Next Article in Journal
Antibody Responses to SARS-CoV-2 Antigens in Humans and Animals
Next Article in Special Issue
Influenza Vaccination and Non-Pharmaceutical Measure Effectiveness for Preventing Influenza Outbreaks in Schools: A Surveillance-Based Evaluation in Beijing
Previous Article in Journal
Specific Antibodies and Arachidonic Acid Mediate the Protection Induced by the Schistosoma mansoni Cysteine Peptidase-Based Vaccine in Mice
Previous Article in Special Issue
Impact of Pre-Existing Immunity on Live Attenuated Influenza Vaccine-Induced Cross-Protective Immunity
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Impact of Pre-Existing Immunity to Influenza on Live-Attenuated Influenza Vaccine (LAIV) Immunogenicity

Department of Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA
The School of Chemistry and Molecular Biosciences, The Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Queensland 4072, Australia
Author to whom correspondence should be addressed.
Vaccines 2020, 8(4), 683;
Submission received: 23 October 2020 / Revised: 10 November 2020 / Accepted: 11 November 2020 / Published: 16 November 2020


During the previous influenza seasons, between 2010 and 2016, the live attenuated influenza vaccine (LAIV) provided variable efficacy against influenza in the U.S., causing the recommendation against the use of the LAIV. In striking contrast, pre-clinical studies have repeatedly demonstrated superior efficacy of LAIV against mismatched influenza viruses, compared to inactivated influenza vaccines (IIV). This disparity in reported vaccine efficacies between pre-clinical and clinical studies may in part be explained by limitations of the animal models of influenza. In particular, the absence of pre-existing immunity in animal models has recently emerged as a potential explanation for the discrepancies between preclinical findings and human studies. This commentary focuses on the potential impact of pre-existing immunity on LAIV induced immunogenicity with an emphasis on cross-protective immunity.

1. Protective Immune Correlates of LAIV Compared to IIV

The live attenuated influenza vaccine (LAIV) can be delivered via the natural route of influenza virus infection and replicates in the nasal cells to induce broad immune responses comprising of both cellular and humoral immunity. Although mucosal vaccination with LAIV generates virus-specific cytotoxic CD8+ T lymphocytes (CTL), the systemic hemagglutinin (HA)-specific neutralizing antibodies generated are generally less robust compared to inactivated influenza vaccines (IIVs) [1,2,3]. Instead, some studies have shown that local Immunoglobulin (Ig)A antibodies elicited following LAIV vaccination contribute towards suppression of influenza associated morbidity [4,5,6] and protect against heterologous influenza viral strains [7]. In contrast, parenteral administration of IIV elicits excellent systemic IgG and IgM neutralizing antibodies that primarily target the influenza virus HA and neuraminidase (NA) glycoproteins, but promote lower concentrations of neutralizing IgA antibodies in the lung mucosa [8,9,10,11,12]. Since LAIV is a whole virus vaccine, it presents a broader repertoire of antigens, including internal proteins that are highly conserved among influenza A viruses. In contrast, IIV primarily consists of two viral surface antigens: HA and NA, which are highly variable. Consequently, LAIV can elicit a broader immune response and theoretically, superior cross-protective immunity compared to IIV [reviewed in [13]. Indeed, pre-clinical studies in mice have shown that the seasonal trivalent LAIV provides significant protection against influenza, specifically influenza A viruses [14,15] as well as superior T cell-mediated cross-protective efficacy against heterologous H1N1 and H3N2 infections compared to trivalent IIV [16]. Furthermore, monovalent LAIV against H3N2 in pigs afforded antibody-mediated complete protection against antigenically distinct influenza A H3N2 viruses, while only a partial protection was observed by IIV [17].
Compared to IIV, LAIV can better induce CD4+, CD8+ as well as γδ T cell responses [18,19,20]. Importantly, CD4+ helper T cells provide help to B cells and CD8+ T cells to promote antiviral adaptive immunity (reviewed in [21]). LAIV can also activate cytotoxic CD8+ T cells, which can recognize epitopes from internal influenza proteins, such as nucleoprotein, acid polymerase and matrix protein, that are highly conserved, and therefore contribute towards protection against mismatched, heterologous influenza virus strains [22,23,24]. In addition, cytotoxic CD4+ T cells can also respond to core internal proteins. This response has been correlated with enhanced heterotypic immunity and can be induced by LAIV vaccination [13,25]. In contrast, IIV’s capacity to mount potent CD8+ T cell responses is less certain due to conflicting reports [18,26,27,28], but IIV can afford enhanced CD4+ T cell responses, specifically follicular T helper cells that are important for germinal center B cell differentiation [29,30]. In terms of B cell immunogenicity, LAIV has been shown to induce cross-reactive plasmablasts and antibodies, which can target the conserved epitopes on HA including the stalk region [31,32]. It is generally believed that the antibodies against conserved regions, the stem, and the receptor binding site of HA are broadly cross-reactive among HA subtypes and therefore may play a role in cross-protection [33,34,35,36]. Furthermore, LAIV has been shown to elicit non-neutralizing antibodies against H7N9 strain, which may contribute to cross-protection potentially via antibody-dependent cellular cytotoxicity (ADCC) mediated by fragment crystallizable region (Fc)–Fc receptor (FcR) interactions [36]. In the context of IIV, although it has failed to generate cross-protective efficacy against the 2009 pandemic H1N1 influenza [37,38,39], a study has demonstrated that partial cross-protection mediated by non-neutralizing antibodies and CD8+ T cells can be achieved by sequential vaccination with antigenically distinct IIV in animal models [40]. Furthermore, IIV can elicit non-neutralizing antibodies against the highly conserved HA stalk region [31]. Thus, although HA inhibition (HI) antibody titers are a gold standard for correlation of IIV efficacy, especially during pre-clinical LAIV development, measuring cytotoxic T cell responses and mucosal IgA antibodies in addition to HI titers may more accurately predict LAIV efficacy in humans.

2. LAIV Efficacy: Comparing Pre-Clinical and Clinical Studies

Commercially available LAIV and experimental pandemic-LAIVs (pLAIVs) have consistently demonstrated significant protection in animal models such as mice and ferrets (the most attractive small animal models that closely recapitulate human infection) against influenza virus strains of pandemic potential: H1N1, H5N1, H5N2, H7N3, H2N2 and H7N9 [41,42,43,44,45,46,47,48]. These studies have reported significant control of viral replication in the respiratory tract, robust serum HI antibodies, as well as protection against homologous (against vaccine strains) and heterologous strains including mismatched/drifted influenza virus strains [17].
Consistent with pre-clinical data, clinical studies with a monovalent 2009 A/H1N1 LAIV demonstrated significant protective efficacy against the 2009 pandemic H1N1 influenza in children [49,50,51]. Furthermore, the trivalent LAIV also showed moderate [52,53,54] to high efficacy against influenza in children [18,55,56,57]. In the latter studies, the trivalent LAIV elicited significant protective efficacy and immunogenicity against all three vaccine components: H1N1, H3N2 and influenza B virus. It was also demonstrated in a side-by-side comparison that trivalent LAIV is superior to IIV against antigenically similar [18,55] and antigenically drifted influenza strains in some flu seasons [56,57]. However, post licensure of quadrivalent LAIV in the 2013–2016 seasons reported that LAIV efficacies varied between 19–50% in the U.S., along with reduced effectiveness against influenza A viruses [58,59,60,61,62,63,64,65,66]. In addition, reported LAIV efficacies have shown considerable variation in countries other than the U.S. For example, in the same season, a single dose of trivalent LAIV elicited significant protective efficacy against influenza A viruses in Bangladesh, whilst showing no protection against influenza A and B viruses in Senegal [67,68]. Furthermore, compared to the U.S., different LAIV efficacy percentages were reported in countries such as Canada, UK, and Finland [63,69,70,71]. Highly variable LAIV efficacy in the recent influenza seasons and discrepancies between pre-clinical and clinical trials of LAIV raise concerns about the predictive value of animal models used for influenza vaccine research. Towards understanding the underlying reasons behind discrepant reports of LAIV efficacies, pre-existing immunity to influenza has emerged as a potential factor influencing LAIV efficacy [72,73,74,75,76,77,78,79,80]. Concordantly, in our recent study, pre-vaccination with IIV was shown to reduce LAIV (both vaccines expressing same antigens) efficacy against heterologous H1N1 virus [81]. Since cross-reactive antibodies were not detected, we speculate a crucial role of pre-existing antibodies in suppression of LAIV-induced T cell responses that have high cross-reactive potential. Hence, in this commentary, we focused on the role of pre-existing immunity in preventing initial LAIV replication and its subsequent impact on cross-protective immunity.

