Whole-cell pneumococcal vaccines: a future-proof approach to overcoming pneumococcal serotype replacement

Vaccine Insights 2024; 3(1), 17–22

DOI: 10.18609/vac.2024.005

Published: 7 February
Viewpoint
E Brazel, M Alsharifi, L Giorgio et al.



Serotype replacement is an issue associated with currently licensed pneumococcal vaccines, all of which target the serotype-specific capsular polysaccharide. The use of pneumococcal polysaccharide vaccines and pneumococcal conjugate vaccines in particular, have profoundly reduced the burden of invasive pneumococcal disease. However, these advances are being offset by the steady rise in the incidence of disease caused by non-vaccine-covered serotypes, which may be observed soon after the introduction of capsule-based vaccines in a given region [1] [2] [3].


To address changes in serotype prevalence, there has been a need to expand the valency of pneumococcal conjugate vaccines (PCVs) in order to maintain coverage against a reasonable proportion of circulating disease-causing strains. However, these vaccines impose serotype-specific selective pressure and are inevitably poised to drive further replacement disease. The steady trend toward ever-higher valency PCVs may also come at the cost of immunogenicity, with evidence of expanded valency PCVs displaying dampened responses. Numerically lower immunoglobulin G (IgG) geometric mean concentrations were observed recently for PCV20 for those serotypes shared with PCV13 after doses three and four, suggesting that PCV serotype expansion may be approaching its limit [4]Senders S, Klein NP, Lamberth E, et al. Safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in healthy infants in the United States. Pediatr. Infect. Dis. J. 2021; 40(10), 944–951. . The selection of serotypes to include in a PCV also represents a challenge. Even if a vaccine is reformulated to include emerging serotypes, these proportions may differ at the time of their licensure. Geographical regions also display widely varied serotype distributions and selection of capsular antigens is a challenge in the absence of clear dominating serotypes common across regions [5]Cui YA, Patel H, O’Neil WM, Li S, Saddier P. Pneumococcal serotype distribution: A snapshot of recent data in pediatric and adult populations around the world. Hum. Vaccin. Immunother. 2017; 13(6), 1–13.  [6]Lochen A, Croucher NJ, Anderson RM. Divergent serotype replacement trends and increasing diversity in pneumococcal disease in high income settings reduce the benefit of expanding vaccine valency. Sci. Rep. 2020; 10(1), 18977. . These are major shortcomings that will continue to plague further expanded or alternative serotype PCVs.

A potential solution to these challenges may be found by drawing insights from naturally acquired immunity to the pneumococcus, where proteins have been shown to play an important role. In fact, studies of natural exposure to the pneumococcus suggest that capsular polysaccharide is not the dominant target of naturally acquired immunity [7]Turner P, Turner C, Green N, et al. Serum antibody responses to pneumococcal colonization in the first 2 years of life: results from an SE Asian longitudinal cohort study. Clin. Microbiol. Infect. 2013; 19(12), E551–E558. . Rates of invasive pneumococcal disease decline by age 5 years, at which time antibody responses to pneumococcal proteins have been reported to increase [8]Wilson R, Cohen JM, Reglinski M, et al. Naturally acquired human immunity to pneumococcus is dependent on antibody to protein antigens. PLoS Pathog. 2017; 13(1), e1006137. . The increase in disease incidence in older adulthood (over 65 years) also coincides with a decline in anti-protein antibodies, whereas the decline in anti-capsular IgG is far less pronounced [9]Simell B, Lahdenkari M, Reunanen A, Kayhty H, Vakevainen M. Effects of ageing and gender on naturally acquired antibodies to pneumococcal capsular polysaccharides and virulence-associated proteins. Clin. Vaccine Immunol. 2008; 15(9), 1391–1397. . As protein antigens are generally well conserved between serotypes, vaccines that bring forward acquisition in the young, and/or boost immunity to pneumococcal proteins in the elderly, are expected to provide effective broad-spectrum immunity.

