Assessing the impact of dose on infection and vaccination outcomes
Slides: https://www.andreashandel.com/presentations/
2025-04-25
Talk Overview
- Introduction
- Role of dose for infections
- Role of dose for vaccines
- More stuff
Introduction
What we (maybe) know
- Inoculum dose is an important determinant of infection and vaccination outcomes.
- For infection, higher dose is often associated with greater risk of infection (ID50) and more severe outcomes (LD50).
- For vaccines, higher dose is assumed to increase both immunogenicity/efficacy and side effects (morbidity).
Influenza infection in humans
Norovirus infection in humans
Pasteuria ramosa infections of Daphnia magna
Mostly open questions
- If infection occurs what is the impact of dose on outcomes?
- Pathogen kinetics and shedding/transmissibility
- Symptoms/disease severity
- Immune response, protective immunity
- How exactly does dose impact vaccination outcomes?
- Efficacy
- Side effects/morbidity
- What mechanisms of interactions between pathogen/antigen and host produce observed outcomes?
Viral infection kinetics
Virus load for different infections.
Viral kinetics
Viral kinetics modeling
Uninfected cells˙U=−bUVInfected cells˙I=bUV−dII−kMMI−kTTIVirus˙V=pI−dVVMacrophages˙F=(s+gV)(M∗−M−αkMMI)−dMMT cells˙T=rTTVV+hV−dTT
Viral kinetics modeling
With the right types of immune response terms in the models, one can capture patterns seen in the data.
Impact of dose following human norovirus infections
- 6/7/6 individuals experimentally infected at low/medium/high dose.
- Followed for 96h in facility, up to 91 days at home.
- Tracking of virus, symptoms and antibodies.
- Hierarchical/mixed-effects Bayesian statistical models to quantify impact of dose.
Virus load after norovirus infection
Virus load after norovirus infection
Dose dependence of virus kinetics
Impact of dose on symptoms following norovirus infection
Impact of dose on antibodies following norovirus infection
Part 1 Summary
- Given infection occurs, dose influences virus kinetics in some instances (e.g. ADV, IBV) and has little impact in other instances (e.g., norovirus).
- Dose seems to have a minor impact on symptoms and antibody response for norovirus.
- We need to further understand the mechanisms by which dose impacts outcomes.
Part 2 - Vaccines
Background
- Amount of antigen in a vaccine is expected to impact immunogenicity/protection and side effects.
- There might be non-monotone relations between dose and outcomes.
- We don’t understand the mechanisms by which dose impacts outcomes.
Current approaches to dose choice
- A few doses are explored in phase I/II trials, one is chosen for phase III and licensure.
Example of BioNTech/Pfizer COVID Vaccine
Claim: Knowing in more detail how dose impacts host response following vaccination might help optimize vaccines.
Live HPIV (vaccine) modeling
Modeling dose and immune response
Modeling dose and immune response
Uninfected cells˙U=−bUVInfected cells˙I=bUV−dIIDead cells˙D=dIIVirus˙V=pI1+sFF−(dVV+k′AA+b′U)VInnate response˙F=pF−dFF+gF(Fmax−F)VV+hVB cells˙B=FVFV+hFgBBAntibodies˙A=rAB−dAA−kAAV
Modeling dose and immune response
Dose for HPIV vaccine
Conceptual model suggests that protection (and morbidity) could be peaked.
Inactivated influenza vaccine kinetics
Model prediction for inactivated vaccine
See also: Rhodes et al 2016 Vaccine, Rhodes et al 2019 JTB
SD versus HD Influenza Vaccines
- High-dose (HD) influenza vaccine leads to better protection compared to standard-dose (SD) vaccine for the virus strains contained in the vaccine.
- Does HD also induce a better protective antibody response against other influenza strains?
SD versus HD vaccine study
“Raw” data - homologous responses
“Raw” data - heterologous responses
Antibodies after HD/SD vaccine
Antibody kinetics following norovirus vaccination
Data from a phase 2 clincial dose-finding study of a norovirus vaccine candidate. Work in progress.
Antibody kinetics following norovirus vaccination
Part 2 Summary
- Models suggest the impact of dose could be non-monotone.
- Dose seems to have an impact for broad induction of antibodies following influenza vaccination.
- Dose seems to have inconsistent effects on antibodies following norovirus vaccination.
- Modeling could lead to better choice of optimal dose for vaccines - eventually?
Other stuff
R packages to make modeling easier I
For teaching (stable):
R packages to make modeling easier II
For research (WIP):
Online modeling/analysis courses
Acknowledgements
- Collaborators
- Prior work: See published papers
- Ongoing work: Zane Billings, Murphy John, Yang Ge, Ye Shen, Ted Ross, Ben Lopman, Katia Koelle, Robert Atmar, several others…
- Funding
- NIH
Questions?
https://phdcomics.com/
- Slides: https://www.andreashandel.com/presentations/
- Contact: https://www.andreashandel.com
Assessing the impact of dose on infection and vaccination outcomes Slides: https://www.andreashandel.com/presentations/ Andreas Handel 2025-04-25