3. Impact of Pre-Existing Antibodies on T cell Immunogenicity of LAIV

One of the key factors that determine the immunogenicity of LAIV is the replicative fitness of the temperature sensitive, live attenuated virus in the upper respiratory tract [82,83,84]. Successful replication of LAIV in nasal epithelia appears to be a prerequisite for facilitating antigen presentation by the major histocompatibility complex-I (MHC-I) to activate CD8+ T cells for effective viral clearance [3,18,85]. The thermal instability of H1N1 LAIV strain (A/California/07/2009), causing its defective replication in human nasal cells [86,87], has been associated with reduced efficacy of LAIV against H1N1 virus [88]. Indeed, modification to a more stable, replication competent version of LAIV in subsequent influenza seasons (2017–2018) improved its efficacy [89]. Despite the recent recognition of the importance of LAIV replication in LAIV immunogenicity, little is known about the negative impact of pre-existing immunity on the replicative fitness of LAIV. A clinical trial in Bangladesh correlated higher pre-existing baseline antibodies derived from natural influenza A/H3N2 and B infections with low viral shedding/replication of LAIV [73]. In addition, pre-existing antibodies derived from prior vaccination have been associated with reduced immunogenicity of LAIV [90,91,92,93]. Furthermore, LAIV was more effective in protecting against the incidence of influenza-like illness among U.S. military personnel who had lower vaccination rates (potentially due to low baseline antibody levels) compared to those immunized regularly with either IIV or LAIV [94]. Similarly, LAIV was also more efficacious than IIV in preventing influenza-associated illness in children, presumably due to low levels of pre-existing immunity in children compared to adults [18,56]. It remains to be elucidated how pre-existing immunity can impact LAIV-induced immune responses. Our recent studies demonstrated that prior vaccination with IIV reduces efficacy of LAIV against heterologous influenza [81]. As described above, IIV elicits robust IgG antibodies, but limited IgA and cytotoxic T cell responses, suggesting that the presence of IIV-specific IgG negatively influences LAIV efficacy. Pre-existing antibodies have also been shown to reduce the efficacy of a variety of other live attenuated vaccines against other pathogens [95]. Thus, taken together, we hypothesize that pre-existing antibodies derived from IIV vaccination and/or seasonal influenza infections neutralize LAIV viruses and diminish the establishment of mucosal immunity at the vaccination site.
Our recent study also indicated that mice vaccinated with IIV followed by LAIV (expressing the same vaccine antigens) are protected against homologous H1N1 virus challenge [81]. Analysis of serum samples showed induction of strain-specific HI antibodies by IIV, LAIV as well as IIV/LAIV. This indicated that neutralizing antibodies confer strain-specific immunity and thus explains why strain-specific immunity remained unaltered in mice vaccinated with IIV followed by LAIV. However, in this study, prior vaccination of mice with IIV inhibited cross-protective efficacy of LAIV against heterologous H1N1 infection. Since cross-reactive HI antibodies were not associated with LAIV-mediated cross-protection, suppression of cross-reactive T cells by pre-existing serum antibodies is the likely underlying mechanism, although this has not been formally tested in our study. Others have reported that prior vaccination with IIV is associated with suppressed T cell responses in animal models. Bodewas et al. showed that HI antibodies derived from IIV vaccination were associated with prevention of cross-reactive CD8+ T cells induced by homologous influenza infection in mice and ferrets [96,97]. The same authors also showed that prior IIV vaccination of mice prevented viral replication and induction of interferon (IFN)-γ+ CD62Lhi CD127+ memory CD8+ T cells following heterologous infection, crucial for cross-protection against antigenically drifted and non-vaccine strains [98]. Similarly, in humans, pre-existing antibodies derived from prior vaccination with IIV have been correlated with low levels of heterosubtypic immunity mediated by virus-specific T cells [99]. Additionally, in the context of other vaccines, pre-existing anti-vector immunity has been associated with reduced T cell responses upon vaccination with experimental viral vector vaccines. For example, frequent exposure to various human adenovirus subtypes leads to pre-existing antibodies against adenoviral vectors commonly used for vaccine delivery [100]. This minimizes the effectiveness of these vectors in prime–boost vaccination settings especially if the desired outcome is to augment T cell responses following the boost [101,102]. Studies using human viruses as vectors for vaccine delivery in a homologous prime–boost regimen have failed to enhance IFN-γ expressing T cells specific to vaccine antigens [103,104,105]. These studies suggest a crucial role of pre-existing anti-vector immunity, most likely neutralizing antibodies, in the suppression of antigen specific cell-mediated immunity. Thus, it is imperative to understand immune mechanisms underlying how pre-existing antibodies impact LAIV-induced T cell responses so that better vaccination strategies can be developed. This is particularly true now given the ongoing COVID-19 pandemic. One of the COVID-19 vaccines under development in Hong Kong uses live attenuated influenza virus expressing SARS-CoV-2 antigens [106]. We speculate that anti-vector immunity to influenza may also be detrimental to the immunogenicity of this vaccine candidate. Similarly, due to exposure to seasonal human coronaviruses, most humans also possess some degree of immunity against the COVID-19 virus. Therefore, pre-existing immunity to coronaviruses may also impact (positively or negatively) COVID-19 vaccines that are currently being tested in clinical trials.

4. Mechanisms Underlying Suppression of LAIV Immunogenicity by Pre-Existing Immunity: Alternative Vaccination Strategies to Circumvent this Issue

It is important to note that in children aged 6 months–17 years, LAIV demonstrated higher protective efficacy against culture-confirmed influenza illness compared to IIV [18,55,56]. Two doses of trivalent LAIV in a single year followed by a single dose of trivalent LAIV in a subsequent year elicited robust protective efficacy against circulating influenza strains [77,78]. More importantly, similar sequential vaccination with trivalent LAIV also afforded protective efficacy against a drifted circulating H3N2 strain in year two of vaccination in children [75,90]. The latter study also detected cross-reactive antibodies against H3N2 viruses following LAIV vaccination [75]. A retrospective study has shown that multiple vaccinations with LAIV over a period of three years afforded more than 50% protective efficacy against H1N1 as well as cross-protection against H3N2 viruses [107]. A possible explanation for the observed cross-protection in young children is that the first exposure to the influenza virus via LAIV establishes cross-reactive T cell immunity in influenza naïve individuals and subsequent LAIV vaccinations further increase or maintain T cell immunity at protective levels [74]. Thus, the first influenza vaccination in the form of LAIV may be a better vaccination approach compared to IIV first followed by LAIV. However, current influenza vaccination policy recommends IIV over LAIV for infants. This recommendation is based on early clinical trials that have found an association between LAIV and increased wheezing and asthma attacks in young children below the age of 2 years [108,109]. Thus, LAIV is indicated for use in individuals 2 to 49 years of age. However, considering the potential benefits of LAIV, perhaps LAIV should be offered as a first influenza vaccine for infants with no family history of wheezing and/or allergic asthma. Future research is necessary to determine if initial vaccination with LAIV, followed by IIV, establishes better mucosal T cell immunity. Alternatively, certain adjuvants could be a component of IIV to promote cellular immunity. Squalene-based adjuvants, such as MF59, have been approved for human use in the U.S. and have been shown to improve T-cell immunogenicity of IIV in humans [110]. Thus, in a sequential vaccination setting, adjuvanted IIV may circumvent the negative impact of pre-existing antibodies.
Altered vaccine antigen trafficking by pre-existing antibodies may contribute to the reduced efficacy of LAIV. Preliminary studies in our laboratory have revealed that the presence of alveolar macrophages (AMs) is associated with reduced vaccine efficacy. In our mouse model, depletion of AMs at the time of vaccination significantly increased the efficacy of intranasal (i.n.) administered IIV (unpublished data). Likewise, it is possible that the reduced LAIV efficacy in IIV vaccinated mice may entail alveolar macrophages. AMs in a steady state are thought to play a critical role in maintaining lung homeostasis. AMs are effective in clearing inhaled antigens without initiating potentially deleterious immune responses. This is important given that AMs represent more than 95% of immune cells found in the airway and therefore they are the first to contact inhaled particles [111]. AMs can express cytokines such as transforming growth factor β1 (TGF-β1), prostaglandin E2 (PGE2), and platelet-activating factor (PAF), which are involved in immune suppression [112,113,114]. Thus, it is plausible that LAIV viruses opsonized by pre-existing antibodies are taken up by the AMs, as opposed to epithelial cells, which in turn activates immunosuppressive mechanisms. Studies have shown that TGF-β expression by AMs leads to activation of regulatory T cells (Tregs), which are important in mediating suppression of the immune response [115,116,117]. Delineating immune suppressive mechanisms may potentially facilitate alternative strategies to circumvent detrimental processes and mitigate the negative impact of pre-existing antibodies on LAIV efficacy.
In addition to evaluating immune suppressive events, understanding the impact of pre-existing immunity on LAIV-infectivity of lung epithelia and antigen presentation by dendritic cells is important. Successful replication of LAIV in nasal epithelial cells induces pro-inflammatory type 1 (Th1) associated chemokines including chemokine (c-x-c motif) ligand (CXCL) 9 and CXCL11 in the lungs [85,118]. Such chemotactic mediators cause cellular infiltration by antigen presenting cells (APCs) such as CD11b- dendritic cells (DCs), which are mainly known for their cross-presentation of antigens to T cells, favoring Th1 responses for influenza viral clearance [119]. Furthermore, studies using influenza infection models have shown differential roles of CD11b+ conventional DCs (cDCs) and lung resident and cross-presenting CD11b- cDCs in the activation of cross-protective T responses in mice [120,121,122,123]. Thus, neutralization of LAIV by pre-existing antibodies potentially prevents successful infection of nasal epithelia causing reduced Th1 inflammation followed by suboptimal DC recruitment. In addition to pro-inflammatory innate immune responses in the lung mucosae, lung resident memory T and B cells have recently emerged as key players in memory responses against influenza. Recently discovered lung resident memory B cells (BRMs) and tissue resident memory T cells (TRMs) have been described to participate in cross-protection against influenza infection [4,7,124,125]. Therefore, investigating the impact of pre-existing immunity on the establishment of lung resident memory lymphocytes may also enrich our understanding of detrimental effects of pre-existing immunity on the cross-protective efficacy of LAIV.

