Genetic stability of live attenuated vaccines against potentially pandemic influenza viruses
Introduction
Pigs and some avian species are the main reservoir of newly emerging pandemic influenza viruses [1], [2], [3]. Global circulation of all influenza A virus subtypes in avian species pose a constant threat to human public health. As of January 6, 2015, 694 cases of H5N1 influenza virus were reported by World Health Organization (WHO), 402 (58%) of which were fatal [4]. A total of 450 laboratory-confirmed cases of human infection with avian influenza H7N9 virus, including 165 (37%) deaths, have been reported to WHO on June 27, 2014 [5]. Influenza H2N2 viruses are also considered as a probable subtype to cause future pandemic because these viruses have not circulated in the human population since 1968. Therefore, people born after the H2N2 pandemic in 1968 more likely have no immunity to these viruses and may be more vulnerable if the H2N2 subtype returns to circulation [6], [7].
Vaccination remains the principal strategy against both seasonal and pandemic influenza. Over the last years, the interest in the live cold-adapted reassortment influenza vaccine (LAIV) has increased considerably. To a certain degree, it is because WHO recognized the advantages of LAIV in comparison with inactivated vaccine in the event of pandemic situation. These advantages include needle-free administration, higher vaccine virus yield, easier down-stream processing, cross-reactivity of immune responses and the induction of herd immunity [8].
Two types of LAIVs are now available commercially. The first, licensed in 1987 for the prevention of influenza in persons 3 years and older as Ultravac (Microgen, Russia), is based on cold-adapted MDVs, A/Leningrad/134/17/57 (H2N2) and B/USSR/60/69 [9], [10], [11], [12], [13], [14]. Pre-master seed vaccine viruses for LAIV production are developing by IEM (Institute of Experimental Medicine, St Petersburg, Russia).
The second, licensed as FluMist in 2003 (MedImmune, Inc, USA), is based on cold-adapted MDVs, A/Ann Arbor/6/60ca (H2N2) and B/Ann Arbor/1/66ca and uses for the prevention of influenza in persons younger than 49 and older than 2 years of age [15], [16], [17], [18], [19].
Seasonal influenza vaccination does not appear to protect against pandemic or H5N1 influenza viruses [20], [21], [22]. Therefore, in the face of pandemic development of appropriate potentially pandemic LAIVs is of primary strategic importance. A number of potentially pandemic LAIVs already generated by MedImmune [23], [24], [25], [26] and IEM [14], [27], [28], [29]. IEM is preparing a National collection of vaccine strains against potentially pandemic influenza viruses, which may cause serious and fatal disease.
Stability of genotype and phenotype, together with the absence of transmission potency are the main properties of live attenuated vaccines, which ensure their safety profile [30]. Confirmation of genetic and phenotypic stability of an LAIV is especially important in a pandemic situation to guarantee its safety during large-scale immunization campaigns. The lack of person-to-person transmission of Russian live attenuated vaccine was demonstrated in several clinical trials [27], [28], [31]. To our knowledge, there was only a single documented case of an LAIV virus transmission to an unvaccinated child during clinical trials of seasonal LAIVs prepared by MedImmune [32].
The safety profile and immunogenicity of Russian H2N2 [28], H5N2 [29] and H7N3 [27] potentially pandemic LAIVs were already well documented and published. In this paper, we presented the results of molecular genetics and virological studies conducted as a part of three clinical trials. The goal of this paper was to evaluate shedding, transmission and genetic stability of H7N3, H5N2 and H2N2 LAIVs against potentially pandemic influenza viruses developed by IEM (Russia) and to compare our results with published data by MedImmune (USA).
Section snippets
Vaccines tested
Three live attenuated vaccine strains against potentially pandemic influenza viruses, A/17/mallard/Netherlands/00/95 (H7N3) [33], A/17/California/66/395 (H2N2) [34] or A/17/turkey/Turkey/2005/133 (H5N2) [35] were generated in Institute of Experimental Medicine (IEM, St. Petersburg, Russia) by classical reassortment in eggs as pre-master seed viruses (pre-MSVs). Cold-adapted A/Leningrad/134/17/57 (H2N2) virus was used as MDV. H2N2 and H7N3 LAIVs displayed 6:2 genomic composition (six MDV genes
Results and discussion
The safety of live attenuated cold-adapted influenza vaccine is dependent on retention of the ts and ca phenotypes, genetic stability and lack of possible person-to-person transmission. In this study, we examined vaccine viruses shed in nasal secretions from three separate studies of H7N3, H5N2 and H2N2 LAIVs for duration of shedding and to ascertain retention of the appropriate phenotypes and genotypes. The inclusion of placebo controls in the studies, which were conducted as inpatient
Conclusions
Phenotypic (cold adaptation and temperature sensitivity) and genotypic (sequence) analyses conducted on the viruses recovered from the volunteers suggest that the Russian live attenuated vaccine is genetically stable after in vivo passages. All 40 clinical isolates tested retained the ts/ca phenotype of the MDV and were shown to preserve all attenuating mutations described for MDV. These data suggest high level of vaccine virus genetic stability after replication in humans.
Vaccine virus was not
FINANCIAL DISCLOSURE
The clinical part of this work was funded by Program for Appropriate Technologies in Health (PATH, Seattle, WA, USA). Molecular genetics studies were partially supported by Russian Scientific Fund No.14-15-00034 (RSF, Moscow, Russia).
CONFLICT OF INTEREST
The authors have declared that no conflict of interests exist.
ACKNOWLEDGMENTS
Authors would like to thank the study participants and the following collaborators on the study who supported the clinical studies: Vadim Tsvetnitsky (PATH), Maureen Power (PATH), Oleg Kiselev (Institute of Influenza), Marina Stukova (Institute of Influenza) and Marianna Erofeeva (Institute of Influenza) for their expert clinical assistance. We are also very grateful to Nadezhda Konovalova (Institute of Influenza) for collection of specimens and to Larisa Gubareva (CDC) for performing NA
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