scholarly journals Reversion of Cold-Adapted Live Attenuated Influenza Vaccine into a Pathogenic Virus

2016 ◽  
Vol 90 (19) ◽  
pp. 8454-8463 ◽  
Author(s):  
Bin Zhou ◽  
Victoria A. Meliopoulos ◽  
Wei Wang ◽  
Xudong Lin ◽  
Karla M. Stucker ◽  
...  
Keyword(s):  
United States ◽  
Influenza A ◽  
Serial Passage ◽  
The United States ◽  
Temperature Sensitive ◽  
H1n1 Pandemic ◽  
Cold Adapted ◽  
Live Attenuated Influenza Vaccine ◽  
Ann Arbor ◽  
2009 H1n1

ABSTRACTThe only licensed live attenuated influenza A virus vaccines (LAIVs) in the United States (FluMist) are created using internal protein-coding gene segments from the cold-adapted temperature-sensitive master donor virus A/Ann Arbor/6/1960 and HA/NA gene segments from circulating viruses. During serial passage of A/Ann Arbor/6/1960 at low temperatures to select the desired attenuating phenotypes, multiple cold-adaptive mutations and temperature-sensitive mutations arose. A substantial amount of scientific and clinical evidence has proven that FluMist is safe and effective. Nevertheless, no study has been conducted specifically to determine if the attenuating temperature-sensitive phenotype can revert and, if so, the types of substitutions that will emerge (i.e., compensatory substitutions versus reversion of existing attenuating mutations). Serial passage of the monovalent FluMist 2009 H1N1 pandemic vaccine at increasing temperaturesin vitrogenerated a variant that replicated efficiently at higher temperatures. Sequencing of the variant identified seven nonsynonymous mutations, PB1-E51K, PB1-I171V, PA-N350K, PA-L366I, NP-N125Y, NP-V186I, and NS2-G63E. None occurred at positions previously reported to affect the temperature sensitivity of influenza A viruses. Synthetic genomics technology was used to synthesize the whole genome of the virus, and the roles of individual mutations were characterized by assessing their effects on RNA polymerase activity and virus replication kinetics at various temperatures. The revertant also regained virulence and caused significant disease in mice, with severity comparable to that caused by a wild-type 2009 H1N1 pandemic virus.IMPORTANCEThe live attenuated influenza vaccine FluMist has been proven safe and effective and is widely used in the United States. The phenotype and genotype of the vaccine virus are believed to be very stable, and mutants that cause disease in animals or humans have never been reported. By propagating the virus under well-controlled laboratory conditions, we found that the FluMist vaccine backbone could regain virulence to cause severe disease in mice. The identification of the responsible substitutions and elucidation of the underlying mechanisms provide unique insights into the attenuation of influenza virus, which is important to basic research on vaccines, attenuation reversion, and replication. In addition, this study suggests that the safety of LAIVs should be closely monitored after mass vaccination and that novel strategies to continue to improve LAIV vaccine safety should be investigated.

scholarly journals Comparative Study of the Temperature Sensitive, Cold Adapted and Attenuated Mutations Present in the Master Donor Viruses of the Two Commercial Human Live Attenuated Influenza Vaccines

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 928 ◽  
Author(s):  
Laura Rodriguez ◽  
Pilar Blanco-Lobo ◽  
Emma C. Reilly ◽  
Tatsuya Maehigashi ◽  
Aitor Nogales ◽  
...  
Keyword(s):  
Influenza A ◽  
Viral Disease ◽  
The United States ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Temperature Sensitive ◽  
Cold Adapted ◽  
Ann Arbor

Influenza viruses cause annual, seasonal infection across the globe. Vaccination represents the most effective strategy to prevent such infections and/or to reduce viral disease. Two major types of influenza vaccines are approved for human use: inactivated influenza vaccines (IIVs) and live attenuated influenza vaccines (LAIVs). Two Master Donor Virus (MDV) backbones have been used to create LAIVs against influenza A virus (IAV): the United States (US) A/Ann Arbor/6/60 (AA) and the Russian A/Leningrad/134/17/57 (Len) H2N2 viruses. The mutations responsible for the temperature sensitive (ts), cold-adapted (ca) and attenuated (att) phenotypes of the two MDVs have been previously identified and genetically mapped. However, a direct comparison of the contribution of these residues to viral attenuation, immunogenicity and protection efficacy has not been conducted. Here, we compared the In vitro and in vivo phenotype of recombinant influenza A/Puerto Rico/8/34 H1N1 (PR8) viruses containing the ts, ca and att mutations of the US (PR8/AA) and the Russian (PR8/Len) MDVs. Our results show that PR8/Len is more attenuated in vivo than PR8/AA, although both viruses induced similar levels of humoral and cellular responses, and protection against homologous and heterologous viral challenges. Our findings support the feasibility of using a different virus backbone as MDV for the development of improved LAIVs for the prevention of IAV infections.