5. Summary and Conclusions

In conclusion, pre-existing immunity to influenza significantly influences LAIV efficacy against influenza viruses; therefore, contributing towards the consistently observed variable efficacies of LAIV in clinical trials. Pre-existing antibodies derived from IIV have been shown to inhibit influenza viral replication causing diminished memory CD8+ T cell responses, which are crucial for cross-protective immunity against antigenically drifted influenza strains. Hence, a similar mechanism may be contributing to the observed ablation of cross-protective efficacy of LAIV in our recent IIV prime/LAIV boost study in mice. However, the precise mechanism by which pre-existing antibodies suppress T cell immunogenicity of LAIV is not fully understood. Further advancement in this field is clearly needed to develop a better vaccination approach that can circumvent the negative impact of IIV on LAIV efficacy.

Author Contributions

S.R. prepared manuscript and conducted the literature research; Y.F., D.K.W. and C.M.W. provided valuable feedback during manuscript preparation. Y.F. conceived the idea. All authors have read and agreed to the published version of the manuscript.


Y.F. is supported by the NIH grant AI146434.


Y.F. and S.R. are supported through The American Association of Immunologists Careers in Immunology Fellowship Program.

Conflicts of Interest

The authors declare no competing interest.


  1. Cao, R.G.; Suarez, N.M.; Obermoser, G.; Lopez, S.M.; Flano, E.; Mertz, S.E.; Albrecht, R.A.; Garcia-Sastre, A.; Mejias, A.; Xu, H.; et al. Differences in antibody responses between trivalent inactivated influenza vaccine and live attenuated influenza vaccine correlate with the kinetics and magnitude of interferon signaling in children. J. Infect. Dis. 2014, 210, 224–233. [Google Scholar] [CrossRef] [Green Version]
  2. Nakaya, H.I.; Wrammert, J.; Lee, E.K.; Racioppi, L.; Marie-Kunze, S.; Haining, W.N.; Means, A.R.; Kasturi, S.P.; Khan, N.; Li, G.M.; et al. Systems biology of vaccination for seasonal influenza in humans. Nat. Immunol. 2011, 12, 786–795. [Google Scholar] [CrossRef] [PubMed]
  3. Sasaki, S.; Jaimes, M.C.; Holmes, T.H.; Dekker, C.L.; Mahmood, K.; Kemble, G.W.; Arvin, A.M.; Greenberg, H.B. Comparison of the influenza virus-specific effector and memory B-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines. J. Virol. 2007, 81, 215–228. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Ambrose, C.S.; Wu, X.; Jones, T.; Mallory, R.M. The role of nasal IgA in children vaccinated with live attenuated influenza vaccine. Vaccine 2012, 30, 6794–6801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Ambrose, C.S.; Yi, T.; Walker, R.E.; Connor, E.M. Duration of protection provided by live attenuated influenza vaccine in children. Pediatr. Infect. Dis. J. 2008, 27, 744–748. [Google Scholar] [CrossRef] [PubMed]
  6. Clements, M.L.; Murphy, B.R. Development and persistence of local and systemic antibody responses in adults given live attenuated or inactivated influenza A virus vaccine. J. Clin. Microbiol. 1986, 23, 66–72. [Google Scholar] [CrossRef] [Green Version]
  7. Asahi-Ozaki, Y.; Yoshikawa, T.; Iwakura, Y.; Suzuki, Y.; Tamura, S.; Kurata, T.; Sata, T. Secretory IgA antibodies provide cross-protection against infection with different strains of influenza B virus. J. Med. Virol. 2004, 74, 328–335. [Google Scholar] [CrossRef]
  8. Brokstad, K.A.; Cox, R.J.; Olofsson, J.; Jonsson, R.; Haaheim, L.R. Parenteral influenza vaccination induces a rapid systemic and local immune response. J. Infect. Dis. 1995, 171, 198–203. [Google Scholar] [CrossRef]
  9. Cox, R.J.; Brokstad, K.A.; Zuckerman, M.A.; Wood, J.M.; Haaheim, L.R.; Oxford, J.S. An early humoral immune response in peripheral blood following parenteral inactivated influenza vaccination. Vaccine 1994, 12, 993–999. [Google Scholar] [CrossRef]
  10. El-Madhun, A.S.; Cox, R.J.; Haaheim, L.R. The effect of age and natural priming on the IgG and IgA subclass responses after parenteral influenza vaccination. J. Infect. Dis. 1999, 180, 1356–1360. [Google Scholar] [CrossRef]
  11. el-Madhun, A.S.; Cox, R.J.; Soreide, A.; Olofsson, J.; Haaheim, L.R. Systemic and mucosal immune responses in young children and adults after parenteral influenza vaccination. J. Infect. Dis. 1998, 178, 933–939. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Cox, R.J. Correlates of protection to influenza virus, where do we go from here? Hum. Vaccin. Immunother. 2013, 9, 405–408. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Sridhar, S.; Brokstad, K.A.; Cox, R.J. Influenza Vaccination Strategies: Comparing Inactivated and Live Attenuated Influenza Vaccines. Vaccines (Basel) 2015, 3, 373–389. [Google Scholar] [CrossRef] [PubMed]
  14. Jang, Y.H.; Lee, E.Y.; Byun, Y.H.; Jung, E.J.; Lee, Y.J.; Lee, Y.H.; Lee, K.H.; Lee, J.; Seong, B.L. Protective efficacy in mice of monovalent and trivalent live attenuated influenza vaccines in the background of cold-adapted A/X-31 and B/Lee/40 donor strains. Vaccine 2014, 32, 535–543. [Google Scholar] [CrossRef]
  15. Rudenko, L.; Kiseleva, I.; Krutikova, E.; Stepanova, E.; Rekstin, A.; Donina, S.; Pisareva, M.; Grigorieva, E.; Kryshen, K.; Muzhikyan, A.; et al. Rationale for vaccination with trivalent or quadrivalent live attenuated influenza vaccines: Protective vaccine efficacy in the ferret model. PLoS ONE 2018, 13, e0208028. [Google Scholar] [CrossRef] [Green Version]
  16. Li, J.; Arevalo, M.T.; Chen, Y.; Chen, S.; Zeng, M. T-cell-mediated cross-strain protective immunity elicited by prime-boost vaccination with a live attenuated influenza vaccine. Int. J. Infect. Dis. 2014, 27, 37–43. [Google Scholar] [CrossRef] [Green Version]
  17. Abente, E.J.; Rajao, D.S.; Santos, J.; Kaplan, B.S.; Nicholson, T.L.; Brockmeier, S.L.; Gauger, P.C.; Perez, D.R.; Vincent, A.L. Comparison of Adjuvanted-Whole Inactivated Virus and Live-Attenuated Virus Vaccines against Challenge with Contemporary, Antigenically Distinct H3N2 Influenza A Viruses. J. Virol. 2018, 92. [Google Scholar] [CrossRef] [Green Version]
  18. Ashkenazi, S.; Vertruyen, A.; Aristegui, J.; Esposito, S.; McKeith, D.D.; Klemola, T.; Biolek, J.; Kuhr, J.; Bujnowski, T.; Desgrandchamps, D.; et al. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Pediatr. Infect. Dis. J. 2006, 25, 870–879. [Google Scholar] [CrossRef] [Green Version]
  19. Hoft, D.F.; Babusis, E.; Worku, S.; Spencer, C.T.; Lottenbach, K.; Truscott, S.M.; Abate, G.; Sakala, I.G.; Edwards, K.M.; Creech, C.B.; et al. Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J. Infect. Dis. 2011, 204, 845–853. [Google Scholar] [CrossRef]
