Immunogenicity and protective immunity against otitis media caused by pneumococcus in mice of Hib conjugate vaccine with PsaA protein carrier

Abstract

This study evaluated the immunogenicity and protective immunity of a Hemophilus influenzae b (Hib) polysaccharide conjugate vaccine with the pneumococcal surface adhesin A (PsaA) protein carrier in young mice. The Hib polysaccharide was conjugated with the rPsaA protein carrier, which was produced using recombinant DNA technology. A total of 15 young mice aged 3 weeks to 5 weeks were immunized with the conjugate vaccine, and another 15 young mice of the same age were immunized with the licensed Hib-tetanus toxoid (TT) vaccine. Furthermore, the third group of 15 young mice was inoculated with phosphate buffer saline as control. The immunized mice were inoculated with pneumococcus in the middle ear. Results showed that IgG antibody responses against both the PsaA protein and Hib polysaccharide were observed in the Hib-PsaA group. However, no statistical difference was observed in the titer of IgG against the Hib polysaccharide between Hib-PsaA and Hib-TT groups. The elimination rate of pneumococcus and the inflammation of the middle ear showed the effectiveness of protective immunity against otitis media caused by pneumococcus. Our results suggest that the Hib polysaccharide can be successfully conjugated with rPsaA via amide condensation. This new Hib-PsaA conjugate vaccine can induce both anti-PsaA and anti-Hib immune responses in young mice and elicit effective protection against acute otitis media caused by pneumococcus.

Keywords

conjugate vaccine / pneumococcal surface adhesin A / Hemophilus influenzae b / immunogenicity / otitis media

References

[1] Hasegawa J, Mori M, Showa S, Matsushima A, Ohnishi H, Tsugawa T, Yoto Y, Tsutsumi H. Pneumococcal vaccination reduced the risk of acute otitis media: cohort study. Pediatr Int 2015; 57(4): 582–585

[2] Intakorn P, Sonsuwan N, Noknu S, Moungthong G, Pirçon JY, Liu Y, Van Dyke MK, Hausdorff WP. Haemophilus influenzae type b as an important cause of culture-positive acute otitis media in young children in Thailand: a tympanocentesis-based, multi-center, cross-sectional study. BMC Pediatr 2014; 14(1): 157

[3] Kim KH, Lee H, Chung EH, Kang JH, Kim JH, Kim JS, Lee HJ, Oh SH, Park EA, Park SE. Immunogenicity and safety of two different Haemophilus influenzae type b conjugate vaccines in Korean infants. J Korean Med Sci 2008; 23(6): 929–936

[4] Yatsyshina S, Mayanskiy N, Shipulina O, Kulichenko T, Alyabieva N, Katosova L, Lazareva A, Skachkova T, Elkina M, Matosova S, Shipulin G. Detection of respiratory pathogens in pediatric acute otitis media by PCR and comparison of findings in the middle ear and nasopharynx. Diagn Microbiol Infect Dis 2016; 85(1): 125–130

[5] Pumarola F, Marès J, Losada I, Minguella I, Moraga F, Tarragó D, Aguilera U, Casanovas JM, Gadea G, Trías E, Cenoz S, Sistiaga A, García-Corbeira P, Pirçon JY, Marano C, Hausdorff WP. Microbiology of bacteria causing recurrent acute otitis media (AOM) and AOM treatment failure in young children in Spain: shifting pathogens in the post-pneumococcal conjugate vaccination era. Int J Pediatr Otorhinolaryngol 2013; 77(8): 1231–1236

[6] Dagan R, Eskola J, Leclerc C, Leroy O. Reduced response to multiple vaccines sharing common protein epitopes that are administered simultaneously to infants. Infect Immun 1998; 66(5): 2093–2098

[7] Insel RA. Potential alterations in immunogenicity by combining or simultaneously administering vaccine components. Ann N Y Acad Sci 1995; 754(1 Combined Vacc): 35–47

[8] Sabirov A, Kodama S, Hirano T, Suzuki M, Mogi G. Intranasal immunization enhances clearance of nontypeable Haemophilus influenzae and reduces stimulation of tumor necrosis factor alpha production in the murine model of otitis media. Infect Immun 2001; 69(5): 2964–2971

[9] Sipilä M, Pukander J, Karma P. Incidence of acute otitis media up to the age of 1 1/2 years in urban infants. Acta Otolaryngol 1987; 104(1-2): 138–145

