<commit_before>\documentclass[11pt,oneside,letterpaper]{article}

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%%% TITLE %%%
\title{\vspace{2cm} \Large \bf 
Seasonal influenza circulation patterns and future projections
}

\author[1]{<NAME>}
\author[2]{<NAME>}

\affil[1]{Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.}
\affil[2]{Max Planck Institute for Developmental Biology, T\"ubingen, Germany.}

\date{February 16, 2016}

\begin{document}

\maketitle

\tableofcontents

\pagebreak

%%% A/H3N2 %%%
\section*{A/H3N2}
\addcontentsline{toc}{section}{A/H3N2}

\textbf{We expect clade 3c2.a viruses to continue to predominate over 3c3.a and 3c3.b viruses. Diversity within 3c2.a is beginning to accrue with the emergence of several clades of appreciable frequency, the most notable of which is the 171K/77V clade that has very recently risen to high frequency.}

Throughout 2015, clade 3c2.a viruses predominated over 3c3.a and 3c3.b viruses (Fig.\ \ref{H3N2_clades}). The only exception to this trend has been the recent reemergence of 3c3.a viruses in Europe. However, this clade of European 3c3.a viruses lacks recent amino acid substitutions relative to the 3c3.a parent. Thus it appears that the reemergence of 3c3.a viruses in Europe is due to epidemiological factors, rather than genetic factors. In addition, we estimate that 3c2.a viruses still predominate in Europe over 3c3.a viruses despite their recent uptick and 3c3.a isolates have been declining in recent weeks.

\begin{figure}[h!]
	\centering		
	\includegraphics[width=0.9\textwidth]{../figures/feb-2016/H3N2_clades.png}
	\caption{\textbf{Frequency trajectories of H3N2 clades.} 
	}
	\label{H3N2_clades}
\end{figure}

Within clade 3c2.a, there have emerged multiple circulating amino acid variants including HA1:114T, HA1:142K/197R and (HA1:171K, HA2:77V/155E) (Fig.\ \ref{H3N2_3c2a_tree}). This last clade corresponds to HA1:171K/406V/484E. The substitution 171K has emerged twice within 3c3.a. The earlier substitution did not spread far, however, the recent substitution has occurred alongside HA2:77V/155E and is present in more recent viral isolates.

\begin{figure}[h!]
	\centering		
	\includegraphics[width=0.8\textwidth]{../figures/feb-2016/H3N2_3c2a_tree.png}
	\caption{\textbf{H3N2 / 3c2.a phylogeny colored by genotype.} 
	}
	\label{H3N2_3c2a_tree}
\end{figure}

These variants show varying dynamics (Fig.\ \ref{H3N2_mutations}). The 114T variant peaked in frequency around July 2015 and similarly the 142K variant has been around for more than a year with a low but even geographic distribution. Consequently, we expect neither of these variants to be under strong positive selection. The T160K substitution is observed scattered within clade 3c2.a and overrepresented in sequences obtained from cultured virus. However, we observe a recent rapid increase in frequency of (HA1:171K, HA2:77V/155E) especially in Asia and North America. This has been the fastest growing variant within 3c2.a that we have observed. This clade also shows rapid phylogenetic branching \cite{neher2014predicting}, corroborating its rapid rise. Barring substantial changes in other clades, we predict the (HA1:171K, HA2:77V/155E) variant to dominate.

\begin{figure}[h!]
	\centering		
	\includegraphics[width=0.9\textwidth]{../figures/feb-2016/H3N2_mutations.png}
	\caption{\textbf{Frequency trajectories of 3c2.a subclades.} 
	}
	\label{H3N2_mutations}
\end{figure}

Due to poorly performing HI assays on 3c2.a samples and the lack of recent data, antigenic diversity within 3c2.a is hard to assess. The data available to us do not suggest significant antigenic evolution. Here we show recent antigenic data using sera against A/HongKong/5738/2014 from the Crick Worldwide Influenza Centre alongside model fits \cite{neher2015prediction} (Fig.\ \ref{H3N2_HI}). Cooler color indicate greater antigenic similarity. Note that we lack HI data for (HA1:171K, HA2:77V/155E) viruses.

