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. 2021 Jan 13;29(1):32-43.e4.
doi: 10.1016/j.chom.2020.10.011. Epub 2020 Nov 18.

The Early Evolution of Oral Poliovirus Vaccine Is Shaped by Strong Positive Selection and Tight Transmission Bottlenecks

Andrew L Valesano  1 , Mami Taniuchi  2 , William J Fitzsimmons  3 , Md Ohedul Islam  4 , Tahmina Ahmed  4 , Khalequ Zaman  4 , Rashidul Haque  4 , Wesley Wong  5 , Michael Famulare  5 , Adam S Lauring  6
Affiliations

The Early Evolution of Oral Poliovirus Vaccine Is Shaped by Strong Positive Selection and Tight Transmission Bottlenecks

Andrew L Valesano et al. Cell Host Microbe. .

Abstract

The emergence of circulating vaccine-derived polioviruses through evolution of the oral polio vaccine (OPV) poses a significant obstacle to polio eradication. Understanding the early genetic changes that occur as OPV evolves and transmits is important for preventing future outbreaks. Here, we use deep sequencing to define the evolutionary trajectories of type 2 OPV in a vaccine trial. By sequencing 497 longitudinal stool samples from 271 OPV2 recipients and household contacts, we were able to examine the extent of convergent evolution in vaccinated individuals and the amount of viral diversity that is transmitted. In addition to rapid reversion of key attenuating mutations, we identify strong selection at 19 sites across the genome. We find that a tight transmission bottleneck limits the onward transmission of these early adaptive mutations. Our results highlight the distinct evolutionary dynamics of live attenuated virus vaccines and have important implications for the success of next-generation OPV.

Keywords: evolution; live vaccines; poliovirus; sequencing; transmission bottlenecks; vaccine evolution.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

Figures

None
Graphical abstract
Figure 1
Figure 1
Overview of Study and Sequence Data (A) Schematic of study design and sample processing. The clinical trial had three arms with lead-up vaccination as indicated. tOPV, trivalent OPV; bOPV, bivalent OPV; IPV, inactivated polio vaccine. All individuals (n = 788) then received mOPV2. Stool samples were collected weekly from mOPV2 recipients and household contacts (HHC). Only 52 household contacts had detectable shedding of OPV2. Total nucleic acid (TNA) was extracted from stools. Poliovirus genomes were amplified from each sample as four overlapping RT-PCR amplicons. For each sample, these amplicons were pooled and prepared for sequencing. (B) Line graph of sequencing coverage of four selected samples in three coverage groups. Log10 of coverage depth on the y axis and genome position on the x axis. One variant-quality sample shown in red, one consensus-quality sample shown in dark blue, and two partial-genome samples shown in light blue. Amplicons are shown as black bars (top). Dotted lines show cutoffs at 200× and 10× used for defining coverage groups. (C) Coverage groups of samples sequenced in this study. Each sample is shown as a point with OPV2 copies per gram of stool on the y axis and weeks post-vaccination on the x axis. Pie charts above each week indicate the proportion of samples with variant-quality data (red), consensus quality data (dark blue), partial genome sequence data (light blue), and no data (gray). The region in between the dotted lines shows the samples that were sequenced in duplicate.
Figure 2
Figure 2
Within-Host Diversity in 101 Variant-Quality Samples from mOPV2 Vaccine Recipients (A) Minor iSNV shown as points, with frequency on the y axis and genome position on the x axis. Non-coding iSNV are shown in light blue, nonsynonymous iSNV in yellow, and synonymous iSNV in dark blue. (B) Number of minor iSNV (y axis) versus log10 of genome copies per gram of stool (x axis). Color of each point is shown by the week post-vaccination of sample collection. (C) Histogram of minor iSNV in polyprotein by frequency with bin width of 0.05. Nonsynonymous iSNV are shown in yellow and synonymous iSNV in dark blue. (D) Histogram of minor iSNV by protein-coding region in the polyprotein. Nonsynonymous iSNV are shown in yellow and synonymous iSNV in dark blue.
Figure 3
Figure 3
Selection of Gatekeeper Mutations in Vaccine Recipients (A) Frequency of A481G, VP1-143X, and U398C by time from vaccination. Each point represents one sample, and boxplots are shown for weeks with five or more data points. Boxplots represent the median and 25th and 75th percentiles, with whiskers extending to the most extreme point within the range of the median ±1.5-times the interquartile range. (B) Frequency of A481G, VP1-143X, and U398C by time from vaccination. Each point represents one sample, with lines connecting samples from the same individual. (C) Barplot showing the number of samples with the indicated residues present at a frequency of 5% or above at VP1-143. (D) Change in frequency per week of three gatekeeper mutations prior to reaching fixation. Boxplots represent the median and 25th and 75th percentiles, with whiskers extending to the most extreme point within the range of the median ±1.5-times the interquartile range.
Figure 4
Figure 4
Mutations Arising in Multiple mOPV2 Vaccine Recipients (A) Stacked barplot of the number of mutations identified (y axis) by the number of individuals with each mutation (x axis). Mutations in ≥3 individuals were statistically significant by permutation test, see text. Colors show the category of each mutation. (B and C) (B) Structure of type 2 poliovirus capsid pentamer (PDB: 1EAH) and side view (C), where highlighted residues are color-coded by number of mOPV2 vaccine recipients with nonsynonymous substitutions at that amino acid site.
Figure 5
Figure 5
Shared Viral Diversity across Transmission Pairs and Transmission Bottleneck (A) iSNV for four pairs of mOPV2 recipients and their household contacts. Each iSNV is plotted as a point with its frequency in the recipient (y axis) versus its frequency in the donor (x axis). (B) Presence-absence bottleneck model fit compared with data. Frequency of donor iSNV on the x axis and probability of transmission on the y axis. Transmitted iSNV are shown along the top of the plot and non-transmitted iSNV are shown along the bottom. The red line shows the probability of transmission as a function of donor frequency given the mean bottleneck estimate, with a 95% confidence interval shown by the shaded area. The blue line shows the probability of transmission given a bottleneck size of 10 unique genomes. The black points on the graph represent the probability of transmission from the measured iSNV using a sliding window of 3% width and a step size of 1.5%.
Figure 6
Figure 6
Impact of a Tight Bottleneck on Transmission of Gatekeeper Mutations (A) The probability of transmission of each gatekeeper mutation calculated from the median frequency over time in the mOPV2 recipients given the estimated bottleneck. The shaded areas represent 95% confidence intervals based on the model fit. (B) The fraction of each gatekeeper mutation present above a frequency of 5% in samples from household contacts as a function of time since the vaccination campaign.
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