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The kinetics of the systemic and local immune response to parenteral influenza vaccination
International Congress Series 1263 (2004) 515 – 518
www.ics-elsevier.com
The kinetics of the systemic and local immune response to parenteral influenza vaccination Abdullah Madhun a, Rebecca Cox a, Lars R. Haaheim a, Roland Jonsson b, Karl Albert Brokstad b,* b
a The Influenza Centre, The Gade Institute, University of Bergen, N-5021 Bergen, Norway Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Armauer Hansen Building, N-5021 Bergen, Norway
Abstract. Studying the humoral immune response after influenza vaccination, with focus on the immune activity occurring locally at mucosal surfaces and in associated lymphoid tissue, provides a valuable tool for understanding immunity to influenza. Here we summarize our work addressing the kinetics of the local and the systemic immune responses after influenza vaccination in humans. Our studies have shown that inactivated influenza vaccine induced a rapid systemic immune response, which was associated with a local response in tonsils and oral fluid in healthy adults. However, the response in tonsils and oral fluid was impaired in young children (under 3 years old). The rapidity and the magnitude of the immune response did not seem to be impaired in diabetic patients and was not altered by treatment of healthy adults with the antiviral zanamivir. High frequencies of influenzaspecific antibody secreting cells (ASC) were detected in nasal mucosa of healthy adults. However, parenteral vaccination did not induce an increase in frequency or the number of these ASC. Ongoing studies are investigating the characteristics of influenza-specific T- and B-cells induced locally and systemically after vaccination in man. D 2004 Elsevier B.V. All rights reserved. Keywords: Vaccine; Human; Immune response
1. Introduction Current inactivated influenza vaccines offer approx. 60 –90% protection. However, there is still room for improvement in effectiveness, duration of response, ease of administration and compliance rate. Successful development of new vaccines and vaccination strategies are very dependent on detailed knowledge of the protective immunity and immune processes occurring in the upper respiratory tract (reviewed in [19]). We have focused on the kinetics of the systemic and local immune response to parenteral influenza vaccine in humans. In this report, we summarize our research aimed at understanding the immune response to parenteral influenza vaccination in humans. * Corresponding author. Tel.: +47-55-97-46-22; fax: +47-55-97-58-17. E-mail address: [email protected] (K.A. Brokstad). 0531-5131/ D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.02.151
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A. Madhun et al. / International Congress Series 1263 (2004) 515–518
2. Discussion Our work was initiated by the observation by Zuckerman et al. [1] who found that the serum HI antibody response to current inactivated vaccines appeared earlier than first anticipated and this was confirmed in further studies [2 –4]. By examining the kinetics of the early systemic immune response to subcutaneous/intramuscular trivalent split virus vaccine [5], we observed that the serological immune responses occurred in less than a week, with a peak in response between 1 and 2 weeks post-vaccination. In addition, the peak in number of influenza-specific antibody secreting cells (ASC) in peripheral blood appeared earlier, at about 7 days post-vaccination [5]. The serum influenza-specific postvaccination antibody class distribution was IgGHIgM>IgA. However, the class distribution of influenza-specific ASC response in peripheral blood was IgGHIgA>IgM. This finding suggested that the influenza-specific IgA ASCs detected in peripheral blood after vaccination may be homing to mucosal tissues. Therefore, we investigated the kinetics of local respiratory immune response in tonsils (a respiratory secondary lymphatic organ) and oral fluid [6,7]. These studies [6,7] showed that parenteral vaccination was able to induce a local immune response in the tonsils and in saliva/oral fluid. In the tonsils, IgA followed by IgM dominated the influenza-specific ASC response. In oral fluid, the antibody response was dominated by IgA1 (and to a lesser degree IgA2) which was bound to secretory component [6,7]. These findings raised the question whether mucosal priming through infection with influenza virus is essential to mount such a local response. It was evident in our study of young children (2– 3 years old) [8] that natural priming was essential to mount strong ASC and antibody responses of the IgG and IgA classes in peripheral blood. However, the IgA response in tonsils and oral fluid was significantly lower in children than adults, suggesting that the IgA response was dependent on age and not