Epidemiology of Pertussis After the COVID-19 Pandemic: Analysis of the Factors Involved in the Resurgence of the Disease in High-, Middle-, and Low-Income Countries

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In the following lines I provide you with my comments on your review with title: Epidemiology of pertussis after the COVID-19 pandemic: analysis of the factors involved in the resurgence of the disease in 3 high-, middle-, and low-income countries

The review would benefit from a clearer comparison of pertussis incidence rates before and after the COVID-19 pandemic. Given that incidence rates significantly declined during the pandemic due to public health measures and enhanced hygiene practices, a detailed analysis of this trend would provide valuable insights into the epidemiology of pertussis during this period.

The observation that high-income countries (HICs) reported higher incidence rates of pertussis compared to middle- and low-income countries (MICs, LICs) seems to contradict the theory that vaccine coverage rates (VCRs) are directly associated with the resurgence of pertussis. It would be beneficial to explore this discrepancy further, possibly by considering factors such as differences in vaccine types, surveillance sensitivity, or public health reporting systems.

The review does not clearly differentiate the immune responses elicited by whole-cell pertussis (wP) vaccines versus acellular pertussis (aP) vaccines. If the resurgence of pertussis in high-income countries is being linked to the type of vaccine used, it is important to include a discussion on the efficacy of each vaccine type based on scientific data. This would strengthen the argument and provide a clearer understanding of how vaccine type may influence disease resurgence.

The review lightly touches on the morbidity and mortality of pertussis in the post-COVID-19 era. However, it predominantly focuses on incidence rates, which are noted to be higher among older age groups. Given that infants are the most vulnerable to severe outcomes from pertussis, a more comprehensive analysis of morbidity and mortality across different age groups, particularly infants, would be valuable.

There are several grammatical errors throughout the second part of the review, particularly in the discussion section. A careful revision of the language and grammar is recommended to enhance the readability and clarity of the manuscript. The manuscript may further benefit by quoting the following reference: 10.3390/v13061143.

Comments on the Quality of English Language

My comments are included above.

Author Response

Answers - Reviewer 1

1. The review would benefit from a clearer comparison of pertussis incidence rates before and after the COVID-19 pandemic. Thanks for your suggestions. We included pertussis IR global, regional, and in selected countries, in the last 10 years.
2. Given that incidence rates significantly declined during the pandemic due to public health measures and enhanced hygiene practices, a detailed analysis of this trend would provide valuable insights into the epidemiology of pertussis during this period. The observation that high-income countries (HICs) reported higher incidence rates of pertussis compared to middle- and low-income countries (MICs, LICs) seems to contradict the theory that vaccine coverage rates (VCRs) are directly associated with the resurgence of pertussis. It would be beneficial to explore this discrepancy further, possibly by considering factors such as differences in vaccine types, surveillance sensitivity, or public health reporting systems. We agree with your comments, but we think that during discussion we mention the most relevant factors associated with outbreaks.
3. The review does not clearly differentiate the immune responses elicited by whole-cell pertussis (wP) vaccines versus acellular pertussis (aP) vaccines. Clearly there are differences in immune response to wP and aP. As we mention in III.4 Characteristics of the type of vaccine used in primary series (pg 11)
4. If the resurgence of pertussis in high-income countries is being linked to the type of vaccine used, it is important to include a discussion on the efficacy of each vaccine type based on scientific data. This would strengthen the argument and provide a clearer understanding of how vaccine type may influence disease resurgence. We believe that pertussis resurgence (both in HIC and LMIC) was not related only to the type of vaccine used and included the most relevant topics in the discussion (pg 8-13): specificities of the disease, VCR and vaccination schedules, characteristics of surveillance systems.
5. The review lightly touches on the morbidity and mortality of pertussis in the post-COVID-19 era. However, it predominantly focuses on incidence rates, which are noted to be higher among older age groups. Given that infants are the most vulnerable to severe outcomes from pertussis, a more comprehensive analysis of morbidity and mortality across different age groups, particularly infants, would be valuable. We emphasized that infants are the most vulnerable age group for pertussis complications, hospitalizations, and deaths. On pg 5, we included the information that in Europe, from Jan to April 2024, there were more than 32.000 pertussis cases and 19 pertussis deaths. In the same page there was the information about deaths by age group in Europe 58% in infants, and 42% in elderly.  And on pg 7, we discussed that the number of deaths in developing countries is higher vs HC. For example, in Peru, 144 cases and 6 deaths (CFR = 4.2%) and in Europe, CFR = 0.06% (19/32.000). We included also the most recent information for Brazil, 12 deaths among 2900 cases. As we mention, pertussis also occurs in adolescents and elderly in MIC, and included information from Brazil in 2024, when for the first time, the pertussis median age was 12 years (until last year, the median age was 1 year). The surveillance systems are different in HIC and LIC/MID, where there are limitations in making pertussis diagnosis in adolescents/adults (because lack of access to PCR, serology) and low awareness about pertussis occurrence in these groups. We have also included many references about seroepidemiologic trials showing that pertussis is common in all age groups.
6. There are several grammatical errors throughout the second part of the review, particularly in the discussion section. A careful revision of the language and grammar is recommended to enhance the readability and clarity of the manuscript. The manuscript may further benefit by quoting the following reference: 10.3390/v13061143. We done a careful revision on the language, and will share the new version in the site.