  20. Shi, J.; Wen, Z.; Guo, J.; Zhang, Y.; Deng, G.; Shu, Y.; Wang, D.; Jiang, Y.; Kawaoka, Y.; Bu, Z.; et al. Protective efficacy of an H1N1 cold-adapted live vaccine against the 2009 pandemic H1N1, seasonal H1N1, and H5N1 influenza viruses in mice. Antiviral. Res. 2012, 93, 346–353. [Google Scholar] [CrossRef]
  21. Swain, S.L.; McKinstry, K.K.; Strutt, T.M. Expanding roles for CD4(+) T cells in immunity to viruses. Nat. Rev. Immunol. 2012, 12, 136–148. [Google Scholar] [CrossRef] [PubMed]
  22. Kees, U.; Krammer, P.H. Most influenza A virus-specific memory cytotoxic T lymphocytes react with antigenic epitopes associated with internal virus determinants. J. Exp. Med. 1984, 159, 365–377. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Kreijtz, J.H.; Bodewes, R.; van den Brand, J.M.; de Mutsert, G.; Baas, C.; van Amerongen, G.; Fouchier, R.A.; Osterhaus, A.D.; Rimmelzwaan, G.F. Infection of mice with a human influenza A/H3N2 virus induces protective immunity against lethal infection with influenza A/H5N1 virus. Vaccine 2009, 27, 4983–4989. [Google Scholar] [CrossRef] [PubMed]
  24. Marshall, D.R.; Turner, S.J.; Belz, G.T.; Wingo, S.; Andreansky, S.; Sangster, M.Y.; Riberdy, J.M.; Liu, T.; Tan, M.; Doherty, P.C. Measuring the diaspora for virus-specific CD8+ T cells. Proc. Natl. Acad. Sci. USA 2001, 98, 6313–6318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Wilkinson, T.M.; Li, C.K.; Chui, C.S.; Huang, A.K.; Perkins, M.; Liebner, J.C.; Lambkin-Williams, R.; Gilbert, A.; Oxford, J.; Nicholas, B.; et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat. Med. 2012, 18, 274–280. [Google Scholar] [CrossRef]
  26. He, X.S.; Holmes, T.H.; Mahmood, K.; Kemble, G.W.; Dekker, C.L.; Arvin, A.M.; Greenberg, H.B. Phenotypic changes in influenza-specific CD8+ T cells after immunization of children and adults with influenza vaccines. J. Infect. Dis. 2008, 197, 803–811. [Google Scholar] [CrossRef] [Green Version]
  27. Long, B.R.; Michaelsson, J.; Loo, C.P.; Ballan, W.M.; Vu, B.A.; Hecht, F.M.; Lanier, L.L.; Chapman, J.M.; Nixon, D.F. Elevated frequency of gamma interferon-producing NK cells in healthy adults vaccinated against influenza virus. Clin. Vaccine Immunol. 2008, 15, 120–130. [Google Scholar] [CrossRef] [Green Version]
  28. Subbramanian, R.A.; Basha, S.; Shata, M.T.; Brady, R.C.; Bernstein, D.I. Pandemic and seasonal H1N1 influenza hemagglutinin-specific T cell responses elicited by seasonal influenza vaccination. Vaccine 2010, 28, 8258–8267. [Google Scholar] [CrossRef]
  29. Bentebibel, S.E.; Lopez, S.; Obermoser, G.; Schmitt, N.; Mueller, C.; Harrod, C.; Flano, E.; Mejias, A.; Albrecht, R.A.; Blankenship, D.; et al. Induction of ICOS+CXCR3+CXCR5+ TH cells correlates with antibody responses to influenza vaccination. Sci. Transl. Med. 2013, 5, 176ra132. [Google Scholar] [CrossRef] [Green Version]
  30. Spensieri, F.; Borgogni, E.; Zedda, L.; Bardelli, M.; Buricchi, F.; Volpini, G.; Fragapane, E.; Tavarini, S.; Finco, O.; Rappuoli, R.; et al. Human circulating influenza-CD4+ ICOS1+IL-21+ T cells expand after vaccination, exert helper function, and predict antibody responses. Proc. Natl. Acad. Sci. USA 2013, 110, 14330–14335. [Google Scholar] [CrossRef] [Green Version]
  31. Kubo, M.; Miyauchi, K. Breadth of Antibody Responses during Influenza Virus Infection and Vaccination. Trends Immunol. 2020, 41, 394–405. [Google Scholar] [CrossRef] [PubMed]
  32. Sasaki, S.; Holmes, T.H.; Albrecht, R.A.; Garcia-Sastre, A.; Dekker, C.L.; He, X.S.; Greenberg, H.B. Distinct cross-reactive B-cell responses to live attenuated and inactivated influenza vaccines. J. Infect. Dis. 2014, 210, 865–874. [Google Scholar] [CrossRef] [PubMed]
  33. Halliley, J.L.; Khurana, S.; Krammer, F.; Fitzgerald, T.; Coyle, E.M.; Chung, K.Y.; Baker, S.F.; Yang, H.; Martinez-Sobrido, L.; Treanor, J.J.; et al. High-Affinity H7 Head and Stalk Domain-Specific Antibody Responses to an Inactivated Influenza H7N7 Vaccine After Priming With Live Attenuated Influenza Vaccine. J. Infect. Dis. 2015, 212, 1270–1278. [Google Scholar] [CrossRef] [Green Version]
  34. Isakova-Sivak, I.; Korenkov, D.; Smolonogina, T.; Kotomina, T.; Donina, S.; Matyushenko, V.; Mezhenskaya, D.; Krammer, F.; Rudenko, L. Broadly protective anti-hemagglutinin stalk antibodies induced by live attenuated influenza vaccine expressing chimeric hemagglutinin. Virology 2018, 518, 313–323. [Google Scholar] [CrossRef] [PubMed]
  35. Nachbagauer, R.; Liu, W.C.; Choi, A.; Wohlbold, T.J.; Atlas, T.; Rajendran, M.; Solorzano, A.; Berlanda-Scorza, F.; Garcia-Sastre, A.; Palese, P.; et al. A universal influenza virus vaccine candidate confers protection against pandemic H1N1 infection in preclinical ferret studies. NPJ Vaccines 2017, 2, 26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Henry Dunand, C.J.; Leon, P.E.; Huang, M.; Choi, A.; Chromikova, V.; Ho, I.Y.; Tan, G.S.; Cruz, J.; Hirsh, A.; Zheng, N.Y.; et al. Both Neutralizing and Non-Neutralizing Human H7N9 Influenza Vaccine-Induced Monoclonal Antibodies Confer Protection. Cell Host Microbe 2016, 19, 800–813. [Google Scholar] [CrossRef] [Green Version]
  37. Chen, G.L.; Min, J.Y.; Lamirande, E.W.; Santos, C.; Jin, H.; Kemble, G.; Subbarao, K. Comparison of a live attenuated 2009 H1N1 vaccine with seasonal influenza vaccines against 2009 pandemic H1N1 virus infection in mice and ferrets. J. Infect. Dis. 2011, 203, 930–936. [Google Scholar] [CrossRef] [Green Version]
  38. Ellebedy, A.H.; Ducatez, M.F.; Duan, S.; Stigger-Rosser, E.; Rubrum, A.M.; Govorkova, E.A.; Webster, R.G.; Webby, R.J. Impact of prior seasonal influenza vaccination and infection on pandemic A (H1N1) influenza virus replication in ferrets. Vaccine 2011, 29, 3335–3339. [Google Scholar] [CrossRef] [Green Version]
  39. Pascua, P.N.; Song, M.S.; Lee, J.H.; Park, K.J.; Kwon, H.I.; Baek, Y.H.; Hong, S.P.; Rho, J.B.; Kim, C.J.; Poo, H.; et al. Evaluation of the efficacy and cross-protectivity of recent human and swine vaccines against the pandemic (H1N1) 2009 virus infection. PLoS ONE 2009, 4, e8431. [Google Scholar] [CrossRef] [Green Version]
  40. Dong, W.; Bhide, Y.; Sicca, F.; Meijerhof, T.; Guilfoyle, K.; Engelhardt, O.G.; Boon, L.; de Haan, C.A.M.; Carnell, G.; Temperton, N.; et al. Cross-Protective Immune Responses Induced by Sequential Influenza Virus Infection and by Sequential Vaccination With Inactivated Influenza Vaccines. Front. Immunol. 2018, 9, 2312. [Google Scholar] [CrossRef]
  41. Carter, D.M.; Bloom, C.E.; Kirchenbaum, G.A.; Tsvetnitsky, V.; Isakova-Sivak, I.; Rudenko, L.; Ross, T.M. Cross-protection against H7N9 influenza strains using a live-attenuated H7N3 virus vaccine. Vaccine 2015, 33, 108–116. [Google Scholar] [CrossRef] [PubMed]