priming. Based on our results, we proposed that the association between the systemic and the mucosal parts of the humoral immune system is not fully matured in young children and this could be due to a lack of functional homing receptors on the ASC or cell adhesion molecules on the endothelium of mucosal effector sites. By studying the immunoglobulin subclass response [9], we found that distribution of influenza-specific IgG1, IgG3, IgG4, IgA1 and IgA2 responses in serum after vaccination was not dependent on age or previous priming. In contrast, the IgG2 response was dependent on priming and may mature later than other IgG subclasses in young children. The immune response induced after parenteral administered influenza vaccine in adults is also highly cross-reactive, giving cross protection against earlier as well as more recent virus strains [10]. Immunisation with split virus vaccine stimulates a strong antibody response towards the surface virus glycoproteins (HA and NA), but also in some cases a marked immune response to the internal virus proteins (M and NP) [11]. This also applies to subunit vaccines containing HA and NA, but which may contain traces of the internal proteins [11]. Individuals with juvenile diabetes are, in most western countries, considered to be a risk group for influenza, hence are recommended for annual influenza vaccination. Earlier reports have suggested that type 1 diabetics had a lower antibody response than healthy
A. Madhun et al. / International Congress Series 1263 (2004) 515–518
517
individuals after vaccination [12,13]. In our study [14], we showed that there were no differences in the kinetics or the magnitude of the humoral immune response in juvenile diabetes patients compared with healthy controls. In healthy subjects, treatment with zanamivir did not influence the rapidity or the magnitude of the immune response to parenteral influenza vaccination [15], suggesting that the neuraminidase inhibitors can be safely used to provide protection against influenza during the first week post-vaccination and antiviral drug can be combined with vaccination in an effort to protect against influenza infection. We have found a high frequency of plasma cells actively secreting anti-influenza antibodies among the lymphoid cells inhabiting the lamina propria/intra-epithelial layer of the nasal mucosa [16]. However, contrary to our earlier findings in tonsils, parenteral vaccination did not induce an increase in the level of influenza-specific ASC in the nasal mucosa [17]. This finding may suggest that parenteral influenza vaccination only partially activates the local immunity. We have previously suggested that the tonsils and probably the oral mucosa retain circulating influenza-specific plasma cells that originated from the draining lymphoid tissue. This is supported by a new study [18], where we, by a novel histological staining technique, have observed that influenza specific plasma cells are found as individual cells scattered around the tonsils indicating that these lymphocytes are probably not activated in the tonsils. Parenteral influenza vaccination may also alter the pattern of lymphocyte populations in the tonsils, where the number of CD4 + T helper (Th) cells fell significantly after vaccination [18]. The function of this drop is not known but the CD4 + Th cells may be recruited to other lymphoid tissue to aid in antibody production. We are currently conducting studies to further explore the processes that occur systemically and locally after parenteral influenza vaccination. Acknowledgements We wish to thank the following who have supported our research; European Union (Flupan QLK2-CT-2001-01786), the Norwegian Department of Health, Broegelmann Foundation and the Norwegian Research Council. References [1] M. Zuckerman, et al., Influenza A (H3N2) component of recommended vaccine induces antibody to current virus, Lancet 335 (1990) 179 – 180. [2] M.A. Zuckerman, et al., Serological responses in volunteers to inactivated trivalent subunit influenza vaccine: antibody reactivity with epidemic influenza A and B strains and evidence of a rapid immune response, J. Med. Virol. 2 (1991) 133 – 137. [3] M. Zuckerman, et al., Activity of influenza vaccine against virus strains now circulating, Lancet 339 (1992) 118. [4] M. Zuckerman, et al., Rapid immune response to influenza vaccination, Lancet 342 (1993) 1113. [5] R.J. Cox, et al., An early humoral immune response in peripheral blood following parenteral inactivated influenza vaccination, Vaccine 12 (1994) 993 – 999. [6] K.A. Brokstad, et al., Parenteral influenza vaccination induces a rapid systemic and local immune response, J. Infect. Dis. 171 (1995) 198 – 203. [7] K.A. Brokstad, et al., IgA, IgA subclasses, and secretory component levels in oral fluid collected from subjects after parental influenza vaccination, J. Infect. Dis. 171 (1995) 1072 – 1074.