Reviewer 2 Report

Comments and Suggestions for Authors

Review to Manuscript

This review is short, well written, focused on a specific topic. The work is provided with a sufficient number of references to relevant works of other authors. However, for clarity of understanding of the text, the introduction should be written in more detail.

1. The introduction provides an overview of the key points that are covered in the subsequent study. Therefore, the introduction needs to be supplemented. Not only children but also adults are susceptible to the disease. This has been known for a long time.

1.2. What are the differences in the formation of immunity after the administration of a cellular or acellular vaccine?

1.3. Line 44 - Explain why the level of immunity decreases after vaccination.

1.4. Explain why most outbreaks occur in developed countries.

2. Compared to 2019, the number of cases of the disease is half that of 2019, taking into account the waves of refugees and various social upheavals that occurred in 2022. It is important to make a comparison with the previous year, 2020, which was the year of the epidemic (see Table 2). All comparisons should be made with the pre-epidemic period. Please justify the chosen year of comparison.

3. The effectiveness of different types of vaccines varies depending on many factors. For example, a comparison of whooping cough rates in countries with and without BCG vaccination shows that countries using DPT vaccine after BCG have a 10-fold lower whooping cough rate than countries using diphtheria, tetanus and whole-cell pertussis (DPT). More attention should be paid to country specifics - whether countries are developing their own vaccines, based on locally circulating strains, or whether countries are using imported vaccines.

7. Please remove the repeated abbreviations (line 51 and line 85).

 

8. The abstract should be expanded to include conclusions drawn from the paper's results. A response to the paper's title should be provided.

Author Response

Reviewer 2

 

This review is short, well written, focused on a specific topic. The work is provided with a sufficient number of references to relevant works of other authors. However, for clarity of understanding of the text, the introduction should be written in more detail.

Dear colleague. Thanks for your comments and valuable suggestions. Our answers are in red bellow:

1. The introduction provides an overview of the key points that are covered in the subsequent study. Therefore, the introduction needs to be supplemented. Not only children but also adults are susceptible to the disease. This has been known for a long time. In the introduction (pg 2 L5), we emphasized that pertussis affects all age groups, and that vaccines provide incomplete and non-sterilizing immunity, making boosters necessary through life (L 25-27). We also returned to this topic when presented results for Europe, USA and Canada and commented about deaths in Europe (42% in elderly) - pg 5

1.2. What are the differences in the formation of immunity after the administration of a cellular or acellular vaccine? This topic was discussed on pg 11 – L26-29: “There are clear differences in the immune response to wP and aP vaccines. Although wP  vaccines induce an immune response that appears closer in nature to that induced by natural infections and may have a greater impact on reducing respiratory tract colonization according to data in non -human primate infection models, its still unclear what is the real role of this in the epidemiology of the disease.”

1.3. Line 44 - Explain why the level of immunity decreases after vaccination. In the introduction 2, we explained that “vaccines provide incomplete and non-sterilizing immunity, making booster doses necessary through life to maintain protection.

1.4. Explain why most outbreaks occur in developed countries. We did not agree that most outbreaks occur in developed countries. As we discussed, HIC have better surveillance systems, better access to lab tests to confirm pertussis (especially in ado/adults) and in LIC and MIC, the majority of cases are reported only in children. It´s not possible to compare data from HIC with LIC and MIC. Most of LIC did not report pertussis, despite the very low VCR.  