Several protein-based vaccines have progressed to clinical evaluation and have been reviewed extensively elsewhere [10]Pichichero ME, Khan MN, Xu Q. Next generation protein based Streptococcus pneumoniae vaccines. Hum. Vaccin. Immunother. 2016; 12(1), 194–205.  [11]Briles DE, Paton JC, Mukerji R, Swiatlo E, Crain MJ. Pneumococcal vaccines. Microbiol. Spectr. 2019; 7(6).  [12]Li S, Liang H, Zhao SH, Yang XY, Guo Z. Recent progress in pneumococcal protein vaccines. Front. Immunol. 2023; 14, 1278346. . However, there are limitations associated with this approach. Purified protein vaccines rely on the selection of a small number of target antigens relative to the 270 surface proteins expressed on the pneumococcus [13]Morsczeck C, Prokhorova T, Sigh J, et al. Streptococcus pneumoniae: proteomics of surface proteins for vaccine development. Clin. Microbiol. Infect. 2008; 14(1), 74–81. , and these may be susceptible to immune evasion through small changes to their protein structure or by dampening their expression [14]Sempere J, Llamosi M, Del Rio Menendez I, et al. Pneumococcal choline-binding proteins involved in virulence as vaccine candidates. Vaccines (Basel) 2021; 9(2), 181.. There is also potential for large-scale manufacture of protein antigens to cause changes in protein conformation, which may impact epitopes important for vaccine efficacy. In addition, adjuvants are required to enhance the immunogenicity of protein-based vaccines [15]Lagousi T, Basdeki P, Routsias J, Spoulou V. Novel protein-based pneumococcal vaccines: assessing the use of distinct protein fragments instead of full-length proteins as vaccine antigens. Vaccines (Basel) 2019; 7(1), 9. and there are few adjuvants (such as alum, AS04, MF59, AS03, CpG, and AS01b) approved by regulatory authorities for human use. Commonly used alum adjuvants induce T helper cell 2-based responses; however, antibody isotypes associated with T helper cell 1 responses (IgG2a in mice and IgG1 in humans) are known to have high affinity to Fc receptors involved in inducing functional antibody responses with opsonophagocytic activity [17]Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 2014; 5, 520. . Despite protein-based pneumococcal vaccines having undergone significant evaluation in preclinical and clinical trials, to our knowledge, no protein vaccine has outperformed or even matched a licensed PCV using the gold standard correlate of protection, the opsonophagocytic assay (OPA). The capacity to elicit an OPA response that is not deemed inferior to existing PCVs is a key consideration for licensure of new expanded formulations, and candidate vaccines that can meet this bar will be well positioned for further progression and licensure [18]Jodar L, Butler J, Carlone G, et al. Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. Vaccine 2003; 21(23), 3265–3272. .

Another promising approach that targets non-capsular antigens is whole-cell vaccines (WCVs), comprised of inactivated and/or attenuated bacteria [19]Malley R, Lipsitch M, Stack A, et al. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect. Immun. 2001; 69(8), 4870–4873.  [20]Malley R, Morse SC, Leite LC, et al. Multiserotype protection of mice against pneumococcal colonization of the nasopharynx and middle ear by killed nonencapsulated cells given intranasally with a nontoxic adjuvant. Infect. Immun. 2004; 72(7), 4290–4292.  [21]Babb R, Chen A, Hirst TR, et al. Intranasal vaccination with gamma-irradiated Streptococcus pneumoniae whole-cell vaccine provides serotype-independent protection mediated by B-cells and innate IL-17 responses. Clin. Sci. (Lond.) 2016; 130(9), 697–710.  [22]Jwa MY, Jeong S, Ko EB, et al. Gamma-irradiation of Streptococcus pneumoniae for the use as an immunogenic whole cell vaccine. J. Microbiol. 2018; 56(8), 579–585.  [23]David SC, Laan Z, Minhas V, et al. Enhanced safety and immunogenicity of a pneumococcal surface antigen A mutant whole-cell inactivated pneumococcal vaccine. Immunol. Cell Biol. 2019; 97(8), 726–739.  [24]Chan WY, Entwisle C, Ercoli G, et al. A novel, multiple-antigen pneumococcal vaccine protects against lethal Streptococcus pneumoniae challenge. Infect. Immun. 2019; 87(3), e00846-18.  [25]Jang AY, Ahn KB, Zhi Y, et al. Serotype-independent protection against invasive pneumococcal infections conferred by live vaccine with lgt deletion. Front. Immunol. 2019; 10, 1212.  [26]Ramos-Sevillano E, Ercoli G, Felgner P, et al. Preclinical development of virulence-attenuated Streptococcus pneumoniae strains able to enhance protective immunity against pneumococcal infection. Am. J. Respir. Crit. Care Med. 2021; 203(8), 1037–1041. . Such vaccines have been utilized effectively for many years for the control of pertussis and tuberculosis in children. In addition to presenting antigens in a manner most likely to resemble the natural conformation of proteins, WCVs have the potential to elicit responses to a breadth of antigens surpassing all polysaccharide- or purified protein-based vaccine approaches. Such vaccines could provide a future-proof approach to effectively target emerging and entirely new pneumococcal serotypes that may arise. To date, however, there are few reports of WCVs eliciting robust OPA responses. It is important to note that chemical inactivation using formalin or beta-propiolactone is associated with cross-linking between proteins and reduced immunogenicity, while live attenuated vaccines pose a significant biological and health risk. The use of γ-irradiation has been reported as an effective alternative inactivation method for the development of highly immunogenic and safe WCVs [27]Alsharifi M, Mullbacher A. The gamma-irradiated influenza vaccine and the prospect of producing safe vaccines in general. Immunol. Cell Biol. 2010; 88(2), 103–104.

