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2 Department of Microbiology and Immunology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA

3 Sanofi Pasteur, Asia and JPAC Region, Singapore, Singapore

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**Section 4**

**Preparation of Vaccines Against Potential**

**Pandemic Influenza**

**Preparation of Vaccines Against Potential Pandemic Influenza**

**Chapter 4**

**Provisional chapter**

**Preparing Live Influenza Vaccines against Potential**

**Preparing Live Influenza Vaccines against Potential** 

DOI: 10.5772/intechopen.76980

**Influenza Viruses and Cold-Adapted Master Donor**

**Influenza Viruses and Cold-Adapted Master Donor** 

As part of an influenza pandemic preparedness program, the WHO analyzes a range of potentially pandemic influenza viruses for appropriate vaccines development. Several vaccine candidates were prepared using classical genetic reassortment, with the coldadapted A/Leningrad/134/17/57(H2N2) (Len/17) master donor strain (MDS) which is licensed in the Russia for the live influenza vaccine (LAIV) strains type A production for adults and children. The nonpathogenic avian viruses of different subtypes were used for reassortant vaccine strains preparation. All vaccine candidates demonstrated a high reproductive capacity and cold-adapted (*ca-*) phenotype in chick embryos. In mice, the LAIV of H5N2, H7N3, and H9N2 subtypes provided protection against infection with distant influenza viruses. The immunogenicity and protective efficacy of H7N3 LAIV was also demonstrated in ferrets. The H5N2 and H7N3 vaccine candidates demonstrated the inability to reproduce in chickens, which confirms the safety of their use in areas with highly developed agriculture. When tested in clinical trials, vaccine strains of H5N2 and H7N3 subtypes induce the conversions of antibodies homologous and antigenically distant variants. The use of LAIV can be effective against highly pathogenic influenza viruses even in the case of incomplete antigenic correspondence between the vaccine

**Keywords:** live influenza vaccine, avian influenza, attenuation, reassortment,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Pandemic Influenza Using Nonpathogenic Avian**

**Pandemic Influenza Using Nonpathogenic Avian** 

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76980

strain and the infectious virus.

cross-protection

**Strain**

**Strain**

Yulia Desheva

**Abstract**

Yulia Desheva

**Preparing Live Influenza Vaccines against Potential Pandemic Influenza Using Nonpathogenic Avian Influenza Viruses and Cold-Adapted Master Donor Strain Preparing Live Influenza Vaccines against Potential Pandemic Influenza Using Nonpathogenic Avian Influenza Viruses and Cold-Adapted Master Donor Strain**

DOI: 10.5772/intechopen.76980

#### Yulia Desheva Yulia Desheva

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.76980

#### **Abstract**

As part of an influenza pandemic preparedness program, the WHO analyzes a range of potentially pandemic influenza viruses for appropriate vaccines development. Several vaccine candidates were prepared using classical genetic reassortment, with the coldadapted A/Leningrad/134/17/57(H2N2) (Len/17) master donor strain (MDS) which is licensed in the Russia for the live influenza vaccine (LAIV) strains type A production for adults and children. The nonpathogenic avian viruses of different subtypes were used for reassortant vaccine strains preparation. All vaccine candidates demonstrated a high reproductive capacity and cold-adapted (*ca-*) phenotype in chick embryos. In mice, the LAIV of H5N2, H7N3, and H9N2 subtypes provided protection against infection with distant influenza viruses. The immunogenicity and protective efficacy of H7N3 LAIV was also demonstrated in ferrets. The H5N2 and H7N3 vaccine candidates demonstrated the inability to reproduce in chickens, which confirms the safety of their use in areas with highly developed agriculture. When tested in clinical trials, vaccine strains of H5N2 and H7N3 subtypes induce the conversions of antibodies homologous and antigenically distant variants. The use of LAIV can be effective against highly pathogenic influenza viruses even in the case of incomplete antigenic correspondence between the vaccine strain and the infectious virus.

**Keywords:** live influenza vaccine, avian influenza, attenuation, reassortment, cross-protection

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **1. Introduction**

Influenza viruses belong to the family *Orthomyxoviridae*. These are RNA-containing viruses possessing a negative fragmented genome. To date, there are four types (serotype) of influenza viruses—influenza A, B, C, and D. Influenza A viruses affect humans and a wide range of mammals (horses, pigs, dogs, wild and domestic cats, seals, ferrets) and birds (chickens, wild waterfowl, gulls, etc.). Only influenza A viruses are known as causative agents of severe epidemics and pandemics. The antigenic properties of influenza A viruses are based on two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA).

**2. Avian influenza in humans**

**2.1. H5N1 influenza viruses**

and chickens [19].

confirmed in another 17 people, five of whom died [17].