2. Compared to 2019, the number of cases of the disease is half that of 2019, taking into account the waves of refugees and various social upheavals that occurred in 2022. It is important to make a comparison with the previous year, 2020, which was the year of the epidemic (see Table 2). All comparisons should be made with the pre-epidemic period. Please justify the chosen year of comparison. We agree, and substituted the tables 1 to 3, including the period of 10 years (2014to 2024), leaving in bold the highest IR in the period pre-pandemic , and in red bold the highest IR in the last 10 years.
3. The effectiveness of different types of vaccines varies depending on many factors. For example, a comparison of whooping cough rates in countries with and without BCG vaccination shows that countries using DPT vaccine after BCG have a 10-fold lower whooping cough rate than countries using diphtheria, tetanus and whole-cell pertussis (DPT). More attention should be paid to country specifics - whether countries are developing their own vaccines, based on locally circulating strains, or whether countries are using imported vaccines. In the last 10 years, most of vaccines that used to be produced by European based pharmaceutical companies and wP vaccine produced in some developing countries, like Brazil, were substituted by wP vaccines prequalified by WHO. The majority are produced in India, and we do not know if they are more adapted or not to strains circulating in LIC. These vaccines, as we discussed were studies in a limited number of children, and there is no efficacy data. Discussion on iten III.4 pg 11 -12.
4. Please remove the repeated abbreviations (line 51 and line 85). removed

 

8. The abstract should be expanded to include conclusions drawn from the paper's results. A response to the paper's title should be provided. We added the conclusions in the abstract according to your suggestion.

Reviewer 3 Report

Comments and Suggestions for Authors

This is a very interesting review paper. 

However, I miss one point in the discussion: why is the post-Covid rebound so high?

My opinion, based on the paper by Berbers et al (see below, and I precise that I am not a co-author), is that B. pertussis reinfections are frequent in the adult population. Covid measures did interrupt these natural boosters of the adult population, that now acts as an infection source for young children, especially below one year old.

I suggest to add some discussion about that.

One minor remark: 

Line 37: “The period of peak transmissibility” is strangely formulated. In my opinion, you mean “The peak of transmissibility…”

Ref: Berbers G, van Gageldonk P, Kassteele JV, Wiedermann U, Desombere I, Dalby T, Toubiana J, Tsiodras S, Ferencz IP, Mullan K, Griskevicius A, Kolupajeva T, Vestrheim DF, Palminha P, Popovici O, Wehlin L, Kastrin T, Maďarová L, Campbell H, Ködmön C, Bacci S, Barkoff AM, He Q; Serosurveillance Study Team. Circulation of pertussis and poor protection against diphtheria among middle-aged adults in 18 European countries. Nat Commun. 2021 May 17;12(1):2871. doi: 10.1038/s41467-021-23114-y. PMID: 34001895; PMCID: PMC8128873.

Author Response

Answer to reviewer 3.

This is a very interesting review paper. Thanks a lot for your suggestions and comments. Bellow our  answers in red.

 

1. However, I miss one point in the discussion: why is the post-Covid rebound so high? The post-COVID 19 pandemic varied a lot, country by country as showed in tables 1 to 3, that according to other reviewers’ suggestions, we modified showing the IR in the last decade (2014 to 2023). Despite the fact that few countries had reported the highest pertussis IR in 2022-2023, most of HIC use to report higher IR vs MIC/LIC. We believe that most likely the higher rates now are a combination of the previous none to low exposure to the bacteria in the last 5 years  and the absence of large outbreaks in the years before Covid-19 created a particularly large cohort of susceptible individuals to pertussis. This in addition to easier testing methods, and widespread availability of PCR and multi pathogen assays.

 

2. My opinion, based on the paper by Berbers et al (see below, and I precise that I am not a co-author), is that pertussis reinfections are frequent in the adult population. Covid measures did interrupt these natural boosters of the adult population, that now acts as an infection source for young children, especially below one year old. We agree that pertussis affect people of all age groups as we cited in the introduction (pg 2 L7), and that vaccines provide incomplete and non-sterilizing immunity (pg 2 L28-L29)

 

 

3. I suggest to add some discussion about that. We included data about pertussis in adolescents and adults especially in HIC (USA, Canada, Europe) including data about the proportion of deaths in elderly in Europe (pg 5) and the most recent information from Brazil.. Additionally, in the topic characteristics of the type of vaccine, we discussed the relevance of seroepidemiological studies that showed that pertussis occurs in adolescents and adults independently of the type of vaccine used (wP and aP). We also add some recent information from Brazil, where this year there is a pertussis outbreak with 38% of confirmed cases in adolescents, 33% in children, and 29% in adults, including elderly. We also added the reference Berbers et al (2021)

 

4. One minor remark: Line 37: “The period of peak transmissibility” is strangely formulated. In my opinion, you mean “The peak of transmissibility…” Thanks we correct it.