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A. Madhun et al. / International Congress Series 1263 (2004) 515–518
[8] A.S. El-Madhun, et al., Systemic and mucosal immune responses in young children and adults after parenteral influenza vaccination, J. Infect. Dis. 178 (1998) 933 – 939. [9] A.S. El-Madhun, R.J. Cox, L.R. Haaheim, The effect of age and natural priming on the IgG and IgA subclass responses after parenteral influenza vaccination, J. Infect. Dis. 180 (1999) 1356 – 1360. [10] K.A. Brokstad, et al., Cross-reaction but no avidity change of the serum antibody response after influenza vaccination, Vaccine 13 (1995) 1522 – 1528. [11] R.J. Cox, K.A. Brokstad, The postvaccination antibody response to influenza virus proteins, APMIS 107 (1999) 289 – 296. [12] R.J. Diepersloot, et al., Humoral immune response and delayed type hypersensitivity to influenza vaccine in patients with diabetes mellitus, Diabetologia 30 (1987) 397 – 401. [13] H. Kaneshige, Nonenzymatic glycosylation of serum IgG and its effect on antibody activity in patients with diabetes mellitus, Diabetes 36 (1987) 822 – 828. [14] A.S. El-Madhun, et al., Systemic and local immune responses after parenteral influenza vaccination in juvenile diabetic patients and healthy controls: results from a pilot study, Vaccine 16 (1998) 156 – 160. [15] R.J. Cox, et al., The effect of zanamivir treatment on the early immune response to influenza vaccination, Vaccine 19 (2001) 4743 – 4749. [16] K.A. Brokstad, et al., High prevalence of influenza specific antibody secreting cells in nasal mucosa, Scand. J. Immunol. 54 (2001) 243 – 247. [17] K.A. Brokstad, et al., Parenteral vaccination against influenza does not induce a local antigen-specific immune response in the nasal mucosa, J. Infect. Dis. 185 (2002) 878 – 884. [18] J.C. Eriksson, et al., Lymphocyte distribution in the tonsils prior to and after influenza vaccination, Vaccine 22 (2003) 57 – 63. [19] R.J. Cox, K.A. Brokstad, P. Ogra, Influenza virus: immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines, Scand. J. Immunol. 59 (2004) 1 – 15.
www.ics-elsevier.com
The kinetics of the systemic and local immune response to parenteral influenza vaccination Abdullah Madhun a, Rebecca Cox a, Lars R. Haaheim a, Roland Jonsson b, Karl Albert Brokstad b,* b
a The Influenza Centre, The Gade Institute, University of Bergen, N-5021 Bergen, Norway Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Armauer Hansen Building, N-5021 Bergen, Norway
Abstract. Studying the humoral immune response after influenza vaccination, with focus on the immune activity occurring locally at mucosal surfaces and in associated lymphoid tissue, provides a valuable tool for understanding immunity to influenza. Here we summarize our work addressing the kinetics of the local and the systemic immune responses after influenza vaccination in humans. Our studies have shown that inactivated influenza vaccine induced a rapid systemic immune response, which was associated with a local response in tonsils and oral fluid in healthy adults. However, the response in tonsils and oral fluid was impaired in young children (under 3 years old). The rapidity and the magnitude of the immune response did not seem to be impaired in diabetic patients and was not altered by treatment of healthy adults with the antiviral zanamivir. High frequencies of influenzaspecific antibody secreting cells (ASC) were detected in nasal mucosa of healthy adults. However, parenteral vaccination did not induce an increase in frequency or the number of these ASC. Ongoing studies are investigating the characteristics of influenza-specific T- and B-cells induced locally and systemically after vaccination in man. D 2004 Elsevier B.V. All rights reserved. Keywords: Vaccine; Human; Immune response
1. Introduction Current inactivated influenza vaccines offer approx. 60 –90% protection. However, there is still room for improvement in effectiveness, duration of response, ease of administration and compliance rate. Successful development of new vaccines and vaccination strategies are very dependent on detailed knowledge of the protective immunity and immune processes occurring in the upper respiratory tract (reviewed in [19]). We have focused on the kinetics of the systemic and local immune response to parenteral influenza vaccine in humans. In this report, we summarize our research aimed at understanding the immune response to parenteral influenza vaccination in humans. * Corresponding author. Tel.: +47-55-97-46-22; fax: +47-55-97-58-17. E-mail address: [email protected] (K.A. Brokstad). 0531-5131/ D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ics.2004.02.151