scholarly journals A single amino acid substitution in PB1 of pandemic H1N1 with A/Ann Arbor/6/60 master donor virus mutations as a novel live-attenuated influenza virus vaccine

2022 ◽  
Author(s):  
Aitor Nogales ◽  
John Steel ◽  
Wen-Chun Liu ◽  
Anice C Lowen ◽  
Laura Rodriguez ◽  
...  
Keyword(s):  
Amino Acid ◽  
Guinea Pigs ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Infection ◽  
The United States ◽  
Single Amino Acid ◽  
Temperature Sensitive ◽  
Ann Arbor ◽  
The U.S

Influenza A viruses (IAV) remain emerging threats to human public health. Live-attenuated influenza vaccines (LAIV) are one of the most effective prophylactic options to prevent disease caused by influenza infections. However, licensed LAIV remain restricted for use in 2- to 49-year old healthy and non-pregnant people. Therefore, development of LAIV with increased safety, immunogenicity, and protective efficacy is highly desired. The United States (U.S.) licensed LAIV is based on the master donor virus (MDV) A/Ann Arbor/6/60 H2N2 backbone, which was generated by adaptation of the virus to growth at low temperatures. Introducing the genetic signature of the U.S. MDV into the backbone of other IAV strains resulted in varying levels of attenuation. While the U.S. MDV mutations conferred an attenuated phenotype to other IAV strains, the same amino acid changes did not significantly attenuate the pandemic A/California/04/09 H1N1 (pH1N1) strain. To attenuate pH1N1, we replaced the conserved leucine at position 319 with glutamine (L319Q) in PB1 and analyzed the in vitro and in vivo properties of pH1N1 viruses containing either PB1 L319Q alone or in combination with the U.S. MDV mutations using two animal models of influenza infection and transmission, ferrets and guinea pigs. Our results demonstrated that L319Q substitution in the pH1N1 PB1 alone or in combination with the mutations of the U.S. MDV resulted in reduced pathogenicity (ferrets) and transmission (guinea pigs), and an enhanced temperature sensitive phenotype. These results demonstrate the feasibility of generating an attenuated MDV based on the backbone of a contemporary pH1N1 IAV strain.

scholarly journals Lessons from the Past: Comparison of the Disease Burden of the Influenza A (H1N1) Pandemic 2009-10 and Seasonal Influenza 2010-2019 in the United States

2021 ◽  
Author(s):  
James A Koziol
Keyword(s):  
United States ◽  
Influenza A ◽  
Disease Burden ◽  
Seasonal Influenza ◽  
The United States ◽  
H1n1 Pandemic ◽  
Elderly Adults ◽  
The Past ◽  
Medical Visits ◽  
Influenza A H1n1

Abstract Background Annual influenza outbreaks constitute a major public health concern, both in the United States and worldwide. Comparisons of the health burdens of outbreaks might lead to the identification of specific at-risk populations, for whom public health resources should be marshaled appropriately and equitably. Methods We examined the disease burden of the 2009-10 influenza A (H1N1) pandemic relating to illnesses, medical visits, hospitalizations, and mortality, compared to influenza seasons 2010 to 2019, in the United States, as compiled by the Centers for Disease Control. Results With regard to seasonal influenza, rates of illnesses and medical visits were highest in infants aged 0–4 years, followed by adults aged 50–64 years. Rates of hospitalizations and deaths evinced a starkly different pattern, both dominated by elderly adults aged 65 and over. Youths aged 0 to 17 years were especially adversely affected by the H1N1 pandemic relative to hospitalizations and mortality compared to seasonal influenza; but curiously the opposite pattern was observed in elderly adults (aged 65 and older). Conclusions The disease burden of the 2009-10 influenza A pandemic was strikingly unlike that observed in the subsequent influenza seasons 2010 to 2019, in the United States: the past did not predict the future.

scholarly journals Anomalous influenza seasonality in the United States and the emergence of novel influenza B viruses