[28]David SC, Lau J, Singleton EV, et al. The effect of gamma-irradiation conditions on the immunogenicity of whole-inactivated Influenza A virus vaccine. Vaccine 2017; 35(7), 1071–1079. David SC, Lau J, Singleton EV, et al. The effect of gamma-irradiation conditions on the immunogenicity of whole-inactivated Influenza A virus vaccine. Vaccine 2017; 35(7), 1071–1079. , because of reduced protein damage and maintenance of the structural integrity of inactivated pathogens [29]Singleton EV, Gates CJ, David SC, et al. Enhanced immunogenicity of a whole-inactivated influenza A virus vaccine using optimised irradiation conditions. Front. Immunol. 2021; 12, 761632. . γ-irradiated vaccines have been found to mimic live pathogens in terms of stimulating both innate and adaptive responses [28]David SC, Lau J, Singleton EV, et al. The effect of gamma-irradiation conditions on the immunogenicity of whole-inactivated Influenza A virus vaccine. Vaccine 2017; 35(7), 1071–1079. .

A recent WCV that has advanced to the clinical stages of evaluation is a γ-irradiated vaccine developed by GPN Vaccines Ltd (Gamma-PN) [21]Babb R, Chen A, Hirst TR, et al. Intranasal vaccination with gamma-irradiated Streptococcus pneumoniae whole-cell vaccine provides serotype-independent protection mediated by B-cells and innate IL-17 responses. Clin. Sci. (Lond.) 2016; 130(9), 697–710.  [23]David SC, Laan Z, Minhas V, et al. Enhanced safety and immunogenicity of a pneumococcal surface antigen A mutant whole-cell inactivated pneumococcal vaccine. Immunol. Cell Biol. 2019; 97(8), 726–739. . Gamma-PN is differentiated from other WCV approaches in both design and formulation, which ultimately are associated with improved immune responses. A modification was introduced to remove a manganese import gene from the Gamma-PN vaccine strain, which was associated with enhanced survival after experimental challenge in immunized mice [23]David SC, Laan Z, Minhas V, et al. Enhanced safety and immunogenicity of a pneumococcal surface antigen A mutant whole-cell inactivated pneumococcal vaccine. Immunol. Cell Biol. 2019; 97(8), 726–739.  [30]McAllister LJ, Tseng HJ, Ogunniyi AD, et al. Molecular analysis of the PSA permease complex of Streptococcus pneumoniae. Mol. Microbiol. 2004; 53(3), 889–901. . Restriction of manganese availability is a key feature of the host innate response to an infection [31]Aggarwal S, Kumaraswami M. Managing manganese: the role of manganese homeostasis in streptococcal pathogenesis. Front. Cell Dev. Biol. 2022; 10, 921920.  and the improved protective efficacy may be attributable to changes in the antigenic profile of the vaccine strain, which better reflects that of pneumococci during an infection. A subsequent study in rabbits demonstrated that vaccination with Gamma-PN induced antibodies against a broad range of pneumococcal proteins known to be associated with natural immunity; with significant reactivity to 50 antigens reported [32]David SC, Brazel EB, Singleton EV, et al. A nonadjuvanted whole-inactivated pneumococcal vaccine induces multiserotype opsonophagocytic responses mediated by noncapsule-specific antibodies. mBio 2022; 13(5), e0236722.David SC, Brazel EB, Singleton EV, et al. A nonadjuvanted whole-inactivated pneumococcal vaccine induces multiserotype opsonophagocytic responses mediated by