Kinetics of viral shedding and immune responses in adults following administration of cold-adapted influenza vaccine

Hammitt, Laura L.; Bartlett, Julie Patterson; Li, Shaobing; Rahkola, Jeremy; Lang, Nancy; Janoff, Edward N.; Levin, Myron J.; Weinberg, Adriana

doi:10.1016/j.vaccine.2009.09.041

Cited by 28 publications

(27 citation statements)

References 41 publications

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“…In the case of influenza virus, the more common subunit vaccine is administered by intramuscular immunization, while the live attenuated influenza virus vaccine (LIAV), which is more commonly used for younger individuals, is administered intranasally. Both types of vaccine have been optimized for the generation of protective antibodies; however, both vaccines can induce circulating virus-specific T cells (112, 113) with the LIAV vaccine thought to generate more tissue-tropic T cells (114). A vaccine that induces memory T cells that recognize conserved epitopes from internal viral proteins could form the basis of a universal influenza virus vaccine.…”

Section: Implications For Vaccinesmentioning

confidence: 99%

Mucosal Resident Memory CD4 T Cells in Protection and Immunopathology

2014

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Tissue-resident memory T cells (TRM) comprise a newly defined subset, which comprises a major component of lymphocyte populations in diverse peripheral tissue sites, including mucosal tissues, barrier surfaces, and in other non-lymphoid and lymphoid sites in humans and mice. Many studies have focused on the role of CD8 TRM in protection; however, there is now accumulating evidence that CD4 TRM predominate in tissue sites, and are integral for in situ protective immunity, particularly in mucosal sites. New evidence suggests that mucosal CD4 TRM populations differentiate at tissue sites following the recruitment of effector T cells by local inflammation or infection. The resulting TRM populations are enriched in T-cell specificities associated with the inducing pathogen/antigen. This compartmentalization of memory T cells at specific tissue sites may provide an optimal design for future vaccination strategies. In addition, emerging evidence suggests that CD4 TRM may also play a role in immunoregulation and immunopathology, and therefore, targeting TRM may be a viable therapeutic approach to treat inflammatory diseases in mucosal sites. This review will summarize our current understanding of CD4 TRM in diverse tissues, with an emphasis on their role in protective immunity and the mechanisms by which these populations are established and maintained in diverse mucosal sites.

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Section: Implications For Vaccinesmentioning

confidence: 99%

Mucosal Resident Memory CD4 T Cells in Protection and Immunopathology

2014

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“…We have previously used live attenuated influenza virus (LAIV), an influenza vaccine that induces immune responses to generate viral memory without causing actual disease [7–9], to demonstrate that smokers have markers of increased viral replication in nasal washes following inoculation [3]. LAIV generates secretion of lymphokines, including IP-10, within the nasal passages that are suppressed in smokers [3].…”

Section: Introductionmentioning

confidence: 99%

Live Attenuated Influenza Virus (LAIV) induces different mucosal T cell function in nonsmokers and smokers

Horvath

Brighton

Herbst

et al. 2012

Clinical Immunology

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Smokers are more susceptible to respiratory infections, including influenza. To explore the effect of smoking on influenza-induced responses within the nasal mucosa, we have developed a protocol using inoculation with live attenuated influenza virus (LAIV) vaccine followed by sampling of the nasal mucosa. Mucosal cell populations were harvested through superficial biopsy of the nasal inferior turbinate pre and post LAIV inoculation and analyzed using flow cytometry. The majority of nasal biopsy CD45+ immune cells at baseline were CD3+ T lymphocytes. Following LAIV, these lymphocytes increased in nonsmokers but not in smokers. A subset of individuals was negative for helper T cell marker CD4 and cytotoxic T cell marker CD8 but positive for the γδ T cell receptor (TCR). Increases in γδ TCR+ cells were greater in nonsmokers, than in smokers. Thus, LAIV-induced changes in CD3 T as well as γδ T lymphocyte percentages are suppressed in smokers compared to nonsmokers.

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“…Nevertheless, recent studies on the genetic stability of FluMist reported that mutations can occur in the manufacturing process and in the replication of the virus in vaccinated children (40,41). As FluMist is shed from children and adults postvaccination (42)(43)(44), the potential of the mutations for enhanced transmission and increased virulence should not be neglected. Consequently, we sought to evaluate the phenotypic and genetic stability of FluMist by investigating the following questions.…”

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confidence: 99%

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

Zhou

Meliopoulos

Wang

et al. 2016

J Virol

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The 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 temperatures in vitro generated 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.A nnual influenza epidemics are caused by influenza A (H1N1 and H3N2) and influenza B viruses that infect 5% to 10% of adults and 20% to 30% of children (1). Disease outcomes range from subclinical infections to severe infections that result in very high mortality. The estimated 3 to 5 million cases of severe illness and 250,000 to 500,000 deaths each year, as well as significant socioeconomic losses, warrant continuous improvements in influenza preventi...

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Kinetics of viral shedding and immune responses in adults following administration of cold-adapted influenza vaccine

Cited by 28 publications

References 41 publications

Mucosal Resident Memory CD4 T Cells in Protection and Immunopathology

Mucosal Resident Memory CD4 T Cells in Protection and Immunopathology

Live Attenuated Influenza Virus (LAIV) induces different mucosal T cell function in nonsmokers and smokers

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

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