[10] Faden H, Duffy L, Boeve M. Otitis media: back to basics. Pediatr Infect Dis J 1998; 17(12): 1105–1112, quiz 1112–1113

[11] Qureishi A, Lee Y, Belfield K, Birchall JP, Daniel M. Update on otitis media —prevention and treatment. Infect Drug Resist 2014; 7(1): 15–24

[12] Dowell SF, Butler JC, Giebink GS, Jacobs MR, Jernigan D, Musher DM, Rakowsky A, Schwartz B. Acute otitis media: management and surveillance in an era of pneumococcal resistance—a report from the Drug-resistant Streptococcus pneumoniae Therapeutic Working Group. Pediatr Infect Dis J 1999; 18(1): 1–9

[13] O’Brien KL, Dagan R, Mäkelä PH. Nasopharyngeal carriage. In: Siber GR, Klugman KP, Mäkelä PH. Pneumococcal Vaccines: the Impact of Conjugate Vaccine. Washington, DC: ASM Press, 2008:279–300

[14] Henrichsen J. Six newly recognized types of Streptococcus pneumoniae. J Clin Microbiol 1995; 33(10): 2759–2762

[15] Dhooge IJ, van Kempen MJ, Sanders LA, Rijkers GT. Deficient IgA and IgG2 anti-pneumococcal antibody levels and response to vaccination in otitis prone children. Int J Pediatr Otorhinolaryngol 2002; 64(2): 133–141

[16] Sniadack DH, Schwartz B, Lipman H, Bogaerts J, Butler JC, Dagan R, Echaniz-Aviles G, Lloyd-Evans N, Fenoll A, Girgis NI, Henrichsen J, Klugman K, Lehmann D, Takala AK, Vandepitte J, Gove S, Breiman RF. Potential interventions for the prevention of childhood pneumonia: geographic and temporal differences in serotype and serogroup distribution of sterile site pneumococcal isolates from children—implications for vaccine strategies. Pediatr Infect Dis J 1995; 14(6): 503–510

[17] Briles DE, Hollingshead SK, Crain MJ, Ren B, Mirza S, Watt J, Johnston J. Pneumococcal proteins that may constitute the next generation vaccine for pneumococcal disease. Int Congr Ser 2003; 1257: 27–31

[18] Briles DE, Hollingshead S, Brooks-Walter A, Nabors GS, Ferguson L, Schilling M, Gravenstein S, Braun P, King J, Swift A. The potential to use PspA and other pneumococcal proteins to elicit protection against pneumococcal infection. Vaccine 2000; 18(16): 1707–1711

[19] Bogaert D, Hermans PW, Adrian PV, Rümke HC, de Groot R. Pneumococcal vaccines: an update on current strategies. Vaccine 2004; 22(17-18): 2209–2220

[20] Briles DE, Hollingshead SK, Nabors GS, Paton JC, Brooks-Walter A. The potential for using protein vaccines to protect against otitis media caused by Streptococcus pneumoniae. Vaccine 2000; 19(Suppl 1): S87–S95

[21] Butler JC, Breiman RF, Lipman HB, Hofmann J, Facklam RR. Serotype distribution of Streptococcus pneumoniae infections among preschool children in the United States, 1978–1994: implications for development of a conjugate vaccine. J Infect Dis 1995; 171(4): 885–889

[22] Mayanskiy N, Alyabieva N, Ponomarenko O, Pakhomov A, Kulichenko T, Ivanenko A, Lazareva M, Lazareva A, Katosova L, Namazova-Baranova L, Baranov A. Bacterial etiology of acute otitis media and characterization of pneumococcal serotypes and genotypes among children in Moscow, Russia. Pediatr Infect Dis J 2015; 34(3): 255–260

Acknowledgements

This research work was funded by the Natural Science Foundation of Shanghai from the Science and Technology Commission of Shanghai Municipality (No. 14ZR1405700).

Compliance with ethics guidelines

Zeyu Chen, Rong Guo, Jianghong Xu, and Chuangjun Qiu declare that they have no conflict of interest. All institutional and national guidelines for the care and use of laboratory animals were followed.

RIGHTS & PERMISSIONS

2016 Higher Education Press and Springer-Verlag Berlin Heidelberg