\begin{figure}[h!]
	\centering		
	\includegraphics[width=1.0\textwidth]{../figures/feb-2016/H3N2_HI.png}
	\caption{\textbf{H3N2 phylogeny colored by antigenicity.} 
	}
	\label{H3N2_HI}
\end{figure}

\clearpage
\pagebreak

%%% A/H1N1pdm %%%
\section*{A/H1N1pdm}
\addcontentsline{toc}{section}{A/H1N1pdm}

\textbf{Within clade 6b, the clade 6b.1, comprising 84N/162N/216T, has rapidly risen to predominate the H1N1pdm population in the latter half of 2015. Although there is no obvious serological evidence for antigenic novelty of 6b.1, its extremely rapid rise in frequency suggests a selective mechanism promoting its spread.}

Within clade 6b, genetic variants have begun to emerge, most notably HA1:84N/162N/216T, referred to here as clade 6b.1, and (HA1:152T, HA2:174E), referred to here as clade 6b.2 (Fig.\ \ref{H1N1pdm_tree}). The 6b.2 clade corresponds to HA1:152T/501E.

\begin{figure}[h!]<commit_msg>Update Feb report TeX.<commit_after>\documentclass[11pt,oneside,letterpaper]{article}

% graphicx package, useful for including eps and pdf graphics
\usepackage{graphicx}
\DeclareGraphicsExtensions{.pdf,.png,.jpg}

% basic packages
\usepackage{color} 
\usepackage{parskip}
\usepackage{float}

% text layout
\usepackage{geometry}
\geometry{textwidth=16.25cm} % 15.25cm for single-space, 16.25cm for double-space
\geometry{textheight=22.5cm} % 22cm for single-space, 22.5cm for double-space

% helps to keep figures from being orphaned on a page by themselves
\renewcommand{\topfraction}{0.85}
\renewcommand{\textfraction}{0.1}

% bold the 'Figure #' in the caption and separate it with a period
% Captions will be left justified
\usepackage[labelfont=bf,labelsep=period,font=small]{caption}

% review layout with double-spacing
%\usepackage{setspace} 
%\doublespacing
%\captionsetup{labelfont=bf,labelsep=period,font=doublespacing}

% cite package, to clean up citations in the main text. Do not remove.
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%\renewcommand\citeleft{(}
%\renewcommand\citeright{)}
%\renewcommand\citeform[1]{\textsl{#1}}

% Remove brackets from numbering in list of References
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%%% TOC
\usepackage{patchcmd}
\makeatletter
\patchcommand\@starttoc{\begin{quote}}{\end{quote}}
\usepackage{tocloft}
\renewcommand{\cftsecleader}{\cftdotfill{\cftdotsep}}

%%% TITLE %%%
\title{\vspace{2cm} \Large \bf 
Seasonal influenza circulation patterns and future projections
}

\author[1]{<NAME>}
\author[2]{<NAME>}

\affil[1]{Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.}
\affil[2]{Max Planck Institute for Developmental Biology, T\"ubingen, Germany.}

\date{February 16, 2016}

\begin{document}

\maketitle

\tableofcontents

\pagebreak

%%% A/H3N2 %%%
\section*{A/H3N2}
\addcontentsline{toc}{section}{A/H3N2}

\textbf{We expect clade 3c2.a viruses to continue to predominate over 3c3.a and 3c3.b viruses. Diversity within 3c2.a is beginning to accrue with the emergence of several clades of appreciable frequency, the most notable of which is the new 171K clade that has very recently risen to high frequency.}

Throughout 2015, clade 3c2.a viruses predominated over 3c3.a and 3c3.b viruses (Fig.\ \ref{H3N2_clades}). The only exception to this trend has been the recent reemergence of 3c3.a viruses in Europe. However, this clade of European 3c3.a viruses lacks recent amino acid substitutions relative to the 3c3.a parent. Thus it appears that the reemergence of 3c3.a viruses in Europe is due to epidemiological factors, rather than genetic factors. In addition, we estimate that 3c2.a viruses still predominate in Europe over 3c3.a viruses despite their recent uptick and 3c3.a isolates have been declining in recent weeks.

\begin{figure}[h!]
	\centering		
	\includegraphics[width=0.9\textwidth]{../figures/feb-2016/H3N2_clades.png}
	\caption{\textbf{Frequency trajectories of H3N2 clades.} 
	}
	\label{H3N2_clades}
\end{figure}

