biopreparatБИОпрепараты. Профилактика, диагностика, лечениеBiological Products. Prevention, Diagnosis, Treatment2221-996X2619-1156Scientific Centre for Expert Evaluation of Medicinal Products10.30895/2221-996X-2021-21-4-234-243biopreparat-350Research ArticleОБЗОРЫREVIEWSОбзор мирового опыта применения зарегистрированных вакцин и разработки новых вакцин для профилактики пневмококковой инфекцииReview of global use of licensed vaccines and development of new vaccines for the prevention of pneumococcal infectionhttps://orcid.org/0000-0002-8527-2157СавкинаМ. В.SavkinaM. V.

Савкина Мария Владимировна, кандидат биологических наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Maria V. Savkina, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

savkina@expmed.ruhttps://orcid.org/0000-0002-2003-1264КривыхМ. А.KrivykhM. A.

Кривых Максим Андреевич, кандидат фармацевтических наук

Петровский б-р, д. 8, стр. 2, Москва, 127051 

Maksim A. Krivykh, Cand. Sci. (Pharm.)

8/2 Petrovsky Blvd, Moscow 127051

Krivykh@expmed.ruhttps://orcid.org/0000-0003-4624-9189ГавриловаН. А.GavrilovaN. A.

Гаврилова Наталья Андреевна, кандидат биологических наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Natalia A. Gavrilova, Cand. Sci. (Biol.)

8/2 Petrovsky Blvd, Moscow 127051

gavrilova@expmed.ruhttps://orcid.org/0000-0003-2272-2621СаяпинаЛ. В.SayapinaL. V.

Саяпина Лидия Васильевна, доктор медицинских наук

Петровский б-р, д. 8, стр. 2, Москва, 127051

Lidia V. Sayapina, Dr. Sci. (Med.)

8/2 Petrovsky Blvd, Moscow 127051

Sayapina@expmed.ruhttps://orcid.org/0000-0002-7729-9800ОбуховЮ. И.ObukhovYu. I.

Обухов Юрий Иванович

Петровский б-р, д. 8, стр. 2, Москва, 127051

Yuriy I. Obukhov

8/2 Petrovsky Blvd, Moscow 127051

Obukhov@expmed.ruhttps://orcid.org/0000-0003-4891-973XМеркуловВ. А.MerkulovV. A.

Меркулов Вадим Анатольевич, доктор медицинских наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051Трубецкая ул., д. 8, стр. 2, Москва, 119991

Vadim A. Merkulov, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 1270518/2 Trubetskaya St., Moscow 119991

merkulov@expmed.ruhttps://orcid.org/0000-0001-6472-6386БондаревВ. П.BondarevV. P.

Бондарев Владимир Петрович, доктор медицинских наук, профессор

Петровский б-р, д. 8, стр. 2, Москва, 127051

Vladimir P. Bondarev, Dr. Sci. (Med.), Professor

8/2 Petrovsky Blvd, Moscow 127051

bondarev@expmed.ruФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской ФедерацииРоссияScientific Centre for Expert Evaluation of Medicinal ProductsRussian FederationФедеральное государственное бюджетное учреждение «Научный центр экспертизы средств медицинского применения» Министерства здравоохранения Российской Федерации; Федеральное государственное автономное образовательное учреждение высшего образования «Первый Московский государственный медицинский университет им. И.М. Сеченова» Министерства здравоохранения Российской Федерации (Сеченовский Университет)РоссияScientific Centre for Expert Evaluation of Medicinal Products; I. M. Sechenov First Moscow State Medical University (Sechenov University)Russian Federation202115122021214234243Copyright © Савкина М.В., Кривых М.А., Гаврилова Н.А., Саяпина Л.В., Обухов Ю.И., Меркулов В.А., Бондарев В.П., 20212021Савкина М.В., Кривых М.А., Гаврилова Н.А., Саяпина Л.В., Обухов Ю.И., Меркулов В.А., Бондарев В.П.Savkina M.V., Krivykh M.A., Gavrilova N.A., Sayapina L.V., Obukhov Y.I., Merkulov V.A., Bondarev V.P.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.biopreparations.ru/jour/article/view/350

Инфекция, вызванная Streptococcus pneumoniae, является наиболее частой причиной высокой заболеваемости и смертности среди детей до 5 лет, людей с ослабленным иммунитетом и пожилых. Несмотря на значительный успех, одобренные пневмококковые конъюгированные и полисахаридные вакцины имеют ограниченную эффективность, обеспечивая защиту от небольшой части известных серотипов пневмококков. Быстрое распространение мультирезистентных штаммов усугубляет глобальную проблему лечения инфекционного заболевания, вызванного S. pneumoniae. При этом появление новых штаммов возбудителя диктует необходимость включения новых серотипов в состав вакцин. Ввиду этого дальнейшее совершенствование вакцин для профилактики пневмококковых инфекций является актуальной задачей. Цель работы — рассмотрение достижений в разработке пневмококковых вакцин (полисахаридных, конъюгированных, цельноклеточных), а также вакцин на основе белковых антигенов и вакцин, снабженных системой доставки антигена. В настоящее время на основе данных геномики и протеомики усовершенствованы подходы к созданию полисахаридных и белковых вакцин, а также созданию цельноклеточных вакцин, имеющих потенциал для профилактического охвата населения от различных серотипов пневмококков, не вошедших в состав зарегистрированных пневмококковых вакцин. Важное значение при разработке вакцин имеет способ доставки антигена в клетку. Наиболее перспективной стратегией усовершенствования пневмококковых вакцин является создание вакцин на основе бактериоподобных или синтетических частиц, несущих несколько антигенов, в том числе поверхностные белки пневмококка. В заключение необходимо отметить, что наиболее приоритетными пневмококковыми вакцинами являются те, которые обеспечивают широкий комплекс защиты в отношении спектра циркулирующих серотипов пневмококка и, помимо развития системного иммунного ответа, вызывают индукцию местного иммунитета.