516
A. Madhun et al. / International Congress Series 1263 (2004) 515–518
2. Discussion Our work was initiated by the observation by Zuckerman et al. [1] who found that the serum HI antibody response to current inactivated vaccines appeared earlier than first anticipated and this was confirmed in further studies [2 –4]. By examining the kinetics of the early systemic immune response to subcutaneous/intramuscular trivalent split virus vaccine [5], we observed that the serological immune responses occurred in less than a week, with a peak in response between 1 and 2 weeks post-vaccination. In addition, the peak in number of influenza-specific antibody secreting cells (ASC) in peripheral blood appeared earlier, at about 7 days post-vaccination [5]. The serum influenza-specific postvaccination antibody class distribution was IgGHIgM>IgA. However, the class distribution of influenza-specific ASC response in peripheral blood was IgGHIgA>IgM. This finding suggested that the influenza-specific IgA ASCs detected in peripheral blood after vaccination may be homing to mucosal tissues. Therefore, we investigated the kinetics of local respiratory immune response in tonsils (a respiratory secondary lymphatic organ) and oral fluid [6,7]. These studies [6,7] showed that parenteral vaccination was able to induce a local immune response in the tonsils and in saliva/oral fluid. In the tonsils, IgA followed by IgM dominated the influenza-specific ASC response. In oral fluid, the antibody response was dominated by IgA1 (and to a lesser degree IgA2) which was bound to secretory component [6,7]. These findings raised the question whether mucosal priming through infection with influenza virus is essential to mount such a local response. It was evident in our study of young children (2– 3 years old) [8] that natural priming was essential to mount strong ASC and antibody responses of the IgG and IgA classes in peripheral blood. However, the IgA response in tonsils and oral fluid was significantly lower in children than adults, suggesting that the IgA response was dependent on age and not priming. Based on our results, we proposed that the association between the systemic and the mucosal parts of the humoral immune system is not fully matured in young children and this could be due to a lack of functional homing receptors on the ASC or cell adhesion molecules on the endothelium of mucosal effector sites. By studying the immunoglobulin subclass response [9], we found that distribution of influenza-specific IgG1, IgG3, IgG4, IgA1 and IgA2 responses in serum after vaccination was not dependent on age or previous priming. In contrast, the IgG2 response was dependent on priming and may mature later than other IgG subclasses in young children. The immune response induced after parenteral administered influenza vaccine in adults is also highly cross-reactive, giving cross protection against earlier as well as more recent virus strains [10]. Immunisation with split virus vaccine stimulates a strong antibody response towards the surface virus glycoproteins (HA and NA), but also in some cases a marked immune response to the internal virus proteins (M and NP) [11]. This also applies to subunit vaccines containing HA and NA, but which may contain traces of the internal proteins [11]. Individuals with juvenile diabetes are, in most western countries, considered to be a risk group for influenza, hence are recommended for annual influenza vaccination. Earlier reports have suggested that type 1 diabetics had a lower antibody response than healthy
A. Madhun et al. / International Congress Series 1263 (2004) 515–518
517
individuals after vaccination [12,13]. In our study [14], we showed that there were no differences in the kinetics or the magnitude of the humoral immune response in juvenile diabetes patients compared with healthy controls. In healthy subjects, treatment with zanamivir did not influence the rapidity or the magnitude of the immune response to parenteral influenza vaccination [15], suggesting that the neuraminidase inhibitors can be safely used to provide protection against influenza during the first week post-vaccination and antiviral drug can be combined with vaccination in an effort to protect against influenza infection. We have found a high frequency of plasma cells actively secreting anti-influenza antibodies among the lymphoid cells inhabiting the lamina propria/intra-epithelial layer of the nasal mucosa [16]. However, contrary to our earlier findings in