Reviewer 4 Report

Comments and Suggestions for Authors

The paper provides a pretty good overview of a very contemporary and important topic. The discussion concerning the type of vaccine and problems with monitoring is well presented.

 

There does not seem to be clear documentation of the reduction of vaccination in the pandemic and whether this was an important factor especially for the rebound that is being faced today. As per page 2 a decline from 86% coverage to 83% does not seem catastrophic. Some revision to elaborate on this point would be an improvement.

 

The presentation of the point made about co-infection could also be improved. RSV is mentioned but is it the only significant player? Does "only search for RSV"  mean that physicians only  make requests for RSV virology tests or that they assume RSV from clinical observations? Do the co-infections cause more severe disease?

 

A less important point is that it would be an improvement if the paper specified the survival time outside of the host instead of just describing it is as limited. The review of Kamer (doi: 10.1186/1471-2334-6-130) reports 3-5 days which does give scope for transmission from inanimate objects. Although not central to this paper a reminder that gastrointestinal infections also decreased in the pandemic would be useful for perspective.

Author Response

Answer to reviewer 4

 

The paper provides a pretty good overview of a very contemporary and important topic. The discussion concerning the type of vaccine and problems with monitoring is well presented. Thanks for your comments and suggestions. Comments in red bellow

 

1. There does not seem to be clear documentation of the reduction of vaccination in the pandemic and whether this was an important factor especially for the rebound that is being faced today. As per page 2 a decline from 86% coverage to 83% does not seem catastrophic. Some revision to elaborate on this point would be an improvement. We added a table with VCR in selected MIC/LIC as supplementary material, showing that the reduction of VCRs in these countries was > 10%. In HIC the COVID-19 pandemic had lower impact in VCR (2-3%) proving that the pertussis resurgence is not related only to VCR (or type of vaccine). As discussed in the paper, several MIC and LIC have low VCR and low pertussis IR.
2.  The presentation of the point made about co-infection could also be improved. RSV is mentioned but is it the only significant player? Does "only search for RSV"  mean that physicians only  make requests for RSV virology tests or that they assume RSV from clinical observations? Do the co-infections cause more severe disease?  There are several papers discussing the role of co-infection with virus and bacteria. In infants, RSV is the most relevant, but added some other references to show that it´s not the only one. In adults, other co-infections with COVID and influenza, for example, were detected, especially in people with co-morbidities and can worse the prognosis. A recent meta-analysis performed in adults by Krumbein et al.  Respiratory viral co-infections in patients with COVID-19 and associated outcomes: A systematic review and meta-analysis. Rev Med Virol. 2023 Jan;33(1):e2365. doi: 10.1002/rmv.2365. Epub 2022 Jun 10. PMID: 35686619; PMCID: PMC9347814, showed that in adults co-infections are also related with higher morbidity and mortality, but they did not identify B. pertussis. The prevalence of co-infections  depends on seasonality (influenza, RSV) and occurrence of outbreaks. In China, for example, the possibility of co-infection with other pathogens is higher than in countries where there is low circulation of B. pertussis and lower possibility to make the diagnosis because of lack of access to lab tests.

 

3. A less important point is that it would be an improvement if the paper specified the survival time outside of the host instead of just describing it is as limited. The review of Kamer (doi: 10.1186/1471-2334-6-130) reports 3-5 days which does give scope for transmission from inanimate objects. Although not central to this paper a reminder that gastrointestinal infections also decreased in the pandemic would be useful for perspective. These are also interesting points, but we did not mention the survival of pertussis in inanimate objects because there is no info about the real role of this short survival associated with infection. Additionally, during pandemic, the improvement of  hygienic measures (clean hands and objects), use of masks and social distance probably had more impact in reducing pertussis burden than the possibility of higher transmission associated with survival of this bacteria in inanimate objects.

 

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The paper becomes appropriate for publication after revision