Streptococcus pneumoniae infection is the most common cause of high morbidity and mortality among children under 5 years of age, immunocompromised people, and the elderly. Despite significant success, the approved pneumococcal conjugate and polysaccharide vaccines are of limited efficacy, providing protection against a small fraction of the known pneumococcal serotypes. The rapid spread of multidrug-resistant strains exacerbates the global challenge of treating infection caused by S. pneumoniae. At the same time, the emerging new strains dictate the need to include new serotypes into vaccines. In view of this, further improvement of vaccines for the prevention of pneumococcal infections is an urgent task. The aim of this study was to review advances in the development of polysaccharide, conjugate, whole-cell pneumococcal vaccines, as well as vaccines based on protein antigens and vaccines with an antigen delivery system. Genomics and proteomics data have helped to improve approaches to the creation of polysaccharide and protein-based vaccines, as well as whole-cell vaccines with the potential for population prophylactic coverage against various pneumococcal serotypes that are not included in the licensed pneumococcal vaccines. The method of antigen delivery to the cell is of great importance in the development of vaccines. The most promising strategy for improving pneumococcal vaccines is the creation of vaccines based on bacterium-like or synthetic particles carrying several antigens, including pneumococcal surface proteins. In conclusion, it should be noted that top-priority vaccines are those that provide a wide range of protection against circulating pneumococcal serotypes and, in addition to eliciting a systemic immune response, also induce local immunity.