noncapsule-specific antibodies. mBio 2022; 13(5), e0236722., although the total number of antigens that reacted with the immune sera exceeded this number. Most critically, this study also reported positive functional antibody responses. For most serotypes tested, Gamma-PN administered with an adjuvant elicited higher OPA titers than PCV13. However, without adjuvant, Gamma-PN performed even better, eliciting OPA titers that were either comparable to or far superior to those elicited by PCV13 or pneumococcal polysaccharide vaccine (PPV)23 for various vaccine-included serotypes (6A, 23F, 11A, 22F, and 33F). Further, this vaccine also induced high OPA titers against serotypes not covered by any current licensed vaccines (9N, 15A, 23B, and 35B) [32]David SC, Brazel EB, Singleton EV, et al. A nonadjuvanted whole-inactivated pneumococcal vaccine induces multiserotype opsonophagocytic responses mediated by noncapsule-specific antibodies. mBio 2022; 13(5), e0236722.David SC, Brazel EB, Singleton EV, et al. A nonadjuvanted whole-inactivated pneumococcal vaccine induces multiserotype opsonophagocytic responses mediated by noncapsule-specific antibodies. mBio 2022; 13(5), e0236722.. This data indicated that a shift toward T helper cell 2 responses in animals vaccinated with adjuvanted Gamma-PN was associated with reduced OPA responses, highlighting the important role of T helper cell 1 responses in the ability of Gamma-PN (without adjuvant) to induce high OPA responses.

While Gamma-PN is still undergoing clinical evaluation in a Phase 1/2a trial, this broad-spectrum approach could eliminate the need to reformulate vaccines to address new serotypes. Indeed, any new serotypes that may emerge could be immediately tested for OPA responses using existing clinical trial serum samples. This future-proof approach could offer significant advantages, circumventing the need for further vaccine reformulation and extensive clinical trials. With current vaccines suffering from diminished usefulness over time and serotype replacement a growing concern, Gamma-PN may offer a solution to provide enduring and broad-spectrum protection against pneumococcal disease.

References

1. Lewnard JA, Hanage WP. Making sense of differences in pneumococcal serotype replacement. Lancet Infect. Dis. 2019; 19(6), e213–e220.  Crossref

2. Feikin DR, Kagucia EW, Loo JD, et al. Serotype-specific changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction: a pooled analysis of multiple surveillance sites. PLoS Med. 2013; 10(9), e1001517.  Crossref

3. Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease after pneumococcal vaccination. Lancet 2011; 378(9807), 1962–1973.  Crossref

4. Senders S, Klein NP, Lamberth E, et al. Safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in healthy infants in the United States. Pediatr. Infect. Dis. J. 2021; 40(10), 944–951.  Crossref

5. Cui YA, Patel H, O’Neil WM, Li S, Saddier P. Pneumococcal serotype distribution: A snapshot of recent data in pediatric and adult populations around the world. Hum. Vaccin. Immunother. 2017; 13(6), 1–13.  Crossref

6. Lochen A, Croucher NJ, Anderson RM. Divergent serotype replacement trends and increasing diversity in pneumococcal disease in high income settings reduce the benefit of expanding vaccine valency. Sci. Rep. 2020; 10(1), 18977.  Crossref