Most avian viruses are initially low virulent for birds, causing only transient asymptomatic intestinal infections in wild waterfowl [9]. Viruses of subtypes H5 and H7 can be widespread among poultry, while acquiring the increased pathogenicity. This was observed during outbreaks caused by H5N2 viruses in 1983 or 1994–1995 in North America [10, 11], subtype H7 (H7N7 or H7N2)—in Europe and in Australia [12]. For the first time, "bird plague," a disease caused (as is now known) by highly pathogenic influenza viruses, was described in 1878 during an outbreak among chickens in Italy. The outbreak causative agent was isolated in 1902 (virus A/Chicken/Brescia/1902 (H7N7)). During similar outbreaks, repeatedly observed in Europe and around the world, several other viruses of H7 subtype were isolated. In 1955, those viruses were identified as belonging to a group of influenza viruses [13]. The first of the highly pathogenic (HP) viruses of the H5N3 subtype—the A/Tern/South Africa/61—was isolated in 1961 [14]. HP avian influenza viruses can cause a mass death of chickens in a short time as a result of dissemination of infection in poultry with rapidly progressive neurologic symptoms, diarrhea, and fatal outcome. Until 1997, there was no obvious evidence of direct infection of humans with avian viruses. Nevertheless, serological studies revealed the presence of antibodies against avian viruses of various subtypes in human sera in southern China, Hong Kong, and East Asia, indicating exposure of some people to avian influenza viruses [15].

Preparing Live Influenza Vaccines against Potential Pandemic Influenza Using Nonpathogenic…

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For the first time, attention to H5 avian influenza viruses as possible pandemic agents was brought in May 1997 in Hong Kong during a mass outbreak among chickens when the avian virus H5N1 was isolated from a child who died from viral pneumonia [16]. To the end of 1997, an infection with the virus H5N1 similar to poultry viruses identified in the region was

It is possible that before the appearance of the virus H5N1 in humans, a series of reassortments during the circulation of a number of precursor viruses in birds have occurred. Thus, HA of H5N1 viruses isolated from humans were almost identical to those of the A/Goose/ Guandong/1/96 (H5N1) [18], and NA may have been acquired from the virus H6N1 [24]. It is assumed that the internal genes were borrowed from the same H6N1 virus or H9N2 A/Qail/ Hong Kong/G1/97 (H9N2) influenza viruses during transmission from waterfowl to quails

The mechanisms of avian influenza viruses "step-by-step" adaptation to new hosts are well characterized [20]. The change in host cell specificity and the increase in the pathogenicity of influenza viruses can be influenced either by amino acid substitutions in the receptor binding site of HA or by substitutions affecting the conformation and steric availability of this center. In particular, this can be influenced by changes in the number of glycosylation sites or their localization. High pathogenicity of avian influenza viruses in mammals is polygenic in nature. The HA of H5 or H7 HP viruses with a polybasic cleavage site is known as a primary

Wild waterfowl are considered as a natural reservoir of influenza A viruses which is characterized by high divergence. The 16 HA subtypes and nine NA subtypes were detected in migratory waterfowl and poultry [1]. Sometimes, avian influenza viruses overcome the interspecies barrier and infect poultry and mammals. Avian influenza viruses of subtypes H5N1, H7N3, H7N7, H7N9, and H9N2 may become pathogenic for humans and occasionally cause very severe infections. As part of an influenza pandemic preparedness program, the World Health Organization (WHO) analyzes a range of zoonotic and potentially pandemic influenza viruses for the development of appropriate vaccines as seasonal influenza vaccination does not protect against pandemic avian influenza viruses [2].

After isolation of the first influenza viruses in 1933–1936, the development of influenza vaccines in England, the United States, Australia, and in the USSR began. The development of active immunization against influenza using live attenuated vaccines was conducted in Russia under the leadership of A.A. Smorodintsev since 1937, and in the USA since 1960, where the group of H.F. Maassab also obtained cold-adapted attenuated variants of influenza viruses A and B. At present, two types of LAIVs are commercially available. The first, based on cold-adapted master donor viruses (MDVs) A/ Leningrad/134/17/57 (H2N2) and B/USSR/60/69 [3–5], was licensed in 1987 for the people 3 years and older as Ultravac (Microgen, Russia). The second, known as FluMist based on cold-adapted MDVs, A/Ann Arbor/6/60ca (H2N2), and B/Ann Arbor/1/66ca, was licensed in 2003 (MedImmune, Inc., USA). FluMist is used for the prevention of influenza in persons younger than 49 and older than 2 years of age [6]. According to World Health Organization (WHO), vaccination prevents influenza in 80–90% of vaccinated people, and the economic effect of influenza vaccinations is 10–20 times higher than the cost of vaccination. In the past 10 years, attention was paid due to the advantages of LAIV that cause the formation of systemic and strong local (secretory) immunity. By contrast, parenteral inactivated influenza vaccines (IIV) stimulate mainly the formation of serum strain-specific antibodies which offer only limited protection against newly emerging viruses [7]. Intranasal implementation of LAIV produces immune response similar to natural infection and therefore induces an earlier, broader, and more long-lasting protection than inactivated vaccines [8]. Besides, the cost of live vaccine is five times less than inactivated vaccine, and the productivity of the biotechnological production process is significantly higher which is also important in the event of pandemic.