2021 ◽  
Vol 118 (5) ◽  
pp. e2012327118
Author(s):  
Rebecca K. Borchering ◽  
Christian E. Gunning ◽  
Deven V. Gokhale ◽  
K. Bodie Weedop ◽  
Arash Saeidpour ◽  
...  
Keyword(s):  
United States ◽  
Influenza A ◽  
Reproduction Number ◽  
Influenza Season ◽  
The United States ◽  
Influenza B ◽  
Relative Dynamics ◽  
2009 H1n1 ◽  
Kinetics Of ◽  
Early Activity

The 2019/2020 influenza season in the United States began earlier than any season since the 2009 H1N1 pandemic, with an increase in influenza-like illnesses observed as early as August. Also noteworthy was the numerical domination of influenza B cases early in this influenza season, in contrast to their typically later peak in the past. Here, we dissect the 2019/2020 influenza season not only with regard to its unusually early activity, but also with regard to the relative dynamics of type A and type B cases. We propose that the recent expansion of a novel influenza B/Victoria clade may be associated with this shift in the composition and kinetics of the influenza season in the United States. We use epidemiological transmission models to explore whether changes in the effective reproduction number or short-term cross-immunity between these viruses can explain the dynamics of influenza A and B seasonality. We find support for an increase in the effective reproduction number of influenza B, rather than support for cross-type immunity-driven dynamics. Our findings have clear implications for optimal vaccination strategies.

scholarly journals Narcolepsy and influenza A(H1N1) pandemic 2009 vaccination in the United States

Neurology ◽  
2014 ◽  
Vol 83 (20) ◽  
pp. 1823-1830 ◽  
Author(s):  
J. Duffy ◽  
E. Weintraub ◽  
C. Vellozzi ◽  
F. DeStefano ◽  
Keyword(s):  
United States ◽  
Influenza A ◽  
The United States ◽  
H1n1 Pandemic ◽  
Influenza A H1n1

scholarly journals Reassortment between Swine H3N2 and 2009 Pandemic H1N1 in the United States Resulted in Influenza A Viruses with Diverse Genetic Constellations with Variable Virulence in Pigs

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Daniela S. Rajão ◽  
Rasna R. Walia ◽  
Brian Campbell ◽  
Phillip C. Gauger ◽  
Alicia Janas-Martindale ◽  
...  
Keyword(s):  
Public Health ◽  
United States ◽  
Genetic Diversity ◽  
Influenza A ◽  
The United States ◽  
H1n1 Pandemic ◽  
Influenza A Viruses ◽  
Swine Industry ◽  
Viral Shedding ◽  
Increased Risk

ABSTRACT Repeated spillovers of the H1N1 pandemic virus (H1N1pdm09) from humans to pigs resulted in substantial evolution of influenza A viruses infecting swine, contributing to the genetic and antigenic diversity of influenza A viruses (IAV) currently circulating in swine. The reassortment with endemic swine viruses and maintenance of some of the H1N1pdm09 internal genes resulted in the circulation of different genomic constellations in pigs. Here, we performed a whole-genome phylogenetic analysis of 368 IAV circulating in swine from 2009 to 2016 in the United States. We identified 44 different genotypes, with the most common genotype (32.33%) containing a clade IV-A HA gene, a 2002-lineage NA gene, an M-pdm09 gene, and remaining gene segments of triple reassortant internal gene (TRIG) origin. To understand how different genetic constellations may relate to viral fitness, we compared the pathogenesis and transmission in pigs of six representative genotypes. Although all six genotypes efficiently infected pigs, they resulted in different degrees of pathology and viral shedding. These results highlight the vast H3N2 genetic diversity circulating in U.S. swine after 2009. This diversity has important implications in the control of this disease by the swine industry, as well as a potential risk for public health if swine-adapted viruses with H1N1pdm09 genes have an increased risk to humans, as occurred in the 2011-2012 and 2016 human variant H3N2v cases associated with exhibition swine. IMPORTANCE People continue to spread the 2009 H1N1 pandemic (H1N1pdm09) IAV to pigs, allowing H1N1pdm09 to reassort with endemic swine IAV. In this study, we determined the 8 gene combinations of swine H3N2 IAV detected from 2009 to 2016. We identified 44 different genotypes of H3N2, the majority of which contained at least one H1N1pdm09 gene segment. We compared six representative genotypes of H3N2 in pigs. All six genotypes efficiently infected pigs, but they resulted in different degrees of lung damage and viral shedding. These results highlight the vast genetic diversity of H3N2 circulating in U.S. swine after 2009, with important implications for the control of IAV for the swine industry. Because H1N1pdm09 is also highly adapted to humans, these swine viruses pose a potential risk to public health if swine-adapted viruses with H1N1pdm09 genes also have an increased risk for human infection.

Sign in / Sign up

Export Citation Format

Share Document