produces vaccine strains using reverse genetics technique. For other countries, this approach for obtaining vaccines is limited due to the need to purchase a license from the patent holders. In Russia, genetic manipulations with strains for the seasonal live influenza vaccine are not yet allowed; reassortants for the Russian live influenza vaccine are created only by classical reassortment in embryonated chicken eggs. Vaccine candidates for the inactivated influenza vaccine are prepared by the classical reassortment method, the requirements for them are more flexible and allow to use diverse genes combinations from “wild type” virus and master donor virus. High-yielding viruses such as A/PR/8/34 (H1N1), A/Texas/1/77 (H3N2), B/Lee/40 and some others are used as donors of internal genes. Unfortunately, the classical reassortment method does not always allow to promptly obtain a reassortant virus with a 6:2 genome formula. This is hindered by a number of reasons, ranging from the unique properties of a certain epidemic virus ending up with the constellation of genes. The reverse genetics method based on plasmids is an alternative approach to create reassortant vaccine strains allowing to reliably and quickly obtain reassortant viruses of a set 6:2 genome formula. However, this method also has certain weaknesses. This review discusses the advantages and disadvantages of development of conventional influenza vaccine candidates by reverse genetics and classical reassortment in developing chick embryos.

About the authors

Irina V. Kiseleva

Institute of Experimental Medicine

Author for correspondence.
Email: irina.v.kiseleva@mail.ru

DSc (Biology), Professor, Head of the Laboratory of General Virology; Professor, Department of Fundamental Problems of Medicine and Medical technologies

Russian Federation, St. Petersburg

Larisa G. Rudenko

Institute of Experimental Medicine

Email: irina.v.kiseleva@mail.ru

DSc (Мedicine), Professor, Head of the A.A. Smorodintsev Department of Virology

Russian Federation, St. Petersburg

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2. Figure. Genome composition (%) of reassortant influenza virus strains derived by classical reassortment of cold-adapted master donor viruses with A(H1N1), A(H2N2), A(H3N2), B/Victoria lineage, and B/Yamagata lineage wild type influenza viruses: (A) 20 resistant or (B) 20 sensitive to nonspecific thermostable gamma-inhibitors (based on [2, 21])Note. 6:2 genome composition — HA and NA are inherited from the wild type parent, and 6 internal genes are inherited from master donor virus; 5:3 genome composition — HA, NA and one of the internal genes are inherited from the wild type parent virus strain, the other five internal genes are inherited from master donor virus; 7:1 genome composition — HA is inherited from wild type parent, all internal genes and NA are inherited from master donor virus.

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