Streptococcus pneumoniaeконъюгированные вакциныполисахаридные вакциныцельноклеточные вакциныпневмококковые вакцины на основе белковых антигеновпневмококковые вакциныснабженные системой доставки антигеновStreptococcus pneumoniaconjugate vaccinespolysaccharide vaccineswhole-cell vaccinesprotein-based pneumococcal vaccinespneumococcal vaccines with an antigen delivery systemРабота выполнена в рамках государственного задания ФГБУ «НЦЭСМП» Минздрава России № 056-00005-21-00 на проведение прикладных научных исследований (номер государственного учета НИР 121022000147-4).The study reported in this publication was carried out as part of a publicly funded research project No. 056-00005-21-00 and was supported by the Scientific Centre for Expert Evaluation of Medicinal Products (R&D public accounting No. 121022000147-4).ReferencesBlack RE, Cousens S, Johnson HL, Lawn JE, Rudan I, Bassani DG, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet. 2010;375(9730):1969–87. https://doi.org/10.1016/S0140-6736(10)60549-1Black RE, Cousens S, Johnson HL, Lawn JE, Rudan I, Bassani DG, et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet. 2010;375(9730):1969–87. https://doi.org/10.1016/S0140-6736(10)60549-1Wunderink RG, Waterer GW. Community-acquired pneumonia. N Engl J Med. 2014;370:543–51. https://doi.org/10.1056/NEJMcp1214869Wunderink RG, Waterer GW. Community-acquired pneumonia. N Engl J Med. 2014;370:543–51. https://doi.org/10.1056/NEJMcp1214869Kadioglu A, Weiser JN, Paton JC, Andrew PW. The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nat Rev Microbiol. 2008;6(4):288–301. https://doi.org/10.1038/nrmicro1871Kadioglu A, Weiser JN, Paton JC, Andrew PW. The role of Streptococcus pneumoniae virulence factors in host respiratory colonization and disease. Nat Rev Microbiol. 2008;6(4):288–301. https://doi.org/10.1038/nrmicro1871Masomian M, Ahmad Z, Gew LT, Poh CL. Development of next generation Streptococcus pneumoniae vaccines conferring broad protection. Vaccines. 2020;8(1):132. https://doi.org/10.3390/vaccines8010132Masomian M, Ahmad Z, Gew LT, Poh CL. Development of next generation Streptococcus pneumoniae vaccines conferring broad protection. Vaccines. 2020;8(1):132. https://doi.org/10.3390/vaccines8010132Kwambana-Adams BA, Mulholland EK, Satzke C, ISPPD group. State-of-the-art in the pneumococcal field: Proceedings of the 11th International symposium on pneumococci and pneumococcal diseases (ISPPD-11). Pneumonia. 2020;12:2. https://doi.org/10.1186/s41479-019-0064-yKwambana-Adams BA, Mulholland EK, Satzke C, ISPPD group. State-of-the-art in the pneumococcal field: Proceedings of the 11th International symposium on pneumococci and pneumococcal diseases (ISPPD-11). Pneumonia. 2020;12:2. https://doi.org/10.1186/s41479-019-0064-yHirst RA, Kadioglu A, O’callaghan C, Andrew PW. The role of pneumolysin in pneumococcal pneumonia and meningitis. Clin Exp Immunol. 2004;138(2):195–201. https://doi.org/10.1111/j.1365-2249.2004.02611.xHirst RA, Kadioglu A, O’callaghan C, Andrew PW. The role of pneumolysin in pneumococcal pneumonia and meningitis. Clin Exp Immunol. 2004;138(2):195–201. https://doi.org/10.1111/j.1365-2249.2004.02611.xShaper M, Hollingshead SK, Benjamin WH Jr, Briles DE. PspA protects Streptococcus pneumoniae from killing by apolactoferrin, and antibody to PspA enhances killing of pneumococci by apolactoferrin. Infect Immun. 2004;72(9):5031–40. https://doi.org/10.1128/IAI.72.9.5031-5040.2004Shaper M, Hollingshead SK, Benjamin WH Jr, Briles DE. PspA protects Streptococcus pneumoniae from killing by apolactoferrin, and antibody to PspA enhances killing of pneumococci by apolactoferrin. Infect Immun. 2004;72(9):5031–40. https://doi.org/10.1128/IAI.72.9.5031-5040.2004van der Poll T, Opal SM. Pathogenesis, treatment, and prevention of pneumococcal pneumonia. Lancet. 2009;374(9700): 1543–56. https://doi.org/10.1016/S0140-6736(09)61114-4van der Poll T, Opal SM. Pathogenesis, treatment, and prevention of pneumococcal pneumonia. Lancet. 2009;374(9700): 1543–56. https://doi.org/10.1016/S0140-6736(09)61114-4Andre GO, Converso TR, Politano WR, Ferraz LF, Ribeiro ML, Leite LCC, Darrieux M. Role of Streptococcus pneumoniae proteins in evasion of complement-mediated immunity. Front Microbiol. 2017;8:224. https://doi.org/10.3389/fmicb.2017.00224Andre GO, Converso TR, Politano WR, Ferraz LF, Ribeiro ML, Leite LCC, Darrieux M. Role of Streptococcus pneumoniae proteins in evasion of complement-mediated immunity. Front Microbiol. 2017;8:224. https://doi.org/10.3389/fmicb.2017.00224Mukerji R, Briles DE. New strategy is needed to prevent pneumococcal meningitis. Pediatr Infect Dis J. 2020;39(4):298–304. https://doi.org/10.1097/INF.0000000000002581Mukerji R, Briles DE. New strategy is needed to prevent pneumococcal meningitis. Pediatr Infect Dis J. 2020;39(4):298–304. https://doi.org/10.1097/INF.0000000000002581Pichichero ME. Pneumococcal whole-cell and protein-based vaccines: changing the paradigm. Expert Rev Vaccines. 