  42. Gustin, K.M.; Maines, T.R.; Belser, J.A.; van Hoeven, N.; Lu, X.; Dong, L.; Isakova-Sivak, I.; Chen, L.M.; Voeten, J.T.; Heldens, J.G.; et al. Comparative immunogenicity and cross-clade protective efficacy of mammalian cell-grown inactivated and live attenuated H5N1 reassortant vaccines in ferrets. J. Infect. Dis. 2011, 204, 1491–1499. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Isakova-Sivak, I.; de Jonge, J.; Smolonogina, T.; Rekstin, A.; van Amerongen, G.; van Dijken, H.; Mouthaan, J.; Roholl, P.; Kuznetsova, V.; Doroshenko, E.; et al. Development and pre-clinical evaluation of two LAIV strains against potentially pandemic H2N2 influenza virus. PLoS ONE 2014, 9, e102339. [Google Scholar] [CrossRef] [PubMed]
  44. Rekstin, A.; Desheva, Y.; Kiseleva, I.; Ross, T.; Swayne, D.; Rudenko, L. Live Attenuated Influenza H7N3 Vaccine is Safe, Immunogenic and Confers Protection in Animal Models. Open Microbiol. J. 2014, 8, 154–162. [Google Scholar] [CrossRef] [Green Version]
  45. Shcherbik, S.; Sergent, S.B.; Davis, W.G.; Shu, B.; Barnes, J.; Kiseleva, I.; Larionova, N.; Klimov, A.; Bousse, T. Application of real time RT-PCR for the genetic homogeneity and stability tests of the seed candidates for live attenuated influenza vaccine production. J. Virol. Methods 2014, 195, 18–25. [Google Scholar] [CrossRef] [Green Version]
  46. Shcherbik, S.V.; Pearce, N.C.; Levine, M.L.; Klimov, A.I.; Villanueva, J.M.; Bousse, T.L. Rapid strategy for screening by pyrosequencing of influenza virus reassortants--candidates for live attenuated vaccines. PLoS ONE 2014, 9, e92580. [Google Scholar] [CrossRef] [Green Version]
  47. Stauft, C.B.; Yang, C.; Coleman, J.R.; Boltz, D.; Chin, C.; Kushnir, A.; Mueller, S. Live-attenuated H1N1 influenza vaccine candidate displays potent efficacy in mice and ferrets. PLoS ONE 2019, 14, e0223784. [Google Scholar] [CrossRef] [Green Version]
  48. Stittelaar, K.J.; Veldhuis Kroeze, E.J.; Rudenko, L.; Dhere, R.; Thirapakpoomanunt, S.; Kieny, M.P.; Osterhaus, A.D. Efficacy of live attenuated vaccines against 2009 pandemic H1N1 influenza in ferrets. Vaccine 2011, 29, 9265–9270. [Google Scholar] [CrossRef]
  49. Griffin, M.R.; Monto, A.S.; Belongia, E.A.; Treanor, J.J.; Chen, Q.; Chen, J.; Talbot, H.K.; Ohmit, S.E.; Coleman, L.A.; Lofthus, G.; et al. Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 U.S. communities. PLoS ONE 2011, 6, e23085. [Google Scholar] [CrossRef] [Green Version]
  50. Hadler, J.L.; Baker, T.N.; Papadouka, V.; France, A.M.; Zimmerman, C.; Livingston, K.A.; Zucker, J.R. Effectiveness of 1 dose of 2009 influenza A (H1N1) vaccine at preventing hospitalization with pandemic H1N1 influenza in children aged 7 months-9 years. J. Infect. Dis. 2012, 206, 49–55. [Google Scholar] [CrossRef] [Green Version]
  51. Uzicanin, A.; Thompson, M.; Smith, P.; Chaves, S.S.; Foster, L.; Dube, N.; Graitcer, S.; Jackson, R.; Ferdinands, J.; Gargiullo, P.; et al. Effectiveness of 1 dose of influenza A (H1N1) 2009 monovalent vaccines in preventing reverse-transcription polymerase chain reaction-confirmed H1N1 infection among school-aged children in maine. J. Infect. Dis. 2012, 206, 1059–1068. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. McLean, H.Q.; Thompson, M.G.; Sundaram, M.E.; Kieke, B.A.; Gaglani, M.; Murthy, K.; Piedra, P.A.; Zimmerman, R.K.; Nowalk, M.P.; Raviotta, J.M.; et al. Influenza vaccine effectiveness in the United States during 2012-2013: Variable protection by age and virus type. J. Infect. Dis. 2015, 211, 1529–1540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Ohmit, S.E.; Thompson, M.G.; Petrie, J.G.; Thaker, S.N.; Jackson, M.L.; Belongia, E.A.; Zimmerman, R.K.; Gaglani, M.; Lamerato, L.; Spencer, S.M.; et al. Influenza vaccine effectiveness in the 2011–2012 season: Protection against each circulating virus and the effect of prior vaccination on estimates. Clin. Infect. Dis. 2014, 58, 319–327. [Google Scholar] [CrossRef] [PubMed]
  54. Treanor, J.J.; Talbot, H.K.; Ohmit, S.E.; Coleman, L.A.; Thompson, M.G.; Cheng, P.Y.; Petrie, J.G.; Lofthus, G.; Meece, J.K.; Williams, J.V.; et al. Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains. Clin. Infect. Dis. 2012, 55, 951–959. [Google Scholar] [CrossRef]
  55. Fleming, D.M.; Crovari, P.; Wahn, U.; Klemola, T.; Schlesinger, Y.; Langussis, A.; Oymar, K.; Garcia, M.L.; Krygier, A.; Costa, H.; et al. Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma. Pediatr. Infect. Dis. J. 2006, 25, 860–869. [Google Scholar] [CrossRef]
  56. Belshe, R.B.; Edwards, K.M.; Vesikari, T.; Black, S.V.; Walker, R.E.; Hultquist, M.; Kemble, G.; Connor, E.M.; CAIV-T Comparative Efficacy Study Group. Live attenuated versus inactivated influenza vaccine in infants and young children. N. Engl. J. Med. 2007, 356, 685–696. [Google Scholar] [CrossRef] [Green Version]
  57. Halloran, M.E.; Piedra, P.A.; Longini, I.M., Jr.; Gaglani, M.J.; Schmotzer, B.; Fewlass, C.; Herschler, G.B.; Glezen, W.P. Efficacy of trivalent, cold-adapted, influenza virus vaccine against influenza A (Fujian), a drift variant, during 2003–2004. Vaccine 2007, 25, 4038–4045. [Google Scholar] [CrossRef] [Green Version]
  58. Caspard, H.; Gaglani, M.; Clipper, L.; Belongia, E.A.; McLean, H.Q.; Griffin, M.R.; Talbot, H.K.; Poehling, K.A.; Peters, T.R.; Veney, N.; et al. Effectiveness of live attenuated influenza vaccine and inactivated influenza vaccine in children 2–17 years of age in 2013–2014 in the United States. Vaccine 2016, 34, 77–82. [Google Scholar] [CrossRef]
  59. Gaglani, M.; Pruszynski, J.; Murthy, K.; Clipper, L.; Robertson, A.; Reis, M.; Chung, J.R.; Piedra, P.A.; Avadhanula, V.; Nowalk, M.P.; et al. Influenza Vaccine Effectiveness Against 2009 Pandemic Influenza A(H1N1) Virus Differed by Vaccine Type During 2013–2014 in the United States. J. Infect. Dis. 2016, 213, 1546–1556. [Google Scholar] [CrossRef]
  60. Ohmit, S.E.; Petrie, J.G.; Malosh, R.E.; Johnson, E.; Truscon, R.; Aaron, B.; Martens, C.; Cheng, C.; Fry, A.M.; Monto, A.S. Substantial Influenza Vaccine Effectiveness in Households With Children During the 2013-2014 Influenza Season, When 2009 Pandemic Influenza A(H1N1) Virus Predominated. J. Infect. Dis. 2016, 213, 1229–1236. [Google Scholar] [CrossRef] [Green Version]
  61. McLean, H.Q.; Caspard, H.; Griffin, M.R.; Poehling, K.A.; Gaglani, M.; Belongia, E.A.; Talbot, H.K.; Peters, T.R.; Murthy, K.; Ambrose, C.S. Effectiveness of live attenuated influenza vaccine and inactivated influenza vaccine in children during the 2014–2015 season. Vaccine 2017, 35, 2685–2693. [Google Scholar] [CrossRef]
