Peer review of: Broadly neutralizing plasma antibodies effective against autologous circulating viruses in (2019)


Reviewers' Comments: 
 
Reviewer #1: 
Remarks to the Author: 
This is a revised paper describing broadly neutralizing plasma antibodies and their characterization in 
a cohort of children from India. This revision is extensive enough that it is almost a new paper, but 
more importantly, this version is vastly improved. The authors have done a good job of addressing the 
concerns of prior reviewers. Furthermore, they have tempered some of the overreach of the prior 
version, and where they have retained strong conclusions, they have supported it with new data. 
 
The manuscript needs some copyediting; there are about a dozen places where I saw some sentences 
that could be tightened. I only have one concern remaining that needs to be addressed. 
 
Line 37: I’m not sure that the references cited support the statement that human clinical trials have 
demonstrated protection from infection with passively administered bnAbs. Certainly, animal studies 
have shown that, but the AMP trial results are not yet published. 
 
Michael Anthony Moody 
 
 
 
Reviewer #2: 
Remarks to the Author: 
The revised manuscript by Mishra et al has been revised to address both my concerns and those of a 
second reviewer, largely through the addition of mapping data and more sequencing data. The revised 
manuscript is improved with the sequence analysis improved, and many of the more tenuous 
interpretations either removed or tempered. 
 
The revised analysis of the breadth of this cohort, removing the Indian viruses, does indeed highlight 
the more average levels of breadth in this cohort, better highlighting the more interesting elite 
neutralizers. 
 
The authors have added more mapping data, as requested. Unfortunately, these experiments have not 
been able to define the true polyclonality of bNAb responses in these donors which would have 
required all plasma to be mapped with all mutants. Some of the data are hard to understand – for 
example in AIMS704, in Figs 2A and B, all viruses tested seem to be neutralized via V2, whereas in Fig 
2D, all viruses are neutralized by MPER with the exception of TRO. How do the authors explain these 
discordant data? In addition, there are technical concerns – for Figure 2B the figure suggests an 
N160K mutants were used. The mutant is well known to confer massive enhancement of neutralization 
sensitivity to HIV positive plasma. In addition, were N332K mutants really used in Figure 2C? The text 
refers to N160A and N332A – this might make more sense. The absence of controls is a concern here. 
 
The extension of the sequencing analysis is welcome addition. I would have preferred to see equal 
sampling between elite and broad neutralizers, but agree that the overall interpretation, that elite 
neutralizers show greater levels of diversity, is of interest. It seems that Figure 3A and B are showing 
different length sequences (V2C5 vs gp160) so the fact that the topologies of the trees are so similar 
is somewhat surprising. Also, despite very different branch lengths, there scale of the two trees is the 
same (0.05). Is this correct? There additional discrepancies between Figures 3 and 4 - In Figure 3, the 
smaller branch of AIMS709 shows variation, whereas the highlight plot indicates that all of these 
sequences are identical? 

 
The value of Supp Fig 7 is unclear – is this all sequences from elite neutralizers combined?