2017;16(12):1181–90. https://doi.org/10.1080/14760584.2017.1393335Pichichero ME. Pneumococcal whole-cell and protein-based vaccines: changing the paradigm. Expert Rev Vaccines. 2017;16(12):1181–90. https://doi.org/10.1080/14760584.2017.1393335Klugman KP, Rodgers GL. Time for a third-generation pneumococcal conjugate vaccine. Lancet Infect Dis. 2021;21(1):14–6. https://doi.org/10.1016/S1473-3099(20)30513-2Klugman KP, Rodgers GL. Time for a third-generation pneumococcal conjugate vaccine. Lancet Infect Dis. 2021;21(1):14–6. https://doi.org/10.1016/S1473-3099(20)30513-2Huang L, Wang L, Li H, Hu Y, Ru W, Han W, et al. A phase III clinical trial to evaluate the safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine (PPV23) in healthy children, adults, and elderly. Hum Vaccin Immunother. 2019;15(1):249–55. https://doi.org/10.1080/21645515.2018.1509648Huang L, Wang L, Li H, Hu Y, Ru W, Han W, et al. A phase III clinical trial to evaluate the safety and immunogenicity of 23-valent pneumococcal polysaccharide vaccine (PPV23) in healthy children, adults, and elderly. Hum Vaccin Immunother. 2019;15(1):249–55. https://doi.org/10.1080/21645515.2018.1509648Stacey HL, Rosen J, Peterson JT, Williams-Diaz A, Gakhar V, Sterling TM, et al. Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV-15) compared to PCV-13 in healthy older adults. Hum Vaccin Immunother. 2019;15(3):530–9. https://doi.org/10.1080/21645515.2018.1532249Stacey HL, Rosen J, Peterson JT, Williams-Diaz A, Gakhar V, Sterling TM, et al. Safety and immunogenicity of 15-valent pneumococcal conjugate vaccine (PCV-15) compared to PCV-13 in healthy older adults. Hum Vaccin Immunother. 2019;15(3):530–9. https://doi.org/10.1080/21645515.2018.1532249Thompson A, Lamberth E, Severs J, Scully I, Tarabar S, Ginis J, et al. Phase 1 trial of a 20-valent pneumococcal conjugate vaccine in healthy adults. Vaccine. 2019;37(42):6201–07. https://doi.org/10.1016/j.vaccine.2019.08.048Thompson A, Lamberth E, Severs J, Scully I, Tarabar S, Ginis J, et al. Phase 1 trial of a 20-valent pneumococcal conjugate vaccine in healthy adults. Vaccine. 2019;37(42):6201–07. https://doi.org/10.1016/j.vaccine.2019.08.048Klein NP, Peyrani P, Yacisin K, Caldwell N, Xu X, Scully IL, et al. A phase 3, randomized, double-blind study to evaluate the immunogenicity and safety of 3 lots of 20-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naive adults 18 through 49 years of age. Vaccine. 2021;39(38):5428–35. https://doi.org/10.1016/j.vaccine.2021.07.004Klein NP, Peyrani P, Yacisin K, Caldwell N, Xu X, Scully IL, et al. A phase 3, randomized, double-blind study to evaluate the immunogenicity and safety of 3 lots of 20-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naive adults 18 through 49 years of age. Vaccine. 2021;39(38):5428–35. https://doi.org/10.1016/j.vaccine.2021.07.004Nagai K, Domon H, Maekawa T, Hiyoshi T, Tamura H, Yonezawa D, et al. Immunization with pneumococcal elongation factor Tu enhances serotype-independent protection against Streptococcus pneumoniae infection. Vaccine. 2019;37(1):160–8. https://doi.org/10.1016/j.vaccine.2018.11.015Nagai K, Domon H, Maekawa T, Hiyoshi T, Tamura H, Yonezawa D, et al. Immunization with pneumococcal elongation factor Tu enhances serotype-independent protection against Streptococcus pneumoniae infection. Vaccine. 2019;37(1):160–8. https://doi.org/10.1016/j.vaccine.2018.11.015Jang A-Y, Ahn KB, Zhi Y, Ji H-J, Zhang J, Han SH, et al. Serotype-independent protection against invasive pneumococcal infections conferred by live vaccine with lgt deletion. Front Immunol. 2019;10:1212. https://doi.org/10.3389/fimmu.2019.01212Jang A-Y, Ahn KB, Zhi Y, Ji H-J, Zhang J, Han SH, et al. Serotype-independent protection against invasive pneumococcal infections conferred by live vaccine with lgt deletion. Front Immunol. 2019;10:1212. https://doi.org/10.3389/fimmu.2019.01212Li Y, Wang S, Scarpellini G, Gunn B, Xin W, Wanda S-Y, et al. Evaluation of new generation Salmonella enterica serovar Typhimurium vaccines with regulated delayed attenuation to induce immune responses against PspA. Proc Natl Acad Sci USA. 2009;106(2):593–8. https://www.jstor.org/stable/40254825Li Y, Wang S, Scarpellini G, Gunn B, Xin W, Wanda S-Y, et al. Evaluation of new generation Salmonella enterica serovar Typhimurium vaccines with regulated delayed attenuation to induce immune responses against PspA. Proc Natl Acad Sci USA. 2009;106(2):593–8. https://www.jstor.org/stable/40254825Briles DE, Hollingshead SK, Nabors GS, Paton JC, Brooks-Walter A. The potential for using protein vaccines to protect against otitis media caused by Streptococcus pneumonia. Vaccine. 2000;19(Suppl 1):S87–95. https://doi.org/10.1016/S0264-410X(00)00285-1Briles DE, Hollingshead SK, Nabors GS, Paton JC, Brooks-Walter A. The potential for using protein vaccines to protect against otitis media caused by Streptococcus pneumonia. Vaccine. 