7. Turner P, Turner C, Green N, et al. Serum antibody responses to pneumococcal colonization in the first 2 years of life: results from an SE Asian longitudinal cohort study. Clin. Microbiol. Infect. 2013; 19(12), E551–E558.  Crossref

8. Wilson R, Cohen JM, Reglinski M, et al. Naturally acquired human immunity to pneumococcus is dependent on antibody to protein antigens. PLoS Pathog. 2017; 13(1), e1006137.  Crossref

9. Simell B, Lahdenkari M, Reunanen A, Kayhty H, Vakevainen M. Effects of ageing and gender on naturally acquired antibodies to pneumococcal capsular polysaccharides and virulence-associated proteins. Clin. Vaccine Immunol. 2008; 15(9), 1391–1397.  Crossref

10. Pichichero ME, Khan MN, Xu Q. Next generation protein based Streptococcus pneumoniae vaccines. Hum. Vaccin. Immunother. 2016; 12(1), 194–205.  Crossref

11. Briles DE, Paton JC, Mukerji R, Swiatlo E, Crain MJ. Pneumococcal vaccines. Microbiol. Spectr. 2019; 7(6).  Crossref

12. Li S, Liang H, Zhao SH, Yang XY, Guo Z. Recent progress in pneumococcal protein vaccines. Front. Immunol. 2023; 14, 1278346.  Crossref

13. Morsczeck C, Prokhorova T, Sigh J, et al. Streptococcus pneumoniae: proteomics of surface proteins for vaccine development. Clin. Microbiol. Infect. 2008; 14(1), 74–81.  Crossref

14. Sempere J, Llamosi M, Del Rio Menendez I, et al. Pneumococcal choline-binding proteins involved in virulence as vaccine candidates. Vaccines (Basel) 2021; 9(2), 181.  Crossref

15. Lagousi T, Basdeki P, Routsias J, Spoulou V. Novel protein-based pneumococcal vaccines: assessing the use of distinct protein fragments instead of full-length proteins as vaccine antigens. Vaccines (Basel) 2019; 7(1), 9.  Crossref

16. Kim H, Yu J, Bai D, Nahm MH, Wang P. Potentiating pneumococcal glycoconjugate vaccine PCV13 with saponin adjuvant VSA-1. Front. Immunol. 2022; 13, 1079047.  Crossref

17. Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 2014; 5, 520.  Crossref

18. Jodar L, Butler J, Carlone G, et al. Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants. Vaccine 2003; 21(23), 3265–3272.  Crossref

19. Malley R, Lipsitch M, Stack A, et al. Intranasal immunization with killed unencapsulated whole cells prevents colonization and invasive disease by capsulated pneumococci. Infect. Immun. 2001; 69(8), 4870–4873.  Crossref

20. Malley R, Morse SC, Leite LC, et al. Multiserotype protection of mice against pneumococcal colonization of the nasopharynx and middle ear by killed nonencapsulated cells given intranasally with a nontoxic adjuvant. Infect. Immun. 2004; 72(7), 4290–4292.  Crossref

21. Babb R, Chen A, Hirst TR, et al. Intranasal vaccination with gamma-irradiated Streptococcus pneumoniae whole-cell vaccine provides serotype-independent protection mediated by B-cells and innate IL-17 responses. Clin. Sci. (Lond.) 2016; 130(9), 697–710.  Crossref

22. Jwa MY, Jeong S, Ko EB, et al. Gamma-irradiation of Streptococcus pneumoniae for the use as an immunogenic whole cell vaccine. J. Microbiol. 2018; 56(8), 579–585.  Crossref

23. David SC, Laan Z, Minhas V, et al. Enhanced safety and immunogenicity of a pneumococcal surface antigen A mutant whole-cell inactivated pneumococcal vaccine. Immunol. Cell Biol. 2019; 97(8), 726–739.  Crossref

24. Chan WY, Entwisle C, Ercoli G, et al. A novel, multiple-antigen pneumococcal vaccine protects against lethal Streptococcus pneumoniae challenge. Infect. Immun. 2019; 87(3), e00846-18.  Crossref

25. Jang AY, Ahn KB, Zhi Y, et al. Serotype-independent protection against invasive pneumococcal infections conferred by live vaccine with lgt deletion. Front. Immunol. 2019; 10, 1212.  Crossref

