Review History


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Summary

  • The initial submission of this article was received on September 8th, 2016 and was peer-reviewed by 3 reviewers and the Academic Editor.
  • The Academic Editor made their initial decision on September 19th, 2016.
  • The first revision was submitted on November 19th, 2016 and was reviewed by 3 reviewers and the Academic Editor.
  • The article was Accepted by the Academic Editor on December 2nd, 2016.

Version 0.2 (accepted)

· · Academic Editor

Accept

The authors have properly addressed all the comments made by the reviewers.

·

Basic reporting

The modifications meet my concerns.

Experimental design

The modifications meet my concerns

Validity of the findings

no comments

Comments for the author

no new comments

Reviewer 2 ·

Basic reporting

The addition of the sheet named ‘Log’ to the raw data file is greatly appreciated. I still feel that a final check of the grammar is required, for instance the sentence beginning on Line 393, although this is not required to pass the editorial criteria.

Experimental design

The authors have provided further details of the mathematical model for obtaining half-lives, which will be appreciated by readers. They have also added in the implications of the potential batch effect.

Validity of the findings

The conclusion of the manuscript is well supported by the authors’ findings, and the findings themselves are valid.

Comments for the author

The authors have adequately revised their manuscript. Note the authors said they had added a positivity cut-off line for the panels in Figure 2; this isn’t reflected in the Figure 2 I have been sent.

Reviewer 3 ·

Basic reporting

The authors have addressed all the comments made by this reviewer.

Experimental design

No comments.

Validity of the findings

No comments.

Comments for the author

No comments.

Version 0.1 (original submission)

· · Academic Editor

Minor Revisions

Your manuscript has been assessed by three expert reviewers. Based on their reports, and my own assessment, I am pleased to inform you that it is potentially acceptable for publication, once you have carried out some essential revisions suggested by them. Please provide more details about antibody responses to P. falciparum antigens across the manuscript.

·

Basic reporting

This manuscript address an important but often not reported issue in that it investigates the T cell memory to malaria antigens during a time period of maleria reduction. The basic reporting is sound and the paper is generally well written with all the relevant data included in the manuscript or as supplemental data.

Experimental design

The experimental design is very straightforward and satisfactory as IFN-g expression in response to specific peptide stimulation is a very common approach used towards understanding if a host was exposed to a specific pathogen.

Validity of the findings

The findings are very relevant to the possible strategy for utilizing malaria vaccines as they become available for testing. Conclusions are reasonable, given the data and appropriate speculation about the possible need for boosters is included.

Comments for the author

This is a very straightforward paper that investigates the memory of a response to malaria antigens during a period of low malaria transmission. The data is straightforward and consistent with a model that would possibly require booster shots that would strengthen the host immune response. I only have a few comments:

1. The authors state the lack of any sex bias but did they compare the sexes within the different age groups?
2. The population was healthy at the start but were there any later infections that might have impacted the results?
3. How were cutoff IFN levels for individual peptides determined?

Reviewer 2 ·

Basic reporting

There are a number of typographical errors in the manuscript – it is suggested that the authors carefully re-read their manuscript and fix these errors to improve the language and readability. The introduction is otherwise well written, clear and easy to understand. Past literature has been adequately cited, although it is recommended that the more recent version of the WHO world malaria report be used. The structure of the manuscript confirms to PeerJ standards. The figures and tables are relevant; some suggestions for improvement have been made (see General Comments). The raw data has been provided, however further information should be included to make this easier to understand i.e. include another sheet in the excel files that provides a description for what each of the variables/headers means.

Experimental design

Overall, the study has a clear research question on the longevity of antigen-specific IFN-y responses following interrupted malaria transmission. This topic will be of interest to the malaria immuno-epidemiology and vaccine fields.

It would have been preferable if the authors had tested IFN-y levels for each individual at all time-points on the one plate. They have tried to account for this by measuring the batch effect. However, they have failed to discuss the results of this experiment. Given its importance this should be discussed, even if just briefly in the results section.