2000;19(Suppl 1):S87–95. https://doi.org/10.1016/S0264-410X(00)00285-1Briles DE, Hollingshead SK, King J, Swift A, Braun PA, Park MK, et al. Immunization of humans with recombinant pneumococcal surface protein A (rPspA) elicits antibodies that passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA. J Infect Dis. 2000;182(6):1694–701. https://doi.org/10.1086/317602Briles DE, Hollingshead SK, King J, Swift A, Braun PA, Park MK, et al. Immunization of humans with recombinant pneumococcal surface protein A (rPspA) elicits antibodies that passively protect mice from fatal infection with Streptococcus pneumoniae bearing heterologous PspA. J Infect Dis. 2000;182(6):1694–701. https://doi.org/10.1086/317602Georgieva M, Kagedan L, Lu Y-J, Thompson CM, Lipsitch M. Antigenic variation in Streptococcus pneumonia PspC promotes immune escape in the presence of variant-specific immunity. mBio. 2018;9(2):e00264-18. https://doi.org/10.1128/mBio.00264-18Georgieva M, Kagedan L, Lu Y-J, Thompson CM, Lipsitch M. Antigenic variation in Streptococcus pneumonia PspC promotes immune escape in the presence of variant-specific immunity. mBio. 2018;9(2):e00264-18. https://doi.org/10.1128/mBio.00264-18Brooks-Walter A, Briles DE, Hollingshead SK. The pspC gene of Streptococcus pneumoniae encodes a polymorphic protein, PspC, which elicits cross-reactive antibodies to PspA and provides immunity to pneumococcal bacteremia. Infect Immun. 1999;67(12):6533–42. https://doi.org/10.1128/IAI.67.12.6533-6542.1999Brooks-Walter A, Briles DE, Hollingshead SK. The pspC gene of Streptococcus pneumoniae encodes a polymorphic protein, PspC, which elicits cross-reactive antibodies to PspA and provides immunity to pneumococcal bacteremia. Infect Immun. 1999;67(12):6533–42. https://doi.org/10.1128/IAI.67.12.6533-6542.1999Khan MN, Pichichero ME. CD4 T cell memory and antibody responses directed against the pneumococcal histidine triad proteins PhtD and PhtE following nasopharyngeal colonization and immunization and their role in protection against pneumococcal colonization in mice. Infect Immun. 2013;81(10):3781–92. https://doi.org/10.1128/IAI.00313-13Khan MN, Pichichero ME. CD4 T cell memory and antibody responses directed against the pneumococcal histidine triad proteins PhtD and PhtE following nasopharyngeal colonization and immunization and their role in protection against pneumococcal colonization in mice. Infect Immun. 2013;81(10):3781–92. https://doi.org/10.1128/IAI.00313-13Godfroid F, Hermand P, Verlant V, Denoël P, Poolman JT. Preclinical evaluation of the Pht proteins as potential crossprotective pneumococcal vaccine antigens. Infect Immun. 2011;79(1):238–45. https://doi.org/10.1128/IAI.00378-10Godfroid F, Hermand P, Verlant V, Denoël P, Poolman JT. Preclinical evaluation of the Pht proteins as potential crossprotective pneumococcal vaccine antigens. Infect Immun. 2011;79(1):238–45. https://doi.org/10.1128/IAI.00378-10Verhoeven D, Perry S, Pichichero ME. Contributions to protection from Streptococcus pneumoniae infection using the monovalent recombinant protein vaccine candidates PcpA, PhtD, and PlyD1 in an infant murine model during challenge. Clin Vaccine Immunol. 2014;21(8):1037–45. https://doi.org/10.1128/CVI.00052-14Verhoeven D, Perry S, Pichichero ME. Contributions to protection from Streptococcus pneumoniae infection using the monovalent recombinant protein vaccine candidates PcpA, PhtD, and PlyD1 in an infant murine model during challenge. Clin Vaccine Immunol. 2014;21(8):1037–45. https://doi.org/10.1128/CVI.00052-14Denoël P, Philipp MT, Doyle L, Martin D, Carletti G, et al. A protein-based pneumococcal vaccine protects rhesus macaques from pneumonia after experimental infection with Streptococcus pneumoniae. Vaccine. 2011;29(33):5495–501. https://doi.org/10.1016/j.vaccine.2011.05.051Denoël P, Philipp MT, Doyle L, Martin D, Carletti G, et al. A protein-based pneumococcal vaccine protects rhesus macaques from pneumonia after experimental infection with Streptococcus pneumoniae. Vaccine. 2011;29(33):5495–501. https://doi.org/10.1016/j.vaccine.2011.05.051Seiberling M, Bologa M, Brookes R, Ochs M, Go K, Ne ve u D, et al. Safety and immunogenicity of a pneumococcal histidine triad protein D vaccine candidate in adults. Vaccine. 2012;30(52): 7455–60. https://doi.org/10.1016/j.vaccine.2012.10.080Seiberling M, Bologa M, Brookes R, Ochs M, Go K, Ne ve u D, et al. Safety and immunogenicity of a pneumococcal histidine triad protein D vaccine candidate in adults. Vaccine. 2012;30(52): 7455–60. https://doi.org/10.1016/j.vaccine.2012.10.080Brookes RH, Ming M, Williams K, Hopfer R, Gurunathan S, Gallichan S, et al. Passive protection of mice against Streptococcus pneumoniae challenge by naturally occurring and vaccine-induced human anti-PhtD antibodies. Hum Vaccin Immunother. 2015;11(7):1836–9. https://doi.org/10.1080/21645515.2015.1039210Brookes RH, Ming M, Williams K, Hopfer R, Gurunathan S, Gallichan S, et al. Passive protection of mice against Streptococcus pneumoniae challenge by naturally occurring and vaccine-induced human anti-PhtD antibodies. Hum Vaccin Immunother. 