  62. Zimmerman, R.K.; Nowalk, M.P.; Chung, J.; Jackson, M.L.; Jackson, L.A.; Petrie, J.G.; Monto, A.S.; McLean, H.Q.; Belongia, E.A.; Gaglani, M.; et al. 2014–2015 Influenza Vaccine Effectiveness in the United States by Vaccine Type. Clin. Infect. Dis. 2016, 63, 1564–1573. [Google Scholar] [CrossRef] [Green Version]
  63. Nohynek, H.; Baum, U.; Syrjanen, R.; Ikonen, N.; Sundman, J.; Jokinen, J. Effectiveness of the live attenuated and the inactivated influenza vaccine in two-year-olds—A nationwide cohort study Finland, influenza season 2015/16. Eurosurveillance 2016, 21. [Google Scholar] [CrossRef]
  64. Jackson, M.L.; Chung, J.R.; Jackson, L.A.; Phillips, C.H.; Benoit, J.; Monto, A.S.; Martin, E.T.; Belongia, E.A.; McLean, H.Q.; Gaglani, M.; et al. Influenza Vaccine Effectiveness in the United States during the 2015–2016 Season. N. Engl. J. Med. 2017, 377, 534–543. [Google Scholar] [CrossRef]
  65. Poehling, K.A.; Caspard, H.; Peters, T.R.; Belongia, E.A.; Congeni, B.; Gaglani, M.; Griffin, M.R.; Irving, S.A.; Kavathekar, P.K.; McLean, H.Q.; et al. 2015–2016 Vaccine Effectiveness of Live Attenuated and Inactivated Influenza Vaccines in Children in the United States. Clin. Infect. Dis. 2018, 66, 665–672. [Google Scholar] [CrossRef] [Green Version]
  66. Valdin, H.L.; Begue, R.E. Influenza vaccines effectiveness 2013–14 through 2015–16, a test-negative study in children. Vaccine 2017, 35, 4088–4093. [Google Scholar] [CrossRef]
  67. Brooks, W.A.; Zaman, K.; Lewis, K.D.; Ortiz, J.R.; Goswami, D.; Feser, J.; Sharmeen, A.T.; Nahar, K.; Rahman, M.; Rahman, M.Z.; et al. Efficacy of a Russian-backbone live attenuated influenza vaccine among young children in Bangladesh: A randomised, double-blind, placebo-controlled trial. Lancet Glob. Health 2016, 4, e946–e954. [Google Scholar] [CrossRef] [Green Version]
  68. Victor, J.C.; Lewis, K.D.; Diallo, A.; Niang, M.N.; Diarra, B.; Dia, N.; Ortiz, J.R.; Widdowson, M.A.; Feser, J.; Hoagland, R.; et al. Efficacy of a Russian-backbone live attenuated influenza vaccine among children in Senegal: A randomised, double-blind, placebo-controlled trial. Lancet Glob. Health 2016, 4, e955–e965. [Google Scholar] [CrossRef] [Green Version]
  69. Pebody, R.; Warburton, F.; Andrews, N.; Ellis, J.; von Wissmann, B.; Robertson, C.; Yonova, I.; Cottrell, S.; Gallagher, N.; Green, H.; et al. Effectiveness of seasonal influenza vaccine in preventing laboratory-confirmed influenza in primary care in the United Kingdom: 2014/15 end of season results. Eurosurveillance 2015, 20. [Google Scholar] [CrossRef] [Green Version]
  70. Pebody, R.; Sile, B.; Warburton, F.; Sinnathamby, M.; Tsang, C.; Zhao, H.; Ellis, J.; Andrews, N. Live attenuated influenza vaccine effectiveness against hospitalisation due to laboratory-confirmed influenza in children two to six years of age in England in the 2015/16 season. Eurosurveillance 2017, 22. [Google Scholar] [CrossRef]
  71. Skowronski, D.M.; Chambers, C.; De Serres, G.; Sabaiduc, S.; Winter, A.L.; Dickinson, J.A.; Gubbay, J.B.; Fonseca, K.; Drews, S.J.; Charest, H.; et al. Serial Vaccination and the Antigenic Distance Hypothesis: Effects on Influenza Vaccine Effectiveness During A(H3N2) Epidemics in Canada, 2010–2011 to 2014–2015. J. Infect. Dis. 2017, 215, 1059–1099. [Google Scholar] [CrossRef] [PubMed]
  72. Bernstein, D.I.; Yan, L.; Treanor, J.; Mendelman, P.M.; Belshe, R.; The Cold-Adapted, Trivalent, Influenza Vaccine Study Group. Effect of yearly vaccinations with live, attenuated, cold-adapted, trivalent, intranasal influenza vaccines on antibody responses in children. Pediatr. Infect. Dis. J. 2003, 22, 28–34. [Google Scholar] [CrossRef] [PubMed]
  73. Brickley, E.B.; Wright, P.F.; Khalenkov, A.; Neuzil, K.M.; Ortiz, J.R.; Rudenko, L.; Levine, M.Z.; Katz, J.M.; Brooks, W.A. The Effect of Preexisting Immunity on Virus Detection and Immune Responses in a Phase II, Randomized Trial of a Russian-Backbone, Live, Attenuated Influenza Vaccine in Bangladeshi Children. Clin. Infect. Dis. 2019, 69, 786–794. [Google Scholar] [CrossRef] [PubMed]
  74. Mohn, K.G.I.; Zhou, F.; Brokstad, K.A.; Sridhar, S.; Cox, R.J. Boosting of Cross-Reactive and Protection-Associated T Cells in Children After Live Attenuated Influenza Vaccination. J. Infect. Dis. 2017, 215, 1527–1535. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Belshe, R.B.; Gruber, W.C.; Mendelman, P.M.; Cho, I.; Reisinger, K.; Block, S.L.; Wittes, J.; Iacuzio, D.; Piedra, P.; Treanor, J.; et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J. Pediatr. 2000, 136, 168–175. [Google Scholar] [CrossRef]
  76. Bracco Neto, H.; Farhat, C.K.; Tregnaghi, M.W.; Madhi, S.A.; Razmpour, A.; Palladino, G.; Small, M.G.; Gruber, W.C.; Forrest, B.D.; The D153-P504 LAIV Study Group. Efficacy and safety of 1 and 2 doses of live attenuated influenza vaccine in vaccine-naive children. Pediatr. Infect. Dis. J. 2009, 28, 365–371. [Google Scholar] [CrossRef]
  77. Tam, J.S.; Capeding, M.R.; Lum, L.C.; Chotpitayasunondh, T.; Jiang, Z.; Huang, L.M.; Lee, B.W.; Qian, Y.; Samakoses, R.; Lolekha, S.; et al. Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia. Pediatr. Infect. Dis. J. 2007, 26, 619–628. [Google Scholar] [CrossRef]
  78. Vesikari, T.; Fleming, D.M.; Aristegui, J.F.; Vertruyen, A.; Ashkenazi, S.; Rappaport, R.; Skinner, J.; Saville, M.K.; Gruber, W.C.; Forrest, B.D.; et al. Safety, efficacy, and effectiveness of cold-adapted influenza vaccine-trivalent against community-acquired, culture-confirmed influenza in young children attending day care. Pediatrics 2006, 118, 2298–2312. [Google Scholar] [CrossRef] [Green Version]
  79. Sasaki, S.; He, X.S.; Holmes, T.H.; Dekker, C.L.; Kemble, G.W.; Arvin, A.M.; Greenberg, H.B. Influence of prior influenza vaccination on antibody and B-cell responses. PLoS ONE 2008, 3, e2975. [Google Scholar] [CrossRef] [Green Version]
  80. Mohn, K.G.; Bredholt, G.; Brokstad, K.A.; Pathirana, R.D.; Aarstad, H.J.; Tondel, C.; Cox, R.J. Longevity of B-cell and T-cell responses after live attenuated influenza vaccination in children. J. Infect. Dis. 2015, 211, 1541–1549. [Google Scholar] [CrossRef]
  81. Roy, S.; Williams, C.M.; Pardo, J.; Wijesundara, D.K.; Furuya, Y. Impact of Pre-Existing Immunity on Live Attenuated Influenza Vaccine-Induced Cross-Protective Immunity. Vaccines (Basel) 2020, 8, 459. [Google Scholar] [CrossRef]