tonsils, parenteral vaccination did not induce an increase in the level of influenza-specific ASC in the nasal mucosa [17]. This finding may suggest that parenteral influenza vaccination only partially activates the local immunity. We have previously suggested that the tonsils and probably the oral mucosa retain circulating influenza-specific plasma cells that originated from the draining lymphoid tissue. This is supported by a new study [18], where we, by a novel histological staining technique, have observed that influenza specific plasma cells are found as individual cells scattered around the tonsils indicating that these lymphocytes are probably not activated in the tonsils. Parenteral influenza vaccination may also alter the pattern of lymphocyte populations in the tonsils, where the number of CD4 + T helper (Th) cells fell significantly after vaccination [18]. The function of this drop is not known but the CD4 + Th cells may be recruited to other lymphoid tissue to aid in antibody production. We are currently conducting studies to further explore the processes that occur systemically and locally after parenteral influenza vaccination. Acknowledgements We wish to thank the following who have supported our research; European Union (Flupan QLK2-CT-2001-01786), the Norwegian Department of Health, Broegelmann Foundation and the Norwegian Research Council. References [1] M. Zuckerman, et al., Influenza A (H3N2) component of recommended vaccine induces antibody to current virus, Lancet 335 (1990) 179 – 180. [2] M.A. Zuckerman, et al., Serological responses in volunteers to inactivated trivalent subunit influenza vaccine: antibody reactivity with epidemic influenza A and B strains and evidence of a rapid immune response, J. Med. Virol. 2 (1991) 133 – 137. [3] M. Zuckerman, et al., Activity of influenza vaccine against virus strains now circulating, Lancet 339 (1992) 118. [4] M. Zuckerman, et al., Rapid immune response to influenza vaccination, Lancet 342 (1993) 1113. [5] R.J. Cox, et al., An early humoral immune response in peripheral blood following parenteral inactivated influenza vaccination, Vaccine 12 (1994) 993 – 999. [6] K.A. Brokstad, et al., Parenteral influenza vaccination induces a rapid systemic and local immune response, J. Infect. Dis. 171 (1995) 198 – 203. [7] K.A. Brokstad, et al., IgA, IgA subclasses, and secretory component levels in oral fluid collected from subjects after parental influenza vaccination, J. Infect. Dis. 171 (1995) 1072 – 1074.
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A. Madhun et al. / International Congress Series 1263 (2004) 515–518
[8] A.S. El-Madhun, et al., Systemic and mucosal immune responses in young children and adults after parenteral influenza vaccination, J. Infect. Dis. 178 (1998) 933 – 939. [9] A.S. El-Madhun, R.J. Cox, L.R. Haaheim, The effect of age and natural priming on the IgG and IgA subclass responses after parenteral influenza vaccination, J. Infect. Dis. 180 (1999) 1356 – 1360. [10] K.A. Brokstad, et al., Cross-reaction but no avidity change of the serum antibody response after influenza vaccination, Vaccine 13 (1995) 1522 – 1528. [11] R.J. Cox, K.A. Brokstad, The postvaccination antibody response to influenza virus proteins, APMIS 107 (1999) 289 – 296. [12] R.J. Diepersloot, et al., Humoral immune response and delayed type hypersensitivity to influenza vaccine in patients with diabetes mellitus, Diabetologia 30 (1987) 397 – 401. [13] H. Kaneshige, Nonenzymatic glycosylation of serum IgG and its effect on antibody activity in patients with diabetes mellitus, Diabetes 36 (1987) 822 – 828. [14] A.S. El-Madhun, et al., Systemic and local immune responses after parenteral influenza vaccination in juvenile diabetic patients and healthy controls: results from a pilot study, Vaccine 16 (1998) 156 – 160. [15] R.J. Cox, et al., The effect of zanamivir treatment on the early immune response to influenza vaccination, Vaccine 19 (2001) 4743 – 4749. [16] K.A. Brokstad, et al., High prevalence of influenza specific antibody secreting cells in nasal mucosa, Scand. J. Immunol. 54 (2001) 243 – 247. [17] K.A. Brokstad, et al., Parenteral vaccination against influenza does not induce a local antigen-specific immune response in the nasal mucosa, J. Infect. Dis. 185 (2002) 878 – 884. [18] J.C. Eriksson, et al., Lymphocyte distribution in the tonsils prior to and after influenza vaccination, Vaccine 22 (2003) 57 – 63. [19] R.J. Cox, K.A. Brokstad, P. Ogra, Influenza virus: immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines, Scand. J. Immunol. 59 (2004) 1 – 15.