2015;11(7):1836–9. https://doi.org/10.1080/21645515.2015.1039210Hermand P, Vandercammen A, Mertens E, Di Paolo E, Verlant V, Denoël P, Godfroid F. Preclinical evaluation of a chemically detoxified pneumolysin as pneumococcal vaccine antigen. Hum Vaccin Immunother. 2017;13(1):220–8. https://doi.org/10.1080/21645515.2016.1234553Hermand P, Vandercammen A, Mertens E, Di Paolo E, Verlant V, Denoël P, Godfroid F. Preclinical evaluation of a chemically detoxified pneumolysin as pneumococcal vaccine antigen. Hum Vaccin Immunother. 2017;13(1):220–8. https://doi.org/10.1080/21645515.2016.1234553Leroux-Roels G, Maes C, De Boever F, Traskine M, Rüggeberg JU, Borys D. Safety, reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults: a phase I/II randomized clinical study. Vaccine. 2014;32(50):6838–46. https://doi.org/10.1016/j.vaccine.2014.02.052Leroux-Roels G, Maes C, De Boever F, Traskine M, Rüggeberg JU, Borys D. Safety, reactogenicity and immunogenicity of a novel pneumococcal protein-based vaccine in adults: a phase I/II randomized clinical study. Vaccine. 2014;32(50):6838–46. https://doi.org/10.1016/j.vaccine.2014.02.052Odutola A, Ota MOC, Antonio M, Ogundare EO, Saidu Y, Foster-Nyarko E, et al. Efficacy of a novel, protein-based pneumococcal vaccine against nasopharyngeal carriage of Streptococcus pneumoniae in infants: a phase 2, randomized, controlled, observer-blind study. Vaccine. 2017;35(19):2531–42. https://doi.org/10.1016/j.vaccine.2017.03.071Odutola A, Ota MOC, Antonio M, Ogundare EO, Saidu Y, Foster-Nyarko E, et al. Efficacy of a novel, protein-based pneumococcal vaccine against nasopharyngeal carriage of Streptococcus pneumoniae in infants: a phase 2, randomized, controlled, observer-blind study. Vaccine. 2017;35(19):2531–42. https://doi.org/10.1016/j.vaccine.2017.03.071Verhoeven D, Xu Q, Pichichero ME. Vaccination with a Streptococcus pneumoniae trivalent recombinant PcpA, PhtD and PlyD1 protein vaccine candidate protects against lethal pneumonia in an infant murine model. Vaccine. 2014;32(26):3205–10. https://doi.org/10.1016/j.vaccine.2014.04.004Verhoeven D, Xu Q, Pichichero ME. Vaccination with a Streptococcus pneumoniae trivalent recombinant PcpA, PhtD and PlyD1 protein vaccine candidate protects against lethal pneumonia in an infant murine model. Vaccine. 2014;32(26):3205–10. https://doi.org/10.1016/j.vaccine.2014.04.004Brooks WA, Chang L-J, Sheng X, Hopfer R. Safety and immunogenicity of a trivalent recombinant PcpA, PhtD, and PlyD1 pneumococcal protein vaccine in adults, toddlers, and infants: a phase I randomized controlled study. Vaccine. 2015;33(36):4610–7. https://doi.org/10.1016/j.vaccine.2015.06.078Brooks WA, Chang L-J, Sheng X, Hopfer R. Safety and immunogenicity of a trivalent recombinant PcpA, PhtD, and PlyD1 pneumococcal protein vaccine in adults, toddlers, and infants: a phase I randomized controlled study. Vaccine. 2015;33(36):4610–7. https://doi.org/10.1016/j.vaccine.2015.06.078Visan L, Rouleau N, Proust E, Peyrot L, Donadieu A, Ochs M. Antibodies to PcpA and PhtD protect mice against Streptococcus pneumoniae by a macrophage- and complement-dependent mechanism. Hum Vaccin Immunother. 2018;14(2):489–94. https://doi.org/10.1080/21645515.2017.1403698Visan L, Rouleau N, Proust E, Peyrot L, Donadieu A, Ochs M. Antibodies to PcpA and PhtD protect mice against Streptococcus pneumoniae by a macrophage- and complement-dependent mechanism. Hum Vaccin Immunother. 2018;14(2):489–94. https://doi.org/10.1080/21645515.2017.1403698Hill S, Entwisle C, Pang Y, Joachim M, McIlgorm A, Dalton K, et al. Immunogenicity and mechanisms of action of PnuBioVax, a multi-antigen serotype-independent prophylactic vaccine against infection with Streptococcus pneumoniae. Vaccine. 2018;36(29):4255–64. https://doi.org/10.1016/j.vaccine.2018.05.122Hill S, Entwisle C, Pang Y, Joachim M, McIlgorm A, Dalton K, et al. Immunogenicity and mechanisms of action of PnuBioVax, a multi-antigen serotype-independent prophylactic vaccine against infection with Streptococcus pneumoniae. Vaccine. 2018;36(29):4255–64. https://doi.org/10.1016/j.vaccine.2018.05.122Entwisle C, Hill S, Pang Y, Joachim M, McIlgorm A, Colaco C, et al. Safety and immunogenicity of a novel multiple antigen pneumococcal vaccine in adults: a phase 1 randomised clinical trial. Vaccine. 2017;35(51):7181–6. https://doi.org/10.1016/j.vaccine.2017.10.076Entwisle C, Hill S, Pang Y, Joachim M, McIlgorm A, Colaco C, et al. Safety and immunogenicity of a novel multiple antigen pneumococcal vaccine in adults: a phase 1 randomised clinical trial. Vaccine. 2017;35(51):7181–6. https://doi.org/10.1016/j.vaccine.2017.10.076Liberman C, Takagi M, Cabrera-Crespo J, Sbrogio-Almeida ME, Dias WO, Leite LCC, Gonçalves VM. Pneumococcal whole-cell vaccine: optimization of cell growth of unencapsulated Streptococcus pneumoniae in bioreactor using animal-free medium. J Ind Microbiol Biotechnol. 