  82. Chan, W.; Zhou, H.; Kemble, G.; Jin, H. The cold adapted and temperature sensitive influenza A/Ann Arbor/6/60 virus, the master donor virus for live attenuated influenza vaccines, has multiple defects in replication at the restrictive temperature. Virology 2008, 380, 304–311. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Isakova-Sivak, I.; Chen, L.M.; Matsuoka, Y.; Voeten, J.T.; Kiseleva, I.; Heldens, J.G.; den Bosch, H.; Klimov, A.; Rudenko, L.; Cox, N.J.; et al. Genetic bases of the temperature-sensitive phenotype of a master donor virus used in live attenuated influenza vaccines: A/Leningrad/134/17/57 (H2N2). Virology 2011, 412, 297–305. [Google Scholar] [CrossRef] [Green Version]
  84. Jin, H.; Lu, B.; Zhou, H.; Ma, C.; Zhao, J.; Yang, C.F.; Kemble, G.; Greenberg, H. Multiple amino acid residues confer temperature sensitivity to human influenza virus vaccine strains (FluMist) derived from cold-adapted A/Ann Arbor/6/60. Virology 2003, 306, 18–24. [Google Scholar] [CrossRef] [Green Version]
  85. Forero, A.; Fenstermacher, K.; Wohlgemuth, N.; Nishida, A.; Carter, V.; Smith, E.A.; Peng, X.; Hayes, M.; Francis, D.; Treanor, J.; et al. Evaluation of the innate immune responses to influenza and live-attenuated influenza vaccine infection in primary differentiated human nasal epithelial cells. Vaccine 2017, 35, 6112–6121. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Cotter, C.R.; Jin, H.; Chen, Z. A single amino acid in the stalk region of the H1N1pdm influenza virus HA protein affects viral fusion, stability and infectivity. PLoS Pathog. 2014, 10, e1003831. [Google Scholar] [CrossRef] [PubMed]
  87. Shcherbik, S.; Pearce, N.; Carney, P.; Bazhenova, E.; Larionova, N.; Kiseleva, I.; Rudenko, L.; Kumar, A.; Goldsmith, C.S.; Dugan, V.; et al. Evaluation of A(H1N1)pdm09 LAIV vaccine candidates stability and replication efficiency in primary human nasal epithelial cells. Vaccine X 2019, 2, 100031. [Google Scholar] [CrossRef]
  88. Caspard, H.; Coelingh, K.L.; Mallory, R.M.; Ambrose, C.S. Association of vaccine handling conditions with effectiveness of live attenuated influenza vaccine against H1N1pdm09 viruses in the United States. Vaccine 2016, 34, 5066–5072. [Google Scholar] [CrossRef] [Green Version]
  89. Grohskopf, L.A.; Sokolow, L.Z.; Fry, A.M.; Walter, E.B.; Jernigan, D.B. Update: ACIP Recommendations for the Use of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4)—United States, 2018-19 Influenza Season. MMWR Morb. Mortal. Wkly. Rep. 2018, 67, 643–645. [Google Scholar] [CrossRef]
  90. Belshe, R.B.; Mendelman, P.M.; Treanor, J.; King, J.; Gruber, W.C.; Piedra, P.; Bernstein, D.I.; Hayden, F.G.; Kotloff, K.; Zangwill, K.; et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N. Engl. J. Med. 1998, 338, 1405–1412. [Google Scholar] [CrossRef]
  91. Nolan, T.; Lee, M.S.; Cordova, J.M.; Cho, I.; Walker, R.E.; August, M.J.; Larson, S.; Coelingh, K.L.; Mendelman, P.M. Safety and immunogenicity of a live-attenuated influenza vaccine blended and filled at two manufacturing facilities. Vaccine 2003, 21, 1224–1231. [Google Scholar] [CrossRef]
  92. Zangwill, K.M.; Droge, J.; Mendelman, P.; Marcy, S.M.; Partridge, S.; Chiu, C.Y.; Jing, J.; Chang, S.J.; Cho, I.; Ward, J.I. Prospective, randomized, placebo-controlled evaluation of the safety and immunogenicity of three lots of intranasal trivalent influenza vaccine among young children. Pediatr. Infect. Dis. J. 2001, 20, 740–746. [Google Scholar] [CrossRef] [PubMed]
  93. Lee, M.S.; Mahmood, K.; Adhikary, L.; August, M.J.; Cordova, J.; Cho, I.; Kemble, G.; Reisinger, K.; Walker, R.E.; Mendelman, P.M. Measuring antibody responses to a live attenuated influenza vaccine in children. Pediatr. Infect. Dis. J. 2004, 23, 852–856. [Google Scholar] [CrossRef] [PubMed]
  94. Eick, A.A.; Wang, Z.; Hughes, H.; Ford, S.M.; Tobler, S.K. Comparison of the trivalent live attenuated vs. inactivated influenza vaccines among U.S. military service members. Vaccine 2009, 27, 3568–3575. [Google Scholar] [CrossRef] [Green Version]
  95. Mok, D.Z.L.; Chan, K.R. The Effects of Pre-Existing Antibodies on Live-Attenuated Viral Vaccines. Viruses 2020, 12, 520. [Google Scholar] [CrossRef]
  96. Bodewes, R.; Kreijtz, J.H.; Baas, C.; Geelhoed-Mieras, M.M.; de Mutsert, G.; van Amerongen, G.; van den Brand, J.M.; Fouchier, R.A.; Osterhaus, A.D.; Rimmelzwaan, G.F. Vaccination against human influenza A/H3N2 virus prevents the induction of heterosubtypic immunity against lethal infection with avian influenza A/H5N1 virus. PLoS ONE 2009, 4, e5538. [Google Scholar] [CrossRef] [Green Version]
  97. Bodewes, R.; Kreijtz, J.H.; Geelhoed-Mieras, M.M.; van Amerongen, G.; Verburgh, R.J.; van Trierum, S.E.; Kuiken, T.; Fouchier, R.A.; Osterhaus, A.D.; Rimmelzwaan, G.F. Vaccination against seasonal influenza A/H3N2 virus reduces the induction of heterosubtypic immunity against influenza A/H5N1 virus infection in ferrets. J. Virol. 2011, 85, 2695–2702. [Google Scholar] [CrossRef] [Green Version]
  98. Bodewes, R.; Kreijtz, J.H.; Hillaire, M.L.; Geelhoed-Mieras, M.M.; Fouchier, R.A.; Osterhaus, A.D.; Rimmelzwaan, G.F. Vaccination with whole inactivated virus vaccine affects the induction of heterosubtypic immunity against influenza virus A/H5N1 and immunodominance of virus-specific CD8+ T-cell responses in mice. J. Gen. Virol. 2010, 91, 1743–1753. [Google Scholar] [CrossRef]
  99. Bodewes, R.; Fraaij, P.L.; Geelhoed-Mieras, M.M.; van Baalen, C.A.; Tiddens, H.A.; van Rossum, A.M.; van der Klis, F.R.; Fouchier, R.A.; Osterhaus, A.D.; Rimmelzwaan, G.F. Annual vaccination against influenza virus hampers development of virus-specific CD8(+) T cell immunity in children. J. Virol. 2011, 85, 11995–12000. [Google Scholar] [CrossRef] [Green Version]
  100. Garnett, C.T.; Erdman, D.; Xu, W.; Gooding, L.R. Prevalence and quantitation of species C adenovirus DNA in human mucosal lymphocytes. J. Virol. 2002, 76, 10608–10616. [Google Scholar] [CrossRef] [Green Version]
  101. Pichla-Gollon, S.L.; Lin, S.W.; Hensley, S.E.; Lasaro, M.O.; Herkenhoff-Haut, L.; Drinker, M.; Tatsis, N.; Gao, G.P.; Wilson, J.M.; Ertl, H.C.; et al. Effect of preexisting immunity on an adenovirus vaccine vector: In vitro neutralization assays fail to predict inhibition by antiviral antibody in vivo. J. Virol. 2009, 83, 5567–5573. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Pine, S.O.; Kublin, J.G.; Hammer, S.M.; Borgerding, J.; Huang, Y.; Casimiro, D.R.; McElrath, M.J. Pre-existing adenovirus immunity modifies a complex mixed Th1 and Th2 cytokine response to an Ad5/HIV-1 vaccine candidate in humans. PLoS ONE 2011, 6, e18526. [Google Scholar] [CrossRef] [PubMed]
  103. Bliss, C.M.; Bowyer, G.; Anagnostou, N.A.; Havelock, T.; Snudden, C.M.; Davies, H.; de Cassan, S.C.; Grobbelaar, A.; Lawrie, A.M.; Venkatraman, N.; et al. Assessment of novel vaccination regimens using viral vectored liver stage malaria vaccines encoding ME-TRAP. Sci. Rep. 2018, 8, 3390. [Google Scholar] [CrossRef] [PubMed]