26. Ramos-Sevillano E, Ercoli G, Felgner P, et al. Preclinical development of virulence-attenuated Streptococcus pneumoniae strains able to enhance protective immunity against pneumococcal infection. Am. J. Respir. Crit. Care Med. 2021; 203(8), 1037–1041.  Crossref

27. Alsharifi M, Mullbacher A. The gamma-irradiated influenza vaccine and the prospect of producing safe vaccines in general. Immunol. Cell Biol. 2010; 88(2), 103–104. Crossref

28. David SC, Lau J, Singleton EV, et al. The effect of gamma-irradiation conditions on the immunogenicity of whole-inactivated Influenza A virus vaccine. Vaccine 2017; 35(7), 1071–1079. Crossref

29. Singleton EV, Gates CJ, David SC, et al. Enhanced immunogenicity of a whole-inactivated influenza A virus vaccine using optimised irradiation conditions. Front. Immunol. 2021; 12, 761632.  Crossref

30. McAllister LJ, Tseng HJ, Ogunniyi AD, et al. Molecular analysis of the PSA permease complex of Streptococcus pneumoniae. Mol. Microbiol. 2004; 53(3), 889–901.  Crossref

31. Aggarwal S, Kumaraswami M. Managing manganese: the role of manganese homeostasis in streptococcal pathogenesis. Front. Cell Dev. Biol. 2022; 10, 921920.  Crossref

32. David SC, Brazel EB, Singleton EV, et al. A nonadjuvanted whole-inactivated pneumococcal vaccine induces multiserotype opsonophagocytic responses mediated by noncapsule-specific antibodies. mBio 2022; 13(5), e0236722.  Crossref

Affiliations

Erin B Brazel
Research Centre for Infectious
Diseases (RCID), and Department of
Molecular and Biomedical Sciences,
The University of Adelaide,
SA, Australia,
and
GPN Vaccines Ltd,
Yarralumla, ACT, Australia

Mohammed Alsharifi
Research Centre for Infectious
Diseases (RCID), and Department of
Molecular and Biomedical Sciences,
The University of Adelaide,
SA, Australia,
and
GPN Vaccines Ltd,
Yarralumla, ACT, Australia

Lauren Giorgio
GPN Vaccines Ltd,
Yarralumla, ACT, Australia

Timothy R Hirst
GPN Vaccines Ltd,
Yarralumla, ACT, Australia

James C Paton
Research Centre for Infectious
Diseases (RCID), and Department of
Molecular and Biomedical Sciences,
The University of Adelaide,
SA, Australia,
and
GPN Vaccines Ltd,
Yarralumla, ACT, Australia

Authorship & Conflict of Interest

Contributions: All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Acknowledgements: None.

Disclosure and potential conflicts of interest: Brazel EB, Alsharifi M, Giorgio L, Hirst TR, and Paton JC are affiliated with, or employed by, GPN Vaccines Ltd and all authors hold an equity interest in the company. EBB is a principal investigator on a sponsored research agreement between the University of Adelaide and GPN Vaccines Ltd. EBB is a co-inventor on provisional and pending patents owned by GPN Vaccines Ltd. Pa-ton JC, Alsharifi M, and Hirst TR hold a sponsored research agreement between the University of Adelaide and GPN Vaccines Ltd. The authors own stock and stock options in GPN Vaccines Ltd. Giorigo L has received the South Australian Government Research Commercialisation & Start Up Grant. The authors possess pa-tents related to matters disclosed in the article have been granted to GPN Vaccines Ltd with costs of filing, prosecution and award being paid by GPN Vaccines.

Funding declaration: EBB has received support, including travel and registration costs, to attend scientific conferences from GPN Vaccines Ltd. The authors receive consultancy payments from GPN Vaccines Ltd.

Article & Copyright Information

Copyright: Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2024 Brazel EB, Alsharifi M, Giorgio L, Hirst TR, and Paton JC. Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited; externally peer reviewed.

Revised manuscript received: Feb 1, 2024; Publication date: Feb 7, 2024.


This article is part of the Respiratory Diseases spotlight