2008;35(11):1441–5. https://doi.org/10.1007/s10295-008-0445-3Liberman C, Takagi M, Cabrera-Crespo J, Sbrogio-Almeida ME, Dias WO, Leite LCC, Gonçalves VM. Pneumococcal whole-cell vaccine: optimization of cell growth of unencapsulated Streptococcus pneumoniae in bioreactor using animal-free medium. J Ind Microbiol Biotechnol. 2008;35(11):1441–5. https://doi.org/10.1007/s10295-008-0445-3Lu YJ, Leite L, Gonçalves VM, Dias WO, Liberman C, Fratelli F, et al. GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis. Vaccine. 2010;28(47):7468–75. https://doi.org/10.1016/j.vaccine.2010.09.031Lu YJ, Leite L, Gonçalves VM, Dias WO, Liberman C, Fratelli F, et al. GMP-grade pneumococcal whole-cell vaccine injected subcutaneously protects mice from nasopharyngeal colonization and fatal aspiration-sepsis. Vaccine. 2010;28(47):7468–75. https://doi.org/10.1016/j.vaccine.2010.09.031Gonçalves VM, Dias WO, Campos IB, Liberman C, Sbrogio-Almeida ME, Silva EP, et al. Development of a whole cell pneumococcal vaccine: BPL inactivation, cGMP production, and stability. Vaccine. 2014;32(9):1113–20. https://doi.org/10.1016/j.vaccine.2013.10.091Gonçalves VM, Dias WO, Campos IB, Liberman C, Sbrogio-Almeida ME, Silva EP, et al. Development of a whole cell pneumococcal vaccine: BPL inactivation, cGMP production, and stability. Vaccine. 2014;32(9):1113–20. https://doi.org/10.1016/j.vaccine.2013.10.091Malley R, Lipsitch M, Stack A, Saladino R, Fleisher G, Pelton S, et al. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect Immun. 2001;69(8):4870–3. https://doi.org/10.1128/IAI.69.8.4870-4873.2001Malley R, Lipsitch M, Stack A, Saladino R, Fleisher G, Pelton S, et al. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect Immun. 2001;69(8):4870–3. https://doi.org/10.1128/IAI.69.8.4870-4873.2001Lu YJ, Yadav P, Clements JD, Forte S, Srivastava A, Thompson CM, et al. Options for inactivation, adjuvant, and route of topical administration of a killed, unencapsulated pneumococcal whole-cell vaccine. Clin Vaccine Immunol. 2010;17(6):1005–12. https://doi.org/10.1128/CVI.00036-10Lu YJ, Yadav P, Clements JD, Forte S, Srivastava A, Thompson CM, et al. Options for inactivation, adjuvant, and route of topical administration of a killed, unencapsulated pneumococcal whole-cell vaccine. Clin Vaccine Immunol. 2010;17(6):1005–12. https://doi.org/10.1128/CVI.00036-10Hogenesch H, Dunham A, Hansen B, Anderson K, Maisonneuve JF, Hem SL. Formulation of a killed whole cell pneumococcus vaccine — effect of aluminum adjuvants on the antibody and IL-17 response. J Immune Based Ther Vaccines. 2011;29(9):5. https://doi.org/10.1186/1476-8518-9-5Hogenesch H, Dunham A, Hansen B, Anderson K, Maisonneuve JF, Hem SL. Formulation of a killed whole cell pneumococcus vaccine — effect of aluminum adjuvants on the antibody and IL-17 response. J Immune Based Ther Vaccines. 2011;29(9):5. https://doi.org/10.1186/1476-8518-9-5Keech CA, Morrison R, Anderson P, Tate A, Flores J, Goldblatt D, et al. A phase 1 randomized, placebo-controlled, observer-blinded trial to evaluate the safety and immunogenicity of inactivated Streptococcus pneumoniae whole-cell vaccine in adults. Pediatr Infect Dis J. 2020;39(4):345–51. https://doi.org/10.1097/inf.0000000000002567Keech CA, Morrison R, Anderson P, Tate A, Flores J, Goldblatt D, et al. A phase 1 randomized, placebo-controlled, observer-blinded trial to evaluate the safety and immunogenicity of inactivated Streptococcus pneumoniae whole-cell vaccine in adults. Pediatr Infect Dis J. 2020;39(4):345–51. https://doi.org/10.1097/inf.0000000000002567Kim EH, Choi SY, Kwon MK, Tran TD, Park SS, Lee KJ, et al. Streptococcus pneumoniae pep27 mutant as a live vaccine for serotype-independent protection in mice. Vaccine. 2012;30:2008–19. https://doi.org/10.1016/j.vaccine.2011.11.073Kim EH, Choi SY, Kwon MK, Tran TD, Park SS, Lee KJ, et al. Streptococcus pneumoniae pep27 mutant as a live vaccine for serotype-independent protection in mice. Vaccine. 2012;30:2008–19. https://doi.org/10.1016/j.vaccine.2011.11.073Seon SH, Choi JA, Yang E, Pyo S, Song MK, Rhee DK. Intranasal immunization with an attenuated pep27 mutant provides protection from influenza virus and secondary pneumococcal infections. J Infect Dis. 2018;217:637–40. https://doi.org/10.1093/infdis/jix594Seon SH, Choi JA, Yang E, Pyo S, Song MK, Rhee DK. Intranasal immunization with an attenuated pep27 mutant provides protection from influenza virus and secondary pneumococcal infections. J Infect Dis. 2018;217:637–40. https://doi.org/10.1093/infdis/jix594Kim SJ, Seon SH, Luong TT, Ghosh P, Pyo S, Rhee DK. Immunization with attenuated non-transformable pneumococcal pep27 and comD mutant provides serotype-independent protection against pneumococcal infection. Vaccine. 2019;37:90–8. https://doi.org/10.1016/j.vaccine.2018.11.027Kim SJ, Seon SH, Luong TT, Ghosh P, Pyo S, Rhee DK. Immunization with attenuated non-transformable pneumococcal pep27 and comD mutant provides serotype-independent protection against pneumococcal infection. Vaccine. 