# Patterns of Adaptive Evolution

> **NIH NIH R01** · UNIVERSITY OF IDAHO · 2021 · $290,667

## Abstract

Project Summary/Abstract
Vaccines are a remarkably effective way to stem the threat posed by infectious diseases. Methods that allow
rapid development of vaccines are vital. Synonymous recoding of viral genomes is a recently developed, general,
and highly promising strategy for producing live attenuated vaccines. From an antigenic perspective, the method
is ideal because it leaves the amino acid sequence of the viral proteins identical to the circulating pathogenic
form. A number of viruses have been attenuated by recoding with non-preferred codons or codon pairs, and at
least eight studies have shown protective immunization of mice. Despite its demonstrated success, there are
fundamental gaps in our knowledge: 1) no effort has been made to compare alternative recoding strategies
within the same virus in the same study; 2) several potential methods of synonymous recoding have not been
tested at all; 3) the way in which attenuation is affected by the combination of multiple recoded genes is not
known; and 4) most importantly, it is unresolved whether viruses attenuated by synonymous recoding are robust
to evolutionary recovery. This proposal tackles these gaps through three Specific Aims. Aim 1: Identify methods
of synonymous recoding and associated sequence features that can be used to generate viral genomes with a
targeted level of attenuation. This aim includes developing empirical measures of individual codon and codon
pair effects on translation rate to guide attenuation. It will also test metrics that have not previously been used
for synonymous recoding. Aim 2: Extend models of adaptive evolution to determine if the attenuating effects,
within and among genes and transcripts, combine in additive or non-additive ways. Aim 3: Determine if some
strategies of attenuation are more robust to recovery than others. This aim will focus on viruses attenuated in
multiple regions and by multiple methods, and also determine if some recovery pathways are broadly beneficial.
The project takes advantage of a bacteriophage model system with well-developed tools for genome
manipulation and methods for rapid experimental evolution relative to eukaryotic viral systems (i.e., a hundred
generations per day at very large population sizes). Achieving these three aims will yield approaches that can
be applied to other systems for designing viruses with targeted levels of attenuation that are robust to
evolutionary recovery. This research is a critical step toward the long-term goal of achieving a general strategy
for fighting infectious diseases by precision design of live vaccines that do not re-evolve virulence when used in
humans.

## Key facts

- **NIH application ID:** 10130543
- **Project number:** 5R01GM076040-13
- **Recipient organization:** UNIVERSITY OF IDAHO
- **Principal Investigator:** Craig R Miller
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $290,667
- **Award type:** 5
- **Project period:** 2006-02-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130543

## Citation

> US National Institutes of Health, RePORTER application 10130543, Patterns of Adaptive Evolution (5R01GM076040-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130543. Licensed CC0.

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