Within clade 3c2.a, there have emerged multiple circulating amino acid variants including HA1:114T, HA1:142K/197R and (HA1:171K, HA2:77V/155E) (Fig.\ \ref{H3N2_3c2a_tree}). This last clade corresponds to HA1:171K/406V/484E. The substitution 171K has emerged twice within 3c3.a. The earlier substitution did not spread far, however, the recent substitution has occurred alongside HA2:77V/155E and is present in more recent viral isolates. Within clade 142K/197R there is a subclade of significant size bearing 168V.

\begin{figure}[h!]
	\centering		
	\includegraphics[width=0.8\textwidth]{../figures/feb-2016/H3N2_3c2a_tree.png}
	\caption{\textbf{H3N2 / 3c2.a phylogeny colored by genotype.} 
	}
	\label{H3N2_3c2a_tree}
\end{figure}

These variants show varying dynamics (Fig.\ \ref{H3N2_mutations}). The 114T variant peaked in frequency around July 2015 and similarly the 142K variant has been around for more than a year with a low but even geographic distribution. Consequently, we expect neither of these variants to be under strong positive selection. The T160K substitution is observed scattered within clade 3c2.a and overrepresented in sequences obtained from cultured virus.

\pagebreak

We observe a recent rapid increase in frequency of (HA1:171K, HA2:77V/155E) especially in Asia and North America. This has been the fastest growing variant within 3c2.a that we have observed. This clade also shows rapid phylogenetic branching \cite{neher2014predicting}, corroborating its rapid rise. Additionally, the subclade bearing HA1:142K/197R/168V has recently risen in frequency, although not as rapidly as the (HA1:171K, HA2:77V/155E) clade. We estimate clade HA1:142K/197R/168V has gone from 1\% global frequency in March 2015 to 19\% global frequency today, while clade (HA1:171K, HA2:77V/155E) has gone from 1\% global frequency in June 2015 to 29\% global frequency today.

Barring substantial changes in other clades, we predict the (HA1:171K, HA2:77V/155E) variant to dominate.

\begin{figure}[h!]
	\centering		
	\includegraphics[width=0.9\textwidth]{../figures/feb-2016/H3N2_mutations.png}
	\caption{\textbf{Frequency trajectories of 3c2.a subclades.} 
	}
	\label{H3N2_mutations}
\end{figure}

\pagebreak

Due to poorly performing HI assays on 3c2.a samples and the lack of recent data, antigenic diversity within 3c2.a is hard to assess. The data available to us do not suggest significant antigenic evolution. Here we show recent antigenic data using sera against A/HongKong/5738/2014 from the Crick Worldwide Influenza Centre alongside model fits \cite{neher2015prediction} (Fig.\ \ref{H3N2_HI}). Cooler color indicate greater antigenic similarity. Note that we lack HI data for (HA1:171K, HA2:77V/155E) viruses. Epitope mutation count would predict that HA1:142K/197R/168V is more drifted than (HA1:171K, HA2:77V/155E) with 2 epitope mutations vs 1 epitope mutation, although this requires confirmation through HI or other antigenic characterization.

\begin{figure}[h!]
	\centering		
	\includegraphics[width=1.0\textwidth]{../figures/feb-2016/H3N2_HI.png}
	\caption{\textbf{H3N2 phylogeny colored by antigenicity.} 
	}
	\label{H3N2_HI}
\end{figure}

\clearpage
\pagebreak

%%% A/H1N1pdm %%%
\section*{A/H1N1pdm}
\addcontentsline{toc}{section}{A/H1N1pdm}

\textbf{Within clade 6b, the clade 6b.1, comprising 84N/162N/216T, has rapidly risen to predominate the H1N1pdm population in the latter half of 2015. Although there is no obvious serological evidence for antigenic novelty of 6b.1, its extremely rapid rise in frequency suggests a selective mechanism promoting its spread.}

Within clade 6b, genetic variants have begun to emerge, most notably HA1:84N/162N/216T, referred to here as clade 6b.1, and (HA1:152T, HA2:174E), referred to here as clade 6b.2 (Fig.\ \ref{H1N1pdm_tree}). The 6b.2 clade corresponds to HA1:152T/501E.

\begin{figure}[h!]
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