2019;37:90–8. https://doi.org/10.1016/j.vaccine.2018.11.027Anish C, Upadhyay AK, Sehgal D, Panda AK. Influences of process and formulation parameters on powder flow properties and immunogenicity of spray dried polymer particles entrapping recombinant pneumococcal surface protein A. Int J Pharm. 2014;466:198–210. https://doi.org/10.1016/j.ijpharm.2014.03.025Anish C, Upadhyay AK, Sehgal D, Panda AK. Influences of process and formulation parameters on powder flow properties and immunogenicity of spray dried polymer particles entrapping recombinant pneumococcal surface protein A. Int J Pharm. 2014;466:198–210. https://doi.org/10.1016/j.ijpharm.2014.03.025Kunda NK, Alfagih IM, Miyaji EN, Figueiredo DB, Gonçalves VM, Ferreira DM, et al. Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles. Int J Pharm. 2015;495:903–12. https://doi.org/10.1016/j.ijpharm.2015.09.034Kunda NK, Alfagih IM, Miyaji EN, Figueiredo DB, Gonçalves VM, Ferreira DM, et al. Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles. Int J Pharm. 2015;495:903–12. https://doi.org/10.1016/j.ijpharm.2015.09.034van Roosmalen ML, Kanninga R, El Khattabi M, Neef J, Audouy S, Bosma T, et al. Mucosal vaccine delivery of antigens tightly bound to an adjuvant particle made from food-grade bacteria. Methods. 2006;38:144–9. https://doi.org/10.1016/j.ymeth.2005.09.015van Roosmalen ML, Kanninga R, El Khattabi M, Neef J, Audouy S, Bosma T, et al. Mucosal vaccine delivery of antigens tightly bound to an adjuvant particle made from food-grade bacteria. Methods. 2006;38:144–9. https://doi.org/10.1016/j.ymeth.2005.09.015Lu J, Guo J, Wang D, Yu J, Gu T, Jiang C, et al. Broad protective immune responses elicited by bacterium-like particle-based intranasal pneumococcal particle vaccine displaying PspA2 and PspA4 fragments. Hum Vaccin Immunother. 2019;15:371–80. https://doi.org/10.1080/21645515.2018.1526556Lu J, Guo J, Wang D, Yu J, Gu T, Jiang C, et al. Broad protective immune responses elicited by bacterium-like particle-based intranasal pneumococcal particle vaccine displaying PspA2 and PspA4 fragments. Hum Vaccin Immunother. 2019;15:371–80. https://doi.org/10.1080/21645515.2018.1526556Gupalova T, Leontieva G, Kramskaya T, Grabovskaya K, Kuleshevich E, Suvorov A. Development of experimental pneumococcal vaccine for mucosal immunization. PLoS One. 2019;14(6):e0218679. https://doi.org/10.1371/journal.pone.0218679Gupalova T, Leontieva G, Kramskaya T, Grabovskaya K, Kuleshevich E, Suvorov A. Development of experimental pneumococcal vaccine for mucosal immunization. PLoS One. 2019;14(6):e0218679. https://doi.org/10.1371/journal.pone.0218679Xu JH, Dai WJ, Chen B, Fan XY. Mucosal immunization with PsaA protein, using chitosan as a delivery system, increases protection against acute otitis media and invasive infection by Streptococcus pneumoniae. Scand J Immunol. 2015;81:177–85. https://doi.org/10.1111/sji.12267Xu JH, Dai WJ, Chen B, Fan XY. Mucosal immunization with PsaA protein, using chitosan as a delivery system, increases protection against acute otitis media and invasive infection by Streptococcus pneumoniae. Scand J Immunol. 2015;81:177–85. https://doi.org/10.1111/sji.12267Haryono A, Salsabila K, Restu WK, Harmami SB, Safari D. Effect of chitosan and liposome nanoparticles as adjuvant codelivery on the immunoglobulin G subclass distribution in a mouse model. J Immunol Res. 2017;2017:9125048. https://doi.org/10.1155/2017/9125048Haryono A, Salsabila K, Restu WK, Harmami SB, Safari D. Effect of chitosan and liposome nanoparticles as adjuvant codelivery on the immunoglobulin G subclass distribution in a mouse model. J Immunol Res. 2017;2017:9125048. https://doi.org/10.1155/2017/9125048Tada R, Suzuki H, Takahashi S, Negishi Y, Kiyono H, Kunisawa J, Aramaki Y. Nasal vaccination with pneumococcal surface protein A in combination with cationic liposomes consisting of DOTAP and DC-chol confers antigen-mediated protective immunity against Streptococcus pneumoniae infections in mice. Int Immunopharmacol. 2018;61:385–93. https://doi.org/10.1016/j.intimp.2018.06.027Tada R, Suzuki H, Takahashi S, Negishi Y, Kiyono H, Kunisawa J, Aramaki Y. Nasal vaccination with pneumococcal surface protein A in combination with cationic liposomes consisting of DOTAP and DC-chol confers antigen-mediated protective immunity against Streptococcus pneumoniae infections in mice. Int Immunopharmacol. 2018;61:385–93. https://doi.org/10.1016/j.intimp.2018.06.027Voß F, Kohler TP, Meyer T, Abdullah MR, van Opzeeland FJ, Saleh M, et al. Intranasal vaccination with lipoproteins confers protection against pneumococcal colonisation. Front Microbiol. 2018;9:2405. https://doi.org/10.3389/fimmu.2018.02405Voß F, Kohler TP, Meyer T, Abdullah MR, van Opzeeland FJ, Saleh M, et al. Intranasal vaccination with lipoproteins confers protection against pneumococcal colonisation. Front Microbiol. 2018;9:2405. https://doi.org/10.3389/fimmu.2018.02405

The authors declare that there are no conflicts of interest present.