Half-lives have been calculated from a start-point when there had already been no malaria exposure for approximately one-year. Hence the IFN-y responses may have already declined significantly since the last exposure. This may result in some variability of the estimate compared to the true IFN-y half-life responses for these antigens. I think the methodology for obtaining the estimated half-lives should be introduced in more detail, either in the materials and methods or results sections.

Validity of the findings

The conclusion of the manuscript is well supported by the authors’ findings, and the findings themselves are valid.

Comments for the author

Introduction
Line 67-69. If studies have suggested the breadth and magnitude of IFN-y responses reduce quickly upon resolution of infection, it would suggest to me that IFN-y responses are more markers of current or recent exposure, not past exposure (as stated in Line 69). ‘Past exposure’ does not define very well how far in the past you mean.

Materials and methods
Line 113. Should include the ethics approval numbers.
Line 121. Define PBMC, peripheral blood mononuclear cells.
Line 122. Also state the median/mean age.
Line 125. Was clinical malaria assessed weekly during the entire study period, i.e. April 2008-April 2009? This is not clear. Were the individuals with symptoms (referred to the local health facilities) tested for malaria, or only at the three visits?
Line 138. Define PHA. I don’t think the details on PBMC culturing are needed here, given this is explained in detail in section 2.5.
Line 145. Define MB2. Which antigen is this?
Section 2.3. Would the peptide information be simpler to read in a table format?

Results
Line 225. I assume this refers to ‘prevalence of seropositivity’ of IgG antibodies to CSP remained unchanged. This should be clarified.
Line 228. I could not locate supplementary table 1 in the materials provided.
Figure 2. Suggest adding in the positivity cut-offs as a line on each graph.
Table 1. The estimated half-lives could be given in days or months, given they are all less than 1 year.

Discussion
Line 276. The results of the antibody ELISA measurements should be mentioned here, given the reason for doing this was to support the assumption that there was no/limited exposure to malaria parasites during the study period.
Line 305. It is interesting that the responses decreased most dramatically in the first 6 months of the study. This potentially suggests that the decay in IFN-y responses is not simply linear, but maybe biphasic, as has been shown for antibody responses (i.e. White MT et al 2014 BMC Med).
Line 310. Were any of the same samples used? It would be interesting to compare the IFN-y responses tested using the two different assays in the same population.
Line 330. Review this sentence: ‘It is notable…’. The grammar needs to be checked to make sure the meaning is clear.
Line 335. Could this also be an effect of comparing individuals from non-malaria endemic areas and malaria endemic areas? For example, often vaccines perform better in trials of individuals from non-malaria endemic regions.

Reviewer 3 ·

Basic reporting

See comments below.

Experimental design

See comments below.

Validity of the findings

See comments below.

Comments for the author

Ayieko et al. aimed to test the specific IFN-gama response in a big cohort of individuals living in an area where malaria transmission was interrupted for more than a year. Three blood collections were performed in one year-interval, and the IFN-g response against six different Plasmodium antigens derived from pre-erythrocytic and erythrocytic phases was tested. During the study period, the incidence of malaria in the area was extremely low (less than 1%). The authors show a significant drop in the % of specific IFN-g positive responses over time.

The paper is well written and is easy to follow. The results add new information on specific IFN-g immune responses in areas where Plasmodium falciparum malaria transmission has been interrupted. This is relevant because IFN-g production has been correlated with protection against malaria, and a drop on this response may lead to increased risk of malaria acquisition, especially in the context of an anti-malaria vaccine. It is important to mention that the authors carefully discuss some articles that reached different conclusions and try to point out the differences among the studies. Overall, this paper adds interesting information on the dynamics of IFN-g responses in areas that may have malaria transmission interrupted for some time.

Minor comments:

1. I could not find Supplementary Table 1 in the submitted material.
2. ELISAs were performed with CSP and schizont extract. Please provide information on both. Which CSP was used? Recombinant protein produced in bacteria? From which Plasmodium clone? What was the concentration added per well? And how was the schizont extract prepared? What was the concentration used in the ELISAs? This information should be added to the materials and methods section.

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