Genetic evolution of influenza viruses among selected countries in Latin America, 2017–2018

Objective Since the 2009 influenza pandemic, Latin American (LA) countries have strengthened their influenza surveillance systems. We analyzed influenza genetic sequence data from the 2017 through 2018 Southern Hemisphere (SH) influenza season from selected LA countries, to map the availability of influenza genetic sequence data from, and to describe, the 2017 through 2018 SH influenza seasons in LA. Methods We analyzed influenza A/H1pdm09, A/H3, B/Victoria and B/Yamagata hemagglutinin sequences from clinical samples from 12 National Influenza Centers (NICs) in ten countries (Argentina, Brazil, Chile, Colombia, Costa Rica, Ecuador, Mexico, Paraguay, Peru and Uruguay) with a collection date from epidemiologic week (EW) 18, 2017 through EW 43, 2018. These sequences were generated by the NIC or the WHO Collaborating Center (CC) at the U.S Centers for Disease Control and Prevention, uploaded to the Global Initiative on Sharing All Influenza Data (GISAID) platform, and used for phylogenetic reconstruction. Findings Influenza hemagglutinin sequences from the participating countries (A/H1pdm09 n = 326, A/H3 n = 636, B n = 433) were highly concordant with the genetic groups of the influenza vaccine-recommended viruses for influenza A/H1pdm09 and influenza B. For influenza A/H3, the concordance was variable. Conclusions Considering the constant evolution of influenza viruses, high-quality surveillance data—specifically genetic sequence data, are important to allow public health decision makers to make informed decisions about prevention and control strategies, such as influenza vaccine composition. Countries that conduct influenza genetic sequencing for surveillance in LA should continue to work with the WHO CCs to produce high-quality genetic sequence data and upload those sequences to open-access databases.

The manuscript addresses the important topic of influenza's genetic diversity in an undersurveilled part of the world. The analyses are appropriately conducted according to standard methods, although the phylogenetic methods themselves are not especially novel. I find that the manuscript could be strengthened by providing more precision about major conclusions regarding the evolution of viruses in Latin American and their clade frequencies relative to other areas of the world. Much of this work can be done through rewriting and clarifying the discussion, but some simple additional analyses would substantially strengthen the manuscript as well.

Major comments
1. The authors state in the discussion that viruses identified in Latin America resemble the viruses that are detected globally (lines 353-355). Although the authors compare the genetic groups that they identify with the vaccine strains selected in different years, they do not provide sufficient analyses to show to what extent the viruses sequenced in Latin America resemble global genetic diversity. To address this important and central question of geographic distributions, it would be helpful to do some of the following, in declining order of difficulty and importance: a. Provide a plot of global clade frequencies to parallel the plots of clade frequencies in Latin America in Figure 6. Generating these clade frequencies directly from global sequence data may be laborious, but the authors may be able to reproduce figures from other papers or to discuss clade frequencies in Latin America in comparison to those reported globally on sites like nextstrain.org.
b. Provide a global phylogeny of influenza that includes some sequences from Latin America (subsampling the dataset would likely be necessary to conduct a more easily interpretable analysis), and label the sequences from Latin America. If these sequences are dispersed through the global tree, then this finding would strengthen the authors' argument that viruses in Latin America resemble global genetic diversity.
c. Various other studies have addressed the geographic distribution of influenza, though not necessarily with respect to Latin America in particular (one example: https://www.ncbi.nlm.nih.gov/pubmed/26053121). The authors should cite more of this relevant literature to provide additional context for their conclusions.
the early part of the 2017 Southern Hemisphere influenza season evolved and changed as compared to those that circulated at the end of the 2018 Southern Hemisphere season" (lines 350-353). This statement is imprecise and could benefit from additional clarification. Evolution could refer to the accumulation of neutral mutations, antigenic drift, competition between clades carrying distinct antigenic mutations, and many other phenomena. In the rest of their study, the authors already identified some of the specific molecular changes that occurred, and while their analyses are not powered to identify the particular evolutionary forces at work, they could make this part of the discussion more detailed and precise.

Minor comments
1. The authors should provide the standard acknowledgements table required for use of GISAID sequences.
2. Axis labels on Figure 1 (1395) is less than the numbers produced by the participating NICs and the number uploaded by the WHO CC at the US CDC (761 + 1169). Please clarify the reason for the discrepancy. Were the excluded sequences ones that had been passaged, or duplicates of other sequences, or was there some other reason?
5. When defining clades and subclades, as in lines 227 and 232-233, for example, please clarify whether and when the clades being defined are part of a standard nomenclature.
6. In lines 365, 375, 382, 391, and 410, the authors write that about the "reduction" of a virus with ferret anti-sera raised against particular viral strains. Perhaps the authors should consider using the more common and clearer term "inhibition" or "hemagglutination inhibition" instead.