  104. Folegatti, P.M.; Ewer, K.J.; Aley, P.K.; Angus, B.; Becker, S.; Belij-Rammerstorfer, S.; Bellamy, D.; Bibi, S.; Bittaye, M.; Clutterbuck, E.A.; et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: A preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020, 396, 467–478. [Google Scholar] [CrossRef]
  105. Lauterbach, H.; Ried, C.; Epstein, A.L.; Marconi, P.; Brocker, T. Reduced immune responses after vaccination with a recombinant herpes simplex virus type 1 vector in the presence of antiviral immunity. J. Gen. Virol. 2005, 86, 2401–2410. [Google Scholar] [CrossRef]
  106. Chen, W.H.; Strych, U.; Hotez, P.J.; Bottazzi, M.E. The SARS-CoV-2 Vaccine Pipeline: An Overview. Curr. Trop. Med. Rep. 2020, 7, 61–64. [Google Scholar] [CrossRef] [Green Version]
  107. McLean, H.Q.; Caspard, H.; Griffin, M.R.; Gaglani, M.; Peters, T.R.; Poehling, K.A.; Ambrose, C.S.; Belongia, E.A. Association of Prior Vaccination With Influenza Vaccine Effectiveness in Children Receiving Live Attenuated or Inactivated Vaccine. JAMA Netw. Open 2018, 1, e183742. [Google Scholar] [CrossRef]
  108. Belshe, R.B.; Ambrose, C.S.; Yi, T. Safety and efficacy of live attenuated influenza vaccine in children 2–7 years of age. Vaccine 2008, 26 (Suppl. 4), D10–D16. [Google Scholar] [CrossRef]
  109. Bergen, R.; Black, S.; Shinefield, H.; Lewis, E.; Ray, P.; Hansen, J.; Walker, R.; Hessel, C.; Cordova, J.; Mendelman, P.M. Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents. Pediatr. Infect. Dis. J. 2004, 23, 138–144. [Google Scholar] [CrossRef]
  110. Galli, G.; Medini, D.; Borgogni, E.; Zedda, L.; Bardelli, M.; Malzone, C.; Nuti, S.; Tavarini, S.; Sammicheli, C.; Hilbert, A.K.; et al. Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels. Proc. Natl. Acad. Sci. USA 2009, 106, 3877–3882. [Google Scholar] [CrossRef] [Green Version]
  111. Martin, T.R.; Frevert, C.W. Innate immunity in the lungs. Proc. Am. Thorac. Soc. 2005, 2, 403–411. [Google Scholar] [CrossRef] [PubMed]
  112. Fadok, V.A.; Bratton, D.L.; Konowal, A.; Freed, P.W.; Westcott, J.Y.; Henson, P.M. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J. Clin. Investig. 1998, 101, 890–898. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Hoffmann, P.R.; Kench, J.A.; Vondracek, A.; Kruk, E.; Daleke, D.L.; Jordan, M.; Marrack, P.; Henson, P.M.; Fadok, V.A. Interaction between phosphatidylserine and the phosphatidylserine receptor inhibits immune responses in vivo. J. Immunol. 2005, 174, 1393–1404. [Google Scholar] [CrossRef]
  114. Huynh, M.L.; Fadok, V.A.; Henson, P.M. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution of inflammation. J. Clin. Investig. 2002, 109, 41–50. [Google Scholar] [CrossRef] [PubMed]
  115. Akilov, O.E.; Wu, M.X.; Jin, Y.; Zhou, Z.; Geskin, L.J.; Falo, L.D.; Hasan, T. Vaccination with photodynamic therapy-treated macrophages induces highly suppressive T-regulatory cells. Photodermatol. Photoimmunol. Photomed. 2011, 27, 97–107. [Google Scholar] [CrossRef] [Green Version]
  116. Coleman, M.M.; Ruane, D.; Moran, B.; Dunne, P.J.; Keane, J.; Mills, K.H. Alveolar macrophages contribute to respiratory tolerance by inducing FoxP3 expression in naive T cells. Am. J. Respir. Cell Mol. Biol. 2013, 48, 773–780. [Google Scholar] [CrossRef]
  117. Liu, G.; Duan, K.; Ma, H.; Niu, Z.; Peng, J.; Zhao, Y. An instructive role of donor macrophages in mixed chimeras in the induction of recipient CD4(+)Foxp3(+) Treg cells. Immunol. Cell Biol. 2011, 89, 827–835. [Google Scholar] [CrossRef]
  118. Lanthier, P.A.; Huston, G.E.; Moquin, A.; Eaton, S.M.; Szaba, F.M.; Kummer, L.W.; Tighe, M.P.; Kohlmeier, J.E.; Blair, P.J.; Broderick, M.; et al. Live attenuated influenza vaccine (LAIV) impacts innate and adaptive immune responses. Vaccine 2011, 29, 7849–7856. [Google Scholar] [CrossRef] [Green Version]
  119. Yan, L.M.; Lau, S.P.N.; Poh, C.M.; Chan, V.S.F.; Chan, M.C.W.; Peiris, M.; Poon, L.L.M. Heterosubtypic Protection Induced by a Live Attenuated Influenza Virus Vaccine Expressing Galactose-alpha-1,3-Galactose Epitopes in Infected Cells. mBio 2020, 11. [Google Scholar] [CrossRef] [Green Version]
  120. GeurtsvanKessel, C.H.; Willart, M.A.; van Rijt, L.S.; Muskens, F.; Kool, M.; Baas, C.; Thielemans, K.; Bennett, C.; Clausen, B.E.; Hoogsteden, H.C.; et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells. J. Exp. Med. 2008, 205, 1621–1634. [Google Scholar] [CrossRef] [Green Version]
  121. Ho, A.W.; Prabhu, N.; Betts, R.J.; Ge, M.Q.; Dai, X.; Hutchinson, P.E.; Lew, F.C.; Wong, K.L.; Hanson, B.J.; Macary, P.A.; et al. Lung CD103+ dendritic cells efficiently transport influenza virus to the lymph node and load viral antigen onto MHC class I for presentation to CD8 T cells. J. Immunol. 2011, 187, 6011–6021. [Google Scholar] [CrossRef] [Green Version]
  122. Ingulli, E.; Funatake, C.; Jacovetty, E.L.; Zanetti, M. Cutting edge: Antigen presentation to CD8 T cells after influenza A virus infection. J. Immunol. 2009, 182, 29–33. [Google Scholar] [CrossRef] [Green Version]
  123. Waithman, J.; Zanker, D.; Xiao, K.; Oveissi, S.; Wylie, B.; Ng, R.; Togel, L.; Chen, W. Resident CD8(+) and migratory CD103(+) dendritic cells control CD8 T cell immunity during acute influenza infection. PLoS ONE 2013, 8, e66136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  124. Wakim, L.M.; Smith, J.; Caminschi, I.; Lahoud, M.H.; Villadangos, J.A. Antibody-targeted vaccination to lung dendritic cells generates tissue-resident memory CD8 T cells that are highly protective against influenza virus infection. Mucosal. Immunol. 2015, 8, 1060–1071. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Wu, T.; Hu, Y.; Lee, Y.T.; Bouchard, K.R.; Benechet, A.; Khanna, K.; Cauley, L.S. Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection. J. Leukoc. Biol. 2014, 95, 215–224. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Roy, S.; Williams, C.M.; Wijesundara, D.K.; Furuya, Y. Impact of Pre-Existing Immunity to Influenza on Live-Attenuated Influenza Vaccine (LAIV) Immunogenicity. Vaccines 2020, 8, 683.

AMA Style

Roy S, Williams CM, Wijesundara DK, Furuya Y. Impact of Pre-Existing Immunity to Influenza on Live-Attenuated Influenza Vaccine (LAIV) Immunogenicity. Vaccines. 2020; 8(4):683.

Chicago/Turabian Style

Roy, Sreeja, Clare M. Williams, Danushka K. Wijesundara, and Yoichi Furuya. 2020. "Impact of Pre-Existing Immunity to Influenza on Live-Attenuated Influenza Vaccine (LAIV) Immunogenicity" Vaccines 8, no. 4: 683.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop