Review Reports
- Xuanxuan Nian1,2,†,
- Hongbo Liu1,2,† and
- Mengyao Cai1,2,†
- et al.
Reviewer 1: Anonymous Reviewer 2: Francesco Massoni
Round 1
Reviewer 1 Report
In this review, the authors address the reemerging immunopreventable respiratory disease called pertussis. In particular, the authors revise the causes of its resurgence, current prevention strategies, and highlight the need for new vaccines. Before considering publication, the authors must revise and clarify several sections that are presented with some vagueness, imprecision, or errors.
Comments:
- Regarding current vaccines, the authors do not differentiate between acellular vaccines for the pediatric population (DTaP) and those used in the population over 7 years of age (Tdap). In pregnant women, the latter is used and not DTaP as described by the authors.
- Regarding the wP vaccine, it is still in use, and given the short duration of the immunity induced by the aP vaccines, the WHO, in its 2015 position paper, recommended continuing with the use of wP and that countries that switched to acellular vaccines for primary doses should ensure boosters. It would be interesting that the authors mentioned the WHO position paper.
- To better assess the use of each vaccine worldwide, the authors should analyze the size of the population currently using each type of vaccine in primary doses instead of analyzing the number of countries.
- The description of the immunity induced by vaccines, particularly aP vaccines, is imprecise and contains errors. DTaP does not induce a predominantly Th1/Th2 response as described. It would be interesting to include among the differences between aP and wP the memory immunity induced by each vaccine.
- The pathogen's evolution is vaguely described. The prevalence of clinical isolates of B. pertussis deficient in PRN expression was almost exclusively described in countries that use aP vaccines. The authors must include this type of information. Regarding the selection pressure of vaccines, it would be important to differentiate between aP and wP vaccines.
- The authors mention the attenuated Gamaleya vaccine but do not provide any information. It would be interesting to incorporate some data.
- Regarding the use of vaccines BPZE, clinical phase 2b data has recently been reported, and the authors should include it. The authors should indicate that this type of vaccine not only affects tetanus and diphtheria but also other components of combined vaccines such as the pentavalent and hexavalent vaccines.
- The cocoon strategy is controversial, and it would be interesting that the authors delve into the pros and cons. There are international recommendations by WHO, ACIP, GPI for different vaccination strategies that the authors should at least mention.
- Vaccination coverage is a relevant topic, and the authors should present data and comment on the impact of the COVID-19 pandemic on them.
A minor comment is that the pathogen's designation as Bordetella pertussis is made the first time, and in subsequent instances, B. pertussis should be used. The authors must review this aspect throughout the manuscript.
Author Response
Regarding current vaccines, the authors do not differentiate between acellular vaccines for the pediatric population (DTaP) and those used in the population over 7 years of age (Tdap). In pregnant women, the latter is used and not DTaP as described by the authors.
Response: Thanks for the advice, we have revised the sentence (Lines 136-138)
In 2011, the Advisory Committee on Immunization Practices (ACIP) recommended that pregnant women and persons having close contact with an infant (aged 0–12 months) be vaccinated with TdaP.
DTaP is a combination vaccine used to provide immunity against 3 serious diseases (Diphtheria, tetanus, and pertussis [whooping cough]) whereas Tdap is used to boost immunity against the same 3 diseases
Tdap contains a lower dose of vaccine than DTaP. This is because Tdap is used to just boost immunity, not build up immunity
DTaP is approved for children from age 6 weeks to under the age of 7 years. Tdap is approved for use in adults and children from age 10 years and during the third trimester of pregnancy (this provides protection against pertussis in infants from the time they are born for at least two months)
- Regarding the wP vaccine, it is still in use, and given the short duration of the immunity induced by the aP vaccines, the WHO, in its 2015 position paper, recommended continuing with the use of wP and that countries that switched to acellular vaccines for primary doses should ensure boosters. It would be interesting that the authors mentioned the WHO position paper.
Response: We appreciate the reviewer’s comments. we had put the point to lines 56-60.
World Health Organization “WHO position papers on Pertussis (2015)” recommended continuing with the use of wP and that countries that switched to aP should ensure additional booster doses and additional strategies such as maternal immunization; meanwhile, only aP-containing vaccines should be used for persons aged ≥7 years[15].
- To better assess the use of each vaccine worldwide, the authors should analyze the size of the population currently using each type of vaccine in primary doses instead of analyzing the number of countries.
Response: Thanks for the adivce, it is better for us to analyze the size of the population currently using wP and aP, but no related paper or web reported the global or different country wP and aP coverage, considering the complexity of vaccination in different regions around world, we provided coverage of the first dose DTP and 3rd DTP in the global from 2012-2022 (lines 60-64)
The global coverage of DTP (both DTaP and DTwP) ranges from 86-90% of the first DTP-containing vaccine and 81-86% of 3rd dose in 2012-2011 years, compared to the global coverage of DTP in 2012-2019, the global coverage of DTP decreased in 2020-2022, the main reason may because of COVID-19 pandemic [16]
- The description of the immunity induced by vaccines, particularly aP vaccines, is imprecise and contains errors. DTaP does not induce a predominantly Th1/Th2 response as described. It would be interesting to include among the differences between aP and wP the memory immunity induced by each vaccine.
Response: Thanks for correction, we has revised it and added the memory immunity (lines 78-85)
Natural infection and immunization with wP were associated with the induction of strong Th1 and Th17 cell response, which promoted rapid antibody responses and cell responses after DTwP vaccination[22-23]. On the other hand, aP vaccines induce higher Th2, and Tdap booster vaccination in children induced lower vaccine antigen-specific humoral, and T-helper 1 (Th1) cell responses in aP-primed compared with wP-primed[24,25]. Tissue-resident memory T cells (TRM cells) induced by wP but not aP have been reported to play an important role against B. pertussis infection[26].
- The pathogen's evolution is vaguely described. The prevalence of clinical isolates of B. pertussis deficient in PRN expression was almost exclusively described in countries that use aP vaccines. The authors must include this type of information. Regarding the selection pressure of vaccines, it would be important to differentiate between aP and wP vaccines.
Response: Thanks for the advice, we has revised it (lines 96-104)
Currently, aP is being used in more than 100 countries and regions worldwide, and B. pertussis presents antigenic drift under immune selection pressure after vaccination, and the emergence of new genotypic strains will impact the protection efficacies of the existing vaccines[30]; such as the discovery of pertactin-deficient clinical isolates and the emergence of the novel Ptx allele strain in the Ptx promoter region of pertussis toxin[31,32]. The antibody pressure to PRN under aP inoculation drove the emergence and spread of PRN-deficient strains [33]. Many studies have demonstrated the antigenic drift in B. pertussis is related to the introduction of aP[34-36].
- The authors mention the attenuated Gamaleya vaccine but do not provide any information. It would be interesting to incorporate some data.
Response: Thanks for the advice, we has added the result of GamaLPV.(lines 378-382)
GamLPV, another Live attenuated vaccine, has already undergone phase I/Ⅱ clinical trials (ClinicalTrials.gov Identifier, NCT03137927, NCT04036526). Both the preclinical and clinical study of GamLPV provided the better immunogenicity and protective activity.
- Regarding the use of vaccines BPZE, clinical phase 2b data has recently been reported, and the authors should include it. The authors should indicate that this type of vaccine not only affects tetanus and diphtheria but also other components of combined vaccines such as the pentavalent and hexavalent vaccines.
Response: Thanks for the advice, we has added the result of clinical phase 2b.(lines 374-377)
It was shown in phase 2b trail that BPZE1 induced broad and consistent B. pertussis-specific mucosal secretory IgA responses, whereas Tdap group in this trail did not induce consistent mucosal secretory IgA responses. BPZE1 was well tolerated, with mild reactogenicity and no serious adverse events related to study vaccination[105].
- The cocoon strategy is controversial, and it would be interesting that the authors delve into the pros and cons. There are international recommendations by WHO, ACIP, GPI for different vaccination strategies that the authors should at least mention.
Response: Thanks for the advice, we has added the recommendations by WHO(lines 147-152)
According to WHO, the overall impact and cost-effectiveness high vaccination coverage for the cocoon strategy was lower than maternal immunization which requires only one dose[55]
- Vaccination coverage is a relevant topic, and the authors should present data and comment on the impact of the COVID-19 pandemic on them.
Response: Thanks for the advice, we has added the coverage during 2012-2022 for the analysis of COVID-19 pandemic (lines 60-63)
The global coverage of DTP (both DTaP and DTwP) rang from 86-90% of 1st DTP-containing vaccine and 81-86% of 3rd dose in 2012-2011 years, compared to the global coverage of DTP in 2012-2019, the global coverage of DTP decreased in 2020-2022, the main reseason may because of COVID-19 pandemic [16]
A minor comment is that the pathogen's designation as Bordetella pertussis is made the first time, and in subsequent instances, B. pertussis should be used. The authors must review this aspect throughout the manuscript.
Response: Thanks for the advice, we has revised it.
Reviewer 2 Report
It is a narrative review with the aim of understanding the reasons for pertussis resurgence, optimizing the existing vaccination regimens, and developing novel effective pertussis vaccines.
An abstract should summarizing the content. Please, insert the results and the discussion/conclusions of your review, specifying that it is a narrative review.
The topic is no original in the field and it no address a specific gap in the field.
It's obvious and intuitive that the pertussis resurgence could be attributed to the variations in pertussis pathogens and epidemiological changes under vaccine selection pressure or that the vaccination policies should be optimized by establishing pertussis monitoring protocols, strengthening the pertussis monitoring, …
About new vaccines it has the limitation (poor reproducibility) of a narrative review and so the work is a poor scientifically sound but high informative sound and it appears interesting and well written.
The references and the tables are appropriate.
Author Response
It is a narrative review with the aim of understanding the reasons for pertussis resurgence, optimizing the existing vaccination regimens, and developing novel effective pertussis vaccines.
An abstract should summarizing the content. Please, insert the results and the discussion/conclusions of your review, specifying that it is a narrative review.
Response: Thanks for the advice, we has revised the abstract as:
Pertussis (Pertussis or Whooping cough) is a respiratory disease caused primarily by Bordetella pertussis, a Gram-negative bacteria. Pertussis is a relatively contagious infectious disease in people of all ages, mainly affecting newborns and infants under 2 months of age. Pertussis is undergoing a resurgence despite decades of high rates of vaccination. To better cope with the challenge of pertussis resurgence, we evaluated its possible causes and potential countermeasures in the narrative review. Expanded vaccination coverage, optimized vaccination strategies, and the development of a new pertussis vaccine may contribute to the control of pertussis.
The topic is no original in the field and it no address a specific gap in the field.
Response: The resurgence of whooping cough is a dynamic problem first identified in the 1990s. But our understanding of what lies behind the pertussis phenomenon is improving. Bassed on previous and the latest research, it is necessary for us to comprehensively and cautiously point out the influencing factors and the coping strategies that have emerged as a result in the recurrence of pertussis, and the review is necessary. For example the DTP coverage and the impact of the COVID-19 pandemic
It's obvious and intuitive that the pertussis resurgence could be attributed to the variations in pertussis pathogens and epidemiological changes under vaccine selection pressure or that the vaccination policies should be optimized by establishing pertussis monitoring protocols, strengthening the pertussis monitoring, …
Response：Thanks for the comments.
About new vaccines it has the limitation (poor reproducibility) of a narrative review and so the work is a poor scientifically sound but high informative sound and it appears interesting and well written.
Response：Thanks for the comments.
The references and the tables are appropriate.
Response：Thanks for the comments.
Round 2
Reviewer 1 Report
The manuscript has been improved but still contains impressions or incorrect data. Many statements remain vague and require further elaboration to avoid sounding erroneous.
Here are some comments:
In lines 46-47, it is stated that wP vaccines were replaced worldwide, which is not correct. Please correct.
In line 84, the authors need to improve the description of the role of the TRM population. Are they involved in preventing infection? Please revise this statement.
In lines 94-97, the use of "will" is confusing to me. Please revise.
The statement in lines 102-103 is not correct. Please revise.
The statement regarding the benefits of booster doses in adolescents in lines 135-137 should be revised. The correct statement is that although booster doses provide specific benefits for this population, their impact on the most vulnerable group, infants under 6 months, is lower. The authors should provide more precise elaboration on this topic.
In lines 137-138, vaccination every 10 years would be beneficial for which population? Please clarify
In line 176, not only IL17, but the induction of Th1 and TRM cells are also necessary.
In line 182, wP has not been almost eliminated, as many populations still use it. The authors should revise this statement.
In line 188, please replace S1 with SA, since S1 is an old nomenclature. The samefor lines 397, 400, 404, and 407.
In line 197, please add references.
In line 206, please clarify what is meant by "challenge protection."
In lines 241-242, the sentence and its relation to protection is not clear.
In line 257, the meningitis vaccine contains OMV, not its components. Please revise.
In line 259, OMV does not contain only 43 proteins. That number was identified, but OMVs have more components. Please revise.
In line 421, the cocoon strategy should be removed from this sentence.
In line 429, please add a reference.
Author Response
The manuscript has been improved but still contains impressions or incorrect data. Many statements remain vague and require further elaboration to avoid sounding erroneous.
Here are some comments:
In lines 46-47, it is stated that wP vaccines were replaced worldwide, which is not correct. Please correct.
Response：the wP in many countries has been replaced by the safer acellular pertussis (aP) for pertussis vaccination.
In line 84, the authors need to improve the description of the role of the TRM population. Are they involved in preventing infection? Please revise this statement.
Response：Thanks for the advice, we has revised this sentence as “wP vaccination was significantly more effective than aP vaccination in conferring persistent protective immunity against B. pertussis due to the respiratory tissue-resident memory T cells (TRM cells) cells inducced by wP”
In lines 94-97, the use of "will" is confusing to me. Please revise.
Response：Thanks for the advice, we has revised this sentence as “the ongoing genetic shift and gene loss of B. pertussis affected the protection efficacies of the existing vaccines”
The statement in lines 102-103 is not correct. Please revise.
Response：Thanks for the advice, we has revised this sentence as“The prevalence of clinical isolates of B. pertussis deficient in PRN expression was almost exclusively described in countries that use aP vaccines”
The statement regarding the benefits of booster doses in adolescents in lines 135-137 should be revised. The correct statement is that although booster doses provide specific benefits for this population, their impact on the most vulnerable group, infants under 6 months, is lower. The authors should provide more precise elaboration on this topic.
Response：Thanks for the advice, we has revised this sentence as“Booster immunization with pertussis at intervals of 10 years has shown good immunogenicity and safety in adolescence in clinical practice, while the impact of the booster immunization in adolescence on the most vulnerable group, infants under 6 months, is lower”
In lines 137-138, vaccination every 10 years would be beneficial for which population? Please clarify
Response：Thanks for the advice, we has revised this sentence as“Booster immunization with pertussis at intervals of 10 years has shown good immunogenicity and safety in adolescence in clinical practice”
In line 176, not only IL17, but the induction of Th1 and TRM cells are also necessary.
Response：Thanks for the advice, we has revised this sentence as“Therefore, the development of novel pertussis vaccines should focus on the increase in response spectrum and Th1, Th17, and and TRM cells mediated responses.”
In line 182, wP has not been almost eliminated, as many populations still use it. The authors should revise this statement.
Response：Thanks for the advice, we has revised this sentence as“At present, the virulence and candidate antigens optimization of existing pertussis vaccine, the optimization of antigen design and adjuvant selection, development of live attenuated vaccines, and application of novel nucleic acid vaccines may be the current and future direction of vaccine development.”
In line 188, please replace S1 with SA, since S1 is an old nomenclature. The samefor lines 397, 400, 404, and 407.
In line 197, please add references.
Response：Thanks for the advice, the reference was [64] SEUBERT A, D'ORO U, SCARSELLI M, PIZZA M. Genetically detoxified pertussis toxin (PT-9K/129G): implications for immunization and vaccines [J]. Expert Rev Vaccines, 2014, 13(10): 1191–1204.
In line 206, please clarify what is meant by "challenge protection."
Response：Challenge means infection in animal model, we has revised it as , “the increased immune response provide protection against the B. pertussis challenge”
In lines 241-242, the sentence and its relation to protection is not clear.
Response：Thanks for the advice, we has revised this sentence as“Of these, the content of surface-exposed bordetella intermediate protein A (BipA) was the most abundant, surface-exposed protein, mice model proved that antibodies to BipA were found to efficiently opsonize bacteria”
In line 257, the meningitis vaccine contains OMV, not its components. Please revise.
Response：Thanks for the advice, we has revised this sentence as“OMVs have been used in two meningitis vaccines”
In line 259, OMV does not contain only 43 proteins. That number was identified, but OMVs have more components. Please revise.
Response：Thanks for the advice, we has revised this sentence as“43 proteins of pertussis OMVs has been identified, such as PT, PRN, ACT-Hly, LOS, and other outer membrane or periplasmic proteins”
In line 421, the cocoon strategy should be removed from this sentence.
Response：Thanks for the advice, we has revised this sentence as“Increasing the number of immunizations, the vaccination regimen for pregnant women are only expedient measures at present.”
In line 429, please add a reference.
Response：Thanks for the advice, “In addition to the traditional antigens, PT, FHA, PRN, and Fim2/3, the new antigens explored (such as BF, BipA, ACTΔ, etc.) as well as OMV pertussis vaccines have the potential to be used in combination with tetanus and diphtheria vaccines, turning them into the novel pertussis-diphtheria-tetanus combined vaccines[65, 67,73, 81].